MXPA06009793A - Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders - Google Patents

Abstract

The present invention provides compounds useful, for example, for modulating insulin levels in a subject and that have the general formula Q-L1-P-L2-M-X-L3-A wherein the definitions of the variables Q, L1, P, L2, M, X, L3 and A are provided herein. The present invention also provides compositions and methods for use of the compounds, for instance, for treatment of type II diabetes.

Description

COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND METHODS. FOR USE IN THE TREATMENT OF METABOLIC DISORDERS Field of the Invention The present invention relates to compounds capable of modulating the GPR40 receptor coupled to G protein, compositions comprising the compounds, and methods for their use to control insulin levels in vivo and for the treatment of conditions such as diabetes II, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high plasma levels or "low lipoproteins, triglycerides or glucose." Background of the Invention The production of insulin is central to the regulation of metabolism of the carbohydrates and lipids.Imbalances in insulin lead to conditions such as diabetes mellitus type II, a serious metabolic disease that afflicts about 5% of the population in Western societies and more than 150 million people worldwide. is secreted from pancreatic ß cells in response to glu high plasma thing that is increased by the presence of fatty acids. The recent recognition of the GPR40 receptor function coupled to G protein in the. modulation of insulin secretion has REF: 175452 provided understanding of the regulation of the metabolism of carbohydrates and lipids in vertebrates, and additionally provided targets for the development of therapeutic agents for disorders such as obesity, diabetes, cardiovascular disease and dyslipidemia. GPR40 is a member of the gene superfamily of G-protein coupled receptors ("GPCR"). GPCRs are membrane proteins characterized as having seven putative transmembrane domains that respond to a variety of molecules by activating intracellular signaling pathways critical to a variety of physiological functions. GPR40 was first identified as an orphan receptor (i.e., a receptor without a known ligand) from a human genomic DNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547. GPR40 is highly expressed in pancreatic β cells and in cell lines that secrete insulin. Activation of GPR40 is linked to the modulation of the Gg family of intracellular signaling proteins and concomitant induction of elevated calcium levels. It has been recognized that fatty acids serve as ligands for GPR40, and that fatty acids regulate insulin secretion through GPR40. Itoh et al., (2003) Nature 422: 173-176; Briscoe et al. (2003) J. Biol. Chem. 278: 11303-11311; Kotars et al., (2003) Biochem. Biophys. Res. Commun. 301: 406-410.

The prevalence of type II diabetes, obesity, hypertension, cardiovascular disease and dyslipidemia accentuate the need for new therapies to effectively treat or prevent these conditions. Brief Description of the Invention Se- provide in the present compounds, pharmaceutical compositions and methods useful for treating or preventing a condition or disorder such as type II diabetes, obesity, hyperglycemia, glucose intolerance, 'insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension,. hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema. In one aspect, the compounds of the invention have the general formula (I): Q-L1-P-L2-M-X-L3-A I wherein Q is hydrogen, aryl, heteroaryl, (Cx-Ce) alkyl or (C2_C6) heteroalkyl; L1 is a bond, (C? -C) alkylene, (C2-C4) eteroalkylene, 0, S (0) m, N (RX), C (0) - (C5-C7) heterocycloalkylene, (C? -C ) alkylene- S02N (R2), (C? ~ 'C) alkylene -N (R2) S02 or C (0) N (R2); P is an aromatic ring, a heteroaromatic ring, (C3-C8) heterocycloalkylene or (C3-C8) cycloalkylene; L2 is a bond, (C? -?) Alkylene, (C2_ C6) heteroalkylene, 0, S (0) m, N? R1), C (0) N (R2), S02N (R2), (C? ~ C4) ) alkylene-C (0) N (R2), (C? -C) alkylene-N (R2) C (0), (C2-C) alkenylene-C (0)? (R2), (C2-C4) alkenylene-N (R2) C (0), (Cx-C4) alkylene-S02N (R2), (C? -C) alkylene-N (R2) S02, (C2-C) alkenylene -S02N (R2) or ( C2-C) alkenylene-N (R2) S02; M is an aromatic ring, a heteroaromatic ring, (C5-C8) cycloalkylene, aryl (C? -C) alkylene or heteroaryl (C? ~ C4) alkylene; X is CR3R4, N (R5), 0 or S (0) n; L3 is a bond, (Cx-Cs) alkylene or (C2-C5) heteroalkylene, with the proviso that L3 is not a bond when L2 is a bond; A is -C02H, tetrazole-5-yl ?, -S03H, -P03H2, -S02? H2, - (0)? HS02CH3, -CHO, -C (0) R5, -C (0)? HR6, -C (0) NH0R7, thiazolidinodion-yl, hydroxyphenyl or pyridyl; R1 is (C? _6) alkyl or (C2_Ce) eteroalkyl; R2 is hydrogen, (C-Ce) alkyl or (C2-Cg) heteroalkyl; R3 is cyano, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, -NR8R9, -C (O) NR10R1: L, -NR12C (0) R13 or - NR12S (0) PR13; R4 is hydrogen, cyano, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl or (C-C8) alkynyl, optionally R3 and R4 combine to form a ring of 3, 4, 5, 6 or 7 members containing from zero to three heteroatoms selected from N, 0 and S; R5 is hydrogen, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or (C3-C8) cycloalkyl; R6 is heteroaryl; R7 is hydrogen or (C? -C5) alkyl; R8 and R9 are independently hydrogen, (C? -C5) alkyl, oxy (C? -Cs) alkyl or carboxy (C? -C5) alkyl, optionally, R8 and R9 combine to form a ring of 4, 5, 6 or 7 members containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, 0 and S; R10, R11 and R12 are independently selected from hydrogen, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) heteroalkyl, (C3-C8) cycloalkyl and (C3-C8) heterocycloalkyl, optionally, R10 and R11 combine to form a 4, 5, 6 or 7 member ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S; R13 is aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) heteroalkyl, (C3-C8) cycloalnyl or (C? -8) heterocycloalkyl; the subscripts and n are independently 0, 1 or 2; and the subscript p is 1 or 2; and wherein the compound is different from 3- (4- (4-methoxybenzyloxy) phenyl) pen-4-inoic acid; β-ethenyl-4-phenylmethoxy-benzenepropanoic acid; 4- (2-quinolinylmethoxy) -β- [4- (2-quinolinylmethoxy) phenyl] -benzenepropanoic acid; N- [4- (benzoylamino) phenyl] -N-phenyl-glycine a; 3- (4- (isopentyloxy) benzamido) -3-phenylpropanoate; 3- (4-isobutoxybenzamido) -3-phenylpropanoate; (R) -2- ((IR, 4R) -4-isopropylcyclohexanecarboxamido) -3-phenylpropanoic acid; (R) - • 3- (4- (benzyloxy) phenyl) -2- (tert-butoxycarbonyl) propanoic acid, - acid 3- (4-chlorophenyl) -2- (furan-2-carboxamido) propanoic; 3- (3,4-dimethoxyphenyl) -3- (furan-2-carboxamido) propanoic acid; 3- (4-chlorobenzamido) -3- (4- (dimethylamino) phenyl) propanoic acid; 3- (2- (2- (3, 4-dimethylphenoxy) ethylthio) -lH-benzo [d] imidazol-1-yl) propanoic acid; acid { 2-bromo-4- [(3,4-dichloro-phenyl) -hydrazone] ethyl] -6-ethoxy-phenoxy} -acetic; 2- (4- (2- (2- (4-chlorophenyl) furan-5-carboxamido) ethyl) phenoxy) -2-methylpropanoic acid; 5- (3- (3, 4-dimethoxyphenyl) -5- (2-fluorophenyl) -4,5-dihydropyrazol-1-yl) -5-oxopentanoic acid; 2- (2- (3- (3,4-Dihydro-2H-benzo [b] [1,4] dioxepin-7-yl) -2-methyl-4-oxo-4H-chromen-7-yloxy) aceta-gone) acetic; 3- (4'-bromo-biphenyl-4-yl) -4- 'phenyl-butyric acid; 3- (4'-bromo-biphenyl-4-yl) -3-phenylsulfanyl-propionic acid; 3- (5- (2-chloro-6-fluoro-4- (trifluorornethyl) phenoxy) -2, -dinitrophenyl) propanoic acid; 3- (3- (2-Chloro-4- (trifluoromethyl) phenoxy) phenyl) propanoic acid; 3- (4- (4-methoxybenzyloxy) phenyl) pen-4-inoic; 3- (4- (4-methoxybenzyloxy) phenyl) -5- (trimethylsilyl) pen-4-ynoic acid; ß, ß-dimethyl-4- [[[4-methyl-2- [4- (trifluoromethyl) phenyl] -5-thiazolyl] ethyl] thio] -benzenepropanoic acid; β-amino-4- [(4-bromo-2,5-dihydro-2-methyl-5-oxo-l-phenyl-1 H -pyrazol-3-yl) ethoxy] -3-methoxy-benzenepropanoic acid; or salts thereof. The compounds of the invention include pharmaceutically acceptable salts, solvates or prodrugs thereof. In certain embodiments, the present invention provides a compound having the formula (Ia): wherein Q, L1, P, L3, A, R3 and R4 are as defined with respect to formula I above. In certain embodiments, the present invention provides a compound having the formula (Ib): Ib where Q, La, P, L3, A and R5 are as defined with respect to formula I above. In another aspect, the compounds of the invention have the granular flux (II): II H-C- - N- wherein Z is I or I R21 is -H, -OH, -NHS (02) CH3, heteroaryl, or -NH- heteroaryl; R22 is - (C2-C8) alkyl; - (C3-C8) alkenyl, -NR23R24, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C = N, or -C = C-R25, or optionally where Z is a hydrogen atom, R22 is -H; R23 and R24 are independently -H, - (C? -Cs) alkyl, or ~ (C? -C5) oxyalkyl; R25 is -H, - (C? -Cs) alkyl, hetero (C? -C5) alkyl, - (C? -C5) oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L is -O-, -S-, -N (R26) -; R26 is -H, - (C? -C5) alkyl, aryl (C? -C? O) substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; And it is absent or is -CH2-, -CH2CH2-, -CH = CH-, -C (0) CH2-, -C (0) CH2CH2-, -C (0) CH = CH-, -S (02) -, S (02) CH2-, S (02) CH2CH2-, -S (02) CH-CH-, or -C (O) -; is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In another aspect, the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of the formula I, Ib or II. In another aspect, the invention provides methods for treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, thrombotic disorders, dermatopathy, dyspepsia, hypoglycemia, hypertension, cancer and edema comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I, Ia, Ib or II. In another aspect, the invention provides methods for treating or preventing a disease or condition responsive to the modulation of GPR40 which comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the formula I, the, Ib or II. In another aspect, the invention provides methods for treating or preventing a disease or condition mediated, regulated or influenced by pancreatic β-cells comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I, or II. In another aspect, the invention provides methods for modulating the function of GPR40 in a cell, which comprises contacting a cell with a compound of the formula I, Ia, Ib or II. In another aspect, the invention provides methods for modulating the function of GPR40 comprising contacting GPR40 with a compound of the. Formula I, the, Ib or II. In another aspect, the invention provides methods for modulating the concentration of insulin in circulation in a subject, which comprises administering a compound of formula I, Ib, or II. Other objects, features and advantages of the invention will become apparent to those skilled in the art from the following description and claims. Brief Description of the Figures Figure 1 provides a reaction scheme for the synthesis of the example compounds of the invention. Detailed Description of the Invention Abbreviations and Definitions The terms "treat", "treating" and "treatment", as used herein, are proposed to include, alleviate or abolish a condition or disease and / or its attendant symptoms and alleviate . The terms "prevent", "prevent" and "prevent", as used herein, refer to a method for delaying or preventing the onset of a condition or disease and / or its accompanying symptoms, by preventing a subject from acquiring a condition or disease or reduction of a subject acquiring a condition or disease. The term "therapeutically effective amount" refers to that amount of the compound that will produce the biological or medical response of a tissue, system or subject that is being sought. The term "therapeutically effective amount" includes that amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some degree, one or more of the symptoms of the condition or disorder being treated in a subject. . The therapeutically effective amount in a subject will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, goats, sheep, horses, dogs, cats, rabbits, rats, mice and similar. In preferred embodiments, the subject is a human. The terms "modulate", "modulation" and the like refer to the ability of a compound to increase or decrease the function or activity of GPR40 either directly or indirectly. Inhibitors are compounds that, for example, bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or reduce the expression of signal transduction, such as, for example, antagonists. Activators are compounds that, for example, bind to, stimulate, increase, activate, facilitate, enhance activation, sensitize or favor the expression of signal transduction, such as agonists, by way of example. Modulation can occur in vi tro or in vivo. As used herein, the term "condition or disorder mediated by GPR40" and the like refers to a condition or disorder characterized by activity of GPR40, inappropriate, for example, less than or greater than normal. A condition or disorder mediated by GPR40 can be mediated completely or partially by inappropriate activity of GPR40. However, a condition or disorder mediated by GPR40 is one in which the modulation of GPR40 results in some effect on the fundamental condition or disease (e.g., a GPR40 modulator results in some improvement in the patient's well-being in at least some patients). Conditions or disorders mediated by GPR40 of e emplo-include cancer and metabolic disorders, eg, diabetes, diabetes II, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia , ketoacidosis, hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X and related disorders, for example, cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia and edema. The term "alkyl", by itself or as part of another substituent, means, unless otherwise indicated, a cyclic or branched or cyclic hydrocarbon radical, or combination thereof, that is completely saturated, having the designated number of carbon atoms (for example, C? -C? or means from one to ten carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropyl, cyclopropylmethyl, homologs and isomers, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl and the like. The term "alkenyl", by itself or as part of another substituent, means a straight or branched chain cyclic hydrocarbon radical, or combination thereof, which may be mono- or poly-unsaturated, having the number of designated carbon atoms (ie, C2-C8 means from two to eight carbon atoms) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1, pentadienyl) and higher homologs and isomers thereof. The term "alkynyl", by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (ie, C2-Cs means from two to eight carbon atoms) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and homologs and higher isomers thereof. The term "alkylene" by itself or as part of other substituents means a divalent alkyl derivative, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 12 or fewer carbon atoms that are preferred in the present invention. A "lower alkyl" - or "lower alkylene" is a shorter chain alkyl or alkylene group, which generally has eight or fewer carbon atoms. The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and - refer to those alkyl groups attached to the rest of the molecule by an oxygen atom, an amino group, or a sulfur atom, respectively. Similarly, the term "dialkylamino" refers to an amino group having two attached alkyl groups which may be the same or different. The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise stated, a cyclic or straight or branched chain hydrocarbon radical, or combinations thereof, consisting of carbon atoms. carbon and one to three heteroatoms selected from the group consisting of 0, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms 0, N and S can be placed at any position of the heteroalkyl group. Examples include -CH2-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-? (CH3) -CH3, "-CH2-S-CH2-CH3, -CH2-CH2-S ( 0) -CH3, -CH2-CH2-S (0) 2-CH3, and -CH2-CH = N-OCH3 Up to two heteroatoms can be consecutive, such as, for example, -CH-NH-OCH3. a prefix such as (C2-C8) to refer to a group • heteroalkyl, the carbon number (from 2 to 8, in this example), is proposed to also include the heteroatoms. For example, a C2-heteroalkyl group is proposed to include, for example, -CH20H (a carbon atom and a hetero atom that replaces a carbon atom) and -CH2SH. To further illustrate the definition of a heteroalkyl group, where the heteroatom is oxygen, a heteroalkyl group is an oxyalkyl group. For example, (C-C5) oxyalkyl is proposed to include, for example, -CH2-0-CH3 (a C3-oxyalkyl group with two carbon atoms and an oxygen replacing a carbon atom), -CH2CH2CH2CH20H and the like. The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S- CH2CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain terms (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for linking groups of alkylene and heteroalkylene, orientation of the linking group is not implied. The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. In this way, the terms "cycloalkyl." and "heterocycloalkyl" is proposed to be included in the terms "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom may occupy the. position in which the heterocycle joins the rest of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl. , tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The term "cycloalkylene" and "heterocycloalkylene", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkylene" and "heteroalkylene", respectively. Thus, the terms "cycloalkylene" and "heterocycloalkylene" are proposed to be included in the terms "alkylene" and "heteroalkylene", respectively. Additionally, for heterocycloalkylene, one or more heteroatoms may occupy positions in which the heterocycle binds to the rest of the molecule. Typically, a heteroalkylene or heterocycloalkylene will have from 3 to 9 atoms that form the ring, more typically from 4 to 7 ring-forming atoms., and even more typically, 5 or 6 atoms will form the cycloalkylene or heterocycloalkylene ring. The terms "halo" or "halogen", by themselves or as part of another substituent, mean, unless otherwise indicated, a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "haloalkyl" are intended to include alkyl substituted with halogen atoms which may be the same or different, in a number ranging from one to (2m '+ 1), where m' is the total number of carbon atoms of the alkyl group. For example, the term "halo (C? -C) alkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, "3-bromopropyl, and the like." Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with a halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m '+ 1) halogen atoms.) The term "perhaloalkyl" means unless in other words, alkyl substituted with (2m '+ 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group, for example, the term "perhalo (C? -C) alkyl) "is proposed to include trifluoromethyl, pentachloroethyl, 1,1-trifluoro-2-bromo-2-chloroethyl, and the like The term" aryl "means, unless otherwise noted, a polyunsaturated hydrocarbon substituent , typically aromatic, which can be a single ring or multiple rings (up to three rings) that they are fused together or linked covalently. The term "heteroaryl" refers to aryl groups (or rings) containing one to four heteroatoms selected from the group consisting of N, 0 and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally Quaternized A heteroaryl group can be attached to the rest of the molecule through a heteroatom.

Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, dibenzofuryl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, benzo [c] [1 , 2, 5] oxadiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1H-indazolyl, carbazolyl, α-carbolinyl, β-carbolinyl, α-carbolinyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl , 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl and 8-quinolyl. Preferably, the term "aryl" refers to a phenyl or naphthyl group that is unsubstituted or substituted. Preferably, the term "heteroaryl" refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl or quinolyl group , which is unsubstituted or substituted For brevity, the term "aryl" when used in combination with other terms (eg, aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. term "arylalkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group "for example, benzyl, phenethyl, pyridylmethyl and the like" including those alkyl groups in which a carbon atom has been replaced (by example, a methylene group) for example by an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like). Each of the foregoing terms (eg, "alkyl", "heteroalkyl", "aryl" and "heteroaryl") is intended to include both substituted and unsubstituted forms of the indicated radical, unless otherwise indicated. Preferred substituents for each type of radical are provided below. The substituents for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be a variety of groups selected from: -OR ', = 0, = NR ', = N-0R', -NR'R 'X -SR', halogen, -OC (0) R ', -C (0) R', -C02R ', -CONR' R '', -0C (0) NR'R ", -? R''C (0) R ', -? R'-C (0)? R" R "', -NR '-S02? R" R' ", -? R''C02R ', -? HC (NH2) = NEÍ, -? R' C (NH2) =? H, -? HC (? H2) =? R ', -SiR'R' 'R "' , -S (0) R ', -S02R', -S02? R'R ", -? R''S02R, -C? And -? 02, in a number that varies from zero to three, with those groups that they have zero, one or two substituents which are particularly preferred R ', R "and R" "each independently refer to hydrogen, (C? -C8) unsubstituted alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with each other three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo (C? -C4) alkyl groups , or aryl- (C? '- C4) alkyl. When R 'and R "are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5, 6 or 7 membered ring. For example, -NR'R "is proposed to include 1-pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or less substituents that are preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. More preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the foregoing discussion of substituents, one skilled in the art will understand that the term "alkyl" is intended to include groups such as trihaloalkyl (e.g., -CF3 and -CH2CF3). Preferred substituents for the alkyl and heteroalkyl radicals are selected from -OR ', = 0, -NR'R ", -SR', halogen, -OC (0) R ', -C (0) R', - C02R ', -CONR'R' ', -OC (0) NR'R' ', -NR''C (0) R', -NR '' C02R ', -? R' -S02NR "R '' ' , S (0) R ', -S02R', -S02? R'R '', -? R''S02R, -CN and -? 02, where R 'and R "are as defined above. Additional preferred substituents are selected from: -OR ', = 0, -NR'R ", halogen, -0C (0) R', -C02R ', -CONR'R", -0C (0) NR'R ", NR" C (0) R ', -NR "C02R', -NR '-S02NR" R' ", -S02R ', -S02? R'R", -? R "S02R, -CN and - No. 2 Similarly, the substituents for the aryl and heteroaryl groups are varied and selected from: halogen, -OR ', -0C (0) R', -? R'R ", -SR ', - R ', -CN, -N02, -C02R', -CO? R'R ", -C (0) R ', -0C (0)? R'R", -? R "C (0) R' , -NR "C (0) 2R ', -? R'-C (0)? R" R "', -? HC (? H2) =? H, -NR 'C (? H2) = NH, - ? HC (NH2) =? R ', -S (0) R', -S (0) 2R ', -S (0) 2? R'R ", -N3, -CH (Ph) 2, perfluoro ( C? ~. C) alkoxy, and perfluoro (C? -C) alkyl, in a number ranging from zero to the total number of open valencies in the aromatic ring system; and wherein R ', R "and R' '' are independently selected from hydrogen, (C? -C8) alkyl and heteroalkyl, aryl and unsubstituted heteroaryl, (unsubstituted aryl) - (C? -C) alkyl, and ( unsubstituted aryl) oxy- (C? C) alkyl Two of the substituents on the adjacent atoms of the aryl or heteroaryl ring can be optionally substituted with a substituent of the formula -TC (O) - (CH2) qU-, wherein T and U are independently -? H-, -0-, -CH2- or an individual bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can be optionally replacing with a substituent of the formula -A- (CH2) rB-, wherein and B are independently -CH2-, -0-, -NH-, -S-, -S (0) -, -S (0 ) 2-, -S (0) 2NR '- or an individual link, and r is an integer from 1 to 3. One of the individual links of the new ring formed in this way can be optionally replaced with a double bond. alternatively, two of the substituents on the adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula -CH2) 5-X- (CH2) t ~, where syt are independently integers from 0 to 3, and X is -0-, -? R'-, -S-, -S (0) -, -S (0) 2-, or -S (0) 2? R'-. The substituent R 'in -? R'- and -S (0) 2NR' - is selected from hydrogen or (C? -C6) unsubstituted alkyl. Otherwise, R 'is as defined above. As used herein, the term "heteroatom" is intended to include oxygen (0), nitrogen (N), and sulfur (S). As used herein, the phrase "biogaster of -C02H" proposes that the substituent -C02H can be optionally replaced with bioisostomeric replacements such as: OH and similar. See, for example, The Practice of Medicinal Chemistry, Wer uth, C.G., Ed., Academic Press: New York, 1996, p. 203. The term "pharmaceutically acceptable salt" is intended to include a salt of the active compound that is prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compound described herein. When a compound of the invention contains relatively acidic functionalities, a base addition salt can be obtained by contacting the neutral form of this compound with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When a compound of the invention contains relatively basic functionalities, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbon, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as the salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are amino acid salts such as arginine and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge et al., (1977), J. Pharm. Sci. 66: 1 -19). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and by isolating the parent compound in a conventional manner. The form of origin of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the source form of the compound for the purposes of the invention. In addition, of the salt forms, the invention provides compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable chemical reagent or enzyme. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, they can be bioavailable by oral administration, whereas the original drug is not. The prodrug may also provide improved solubility in pharmaceutical compositions on the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that depend on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug"), but which is hydrolyzed metabolically to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. As used in this"Solvate" refers to a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of the solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. Certain compounds of the invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and it is proposed that they be within the scope of the invention. Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; Racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. As used herein, and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means a stereoisomer of a compound that is substantially free of other stereoisomers of this compound. For example, a stereomerically pure compound having a chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises more than about 80% - by weight of a stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, still more preferably more than about 95% by weight of a stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and so more preferably more than about 97% by weight of a stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. It should be noted that if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dotted lines, the structure or portion of the structure will be interpreted as encompassing all the stereoisomers of the structure. same The various compounds of the invention contain one or more chiral centers, and there may be racemic mixtures of enantiomers, mixtures of diastereomers, or enantiomerically or optically pure compounds. This invention encompasses the use of stereomerically pure forms of these compounds, as well as the use of mixtures of these forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention can be used in methods and compositions of the invention. These isomers can be synthesized or resolved asymmetrically using normal limits such as chiral columns or chiral resolution agents. See, for example Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley, Interscience, New York, 1981); Wilen, S. H., et al., (1997) Tetrahedron 33: 2725; Eliel, EL, Stereochemistry of Coal Compounds (McGraw-Hill, NY, 1962, and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p 268 (EL Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN , 1972) The compounds of the invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms constituting these compounds For example, the compounds can be radiolabelled with radioactive isotopes, such as for example tritium (3H) , iodine-125 (125I) or carbon-14- (14C) .Radio-labeled compounds are useful as therapeutic or prophylactic agents, research reagents, for example, reagents of GPR40 assays, and diagnostic agents, for example, agents of In vivo imaging All the isotopic variations of the compounds of the invention, whether radioactive or not, are proposed to be encompassed within the scope of the invention.

Modes of the Invention In one aspect, a class of compounds that modulate GPR40 is described herein. Depending on the biological environment (eg, cell type, pathological condition of the subject, etc.), these compounds can modulate, for example, activate or inhibit, the actions of GPR40. By modulating GPR40, the compounds find use as therapeutic agents capable of regulating insulin levels in a subject. The compounds find use as therapeutic agents to modulate diseases and conditions sensitive to modulation of GPR40 and / or mediated by GPR40 and / or mediated by pancreatic β-cells. As noted above, examples of these diseases and conditions include diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, cancer, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, ketoacidosis, hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease, • atherosclerosis, kidney disease, nephropathy, thrombotic disorders, diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia and edema. Additionally, the compounds are useful for the treatment and / or prevention of complications of these diseases and disorders (e.g., type II diabetes, sexual dysfunction, dyspepsia and others). While the compounds of the invention are believed to exert their effects by interacting with GPR40, the mechanism of action by which the compounds act is not a limiting embodiment of the invention. The compounds contemplated by the invention include, without limitation, the exemplary compounds provided herein. Compounds In one aspect, the present invention provides a compound having the formula (I): Q-L1-P-L2-MX-L3-AI wherein Q, L1, P, L2, M, X, L3 and A are as defined later. Q is hydrogen, aryl, heteroaryl, (C? -C6) alkyl or (C2-Ce) heteroalkyl. In preferred embodiments, Q is aryl. In further preferred embodiments, Q is 4- (trifluoromethyl) phenyl or p-tolyl. L1 is a bond, (C? -C) alkylene, (C2-C) heteroalkylene, 0, S (0) m, NIR1), C (0) - (C5- C7) heterocycloalkylene, (C? -C) alkylene - S02N (R2), (C? ~ C4) alkylene -? (R2) S02 or C (0) N (R2). In certain embodiments, L1 is a bond, (C? ~ C) alkylene, (C2-C) heteroalkylene, 0, S (0) m, NIR1) or C (0) N (R2). In certain modalities, L1 is a link, O or N IR1). In preferred embodiments, L1 is a bond. P is an aromatic ring, a heteroaromatic ring, (C3-C8) heterocycloalkylene or (C3-C8) cycloalkylene. In certain embodiments, where P is an aromatic ring, the aromatic term includes aryl. In other embodiments, where P is a heteroaromatic ring, the term "heteroaromatic" includes heteroaryl. In some embodiments, P is an aromatic ring or a heteroaromatic ring. In certain embodiments, P is a monocyclic aromatic ring or a monocyclic heteroaromatic ring. In some embodiments, P is selected from the group consisting of benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline. For example, P can be benzene, naphthalene, pyrrole, pyrazine, pyridine, pyrimidine, pyridazine, purine, indole, carboline, isoquinoline, quinoxaline or quinoline. In some embodiments, P is a benzene, thiazole, or oxazole ring. In preferred embodiments, L1 is a bond, 0 or R1) and P is an aromatic ring or a heteroaromatic ring. L2 is a bond, (C? -C6) alkylene, (C2-C5) eteroalkylene, oxymethylene, O, S (0) m, N (RX C (0) N (R2), S02? (R2), (C) ? -C4) C (0) N (R2), (C? -C4) alkylene-NR1) G (p), (C2-C4) alkylene-C (0)? (R2), (C2-C) alkylene? alkenylene -? (R2) C (0), (Cx-C4) alkylene-S02? (R2), (C? -C4) alkylene-N (R2) -S02, (C2-C) alkenylene-S02? ( R2) or (C2-C) alkenylene-N (R2) S02. In certain modalities, L2 is a link, (C? ~ C) alkylene, (C2_C6) heteroalkylene, oxymethylene, 0, S (0) m,? (RX C (0)? (R2), S02R (R2), (C-C4) alkylene-C (O) N (R2 ), (C2-C) alkenylene-C (0) N (R2), (C? -C) alkylene-S02N (R2) or (C2-C4) alkenylene -S02N (R2) .In certain embodiments, L2 is ( C2-C6) heteroalkylene In some embodiments, L2 is (C2-C4) heteroalkylene In some embodiments, L1 is a bond, 0 or? IR1) and L2 is (C2-Ce) heteroalkylene. In certain embodiments, L2 is oxymethylene or thiomethylene.

In preferred embodiments, L1 is a bond and L2 is oxymethylene or thiomethylene. M is an aromatic ring, a heteroaromatic ring, (C5-C8) cycloalkylene, aryl (C? -C) alkylene or heteroaryl (C? -C) alkylene. In certain embodiments, where M is an aromatic ring, the aromatic term includes aryl. In other embodiments, wherein M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl. In some embodiments, M is an aromatic ring or a heteroaromatic ring. In some embodiments, M is a (C5-C8) cycloalkylene. In certain embodiments, M is a monocyclic aromatic, monocyclic heteroaromatic, or (C5-C8) cycloalkylene ring. In some embodiments, M is an unsubstituted monocyclic aromatic ring or an unsubstituted monocyclic heteroaromatic ring. In certain embodiments, M is a benzene ring or a heteroaromatic ring. In preferred embodiments, M is a benzene ring. In preferred embodiments, P is a. Aromatic ring or a heteroaromatic ring and M is an aromatic ring, a heteroaromatic ring or (C5-C8) cycloalkylene.

X is CR3R4, N (R5), O or S (0) n. In preferred embodiments, X is CR3R4 or? (R5). In further preferred embodiments, X is CHR3. In certain embodiments, M is an unsubstituted or substituted benzene ring and X is for a L2. In certain preferred embodiments, M is an aromatic ring, a heteroaromatic ring or • (Cs-Cs) cycloalkylene and X is CR3R4 or N (R5). In preferred embodiments, P is an aromatic ring or a heteroaromatic ring and X is CR3R4 or N (R5). L3 is a bond (C? -C) alkylene or (C2-C5) heteroalkylene, provided that L3 is not a bond when L2 is a bond. In some embodiments, L3 is (C? -Cs) alkylene or (C2-C5) heteroalkylene. In certain embodiments, L3 is (C? -C3) alkylene. In some embodiments, L3 is methylene. In certain embodiments, L3 is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl. In certain embodiments, X is CR3R4 or N (R5), and L3 is substituted or unsubstituted methylene. In preferred embodiments, L2 is (C2-C) heteroalkylene and L3 is (C? -C3) alkylene. In certain preferred embodiments, L 1 is a bond, O, or N R 1), L 2 is (C 2 -C 4) heteroalkylene, and L 3 is (C 1 -C 3) alkylene. A is -C02H, tetrazole-5-yl ?, -S03H, -P03H2, -S02NH2, -C (0) NHS02CH3, -CHO, -C (0) R5, -C (0) NHR6, -C (0) NHOR7, thiazolidinedione-il, hydroxyphenyl or pyridyl. In certain modalities, A is a bioisoster of - C02H. In certain embodiments, A is -C02H or tetrazol-5-yl, -C (0) NHS02CH3 or -C (0) NHR6. In some embodiments, A is -C02H or tetrazol-5-yl. In preferred embodiments, A is -C0H or a salt thereof. In some embodiments, P is an aromatic ring or a heteroaromatic ring and A is -C02H. In certain embodiments, X is CR3R4 or N (R5) and A is -C02H. In preferred embodiments, M is an aromatic ring, a heteroaromatic (C5-C8) cycloalkylene ring and A is -C02H or tetrazol-5-yl. In certain preferred embodiments, M is an aromatic ring, a heteroaromatic ring or (Cs-C8) cycloalkylene, X is CR3R4 or N (R5), L3 is (C? -C5) alkylene or (C2-Cs) heteroalkylene and A is -C02H R1 is (C? -C6) alkyl, aryl (C? -C3) alkyl or (C2-C?) Heteroalkyl. In certain embodiments, R1 is (C-Ce) alkyl or (C2-Ce) heteroalkyl. R2 is hydrogen, (C6C6) alkyl or (C2Ce) heteroalkyl. R3 is cyano, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkyl, (C2-C8) alkenyl, (C3-C8) alkenyl, (C2-Cs) alkynyl, (C3-C8) alkynyl , -NR8R9, -C (O) NR10R1: L, -NR12C (O) R13 'or NR12S (0) pR13. In certain embodiments, R3 is cyano, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl, (C2-Cs) alkynyl, -? R8R9, -C (0) NR10R? -? R12C (0) R13 O -? R12S (0) PR13. In some embodiments, R3 is cyano, aryl, heteroaryl, (C? -C8) alkyl,. (C2-C6) alkenyl, (C2-C6) alkynyl or -? R8R9. In certain embodiments, R3 is cyano, heteroaryl, (C2 ~ C5) alkenyl or (C2-Ce) alkynyl. In certain embodiments, R3 is (C2-C8) alkynyl, (Cs-Cs) alkenyl or (C3-C8) alkynyl. In some embodiments, R 3 is aryl or heteroaryl. In certain preferred embodiments, R3 is tetrazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, thienyl, or prop-1-ynyl. In certain embodiments, R3 is tetrazolyl, thiazolyl, or prop-1-ynyl. R 4 is hydrogen, cyano, aryl, heteroaryl, (C 1 -C 8) alkyl, (C 2 -C 8) alkenyl or (C 2 -C 8) alkynyl.

Optionally, R3 and R4 combine to form a 3, 4, 5, 6 or 7 member ring containing from zero to three heteroatoms selected from N, 0 and S. The ring formed by combining R3 and R4 may be a ring substituted or unsubstituted. In some embodiments, R4 is hydrogen or methyl. In preferred embodiments, R 4 is hydrogen. In further preferred embodiments, R3 is cyano, aryl, heteroaryl, (C? -8) alkyl, (C2-C8) alkynyl, (C2-C8) alkenyl, (C3-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) alkynyl or -NR8R9 and -R4 is hydrogen. R5 is hydrogen, aryl, heteroaryl, (C? ~ C8) alkynyl, (C2-C8) 'alkenyl, (C2-C8) alkynyl or (Cs-Cs) cycloalkyl. R6 is heteroaryl. R7 is hydrogen or (C? -Cs) alkyl. R8 and R9 are independently hydrogen, (C? -C5) alkyl, oxy (C? -C5) alkyl or carboxy (C? -. Cs) alkyl. Optionally, R8 and R9 combine to form a ring of 4, 5, 6 or 7 members containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S. The ring formed by combining R8 and R9 can be a saturated, unsaturated or aromatic ring. R10, R11 and R12 are independently selected from hydrogen, aryl, heteroaryl, (C? -Cs) alkyl, (C2-C8) heteroalkyl, (C3-C8) cycloalkyl and (C3-Cg) heterocycloalkyl. Optionally, R10 and R11 combine to form a 4, 5, 6 or 7 member ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, 0 and S. The ring formed by combining R10 and R11 can be a saturated, unsaturated or aromatic ring. R13 is aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) heteroalkyl, (C3-C8) cycloalkyl or (Cs-Cs) heterocycloalkyl. The subscripts yn are independently 0, 1 or 2. The subscript p is 1 or 2. In some embodiments, P is an aromatic ring or a heteroaromatic ring, X is CR3R4 and R3 is cyano, aryl, heteroaryl, (C? -C8 ) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl 0 -. 0 -? R8R9. In some embodiments, A is -C02H, X is CR3R4 and R3 is cyano, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, or -NR8R9. In certain embodiments, when P and M are benzene, at least two of L2, X and L3 are different from CH2. In certain embodiments, the compounds of the formula 1 does not include 3- (4- (4-methoxybenkoyloxy) phenyl) pen-4-inoic acid; β-ethenyl-4-phenylmethoxy-benzenepropanoic acid; 4- (2-quinolinylmethoxy) -β- [4- (2-quinolinylmethoxy) phenyl] -benzenepropanoic acid; N- [4- (benzoylamino) phenyl] -N-phenyl-glycine; 3- (4- (isopentyloxy) benzamido) -3-phenylpropanoate; 3- (4-isobutoxybenzamido) -3-phenylpropanoate; (R) -2- ((IR, 4R) -4- isopropylcyclohexanecarboxamido) -3-phenylpropanoic acid; (R) -3- (4- (benzyloxy) phenyl) -2- (tert-butoxycarbonyl) propanoic acid; 3- (4-chlorophenyl) -3- (furan-2-carboxamido) propanoic acid; 3- (3, -dimethoxyphenyl) -3- (furan-2-carboxamido) propanoic acid; 3- (4-chlorobenzamido) -3- (4- (dimethylamino) phenyl) propanoic acid; 3- (2- (2- (3, 4-dimethylphenoxy) ethylthio) -iH-benzo [d] imidazol-1-yl) propanoic acid; acid { 2-bromo-4- [(3, -dichloro-phenyl) -hydrazonomethyl] -6-ethoxy-phenoxy} -acetic; 2- (4- (2- (2- (4-chlorophenyl) furan-5-carboxamido) ethyl) phenoxy) -2-methylpropanoic acid; 5- (3- (3, 4-dimethoxyphenyl) -5- (2-fluorophenyl) -4,5-dihydropyrazol-1-yl) -5-oxopentanoic acid; 2- (2- (3- (3,4-Dihydro-2H-benzo [b] [1,] dioxepin-7-yl) -2-methyl-4-oxo-4H-chromen-7-yloxy) acetamido ) acetic; '3- (4'-bromo-biphenyl-4-yl) -4-phenyl-butyric acid; 3- (4'-bromo-biphenyl-4-yl) -3-phenylsulfanyl-propionic acid; 3- (5- (2-Chloro-6-fluoro-4- (trifluoromethyl) phenoxy) -2,4-dinitrophenyl) propanoic acid; 3- (3- (2-Chloro-4- (trifluoromethyl) phenoxy) phenyl) propanoic acid; acid 3- (4- (4-methoxybenzyloxy) phenyl) pen-4-inoic; or 3- (4- (4-methoxybenzyloxy) phenyl) -5- (trimethylsilyl) pen-4-ynoic acid, salts thereof or esters thereof. In certain embodiments, it is to be understood that the compounds of formula I do not include compounds wherein P is a ring of 1, 2-azol when Q is aryl or heteroaryl, L1 is a bond, M is a monocyclic aromatic ring, X is N (R5), 0 or S (0) n, and A contains a carbonyl group. In certain embodiments, it is to be understood that the compounds of the formula I do not include compounds wherein P is furan or thiophene when Q is aryl, L1 is a bond, M is an aromatic ring, X is CR3R4, 0 or S (0 ) ny A contains a carbonyl group. The compounds of the invention include salts >; solvates or pharmaceutically acceptable prodrugs thereof. In certain embodiments, ester prodrugs are preferred. Those skilled in the art will understand that, unless otherwise indicated, divalent groups such as C (O) N (R2), S02N (R2), (C? -C4) C-0 N (C) N ( R2) and the like, both possible orientations of the groups are allowed. For example, in formula I where L2 is C (0) N (R2), the carbon atom can be bonded to P or M, as shown: OO Q-L1-PC -? - MX-L3-A or Q-L1-P -? - CMX-! > A R2 R2 As another example, in formula I where L2 is (C? ~ C4) alkylene-C (O) N (R2) in the formula la, the alkylene group can be attached to P or M, as shown: Q_L1_P_ In certain embodiments, the present invention provides a compound having the formula (la): wherein Q, L1, P, L3, A R3 and R4 are as defined with respect to formula I above. In some embodiments, of the formula la, Q is substituted or unsubstituted benzene, and L1 is a bond, (C? ~ C4) alkylene, O or S (0) m. In some embodiments, P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline. In certain embodiments, where P is benzene, Q is hydrogen, aryl, heteroaryl or (C? -C6) alkyl, and L1 is a bond, (C? -C) alkylene, O or S (0) m. In some embodiments, L3 is (C? -C5) alkylene. In certain embodiments, L3 is methylene.

In certain embodiments, R3 is cyano, aryl, heteroaryl, (C-C8) alkyl; (C3-C8) alkenyl, (C3-C8) alkynyl, -NR8R9, -C (O) NR10 u, -NR12C (0) R13 or -NR12S (0) PR13 and R4 is hydrogen, cyano, aryl, heteroaryl, (C? -8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl. In certain embodiments, R3 is cyano, a monocyclic aryl or unsubstituted heteroaryl ring, (C2-C8) alkyl, (C3-C8) alkenyl, (C3-C8) alkynyl, or -C (O) NR10R?: L, R4 is hydrogen, and P is selected from the group consisting of benzene, naphthalene, "pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquininoin , quinoxaline and quinoline In some embodiments, R3 is cyano, a monocyclic aryl or unsubstituted heteroaryl ring, (Cs-Cs) alkenyl, (C3-C8) alkynyl, -C (0) NR10R1: L, R4 is hydrogen, and L3 is methylene In certain embodiments Q is aryl, heteroaryl, (C? -C6) alkyl or (C2-C6) heteroalkyl, L1 is a bond (C? ~ C4) alkylene, (C2-C) heteroalkylene, S (0 ) m, N (R1), (C? ~ C4) to uylene-S02N (R2), (C-C4) alkylene-N (R2) S02 or C (0) N (R2), P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline, R3 is cyano, an aromatic monocyclic or unsubstituted heteroaromatic ring, (C2-C8) alkyl, ( C3-C8) alkenyl, (C3-C8) alkynyl, or -C (O) NR10R1: L, R4 is hydrogen, and L3 is methylene. In certain embodiments, the present invention provides a compound having the formula (Ib): Ib where Q, L1, P, L3 A and R5 are as defined with respect to formula I above. In some embodiments of the formula Ib, P is selected. of the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline. In certain embodiments, R 5 is unsubstituted or substituted benzene. In another aspect, the present invention provides a compound having the formula (II): where R21, R22, Z, L, Y and W are as defined below. . R21 is -H, -OH, -NHS (02) CH3, heteroaryl or -NH- heteroaryl. In certain embodiments, R21 is -OH, -? HS (02) CH3, -? H- tetrazolyl or tetrazolyl. In certain embodiments, R21 is tetrazolyl, pyrimidinyl, or pyridinyl. In preferred embodiments, R21 is -OH, or a salt thereof. R22 is -H, - (C? -C8) alkyl, - (C3-C8) alkenyl, -? R23R24, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C = N, or -C = C-R25. In some embodiments, R22 is (C2-C8) alkyl, - (Cs-Cs) alkenyl, -? R23R24, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C = N, or -C = C-R25. In certain embodiments, R22 is - (C2-C3) alkyl, NR23R24, substituted or unsubstituted phenyl, -CH = C (CH3) 2, CH2CH = CH2, or -C = C-R25. In other modalities, R22 is unsubstituted aryl or unsubstituted heteroaryl. In other embodiments, R22 is substituted aryl and the substitution e? the aryl is - (C? -Cs) unsubstituted alkyl, - (C? -Cs) oxyalkyl, or -halo (C? -Cs) alkyl. In certain embodiments, R22 is -C = C-R25 and R25 is (Cx-Cs) alkyl having from 0 to 1 heteroatoms. In preferred embodiments, R22 is -C = CCH3. In some embodiments, R22 is -CH = C (CH3) 2 or -CH2CH = CH2. R23 and R24 are independently -H, - (C? -Cs) alkyl, or - (C? -Cs) oxyalkyl. R25 is -H, - (C? -C5) alkyl, -hetero (C? -C5) alkyl, - (Cx-Cs) oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R25 is (C? -C5) alkyl, - (Cx-Cs) oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 25 is -teroid (C? -Cs) alkyl that does not contain Si. In some embodiments, R 25 is unsubstituted phenyl. In other embodiments, R 25 is a substituted phenyl. In preferred embodiments, R25 is methyl.

H -C- or -N- Z is' • In some embodiments, Z is nitrogen. In other modalities, Z is carbon. L is -O-, -S-, or -N (R26) -. In some modalities, L is -O-. In other modalities, L is -S-. In other embodiments, L is -N (R26) -. In certain embodiments, Z is nitrogen and L is -N (R26) R26 is -H, - (Cx-Cs) alkyl, aryl (C? -C10) substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl . In certain embodiments, R26 is -H, aryl (C? -C? O) substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In some modalities, R26 is -H. In other embodiments, R 26 is substituted or unsubstituted phenyl. And it is absent or is -CH2-, -CH2CH2-, -CH = CH-, -C (O) -CH2-, -C (0) CH2CH2-, -C (0) CH = CH-, -S (02 ) -, -S (02) CH2-, S (02) CH2CH2-, -S (0) 2CH = CH or -C (O) -. In certain embodiments, Y is -CH2-, -CH2CH2-, -CH = CH-, -C (0) CH2-, -C (0) CH2CH2-, -C (0) CH = CH-, -S (02 ) -, -S (02) CH2-, S (02) CH2CH2-, -S (02) CH = CH-. In some modalities, Y is -CH2-. In some modalities L is -O- or -S-, and Y is -CH2, -CH2CH2-. W is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. For example and without limitation, W may be a ring such as benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole , oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline or quinoline, and others. In some embodiments, W is a substituted or unsubstituted monocyclic aryl ring or a substituted or unsubstituted monocyclic heteroaryl ring. In some embodiments, W is substituted or unsubstituted bicyclic aryl ring or substituted or unsubstituted bicyclic fused heteroaryl ring. In certain embodiments, W is a fused aryl ring of 8 to 11 members or a bicyclic fused heteroaryl ring of 8 to 11 members. In other embodiments, W is an aryl ring of 5 or 6 members substituted or unsubstituted or 5 to 6 membered heteroaryl ring substituted or unsubstituted. In certain embodiments, wherein W is a substituted or unsubstituted aryl or heteroaryl ring, the substituent group may be a halogen, (C? -C? O) substituted or unsubstituted alkyl, hetero (C? -C? O) substituted alkyl or unsubstituted, halo (C? -C? 0) substituted or unsubstituted alkyl, aryl (C? -C10) substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, W is a 5-membered ring having two or more heteroatoms. In certain embodiments, W is a 5 member ring selected from the group consisting of: and R27 is (C? -C?) substituted or unsubstituted alkyl, hetero (C? ~ C? o) substituted or unsubstituted alkyl, halo (C? -C? o) substituted or unsubstituted alkyl, aryl (C? -C ?) substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. H -c- In some embodiments, where Z is', R is -OH, L is -O-, -S-, or -NR (R26) - and Y is -CH2-, -CH2CH2-, -CH = CH -, -C (0) CH2-, -C (0) CH2CH2-, -C (0) CH = CH-, or -C (O) -, then W is not furan or thiophene. In certain embodiments, W is a substituted or unsubstituted phenyl. In some embodiments, Z is carbon and R22 is (C2-C8) alkyl, - (C3-C8) alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -C = C-R25. In some embodiments, where Z is carbon, W is a ring of a benzene, R22 is -C = C-R25, R25 is -tero (C? ~ 'C5) alkyl, L is -O- or -S-, then any heteroatom in R25 is not Si. In some embodiments, where R21 is -OH, L is -O-, Y is -CH2-, and W is para-methoxyphenyl, R22 is -C = C-R25, then R25 is not -H. In certain embodiments, where L is -N (R25) -, Z is nitrogen, R22 is a phenyl, R26 is hydrogen or a phenyl and W is a phenyl, then Y is not -C (O) -. It will be appreciated that in embodiments of formula II, H - c- wherein Z is and R22 is - (C2-C8) alkyl, (C3-C8) alkenyl, -NR23R24, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C = N, or -C = C-R25, then the carbon in Z is a chiral carbon as shown:.

In this manner, a compound of the invention can be an S-enantiomer, an R-enantiomer, or a mixture of both an S-enantiomer and an R-enantiomer. In preferred embodiments, a compound is an S-enantiomer.

In certain embodiments, R21 is -OH; L is -O-, or -S-; and Y is -CH2-, or -CH2CH2-, In some embodiments, where Z is nitrogen, then W is not a 1,2-azole ring. In certain different embodiments, the present invention provides a compound having the formula (III) III or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein R22, LY and W are as defined with respect to formula II above. In some embodiments, R22 is -H, - (C2-C3) alkyl, NR23R24, or substituted or unsubstituted phenyl. In certain embodiments, L is -O-, -S-, or NR (R26) -. In some embodiments, R26 is -H, aryl (C? -C? O) substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In some embodiments, Y is -CH2-, -CH2CH2-, -CH = CH-, -C (0) CH2-, -C (0) CH2CH2-, -C (0) CH = CH-, -S (02 CH2, -S (02) CH2CH2-, -C (O) -, OR -S (02) CH = CH. In some embodiments, W is a substituted or unsubstituted 5 to 6 membered aryl ring or 5 to 6 membered heteroaryl ring substituted or unsubstituted with the proviso that if R22 is phenyl, L is -0-, -S-, or -N (R26) -, and W is a benzene ring then Y can not be -C (0) -. In some embodiments, L is - (R26) -, and R26 is hydrogen. In other embodiments, W is not a 1,2-azole ring. In other embodiments, the compound of formula III is selected from the group consisting of: or a salt of it. In further embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R21 is -OH, -NHS (02) CH3, -? H-tetrazolyl, or tetrazolyl; R22 is - (C2-C8) alkyl, -? R23R24, substituted or unsubstituted phenyl, CH = C (CH3) 2, -CH2CH = CH2, or -C = C-R25; R23 and R24 are independently -H, - (C? ~ C5) alkyl, or - (C? -Cs) oxyalkyl; R25 is -H, - (C? -C5) alkyl, - (C? -Cs) oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is H -C- or -? -; L is -0-, -S-, O -? (R26) -; R26 is -H, - (Cx-Cs) alkyl, aryl (C? -C10) substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Y is -CH2-, -CH2CH2-, -CH = CH-, -C (0) CH2-, C (0) CH2CH2-, -C (0) CH = CH-, -S (02) CH2-, - S (02) CH2CH2-, OS (02) CH = CH; and W is a substituted or unsubstituted 5 or 6 membered aryl ring or a substituted or unsubstituted 5 or 6 membered heteroaryl ring. In certain embodiments, the present invention provides compounds according to formula (IV): IV or a pharmaceutically acceptable salt, hydrate or prodrug of the same, wherein R25, W, Y and L are as defined above in the preceding paragraph. In some embodiments, R25 is methyl. In some embodiments, L is -0- or -S- and Y is -CH2-or -CH2CH2-. In some embodiments, W is a 5-membered ring selected from the group consisting of, "-?; R27 is (CC? 0) substituted or unsubstituted alkyl, hetero (C? ~ C? O) substituted or unsubstituted alkyl, halo ( C? -C? 0) substituted or unsubstituted alkyl, aryl (C? -C? O) substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl In certain embodiments, R27 is substituted phenyl. R27 is unsubstituted phenyl In some embodiments, the present invention provides compounds according to formula (V): V or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein R21, R22 and W are as defined above. In some embodiments, R21 is -OH, or a salt thereof. In some embodiments, W is substituted phenyl.

In some embodiments, W is substituted with (C? ~ C? 0) substituted or unsubstituted alkyl, hetero (C? -C? O) substituted or unsubstituted alkyl, halo (C? -C10) substituted or unsubstituted alkyl, aryl (. C? -C?) Substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In other embodiments, W is a 5 member ring selected from the group consisting of: R27 is hydrogen, (C? -C?) Substituted or unsubstituted alkyl, hetero (C? -C? O) substituted or unsubstituted alkyl, halo (C? -C10) substituted or unsubstituted alkyl, aryl (C? -C? 0) substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, a compound of formula V is a racemate. In certain embodiments, the compound of formula V comprises a mixture of (S) and (R) enantiomers. In certain embodiments, the present invention provides compounds having the formula (Va): wherein R21, R22 and W are as defined above in formula V. In other embodiments, the compound has the formula (Vb): Vb wherein R21, R22 and W are as defined above in formula V. In certain embodiments, the present invention provides compounds according to formula (VI): VI or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R25 and W are defined in the preceding paragraphs. In some embodiments, R25 is methyl.

In some embodiments, W is a 5-member ring selected from the group consisting of: R27 is hydrogen, (C? -C10) substituted or unsubstituted alkyl, hetero (C? -C? O) substituted or unsubstituted alkyl, halo (C? -C10) substituted or unsubstituted alkyl, aryl (C? -C? 0) substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, the compound of formula VI comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VI comprises a stereomerically pure R-enantiomer. In still other embodiments, the compound of formula VI comprises a mixture of S and R enantiomers. In certain embodiments, the present invention provides compounds according to formula (VII): VII or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein each R28 is selected from the group consisting of (C? -C?) Substituted or unsubstituted alkyl, hetero (C? -C? O) substituted alkyl or unsubstituted, halo (C? - C? o) substituted or unsubstituted alkyl, aryl (C? -C? o) substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl the subscript q is an integer from 0 to 5, and R24 is as defined above. In some embodiments, the subscript q is 0, 1 or 2. In other embodiments, R28 is a methoxy, ethoxy, trihalomethyl, methyl, halo, or cyano group and the subscript q is 1 or 2. In other embodiments, R28 is a phenyl, methoxyphenyl, methylphenyl, trihalomethylphenyl, benzyl, phenoxy, ethoxyphenyl, cyanophenyl, halophenyl, halobenzyl, pyridyl, methoxybenzyl or pyryl group, and the subscript q is 1 or 2. In other embodiments, R 25 is methyl. In certain embodiments, the compound of formula VII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VII comprises a stereomerically pure R-enantiomer. In still other embodiments, the compound of formula VII comprises a mixture of S and R enantiomers. In other embodiments, the formula is selected from the group consisting of: and salts thereof. In certain embodiments, the present invention provides compounds according to formula (VIII): vip or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R21, R22 and W are defined in the preceding paragraphs and Ar and T are defined below. T is a direct bond, (C? -C) alkylene, hetero (Cx-Cs) alkylene, O, C (O) - (C5-C7) heterocycloalkylene, (C? ~ C4) alkylene-S02NH, or (C? -C) to the uileno-NHS02. In some embodiments, T is a direct bond, (C? ~ Cs) substituted or unsubstituted alkyl or hetero (C? -Cs) substituted or unsubstituted alkyl. Ar is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, Ar is a benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine., pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline or quinoline. In some embodiments, R22 is -C = C-CH3. In some embodiments, R21 is -OH. In certain embodiments, T is a direct bond and Ar is a substituted or unsubstituted benzene ring. In some embodiments, W is phenyl. In other embodiments, W is a 5 member ring selected from the group consisting of: R '27 is Ar-T- In certain embodiments, the compound of formula VIII. comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VIII comprises a stereomerically pure R-enantiomer. In still other embodiments, the compound of formula VIII comprises a mixture of S and R enantiomers. In certain embodiments, the compound is selected from the group consisting of: or a salt of them. In certain embodiments, the present invention provides compounds according to formula (IX): IX or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein W, T and Ar are as defined above in formula VIII. In some modalities, the compound has the formula: or a salt of it. In one embodiment, the compound is selected from the group consisting of: or a salt of them. In certain embodiments, the present invention provides compounds, for example, of the formula III, IV, VI, VII or IX, which include a bioisoster or -C02H instead of -C02H. For illustration, compounds that include a bioisser of -C02H in place of -C02H in example compound 27.1, described in the examples below, may include the following: and the like, without limitation, as recognized by those skilled in the art. See, for example, The Practice of Medicinal Chemistry, Wermuth, C.G., Ed., Academic Press: New York, 1996, incorporated herein by reference in its entirety. In certain embodiments, the invention provides compounds according to the above formulas insofar as the compound is not one of the following acids, or salts thereof, including: 3- (4- (4-methoxybenzyloxy) phenyl) pendant. 4-inoic; β-ethenyl-4-phenylmethoxy-benzenepropanoic acid; 4- (2-quinolinylmethoxy) -β- [4- (2-quinolinylmethoxy) phenyl] -benzenepropanoic acid; N- [4- (benzoylamino) phenyl] -N-f nil-glycine; 3- (4- (isopentyloxy) benza ido) -3-phenylpropanoate; 3- (4-isobutoxybenzamido) -3-phenylpropanoate; (R) -2- ((IR, R) -4-isopropylcyclohexanecarboxamido) -3-phenylpropanoic acid. (R) -3- (4-benzyloxy) phenyl) -2- (tert-butoxycarbonyl) propanoic acid; 3- (4-chlorophenyl) -3- (furan-2-carboxamido) -propanoic acid; 3- (3, -dimethoxyphenyl) -3- (furan-2-carboxamido) propanoic acid; 3- (4-chlorobenzamido) -3- (4- (dimethylamino) -phenyl) propanoic acid; 3- (2- (2- (3, -dimethylphenoxy) ethylthio) -1H-benzo [d] imidazol-1-yl) propanoic acid; acid { 2-bromo- [(3,4-dichloro-phenyl) -hydrazono-methyl] -6-ethoxy-phenoxy} -acetic; 2- (4- (2- (2- (4-chlorophenyl) furan-5-carboxyamy) ethyl) phenoxy) -2-methylpropanoic acid; 5- (3- (3,4-dimethoxyphenyl-5- (2-fluorophenyl) -4,5-dihydropyrazol-1-yl) -5-oxopentanoic acid 2- (2- (3- (3,4-) acid dihydro-2H-benzo [b] [1,4] dioxepin-7-yl) -2-methyl-4-oxo-4H-chromen-7-yloxy) acetamido) acetic acid 3- (4'-bromo-biphenyl) -4-yl) -4-phenyl-butyric acid 3- (4'-bromo-biphenyl-4-yl) -3-phenylsulfanyl-propionic acid 3- (5- (2-chloro-6-fluoro-4) - (trifluoromethyl) -phenoxy) -2,4-dinitrophenyl) propanoic acid 3- (3- (2-chloro-4- (trifluoromethyl) phenoxy) phenyl) propanoic acid 3- (4- (4-methoxybenzyloxy) phenyl ) pen-4-inoic, "3- (4- (4-methoxy-enzyloxy) phenyl) -5- (trimethylsilyl) ent-4-ynyo acid; β, β-dimethyl-4- [[[4-methyl-] 2- [4- (trifluoromethyl) phenyl] -5-thiazolyl] methyl] thio] -benzenepropanoic acid; or β-amino-4- [(4-bromo-2,5-dihydro-2-methyl-5-oxo-) acid. 1-Phenyl-H-pyrazol-3-yl) methoxy] -3-methoxy-benzene-propanoic Preparation of the Compounds The compounds of the invention can be prepared by a variety of synthetic or semi-synthetic techniques. synthetic.

Figure 1 and the following Examples provide a variety of synthetic routes to the compounds provided herein. Suitable starting materials can be prepared by techniques known or apparent to those skilled in the art or starting materials may be commercially available. An expert in. the technique will understand that synthetic routes can be modified to use different starting materials or alternative reagents and that appropriate adjustments can be made under the conditions (eg, temperatures, solvents, etc.) to achieve the desired transformations. Additionally, one skilled in the art will recognize that protective groups may be necessary for the preparation of certain compounds and will be aware of those conditions compatible with a selected protecting group. Accordingly, the exemplary methods and examples described herein are illustrative of the present invention and are not to be construed as limiting the scope thereof. Compositions In another aspect, the invention provides pharmaceutical compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient or diluent. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product resulting from, either directly or indirectly, the combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant that the carrier or excipient is compatible with the other ingredients of the formulation and not harmful to the recipient thereof. In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula II, wherein R 22 comprises an alkynyl containing Si, and wherein R 21, L, Y and W are as defined above in formula II.

In some embodiments, the Si atom is substituted with up to three alkyl groups. In some embodiments, R22 is -C = C-Si (CH3) 3. The formulation of the composition may improve one or more pharmacokinetic properties (eg, oral bioavailability, membrane permeability) of a compound of the formula (referred to herein as the active ingredient). The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of placing the active ingredient in association with the carrier which constitutes one or more auxiliary ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, forming the product in the desired formulation. In the pharmaceutical composition, the subject active compound is included in an amount sufficient to produce the desired effect in the disease process or condition. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, powders or dispersible granules, emulsions, hard or soft capsules, or syrups or elixirs. The compositions proposed for oral use can be prepared according to any method known in the art for the preparation of pharmaceutical compositions. These compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preservatives in order to provide pharmaceutically elegant and tasty preparations. The tablets contain the stainless steel in admixture with other pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, corn starch, or alginic acid, binding, for example starch, gelatin or acacia gum, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate may be employed. or glyceryl distearate. They can also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,116,452 and 4,265,874 to form osmotic therapeutic tablets for release control. Formulations for oral use may also be presented as a hard gelatin capsule, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as gelatin capsules where the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. The aqueous suspensions contain the active materials in admixture with suitable excipients for the preparation of aqueous suspensions. These excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; the dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from degrees-acids and a hexitol such as monooleate polyoxyethylene sorbitol, or condensation products of ethylene oxide with partial esters derived from degrees acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Aqueous suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, sesame oil, olive oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above and the flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient and mix with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example, - olive oil or peanut oil, or a mineral oil, for example, liquid paraffin or mixture thereof. Suitable emulsifying agents may be naturally occurring gums, for example, acacia gum or tragacanth gum, naturally occurring phosphatides, for example, soy, lecithin, and esters or partial esters derived from fatty acids and anhydrides. of hexitol, for example, sorbitan monooleate and condensation products of the partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain an emollient, a preservative and flavoring and coloring agents.

The pharmaceutical compositions can be in the form of an aqueous, oily, injectable, sterile suspension. This suspension can be formulated according to the unknown technique using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils such as a solvent or suspending medium are conventionally employed. For this purpose, any fixed and tasteless oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable products. The pharmaceutical compositions can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but the liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc. are used, which contain the compounds of the invention. As used herein, topical application is also proposed to include the use of mouthwashes and gargles. The pharmaceutical compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, • syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. Methods of use In another aspect, the invention provides methods for treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia. , hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema, which comprises administering a subject in need thereof a therapeutically effective amount of a compound or composition of the invention. In one embodiment, the disease or condition is type II diabetes. In another aspect, the present invention provides a method for treating a condition or disease responsive to modulation of GPR40 which comprises administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention. In some modalities, the disease or condition is selected from the group consisting of diabetes II, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. In certain modalities, the disease or condition is type II diabetes. In some modalities, the disease or condition is obesity. In some modalities, the disease or condition is hypertension. In some embodiments, of administration of the compounds or compositions of the invention, the compound or composition is administered orally. In other embodiments, the compound or composition is administered parenterally. In other embodiments, the compound or composition is administered in combination with a second therapeutic agent. In other embodiments, the second therapeutic agent is an insulin sensitizing agent, such as metformin or a thiazolidinedione, by way of example. In another aspect, the invention provides methods for treating or preventing a disease or disorder responsive to modulation of GPR40 which comprises administering to a subject having a disease or disorder, a therapeutically effective amount of one or more of the present compounds or compositions. In yet another aspect, the invention provides methods for treating or preventing a GPR40 mediated condition, disease or disorder comprising administering to a subject having this condition, disease or disorder, a therapeutically effective condition of one or more of those present. compounds or compositions. In still another aspect, the invention provides methods for modulating GPR40 comprising contacting a cell with one or more of the present compounds or compositions. For example, in some embodiments, a cell that constitutively expresses GPR40 is contacted with one or more of the present compounds or compositions. In certain embodiments, a cell to be contacted may be caused to express or overexpress GPR40, for example, by expressing GPR40 of the heterologous nucleic acid introduced into the cell or, as another example, by promoting the expression of GPR40 of the endogenous nucleic acid to the cell. Depending on the disease to be treated and the condition of the subject, the compounds of the invention may be administered by oral, parenteral administration (eg, intramuscular, intraperitoneal, intravenous, ICV, intracisternal or infusion injection, subcutaneous injection or implant). ), inhalation, nasal, vaginal, rectal, sublingual or topical (for example, transdermal, local) and can be formulated, alone or together, in suitable formulations of unit doses containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants and vehicles. appropriate for each administration route. The invention also contemplates the administration of the compounds of the invention in a. reservoir formulation, in which the active ingredient is released for a defined period of time. In the treatment or prevention of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease , ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema or other conditions or disorders associated with GPR40, an appropriate dose level will generally be approximately 0.001 to 100 mg per kg of body weight of the patient per day that can be administered in single or multiple doses. Preferably, the dose level will be from about 0.01 to about 25 mg / kg per day; more preferably about 0.05 to about 10 mg / kg per day. An appropriate dose level can be from about 0.01 to 25 mg / kg per day, from about 0.05 to 10 mg / kg per day, or from about 0.1 to 5 mg / kg per day. Within this range, the dose can be from 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 5 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dose to the patient to be treated. The compounds can be administered in a regimen of 1 to 4 times per day, preferably once or twice per day. -10 However, it will be understood that the specific dose level and dose frequency for any particular patient can be varied and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and the duration of action of This compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, combination of the drug, the severity of the particular condition, and the host undergoing therapy. The compounds of the invention can be combined or Use in combination with other subtle agents in the treatment, prevention, suppression or amelioration of the diseases or conditions for which the compounds of the invention are useful, including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance. , hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. These other agents, or drugs, can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound of the composition. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing these other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical compositions of the invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound of the invention. Examples of other therapeutic agents that can be combined with a compound of the invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) cholesterol lowering agents such as inhibitors - of HMG-CoA reductase (eg, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and other statins), bile acid sequestrants (eg, cholestyramine and colestipol), vitamin B3 (also known as nicotinic acid, or niacin) , vitamin B6 (pyridoxine), vitamin B? 2 (cyanocobalamin), fibric acid derivatives (for example, gemfibrozil, clofibrate, fenofibrate and benzafibrate), probucol, nitroglycerin, and cholesterol absorption inhibitors (for example, beta-blockers) sitosterol and acylCoA-cholesterol-acylatransierase (ACAT) - such as elinamide), HMG-CoA synthase inhibitors, squalene-epoxidase inhibitors and e-inhibitors. squalene synthetase; (b) antithrombotic agents, such as thrombolytic agents (e.g., streptokinase, alteplase, anistreplase and reteplase), heparin derivatives, hirudin and warfarin, β-blockers (e.g., atenolol), β-adrenergic agonists (e.g., isoproterenol) ), ACE inhibitors and vasodilators (eg, sodium nitroprusside, nicardipine hydrochloride, nitroglycerin and enaloprilat); and (c) anti-diabetic agents such as insulin and insulin mimics, sulfonylureas (e.g., glyburide, meglinatide), biguanides, e.g., metformin (Glucophagem), a-glucosidase (ascarbose) inhibitors, insulin sensitizers, Examples are thiazolidinone compounds, rosiglitazone (Avandiam), troglitazone (Rezulinm), cyclatazone, pioglitazone (Actos * 2 *) and englitazone. The weight ratio of the compound of the invention to the second active ingredient can be varied and will depend on the effective dose of each ingredient. In general, an effective dose of each will be used. Combinations of a compound of the invention and other active ingredients will also generally be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In another aspect, the present invention provides a method for modulating the concentration and circulation of insulin in a subject, which comprises administering a compound or composition of the invention. In some modalities, the concentration of insulin is increased. In other modalities, the insulin concentration is decreased. In certain embodiments, a compound, or composition comprising a compound, can be used according to formula II, wherein R 22 comprises an alkyl, containing Yes, and where R21, L, Y and W are as defined above in formula II. In some embodiments, the Si atom is substituted with up to three alkyl groups. In some embodiments, R22 is -C = C-Si (CH3) 3. The following examples are offered by way of illustration and are not intended to limit the scope of the invention. Those skilled in the art will readily recognize a variety of non-critical parameters that can be modified to produce essentially similar results. EXAMPLES 'EXAMPLE 1 This example illustrates the preparation of (3S) -3- (-hydroxy-phenyl) -hex-4-ynoic acid methyl ester. Diagram 1.1 of Reaction - (4-hydroxy-benzylidene) -2, 2-dimethyl- [1,3] dioxan-4,6-dione (1.1). Condensation was carried out with Meidrum acid according to the method of Bigi et al., (2001) Tetr. Lett. 42: 5203-5205. A 2 L beaker flask was charged with 4-hydroxybenzaldehyde (50 g, 409 mmol) and water (400 mL). The flask was placed in a water bath at 75 ° C and Meldrum acid (62 g, 430 mmol) was added as a slurry in a suspension of 400 L of water. The reaction mixture was stirred for 2 hours then cooled in an ice bath for 2 hours. The product was collected by filtration and rinsed with cold water. After drying completely, 95 g (94%) of the adduct 1.1 was obtained as a fine yellow powder. X H NMR (500 MHz) (DMSO-d 6) d 9.75 (br, s 1 H); 8.27 (s, 1H); 8.24 (d, 2H, J = 10 Hz); 6.98 (d, 2H, J = 10 Hz); 1.76 (s, 6H). MS ESI (pos.) M / e: 519.0 (2M + Na). Diagram 1.2 of Reaction (+/-) -5- [1- (4-hydroxy-phenyl) -but-2-ynyl] -2,2-dimethyl- [1,3] dioxane-4,6-dione (1.2). A 3-neck 3-neck flask dried in the oven equipped with a mechanical stirrer, nitrogen inlet, nitrogen outlet and placed in a water bath at room temperature. After purging with nitrogen for 20 minutes, a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) was added by cannula. In a 500 mL RB flask, dried in the oven and rinsed with nitrogen, separated, compound 1.1 (35 g, 142 mmol) was dissolved in anhydrous THF (350 mL) with moderate heating. The solution of 1.1 was then added for 15 minutes. During the course of the addition, the reaction mixture changed to a thick yellow suspension. After the addition was complete, the reaction mixture was stirred for 15 minutes and then quenched with aqueous NH 4 Cl (0.6 N, 750 mL) and diluted with hexanes (800 mL). The layers were separated and the organic layer was discarded. The aqueous layer was acidified to pH about 2 with saturated aqueous KHS0 and extracted with ethyl acetate (2 x 400 mL). The combined extracts were washed with saturated brine, dried over MgSO, filtered and concentrated to give a light yellow solid (37 g, 91%). RM? A (500 MHz) (acetone-de) d 8.26 (s, 1H), 7.39 (d, 2H, J = 8.5 Hz); 6.76 (d, 2H, J = 8.4 Hz), 4.73 (br s, 1H), 4.46 (d, 1H, J = 2.4 Hz); 1.82 (s, 3H), 1.81 (s, 3H), 1.64 (s, 3H). MS ESI (pos.) M / e: 599.0 (2M + Na). Diagram 1.3 of Reaction Acid (+/-) -3- (4-hydroxy-phenyl) -hex-4-inoic (1.3). A 1 L RB flask was charged with compound 1.2 (37 g), diethyl ketone (160 mL), and water (80 mL). The suspension was heated to reflux for 48 hours. After cooling, the aqueous layer was saturated with NaCl (S > and separated The organic layer was dried over MgSO, filtered, and concentrated to a light brown oil which was recrystallized from hot ethyl acetate: hexanes (1 g). : 2) .After collection and drying, the product was obtained as an off-white powder (20.3 g, 77%). RMN A (500 MHz) (DMSO-d6) d 12.2 (s, 1H), 9.27 (s) , 1H), 7.12 (d, 2H, J = 8.5 Hz), 6.67 (d, 2H, J = 8.6 Hz), 3.87 (m, 1H), 2.54 (m, 2H), 1.82 (d, 3H, J = 2.4 Hz) MS ESI (pos.) M / e: 205.1 (M + H); 227.1 (M + Na) Scheme 1.4 Reaction (3S) -3- (4-Hydroxy-phenyl) -hex-4-inoic acid (1.4). A 5L RB flask was charged with compound 1.3 (66.4 g, 325 mmol) and 2-propanol (1 L) and then heated to 70 ° C. (1S, 2R) -l-amino-2-indanol (46.1 g, 309 mmol) was dissolved in 2-propanol (1 L) with gentle heating. The amine solution was added to the dissolved carboxylic acid and the resulting solution was allowed to cool to room temperature. After 16 hours, the crystals were harvested and dried. The salt was resuspended in 2L of 2-propanol and dissolved by heating under reflux. After allowing to cool to room temperature, the salt was collected after 16 hours. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (column Daicel Chiral PAK AD-H, eluent: 0.1% TFA in hexanes: 2-propanol 90:10) and it was found that It has 75% of us The salt was resuspended in 1.5 L of 2-propanol and dissolved by heating under reflux. After allowing to cool to room temperature, the salt was collected after 16 hours. This material was found to have 96% ee by chiral HPLC. This material was suspended in ethyl acetate (300 mL) and water (100 mL). Aqueous saturated KHS04 (100 mL) was added with vigorous mixing. After two clear layers were obtained, the layers were separated and the aqueous layer was extracted with ethyl acetate (100 L). The combined extracts were saturated with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow oil which crystallized on drying in vacuo. Compound 1.4 was obtained as an off-white solid (23.5 g, 35%). Diagram 1.5 of Reaction 1. 4 1 Methyl ester of (3S) -3- (4-hydroxy-phenyl) -hex-4-inoic acid (1). Phenol 1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHC03 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction was stirred at 40 ° C for 14 hours. An additional portion of methyl iodide (3 mL, 48 mmol) was added and heating continued for 24 hours. The potassium salts were removed by filtration and rinsed thoroughly with acetone. The filtrate was concentrated to an oil which was purified by filtration through a 1 cm plug of silica gel. Elution with 2.5% MeOH in dichloromethane followed by concentration gave phenol 1 (21.5 g, 85%) as a light yellow oil. NMR A (500 MHz) (acetone-de) d 8.2 (br s, 1H); 7.20 (d, 2H, J = 9.5 Hz); 6.77 (d, 2H, J = 9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H); 2.65 (m, 2H); Í.78 (d, 3H, J = 2.-5 Hz). MS ESI (pos.) M / e: 219.1 (M + H); 241.1 (M + Na). Example 2 This example illustrates the preparation of the sodium salt of (3S) -3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -hex-4-ynoic acid. Diagram 2.1 of Reaction 2. 1 3- (4-Trifluoromethylphenyl) -benzoic acid (2.1). The Suzuki coupling was carried out according to the method of Dyer et al. (2001) Tetrahedron Letters 42: 1765-1767. The commercially available 4-Mtrifluoromethyl) phenylboronic acid (15 g, 78.7 mmol) and 3-bromobenzoic acid (15.1 g, 75 mmol) were suspended in 2-propanol: water (1: 4, 72 mL). Pd at 10% / C (1.5 g) was added followed by aqueous Na 2 CO 3 (39 mL, 20% by weight). The resulting mixture was heated at 70 ° C for 4 hours. The precipitate was filtered and rinsed with 20% aqueous NaOC3 solution. The filtrate was diluted with water and acidified to pH = 2. The white solid was filtered and dried in vacuo. The crude material (2.1) (19.69 g) was used in the next step without further purification. Diagram 2.2 of Reaction 3- (4-Trifluoromethylphenyl) -benzyl alcohol (2.2). The carboxylic acid 2.1 (13.3 g, 50 mmol) in anhydrous THF (100 mL) was added dropwise to LiAlH (2.9 g, 75 mmol) in anhydrous THF (150 mL) at 0 ° C for 30 minutes. The resulting mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction was quenched slowly with water (2.9 mL) at 0 ° C, 15% aqueous NaOH solution (2.9 mL) and another portion of water (8.7 L). The mixture was dried over Na2SO4 and concentrated to give a white solid (11.9 g). The crude product (2.2) was used in the next step without further purification. Diagram 2.3 of Reaction Chloride 3- (4-trifluoromethylphenyl) -benzyl (2.3). The alcohol 2.2 (15 g, 59.5 mmol) was dissolved in anhydrous dichloromethane (100 mL). Thionyl chloride (10 mL) was slowly added dropwise to the above solution. The resulting mixture was stirred at room temperature for 24 hours. The organic solvent was removed under vacuum. The residue was then purified by flash chromatography (60 Si02 gel, eluted with 20% DCM in hexanes). The fractions containing the desired product 2.3 were combined and concentrated to give a white solid (14.0 g). NMR A (400 MHz) (CDC13) d 7.73 (4H, s); 7.65 (1H, s); 7.58 (1H, s); 7.52-7.28 (2H,); 4.69 (2H, s).

Scheme 2 4 of Reaction (3S) -3- [4- (4'-Trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -hex-4-ynoic acid methyl ester (2.4). Benzyl chloride 2.3 (28.0 g, 103 mmol) and phenol 1 (21.5 g, 98 mmol) were dissolved in acetone (150 mL) and treated with Cs2CO3 (39.9 g, 122 mmol). The reaction was stirred at 50 ° C for 16 hours, then filtered and concentrated to a pale yellow oil which was purified by column chromatography (silica gel, 33% to 66% dichloromethane in hexanes). The eluate containing compound 2.4 was concentrated to a colorless oil (40.0 g, 92%).

Diagram 2.4 of Reaction Sodium salt of (3S) -3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -hex-4-ynoic acid (2). The methyl ester 2.4 was dissolved in diethyl ether (50 mL). Sodium trimethylsilanolate (0.78 g, 7 mmol) was added in one portion and the reaction mixture was stirred for 48 hours. The precipitate was collected by filtration and recrystallized from ethyl acetate: hexanes. After drying in vacuo, the desired sodium salt was obtained as a white powder (1.3 g). NMR A (500 MHz) (CD3OD) d 7.82 (d, 2H, J = 8.5 Hz); 7. 75-7.73 (m, 3H); 7.62 (, 1H); 7.32 (d, 2H, J = 8.5 Hz); 6. 94 (d, 2H, J = 8.5 Hz); 5.15 (s, 2H); 4.03 (m, 1H); 2.52 (dd, 1H, J = 8.2, 14.5 Hz); 2.45 (dd, 1H, J = 7.0, 14.0 Hz); 1.79 (d, 3H, J = 2.5 Hz).

Example 3 Reaction Scheme 3.1 3. 1 3.2 - (3S) -3 ~ [4- (4-Methyl-2-p-tolyl-thiazol-5-ylmethoxy) -phenyl] -hex-4-ynyoic acid methyl ester (3.2). Compound 3.1 was prepared according to the method described in Example 2 starting from commercially available 4-methyl-2- (4-methylphenyl) -l, 3-thiazole-5-carboxylic acid. Chloride 3.1 (250 mg, 1.1 mmol) and phenol 1 (230 mg, 1.1 mmol) were dissolved in anhydrous DMF (5 mL). Then Cs2C03 was added to fine powder (650 mg, 2.2 mmol) and the reaction mixture was stirred at room temperature for 14 hours. The reaction was poured into water and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over Na 2 SO and concentrated in vacuo to a residue which was used in the next step without further purification.

Diagram 3.1 of Reaction 3. 2 (S) -3- [4- (4-Methyl-2-p-tolyl-thiazol-5-ylmethoxy) -phenyl] -hex-4-ynyoic acid (3). Ester 3.2 was dissolved in 10% THF / MeOH / NaOH (aqueous) solution (1: 1: 1) (15 mL). After stirring at room temperature for 30 minutes, the mixture was acidified with IN HCl (aqueous) to pH =. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over NaSO and concentrated. The crude residue was triturated with 20% ethyl acetate in hexanes (20 L). The precipitate was filtered and compound 3 was purchased as a pale yellow powder (315 mg, 0.8 mmol). MS ESI m / 3: 406 (M-H). NMR XH (500 MHz) (CDC13) d 7.86 (2H, d, J = 7.5 Hz); 7.36 (2H, d, J = 9 Hz); 7.26 (2H, d, J = 8 Hz); 6.96 (2H, d, J = 8.5 Hz); 5.18 (2H, s); 4.1 (1H, m); 2.77 (2H, m); 2.52 (3H, s); 2.42 (3H, s); 1.86 (3H, s). Example 4 This example illustrates the preparation of acid 3-. { 4- [2- (2,6-dichloro-benzyl) -thiazol-4-ylmethoxy] -phenyl} -hex-4-inoic.

Diagram 4.1 of Reaction 4. 1 1.3 Acid 3-. { 4- [2- (2,6-dichloro-benzyl) -thiazol-4-ylmethoxy] -phenyl} -hex-4-inoic (4). The preparation of thiazole 4.1 was carried out according to the method of Bordwell et al. (1990) J. Amer. Chem. Soc. 112: 792-797. Compound 4.1 (58 mg, 0.2 mmol) and phenol 1 (43.6 mg, 0.2 mmol) were dissolved in anhydrous DMF (2 mL) and treated with Cs2CO3 in fine powder (65 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 14 hours. The reaction was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over Na 2 SO, concentrated in vacuo and the residue was dissolved in 10% THF / MeOH / NaOH (aqueous) solution (1: 1: 1) (6 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1N HCl (aqu0SO) until pH = 4. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na 2 SO and concentrated in vacuo.

The crude residue was triturated with 20% ethyl acetate in hexanes (10 mL). The precipitate was filtered and acid 4 was purchased as a pale yellow powder (55 mg, 0.12 mmol). MS ESI m / e: 460 (M-H). X H NMR (400 MHz) (CDC13) d 7.40-7.19 (6H, m); 6.94-6.79 (2H, m); 5.18 (2H, s); 4.73 (2H, s); 4.1-4.06 (1H, m); 2.77 (2H, m); 1.85 (3H, s). Example 5 This example illustrates the preparation of 3- [4- (2-methyl-5-phenyl-furan-3-ylmethoxy) -phenyl] -hex-4-ynoic acid. Diagram 5.1 of Reaction . 1 1.3 3- [4- (2-Methyl-5-phenyl-furan-3-ylmethoxy) -phenyl] -hex-4-ynyoic acid (5). The Mitsunobu reaction was carried out according to the method of Miko et al. (2003) J. Med. Chem. 46: 1523-1530. 5.1 commercially available (37.6 mg 0.2 mmol), PPh3 (52 mg, 0.2 mmol) and phenol 1.3 (43.6 mg, 0.2 mmol) were added to anhydrous THF (3 mL). Then DEAD (45 μL, 0.22 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 14 hours. The reaction was then extracted with ethyl acetate (10 L x 3). The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The resulting residue was dissolved in a solution of THF / MeOH / NaOH (aqueous) 10% (1: 1: 1) (6 mL). The resulting mixture was stirred at room temperature for 30 minutes.

The resulting mixture was stirred at room temperature during minutes. The mixture was acidified with HCl (aqueous) IN until pH = 4.

The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over? A2S0, and concentrated in vacuo. The crude product was filtered by 20% ethyl acetate in hexanes (10 mL). The precipitate was filtered and compound 5 was obtained as a white powder (35 mg, 0.9 mmol). MS ESI m / e: 375 (M-H). RM? XH (500 MHz) (CDC13) d 7.65 (2H, d, J = 8 Hz); 7.40-7.24 (5H, m); 6.96 (2H, d, J = 8.5 Hz), 6.68 (1H, s); 4.88 (2H, s); 4.1 (1H, s); 2.77 (2H, m); 2. 4 (3H, s); 1.86 (3H, s). Example 6 The following compounds were prepared by methods similar to those described in Example 2.

Table 1 The NMR and MS data for compounds 6.13 and 6. 14 are as follows: 6.13 XH NMR (400 MHz) ((CD3) 2SO) d.12.4 (s, 1H), 7.52 (d, 2H, J = 8.1 Hz), 7.48 (d, 2H, J = 8.1 Hz) , 7.28-7.34 (3H), 7.17 (s, 1H), 7.08 (d, 1H, J = 8.1 Hz), 6.98 (d, 2H, J = 8.2 Hz), 5.12 (s, 2H), 4.08 (q, 2H, J = 7.0 Hz), 3.95 (m, 1H), 2.50-2.60 (m, 2H), 1.78 (s, 3H), 1.27 (t, 3H, J = 7.0 Hz).

[M + H] + calculated for C27H25C10: 449.1. Found 449.1 6. X-NMR (400 MHz) ((CD3) 2SO) -d 12.4 (s, 1H), 7.52 (d, 2H, J = 8.0 Hz), 7.46 (d, 2H, J = 8.6 Hz), 7.30 (d, 2H, J = 8.8 Hz), 7.46 (d, 2H, J = 6.0 Hz), 6.98-7.01 (m, 3H), 6.91-6.98 (m, 3H), 5.13 (s, 2H), 3.92-4.04 (, 3H), 2.61 (d, 2H, J = 7.6 Hz), 2.29 (s, 3H), 1.79 (d, 2H, J = 2.0 Hz), 1.59-1.66 (m, 2H), 1.34-1.40 (m, 2H) ), 0.88 (t, 3H, J = 7.6 Hz). [M +? A] + calculated for C30H32O: 471.1. Found 471.1 Example 7 The following compounds were prepared by methods similar to those described in Example 2. Table 2 ' Example 8 The following compounds were prepared by methods similar to those described in Example 3. Table 3 Example 9 The following compounds were prepared by methods similar to those described in Example 3.

Table 4 Example 10 The following compounds were prepared by methods similar to those described in Examples 3-5. The carboxylic acids corresponding to 10.2 and 10.5 were prepared according to the method of Huang et al. (2003) J. Amer. Chem. Soc. 22: 6653-6655, and Admas et al. (1973) Org. Synth Coll. Vol. V: 107, 109, respectively.

Table 5 Example 11 The following compounds were prepared by methods similar to those described in Examples 3-5.

Table 6 Example 12 This example illustrates the preparation of (+/-) 3- (4 - [(4-methoxyphenyl) methoxy] -phenyl) -hex-4-ynoic acid.

Diagram 12.1 of reaction 4 - [(4-methoxyphenol) methoxy] benzaldehyde (12.1). A 500 mL round bottom flask was charged with 4-hydroxybenzaldehyde (40 g, 328 mmol) and DMF (250 L). 4-Methoxybenzyl chloride (57.8 mL, 426 mmol) was added, followed by potassium carbonate (90 g, 656 mmol). Mix Reaction was stirred at room temperature for 5 hours then poured into ice water (2.5 L). The product was collected by filtration and rinsed with water. After drying completely, 78 g (98%) of the aldehyde 12.1 was obtained as a light yellow powder. NMR A (400 MHz) (DMS0-d6) d 9.88 (s, 1H), 7.88 (d, 2H, J = 8.7 Hz); 7.42 (d, 2H, J = 8.8 Hz); 7.21 (d, 2H, J = 8.8 Hz); 6.97 (d, 2H, J = 8.6 Hz); 5.16 (s, .2H); 3.77 (s, 3H). MS ESI (pos.) M / e: 243.1 (M + H). Diagram 12.2 of reaction - [[4 - [(4-methoxyphenyl) methoxy] phenyl] methylene] -2,2-dimethyl- [1,3] dioxane-4,6-dione (12.2): Condensation with Meldrum's acid is carried performed according to the procedure of De Wolf et al. (1989) Biochemistry 28: 3-833-3842. A solution of Meldrum's acid (18 g, 124 mmol), compound 12.1 (30 g, 124 mmol) in toluene (100 mL) was treated with glacial acetic acid (4 mL) and piperidine (2 mL). The reaction mixture was stirred and heated to reflux until the water removal was completed with a Dean-Stark trap. The reaction mixture was cooled to room temperature. And the resulting solid was filtered and washed with cold toluene to yield 28 g (62%) of 12.2 as a light yellow powder. X H NMR (400 MHz) (DMS0-d6) d 8.32 (s, 1H), 8.24 (d, 2H, J = 8.9 Hz); 7.42 (d, 2H, J = 8.6 Hz); 7.17 (d, 2H, J = 9.0 Hz); - 6.97 (d, 2H, J = 8.7 Hz); 5.18 (s, 2H); 3.75 (s, 6H) 1.75 (s, 6H). Diagram 12.3 of reaction 12. 2 12 Acid (+/-) -3- (4 - [(4-methoxyphenyl) methoxy] phenyl) -hex-4-ionic (12). To a stirring solution of THF (120 mL) of compound 12.2 (13.8 g, 37.5 mmol ") under nitrogen was added 1-propynylmagnesium bromide in THF (0.5 N, 97.5 mL) over a period of 20 minutes. The addition was terminated, the reaction mixture was stirred for 20 minutes, quenched with saturated aqueous NHC1 (50 mL) and extracted with ethyl acetate (3 x 50 mL) The combined extracts were washed with water, dried over MgSO4, filtered and concentrated to a brown oil, a solution of this brown oil in pyridine-water 5: 1 (360 mL) was heated at 100 ° C for 36 hours. The reaction mixture was cooled to room temperature. And it was put in an ice-water bath. Concentrated HCl was carefully added to a pH of about 2. The resulting suspension was extracted with ethyl acetate (200 mL x 3), dried over MgSO 4, filtered and concentrated to an off-white solid. Recrystallization from ethanol gave 9. 5 g (78%) of compound 12 as a white powder. RMN A (500 MHz) (DMSO-de) d 12.2 (s, 1H), 7.37 (d, 2H, J = 8.5 Hz); 7.27 (d, 2H, J = 8.5 Hz); 6.95 (d, 2H, J = 8.0 Hz); 6.94 (d, 2H, J = 8.5 Hz); 4.99 (s, 2H); 3.95 (m, 1H); 3.76 (s, 3H); 2.60 (, 2H); 1.78 (d, 3H, J = 1.5 Hz). MS ESI (neg.) M / e: 323.0 (M - 1). Example 13 This example illustrates the preparation of the sodium salt of (3S) -3- [4- (2-methyl-benzyloxy) -phenyl] -hex-4-ynoic acid.

Diagram 13.1 'of reaction 13. 1 Methyl ester of (3S) -3- [4- (2-methyl-benzyloxy) -phenyl] -hex-4-ynoic acid (13.1). 2-Methylbenzyl bromide (0.98 g, 5.3 mmol) and phenol 1 (0.97 g, 4.4 mmol) were dissolved in acetone (9 mL) and treated with Cs2CO3 (1.45 g, 4.4 mmol). The reaction was stirred at room temperature for 16 hours then filtered and concentrated to an oil which was purified by radial chromatography (2 mm silica gel plate, 10% ethyl acetate in hexanes). The eluate containing compound 13.1 was concentrated to a colorless oil (1.37 g, 96%). This material was analyzed by chiral HPLC (column Daicel Chiral PAK AD-H: 0.1% TFA in hexanes: 2-propanol 95: 5) was found to have 94% ee. NMR A (500 MHz) (MeOH-d4) d 7.39 (d, 1H, J = 7 Hz), - 7.28 (d, 2H, J = 8.5 Hz); 7.25-7.15 (m, 3H); 5.05 (s, 2H); 4.02 (m, 1H); 3.64 (s, 3H); 2.68 (m, 2H); 2.36 (s, 3H); 1.80 (d, 3H, J = 2.5 Hz). MS ESI (pos.) M / e: 323.0 (M + H; 245.1 (M + Na).

Diagram 13.2 of reaction Sodium salt of (3S) -3- [4- (2-methyl-benzyloxy) -phenyl] -hex-4-ynyo acid (13). KOH (aqueous) 2 N (3.2 mL) was added to a solution of 13.1 (1.37 g, 4.25 mmol) in methanol (30 mL). The reaction was stirred at room temperature. During the night and then it was taken in abundant water. The aqueous solution was adjusted to pH = 2.0 with HCl (aqueous) IN and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was dissolved in ethanol (4 mL) and treated with 1 equivalent of aqueous sodium bicarbonate. The solvents were removed under reduced pressure and the residue was triturated with diethyl ether. After collection by filtration and drying, sodium salt 13 (1.1 g) was obtained as a fine white powder. NMR A (500 MHz) (D20) d 7.34-7.18 (m, 6H); 6.95 (d, 2H, J = 6.5 Hz); 5.05 (s, 2H); 3.88 (m, 1H); 2.47 (d, 2H, J = 8.5 Hz); 2.28 (s, 3H); 1.72 (d, 3H, J = 2.5 Hz). MS ESI (pos.) M / e: 309.1 (M + H; 331.0 (M + Na). [A] D = + 20.6 °.

Example 14 The following compounds were prepared using methods similar to those described in Example 12. Table 7 Example 15 This example illustrates the preparation of (3S) -3- [4- (2-methyl-benzyloxy) -phenyl] -hex-4-ynoic acid. Diagram 15.1 of reaction Ethyl ester of (+/-) - [4- (4-methoxy-benzyloxy) -phenyl] -hex-4-ionic acid (15.1). A 100 L RB flask was charged with compound 12 (3.00 g, 9.25 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.67 g)., 13.9 mmol), 4-dimethylaminopyridine (1.13 g, 9.25 mmol) and dichloromethane (30 mL), the mixture was stirred in a solution. After 15 minutes, ethyl alcohol (absolute, 1.00 L) was added. After 2 hours, the reaction was quenched with aqueous NaHCO3 (saturated, 100 mL). The layers were separated, and the organic layer was washed with aqueous NaHCO3 (2 X 100 mL), dried over MgSO4 and concentrated to a white powder (3.19 g, 98%) filtered without further purification. Diagram 15.2 of reaction . 1 15.2 Ethyl ester of the acid (+/-) - [4- (2-methyl-benzyloxy) -phenyl] -hex- -ionic acid (15.2). Ester 15.1 (3.19 g, 9 mmol) was taken in glacial acetic acid (100 mL) in a 250 mL RB flask, and the suspension was heated at reflux for 16 hours. The solvent was removed under reduced pressure, and the residue was redissolved in ethyl acetate (200 mL). The solution was washed with HCl (aqueous) IN (200 L) and saturated brine. (200 mL), dried over MgSO4 and concentrated to a thick yellow oil, to which was added 2-methylbenyl bromide. (2.57 g, 13.9 mmol), cesium carbonate (6.03 g, 18.5 mmol) and DMF (20 L). The suspension was heated at 80 ° C overnight. After cooling, the reaction was quenched with water (200 L) and extracted with ethyl acetate (2 X 100 L).

The combined organic layers were washed with NaHCO 3 (saturated, 2 X 100 L), and? aCl (saturated, 3 X 100 mL), dried over MgSO4 and concentrated to a white powder (2.41 g, 79%). . Diagram 15.3 of reaction . 2 15 (3S) -3- [4- (2-Methyl-benzyloxy) -phenyl] -hex-4-ynoic acid (15). Compound 15.2 was dissolved in a mixture of 24 L of methanol and 24 mL of isopropanol with the aid of ultrasound treatment. The solution was filtered in a 50 L glass vial. The racemic product 15.2 was resolved with chiral normal phase HPLC using a ChiralTech AD semi-preparative column (2.0 cm X 25.0 cm), eluting isocratically with hexane / isopropanol (92: 8) at a flow rate of 20 mL / min. Each injection contained 50 mg of ester 15 (1 mL). The absorbance at 220 nm was used for detection. Both enantiomers were collected. After 36. injections, the separated enantiomers were dried to give white solids. Analytical chiral HPLC (Chiraltech AD-H column, 0.4 cm X 25.0 cm, 8% isopropanol / hexane, lmL / min) indicated that both compounds were optically pure. The enantiomers were referred to as A (retention time = 11.5 min) and B (retention time = 15.6 min). A RB flask with the enantiomer A (0.65 g), ethanol (10 mL) and 2N KOH (10 L) was charged and filtered for 2 hours at room temperature. After acidification at pH about 2 with citric acid, the product was extracted with ethyl acetate (100 mL). The organic layers were washed with saturated brine (2 X 50 mL), dried over MgSO4 and concentrated to a yellow oil (0.59 g, 42% of the total). An aliquot (12.0 mg) was made in 1 mL of DMF solution, and the optical rotation was measured. This enantiomer was assigned to (S) according to De Wolf Jr. et al. (1989) Biochemistry 28: 3833-3842. NMR A (400 MHz, acetone-de) d 7.45 (d, 1H, J = 7.15 Hz); 7.37 (d, 2H, J = 8.66 Hz); 7.25 (d, 1H, J = 1.42 Hz); 7. 24 (m, 2H); 7.00 (d, 2H, J = 8.74-Hz); 5.11 (s, 2H); 4.05 ( , 1 HOUR); 2.70 (m, 2H), 2.39 (s, 3H); 2.10 (s, 1H); 1.80 (d, 3H, J = 2.41). MS ESI (neg.) M / e: 307.1 (M-H); 637.2 (2M-H). [a] D20: + 16.32 (cl.2, DMF). Example 16 This example illustrates the preparation of 3- (4-hydroxy-phenyl) -hex-4-ynoic acid ethyl ester. Diagram 16.1 of reaction 3- (4-Hydroxy-phenyl) -hex-4-inoic acid ethyl ester (16). Phenol 1.2 (1.2 g, 4 mmol) was dissolved in pyridine (3 mL) and ethanol (1 mL). The mixture was heated at 90 ° C for 16 hours and then concentrated e? oil that was purified by column chromatography (elution with 1-3% MeOH in dichloromethane). Phenol 16 (0.88 g, 91%) was obtained as an oil. NMR A (500 MHz) (acetone-d6) d 8.24 (s, 1H); 7.21 (d,, 2H, J = 9.5 Hz); 6.78 (d, 2H, J = 9.0 Hz); 4.06 (m, 2H) 3.98 (m, 1H); 2.68-2.59 (, 2H); 1.78 (d, 3H, J = 2.5 Hz) 1.75 (t, 3H, J = 7.0 Hz). MS ESI (pos.) M / e: 233.1 (M + H) 255.1 (M + Na). Example 17 The following compounds were prepared by methods similar to those of Examples 12 and 15.

Table 8 Example 18 This example illustrates the preparation of the acid 3-. { 4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl} -hex-4-inoic. Diagram 18.1 of reaction 18. 1 4,5-Dimethyl-2- (4-trifluoromethyl-phenyl) -oxazole-3-oxide (18.1). A 100 L pear shaped flask was charged with butane mono-oxime-2,3-dione (2.1 g, 20.4 mmol), 4- (trifluoromethyl) benzaldehyde (3.0 mL, 22.4 mmol), and acetic acid (20 mL). L). The mixture was cooled to 0 ° C. A solution of 4N HCl in dioxane (7.0 mL, 28.0 mmol) was added dropwise to the reaction and the resulting mixture was stirred at 0 ° C for 20 minutes. Diethyl ether (30 mL) was added to the reaction and the mixture was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the resulting residue was taken up in water (300 L). NH0H (aqueous) concentrated was added to adjust the pH to 9.0. The mixture was extracted with ethyl acetate (2 x 75 mL), and the combined organic layers were washed with water (100 mL), followed by saturated brine (100 mL). The organic layer was dried (Na2SO) and the solvent was removed under reduced pressure. The resulting residue was purified by radial chromatography (3% MeOH in DCM) to yield 1.8 g (35%) of 4,5-dimethyl-2- (4-trifluoromethyl-phenyl) -oxazole-3-oxide as a white solid . LC / MSD m / e: 258.1 (M + H); RM? A (400 MHz) (acetone-de) d 8.68 (d, 2H, J = 8.0 Hz); 7.89 (d, 2H, J = 8.0 Hz), 2.45 (s, 3H), 2.16 (s, 3H). Diagram 18.2 of reaction 18. 1 18.2 4-chloromethyl-5-methyl-2- (4-r-trifluoromethyl-phenyl) -oxazole (18.2). Phosphorus oxychloride (0.72 mL, 7.8 mmol) was added dropwise to a oven-dried 100 mL pear-shaped flask loaded with 18.1 (1.8 g, 7.00 mmol) and dichloromethane (20 mL). The reaction was refluxed under nitrogen atmosphere for 30 minutes and then cooled to room temperature. The reaction was washed with water (2 x 250 mL) and the combined aqueous layers were again extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue was purified by radial chromatography (15% diethyl ether of hexane) to yield 216 mg (15%) of 4-chloromethyl-5-methyl-2- (4-trifluoromethyl-phenyl) ) -oxazole as a white solid. LC / MSD m / e: 276.0 (M + H); NMR A (400 MHz) (CDC13) d 8.15 (2H, d, J = 8. 0 Hz); .7.73 (2H, d, J = 8.0 Hz), 4.59 (2H, s), 2.48 (2H, s).

Diagram 18.3 of reaction 18. 2 16 18.3 Ethyl ester of acid 3-. { 4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl} -hex-4-inoic (18.3). Cesium carbonate (0.51 g, 1.57 mmol) was added to a solution of 18.2 (216 mg, 0.79 mmol) and phenol 16 (220 mg, 0.79 mmol) in DMF (8 mL). The reaction was stirred at room temperature overnight and then taken in water (500 L). The solution was adjusted to pH = 4.0 with HCl (aqueous) IN and extracted with ethyl acetate (2 x 25 mL). The combined organics were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified by radial chromatography (20% diethyl ether in hexanes) to yield 304 mg (82%) of 3- [4- [5-methyl-2-ethyl] ethyl ester. (4-trifluoroethylphenyl) -oxazol-4-ylmethoxy] -phenyl} -hex-4-inoic. LC / MSD m / e: 472.0 (M + H); NMR A (400 MHz) (CDC13) d 8.16 (2H, d, J = 8.0 Hz); 7.73 (2H, d, J = 8.0 Hz), 7.33 (2H, m), 6.99 (2H, m), 5.01 (2H, s), 4.14 (3H, m), 2.72 (2H, m), 2.48 (3H , s), 1.85 (3H, s), 1.26 (3H, t, J = 8.0 Hz). Diagram 18.4 of reaction 18. 3 18 Acid 3-. { 4- [5-methyl-2- (4-trifluoromethyl-phenyl) -oxazol-4-ylmethoxy] -phenyl} -hex-4-inoic (18). KOH (2N aqueous) was added to a solution of 18.3 (304 mg, 0.65 mmol) in ethanol (5 L). The mixture was stirred at room temperature overnight and then taken in plenty of water. The aqueous solution was adjusted to pH = 2.0 with 1N HCl (aqueous) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified by radial chromatography (40% ethyl acetate in hexanes + 0.1% AcOH) to yield 150 mg (52%) of compound 18 as a glass. LC / MSD m / e: 444.0 (M + H); NMR A (400 MHz) (acetone) d 8.21 (2H, m), 7.89 (2H, d, J = 8.0 Hz), 7.38 (2H, m), 7.03 (2H, m), 5.06 (2H, s), 4.06 (1H, m), 2.70 (2H, m), 2.52 (3H, s), 1.81 (3H, s). Example 19 Examples 19-22 were prepared using methods similar to those described in Example 18. 19 Acid 3-. { 4- [5-methyl-2- (4-chloro-phenyl) -oxazol-4-ylmethoxy] -phenyl} -hex-4-inoic (19). LC / MSD m / e: 410.0 (M + H); NMR A (400 MHz) (acetone-de) d 8.02 (2H, m), 7.49 (2H, m), 7.35 (2H, m), 7.01 (2H, m), 5.04 (2H, s), 4.09 (1H , m), 2.77 (2H, m), 2.48 (3H, s), 1.86 (3H, s).

Example 20 twenty Acid 3-. { 4- [5-methyl-2- (4-methyl-phenyl) -oxazol-4-ylmethoxy] -phenyl} -hex-4-inoic (16). LC / MSD m / e: 390.2 (M + H); NMR A (400 MHz) (CDCl 3) d 7.96 (2H, m), 7.34 (2H, m), 6.70 (2H, m), 5.02 (2H, s), 4.09 (1H,), 2.80 (2H, m) , 2.47 (3H, s), 1.85 (3H, s).

Example 21 21 Acid 3-. { 4- [5-methyl-2- (4-methoxy-phenyl) -oxazol-4-ylmethoxy] -phenyl} -hex-4-inoic (21). LC / MSD m / e: 406.1 (M + H); NMR A (400 MHz) (acetone-de) d 7.89 (2H, d, J = 9.0 Hz), 7.30 (2H, m), 7.09 (2H, d, J = 9.0 Hz), 7.00 (2H,), 4.97 (3H, s), 3.90 (1H, m), 3.84 (3H, s), 2.44 (3H, s), 1.79 (3H, s).

Example 22 22 Acid 3-. { 4- [5-methyl-2- (3-cyano-phenyl) -oxazol-4-ylmethoxy] -phenyl} -hex-4-inoic (22). LC / MSD m / e: 401.2 (M + H); NMR A (400 MHz) (acetone-de) d 8.33 (2H,), 7.91 (lH,), 0 7.79 (1H, m), 7.38 (2H, m), 7.08 (2H, m), 5.06 (2H, s), 4.06 (1H, m), 2.70 (2H, m), 2.51 (3H, s), 1.81 (3H, s). Example 23 The following example illustrates the synthesis of 5-. { 2- [4- (2-methyl-benzyloxy) -phenyl] ~ pent-3-ynyl} -iH-tetrazole Diagram 23.1 of reaction 23. 1 23.2 3- [4- (2-Methyl-benzyloxy) -phenyl] -hex-4-enoic acid amide (23.2). Carbonyl-diimidazole (0.46 g, 2.84 mmol) was added to a solution of 3- [4- (2-methyl-x-benzyloxy) -phenyl] -hex-4-ynoic acid (see Example 13) (0.73 g, 2.37 mmol) in THF anhydrous (10 mL). The mixture was stirred at room temperature for 2 hours. Concentrated NH OH (10 mL) was then added to the mixture, and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water (300 mL) and the solution adjusted to pH = 7 with concentrated HCl. The aqueous layer was then extracted with 3 x 25 mL of ethyl acetate. The combined organic layers were washed with water, followed by brine. The organic layer was then dried (Na2SO) and concentrated under reduced pressure to yield 0.48 g (70%) of 3- [4- (2-methyl-benzyloxy) -phenyl] -hex-4-ynyoic acid amide (23.2). ) as a light yellow solid. LC / MSD m / e: 308.4 (M + H). Diagram 23.2 of reaction .2 23.3 3- [4- (2-methyl-benzyloxy) -phenyl] -hex-4-n-nitrile (23.3). A 50 mL round bottom flask dried in the oven was charged with DMF (8 mL) and a stir bar. The solution was cooled to 0 ° C in an ice bath. Thionyl chloride (160 μL, 1.0 mmol) was added slowly by syringe. The mixture was stirred at 0 ° C for an additional 45 minutes.

Then nitrite 23.2 (300 mg, 0.98 mmol) was added to the mixture as a solution in DMF (2 mL). The reaction was stirred- 0 ° C for one hour, and then allowed to warm gradually to room temperature overnight. The reaction mixture was diluted between ice water and ethyl acetate. The aqueous layer was extracted twice more with 25 mL of ethyl acetate.

Then saturated NaHCO3 was added to the aqueous layer and the aqueous layer was extracted a third time with ethyl acetate. The combined organic layers were washed with saturated NaHCO 3 and concentrated under reduced pressure. The resulting residue was purified by radial chromatography (ethyl acetate % in hexane) to yield 203 mg (72%) of 3- [4- (2-methyl-benzyloxy) -phenyl] -hex-4-n-nitrile (23.3). NMR A (400 MHz) (acetone-d6) d 7.44 (3H, m), 7.24 (3H,), 7.05 (2H, m), 5.13 (2H, s), 4.09 (1H, m), 2.89 (2H, m), 2.39 (3H, s), 1.88 (3H, s). Diagram 23.4 of reaction 23. 3 23 5-. { 2- [4- (2-methyl-benzyloxy) -phenyl] -pent-3-inyl} -lH-tetrazole (23). To a solution of 23.3 (200 mg, 0.51 mmol) in DMF (5 mL) was added sodium azide (35 mg, 0.54 mmol) and ammonium chloride (29 mg, 0.54 mmol). The solution was stirred at 110 ° C for 48 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by HPLC to yield 5 mg (3%) of 5-. { 2- [4- (2-methyl-benzyloxy) -phenyl] -pent-3-ynyl} -lH-tetrazole (23) as a film. LC / MSD m / e: 333.1 (M + H). NMR A (400 MHz) (acetone-d5) d 7.45 (1H, m), 7.34 (2H, m), 7.25 (3H,), 7.00 (2H, m), 5.11 (2H, s), 4.17 (1H, m), 3.37 (2H, d, J = 7 Hz), 2.39 (3H, s), 1.79 (3H, s). Example 24 The following example illustrates the synthesis of thiazol-2-ylamide of 3- [4- (4-methoxy-benzyloxy) -phenyl] -hex-4-ynoic acid. Diagram 24.1 of reaction 12 24 Thiazole-2-ylamide of 3- [4- (4-methoxy-benzyloxy) -phenyl] -hex-4-ynoic acid (24). A pear-shaped flask was charged with a stir bar, compound 12 (50 mg, 0.154 mmol), carbonyl-diimidazole (25 mg, 0.154 mmol) and THF (4 mL). The mixture was refluxed for 1 hour, and then 2-amino-thiazole (16 mg, 0.154 mmol) was added. The reaction was refluxed for 48 hours, poured into water and extracted with ethyl acetate. The organic layer was concentrated and the resulting residue was purified by HPLC to yield 1.0 mg (2%) thiazol-2-ylamide of 3- [4- (4-methoxy-benzyloxy) -phenyl] -hex-4-ynoic acid (24) like a movie. NMR A (400 MHz) (acetone-de) d 7.39 (4H, m), 7.11 (1H, s), 6.95 (3H, m), 5.03 (2H, s), 3.82 (3H, s), 2.95 (2H) , m), 1.79 (3H, s). Example 25 The compounds in the following table were prepared using the method described in Example 24. Table 9 12 Example 26 The following example illustrates the preparation of acid 3- [4- (5-Methyl-2-phenyl-2H- [1,2,3] triazol-4-ylmethoxy) -phenyl] -hex-4-ynoic acid (26). Scheme 26.1 of reaction 16 26.1 Ethyl ester of 3- [4- (5-methyl-2-phenyl-2H- [1, 2, 3] triazol-4-ylmethoxy) -phenyl] -hex-4-ynyo acid (26.2). Cesium carbonate (107 mg, 0.33 mmol) was added to a solution of 16 (60 mg, 0.22 mmol) in DMF (5 L). The mixture was stirred at room temperature for 5 minutes, and 4-chloromethyl-5-methyl-2-phenyl-2H- [1,2,3] triazole (55 mg, 0.22 mmol) was added. The reaction was heated to 60 ° C and stirred overnight. The reaction mixture was then poured into abundant water. HCl (aqueous) 1 N was added to adjust the pH to 4.0. The aqueous layer was extracted with ethyl acetate. The organic layer was then washed with water, followed by brine. The organic layer was dried (Na2SO4) and concentrated. The resulting residue was purified by radial chromatography (20% ethyl acetate in hexanes) to yield 60 mg (66%) of ethyl ester - of 3- [4- (5-methyl-2-phenyl-2H- [1]] , 2, 3] triazol-4-ylmethoxy) -phenyl] -hex-4-inoic (26.2). LC / MSD m / e: 404.2 (M + H). Scheme 26 .2 reaction 26. 2 26 3- [4- (5-Methyl-2-phenyl-2H- [1,2,3] triazol-4-ylmethoxy) -phenyl] -hex-4-ynoic acid (26). 2N KOH (aqueous) (1 mL) was added to a solution of 26.2 (68 mg, 0.17 mmol) in EtOH (2 mL). The mixture was stirred at room temperature overnight and then poured into water. The aqueous mixture was acidified to pH = 2 with HCl (aqueous) IN, and then extracted with ethyl acetate. The organic layer was washed with water, followed by brine. The organic layer was then concentrated under reduced pressure and the resulting residue was purified by radial chromatography (20% ethyl acetate in hexanes) to yield 60.3 mg (95%) of compound 26 as a colorless oil. LC / MSD m / e: 374.0 (M-H). NMR A (400 MHz) (acetone-de) d 8.05 (2H, d, J = 8.0 Hz), 7.56 (2H, t, J = 8.0 Hz), 7.40 (3H, t, J = 8.0 Hz), 7.06 ( 2H, d, J = 8.0 Hz), 5.28 (2H, s), 4.05 (1H, m), 2.70 (2H, m), 2.44 (3H, s), 1.80 (3H, s).

Example 27 The compounds in the following table were prepared using methods similar to those described in Example 26. Table 10 Example 28 The following example illustrates the preparation of 3- [4-2-methyl-benzylsulfanyl) -phenyl] -hex-4-inoic acid (28). Diagram 28.1 of reaction 28. 1 4- (2-methyl-benzylsulfanyl) -benzaldehyde (28.1) 4-Fluoro-benzaldehyde (1.16 g, 9.32 mmol) was added dropwise over 2 minutes to a solution of o-tolyl-methanethiol (1.3.5 g, 9.79 mmol) and cesium carbonate (3.19 g, 9.79 mmol) in DMF (20 mL). The solution was stirred at 40 ° C overnight and then poured into abundant water. The pH of the solution was adjusted to 4 with HCl (aqueous) IN, and the aqueous solution was extracted with ethyl acetate (2 x 35 mL). The combined organic layers were washed with water, followed by brine. The combined organic layers were then dried (NaS04) and the solvent was removed under reduced pressure. The resulting residue was purified by radial chromatography (15% ethyl acetate in hexanes) to yield 1.29 g (54%) of 4- (2-methyl-benzylsufanyl) -benzaldehyde (28.1). LC / MSD m / e: 243.0 (M + H). Scheme 28.2 reaction 28. 1 28.2 2, 2-dimethyl-5- [4- (2-methyl-benzylsulfanyl) -benzylidene] - [1,3] dioxane-4,6-dione (28.2). Pyrrolidine (0.45 mL, 5.27 mmol) was added to a solution of aldehyde 28.1 in diethyl ether (20 mL) and the mixture was treated with ultrasound for 5 minutes. The mixture was then added to a solution of Meldrum's acid (0.73 g, 5.08 mmol) in diethyl ether (20 mL) and the resulting mixture was treated with ultrasound for 5 minutes, forming a solid. The solid was filtered, rinsed with diethyl ether, and then suspended in DCM (10 mL). Then p-toluenesulfonic acid (0.97 g, 5.10 mmol) was added to the suspension and the suspension was treated with ultrasound until it became clear. The solvent was removed under reduced pressure, and the resulting residue was taken up in diethyl ether and partitioned between water and ethyl acetate. The aqueous layer was extracted 2 times with more ethyl acetate. The combined organic layers were washed with water, dried (Na 2 SO 4), and concentrated in vacuo to yield 1.05 g (54%) of 2,2-dimethyl-5- [4- (2-methyl-benzylsulfanyl) -benzylidene] - [l, 3] dioxane-4,6-dione (28.2) as a yellow oil. The resulting yellow oil was used without further purification. LC / MSD m / e: 391.1 (M +? A). Diagram 28.3 of reaction 28. 2 28.3 2, 2-dimethyl-5-. { 1- [4- (2-methyl-benzylsulfanyl) -phenyl] -but-2-ynyl} - [l, 3] dioxane-4,6-dione (28.3). Oven-dried, 100 mL pear-shaped flask, adapted with a kiln-dried stir bar, was charged with a 0.5 M solution of 1-propynyl magnesium bromide in THF (12.5 mL, 6.27 mmol) by cannula The solution was cooled to 0 ° C, and then added to a solution of 28.2 (1.05 g, 2.85 mmol) in anhydrous THF (6 L) for 3 minutes by cannula. The reaction was stirred at 0 ° C for 5 minutes and then stirred at room temperature for 1.5 hours. The reaction mixture was poured into saturated H4Cl (aqu0SO) and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by radial chromatography (20% ethyl acetate in hexanes) followed by recrystallization from hot ethyl acetate and hexanes to yield 162 mg (15%) of 2,2-dimethyl-5-. { 1- [4- (2-methyl-benzylsulfanyl) -phenyl] -but-2-ynyl} - [1, 3] dioxane-4,6-dione (28.3). LC / MSD m / e: 409.1 (M + H). Scheme 28.4 reaction 28. 3 28 3- [4-2-Methyl-benzylsulfanyl) -phenyl] -hex-4-noic acid (28). A solution of 28.3 (20 mg, 0.05 mmol) in pyridine: water 5: 1 (6 L) was heated at 80 ° C for 72 hours. The reaction was poured into 500 mL of water and the solution was acidified with HCl (aqueous) IN (65 mL). The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with water, followed by brine. The combined organic layers were then dried (? A2S0) and concentrated in vacuo. The resulting residue was then purified by radial chromatography (30% ethyl acetate in hexanes) to yield 18 mg (quantitative) of. 3- [4- (2-Methyl-benzylsulfanyl) -phenyl] -hex-4-ynyo acid (28). LC / MSD m / e: 323.1 (M-H). Example 29 The following example illustrates the preparation of 3- (4-o-tolylmethanesulfinyl-phenyl) -hex-4-ynoic acid. Scheme 29.1 reaction 28. 3 29.1 2, 2-dimethyl-5- [l- (4-o-tolylmethanesulfinyl-phenyl) -but-2-ynyl] - [1,3] dioxane-4,6-dione (29.1). Hydrogen peroxide (20 μL, 0.05 mmol) was added to a 0 ° C solution of 28.3 (20 mg, 0.05 mmol) in AcOH (2 mL). The reaction was stirred at 80 ° C for 1.5 hours, then cooled to room temperature and stirred for 16 hours. The reaction mixture was poured into cold water and the resulting solution was acidified to pH = 2 with 6N HCl (aqueous). The aqueous layer was extracted with ethyl acetate and sec-butanol. The organic layers. combined were concentrated to "yield.10 mg (50%) of 2,2-dimethyl-5- [l- (4- o-tolylmethanesulfinyl-phenyl) -but-2-ynyl] - [1,3] dioxane-4 , 6-dione (29.1) LC / MSD m / e: 383.0 (consistent with the di-acid -H) Scheme 29.1 reaction 29. 1 29 3- (4-O-Tolylmethanesulfinyl-phenyl) -hex-4-inoic acid (29). 29.1 (10.0 mg, 0.025 mmol) was hydrolysed using the methods described in Example 28 to yield 3.0 mg (25%) of 3- (4-o-tolylmethanesulfinyl-phenyl) -hex-4-ynoic acid (29).

LC / MSD m / e: 339.1 (M-H); RM? A (400 MHz) (acetone-de) d 7.60 (2H, m), 7.49 (2H, m), 7.21 (2H, m), 7.04 (2H,), 5.63 (2H, s), 4.17 (1H, m ), 2.81 (2H, m), 2.22 (3H, s), 1.88 (3H, s).

Example 30 3- (4-O-Tolylmethanesulfonyl-phenyl) -hex-4-inoic acid (30) was prepared using methods similar to those described in Example 29. LC / MSD m / e: 357.2 (M + H); NMR A (400 MHz) (acetone-de) d 7.69 (3H, m), 7.50 (1H, m), 7.17 (4H, m), 4.53 (2H, s), 4.22 (1H, m), 2.79 (2H, m), 2.27 (3H, s), 1.82 (3H, s).

Example 31 The following example illustrates the preparation of 3- [2-methyl-4- (2-methyl-benzyloxy) -phenyl] -hex-4-enoic acid (31). Reaction scheme 31.1 31. 1 2- (2-methyl-benzyloxy) toluene (31.1). Α-Bromo-o-xylene (2.0 g, 10.81 mmol) was added to a solution of 2-methyl-phenyl (1.06 g, 9.82 mmol) and cesium carbonate (7.99 g, 24.55 mmol) in DMF (20 mL). The reaction was stirred at 80 ° C overnight. The reaction mixture was acidified with 25 mL of HCl (aqueous) IN and poured into abundant water, the aqueous layer was extracted with ethyl acetate and the organic layer was dried (Na 2 SO 4 and concentrated in vacuo. purified by radial chromatography (20% ethyl acetate in hexane) to yield 1.82 g (88%) of 2- (2-methyl-benzyloxy) toluene (31.1) LC / MSD m / e: 213.2 (M + H) Scheme 31.2 reaction 31. 1 31.2 2- (2-methyl-benzyloxy) -5-bromotoluene (31.2). NBS (1.46 g, 8.23 mmol) was added to a solution of 31.1 (1.59 g, 7.48 mmol) in carbon tetrachloride (8 mL). The reaction was stirred at 60 ° C overnight and filtered to remove succinimide. The filtrate was concentrated in vacuo and purified by radial chromatography (15% diethyl ether in hexanes) to yield 0.65 g (25%) of 2- (2-methyl-benzyloxy) -5-bromotoluene (31.2). LC / MSD m / e: 314.2 (M +? A). Diagram 31.3 of reaction 31. 2 31.3 2-methyl-4- (2-methyl-benzyloxy) -benzaldehyde (31.3). A 2.5 M solution of n-BuLi (2.1 mL, 5.26 mmol) in THF was added dropwise to a -78 ° C solution of 31.2 (1.46 g, 5.01 mmol) in THF (25 mL). The reaction was stirred at -78 ° C for 15 minutes and DMF (3.3 mL) was then added. The cooling was removed after 5 minutes and the reaction was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were dried (Na2SO) and concentrated. The resulting residue was purified by radial chromatography (5% ethyl acetate in hexanes) to yield 269 mg (22%) of 2-methyl-4- (2-methy1-benzyloxy) -benzaldehyde (31.3). LC / MSD m / e: 241.2 (M + H). Scheme 31.4 reaction 31. 3 31.4 4- [2-methyl-4- (2-methyl-benzyloxy) -phenyl] -but-3-en-2-one (31.4). HaOH (water) 2 N (0.6 mL) was added to a solution of 31.3 (100 g, 0.42 mmol) in acetone (1 mL). The reaction was stirred at room temperature overnight and then taken in water. The aqueous solution was acidified with HCl (aqueous) IN (1.5 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried (Na2SO), and concentrated in vacuo. The resulting residue was purified by radial chromatography (20% ethyl acetate in hexanes) to yield 74 mg (63%) of 4- [2-methyl-4- (2-methyl-benzyloxy) -phenyl] -but-3 -en-2-one (31.4). LC / MSD m / e: 281.4 (M + H); RM? A (400 MHz) (acetone-de) d 7.83 (1H, d, J = 16), 7.70 (1H, m), 7.46 (1H, m), 7.25 (3H, m), 6.96 (2H, m), 6.63 (1H, d, J = 16 Hz). Scheme 31.5 reaction 31. 4 31.5 4- [2-methyl-4- (2-methyl-benzyloxy) -phenyl] -but-3-en-2-ol (31.5). HAB (20 mg, 0.51 mmol) was added to a solution 0. 4 M of CeCl3 in MeOH (0.65 mL, 0.26 mmol), 31.4 (74 mg, 0.26 mmol), and THF (1 mL). The reaction was stirred, uncovered until the gas emin ceased. The reaction was quenched with water (1.5 mL) and partitioned between water and diethyl ether. The aqueous layer was extracted 2 times with diethyl ether and the combined organic layers were washed with brine and concentrated in vacuo to yield 69 mg (93%) of 4- [2-methyl-4- (2-methyl-benzyloxy) - phenyl] -but-3-en-2-ol (31.5). LC / MSD m / e: 266.3 (M-OH); NMR A (400 MHz) (DMSO-de) d 7.44 (2H, m), 7.25 (3H, O, 6.86 (2H, m), 6.75 (1H, m), 6.08 (1H, m), 5.11 (2H, s), 4.40, (1H, m), 2.-38 (3H, s), 2.32 (3H, s), 1.29 (3H, m). 31. 5 31.6 3- [2-Methyl-4- (2-methyl-benzyloxy) -phenyl] -hex-4-enoic acid ethyl ester (31.6). Propionic acid (catalytic) was added to a solution of 31.5 (69 mg, 0.24 mmol) in 1,1,1-triethoxy-ethane (440 μL, 2.4 mmol). The reaction was stirred at 105 ° C overnight. The solvent was removed under reduced pressure and the resulting residue was purified by radial chromatography (5% ethyl acetate in hexanes) to yield 33 mg (39%) of 3- [2-methyl-4- (2-ethyl) ethyl ester. -methyl-benzyloxy) -phenyl] -hex-4-enoic (31.6). LC / MSD m / e: 375.0 (M + Na). Diagram 31.7 of reaction 31. 6 31 3- [2-Methyl-4- (2-methyl-benzyloxy) -phenyl] -hex-4-enoic acid (31). The hydrolysis of 31.6 (33 mg, 0.094 mmol) was carried out using methods similar to those described in Example 26 to yield 5.7 mg (19%) of 3- [2-methyl-4- (2-methyl-benzyloxy) ) -phenyl] -hex-4-enoic (31) ... RMN A (400 MHz) (acetone) d 7.44 (2H, m), 7.25 (3H,), 6.86 (2H, m), 6.73 (1H, m), 6.10 (1H, m), 5.64 (2H, s), 4.42 (1H, m), 2.38 (3H, s), 1.29 (3H, d, J = 7.0 Hz). Example 32 The following compounds were made using methods similar to those described in Examples 28 and 31. Table 11 32 Compound Rl R2 R3 R4 R5 32.1 Me H Me H 32. 2 H Ph H H - 32.3 Me Me H H 32. 4 Ph H H H - Example 33 The following example illustrates the preparation., Of 3- [4- (3-methoxy-benzyloxy) -phenyl] -5-methyl-hex-4-enoic acid (33). Diagram 33.1 of reaction 33. 1 Dimethyl 2- [4- (3-methoxy-benzyloxy) -benzylidene] -malonic acid ester (33.1). 2C03 was added to a solution of 4-hydroxybenzylidene malonic acid dimethyl ester (6.95 mmol) and 4-methoxybenzyl chloride (7.64 mmol) in DMF (15 ml). - It was stirred at room temperature overnight. The reaction was poured into water, and the product was extracted with ethyl acetate twice. The organic layer was washed with water and saturated brine, dried over Na 2 SO, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate = 2/1) to give compound 33.1 as a white solid (3.2 mmol).

Scheme 33 2 reaction 33. 1 33.2 Dimethyl acid ester 2-. { 1- [4- (3-methoxy-benzyloxy) -phenyl] -3-methyl-but-2-enyl} -malonic (33.2). 2-Methyl-1-propenylmagnesium bromide (3 mL, 0.5 M in THF) was added dropwise to a solution of compound 33.1 (1.0 mmol) in THF. The reaction mixture was stirred at room temperature for 1 hour and then quenched with saturated (aqueous) NHC1 and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated brine, dried over Na 2 SO 4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate = 2/1) to give compound 33.2 as a white solid (0.93 mmol). Diagram 33.3 of reaction 33. 2 33.3 Acid 2-. { 1- [4- (3-methoxy-benzyloxy) -phenyl] -3-methyl-but-2-enyl} -malonic (33.3). To a solution of compound 33.2 (0.50 g, 1.21 mmol) in THF (5 ml), methanol (5 ml) and water (2.5 ml) was added monohydrate lithium hydroxide (1.17 g, 28 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with IN HCl to pH 2-3, and then extracted with ethyl acetate twice. The organic layer was washed with water and brine, dried over Na 2 SO, and concentrated in vacuo. The resulting residue was used for the next reaction without purification. Diagram 33.4 reaction 33. 3 33 3- [4- (3-methoxy-benzyloxy) -phenyl] -5-methyl-hex-4-enoic acid (33). A suspension of compound 33.3 (0.136 mmol) in toluene was refluxed for 16 hours. After removing the solvent, the residue was purified using silica gel column chromatography (TFA / dichloromethane / ethyl acetate = 1/5/40) to give compound 33 as a white solid (0.088 mmol). MS ESI m / e: 339 (M-H) NMR A (500 MHz) (DMS0-d6) d 11.97 (1H, s), 7.31 (1H, t, J = 10 Hz), 7.14 (2H, d, J = 11 Hz); 6.99 (2H, m); 6.87 (3H, _ m); 5.22 (1H,); 5.03 (2H, s); 3.75 (1H, m); 3.75 (3H, s); 2.44-2.53 (2H, m); 1.63 (3H, s); 1.62 (3H, s). EXAMPLE 34 The following compounds were made using the method described in Example 33. Table 12 Compound 34.1. MS ESI m / e: 325 (MH) NMR A (500 MHz) (DMSO-de) d 12.05 (lH, s), 7.36 (2H, d, J = 10 Hz), 7.16 (2H, d, J = 10 Hz); 6.94 (2H, d, J = 10 HZ); 6.90 (2H, d, J = 5 Hz); 5.48-5.58 (1H, m); 5.39-5.43 (1H, m); 4.98 (2H, s); 3.99-4.03 (1H, m); 3.76 (3H, s); 2.46-2.60 (2H, m); 1.64 (3H, d, J = 5 HZ). Compound 34.2. MS ESI m / e: 325 (M-H) NMR A (500 MHz) (DMSO-de) d 11.98 (1H, s), 7.38 (2H, d, J = 10 Hz), 7.13 (2H, m); 6.95 (2H, m); 6.09 (2H, m); 5.63 (1H, m); 4.97 (2H, s); 4.92 (2H, d, J = 10 Hz); 3.76 (3H, s); 3.03 (1H, ni); 2.28- 2.56 (4H, m). Compound 34.3. MS ESI m / e: 311 (M-H) NMR A (500 MHz) (DMSO-de) 'd 12.06 (1H, s); 7.37 (2H, "d, J = 10 Hz), 7.14 (2H, d, J = 10 Hz), 6.92-6.95 (4H, m), 5.92 (1H, m), 5.00 (2H, m), 4.98 ( 2H, s), 3.76 (3H, s), 3.35 (1H, m), 2.54-2.64 (2H, m), Compound 34.4 MS ESI m / e: 325 (MH) NMR A (500 MHz) (DMSO- de) d 12.03 (1H, s), 7.37 (2H, d, J = 10 Hz), 7.09-7.19 (4H,), 6.91-6.99 (4H, m), 4.97 (2H, s), 3.76 (3H, s), 3.63 (1H, m), 2.57-2.71 (2H, m), 2.09 (3H, s), Compound 34.5 MS ESI m / e: 339 (MH) NMR A (500) MHz). { DMSO-de) d 11.97 (lH, s); 7.36 (2H, d, J = 10 Hz); 7.14 (2H, d, J = 10 Hz); 6.94 (2H, d, J = 10 Hz); 6.89 (2H, d, J = Hz); 5.24 (2H, d, J = 10 Hz); 3.85-3.90 (1H, m); 3.76 (3H, s); 2.44-2.57 (2H, m); 1.68 (3H, s); 1.63 (3H, d, J = 10 Hz). Compound 34.6. MS ESI m / e: 339 (M-H) NMR A (500 MHz) (DMSO-de) d 11.97 (1H, s); 7.37 (2H, d, J = 8.5 Hz); 7.10 (2H, d,); 6.90-6.95 (4H, m); 5.23 (lH, d, J = 6.5 Hz); 4.97 (2H, s); 4.29 (1H, m); 3.76 (3H, s); 2.47-2.75 (2H, m); 1.71 (3H, d, J = 6 Hz); 1.56 (3H, s). Compound 34.7. MS ESI m / e: 367 (M-H) NMR A (500 MHz) (DMSO-d6) d 12.18 (1H, s); 7.37 (2H, d, J = 5 Hz); 7.32 (1H, m); 7.21 (2H, d, J = 10 Hz); 6.92-6.95 (6H,); 4.98 (2H, s); 4.58 (1H, m); 3.76 (3H, s); 3.01 (lH, m); 2.94 (1H, m). Compound 34.9. MS ESI m / e: 339 (M-H) NMR A (500 MHz) (DMSO-de) d 11.99 (1H, s); 7.37 (2H, m); 7.14 (2H, d, J = 10.Hz); 7.04 (2H, d, J = 10 Hz); 6.96 (1H, t, J = 10 Hz); 6.88 (2H, d, J = 10 Hz); 5.24 (2H, d, J = 10 Hz); 5.00 (2H, s); 3.87 (1H, m); 3.87 (3H, s); 2.45-2.55 (2H, m); 1.63 (3H, s): Compound 34.10. MS ESI m / e: 323 (M-H) NMR A (500 MHz) (DMSO-d6) d 12.10 (1H, s); 7.25-7.32 (3H, m); 7.01 (2H, d, J = 9 Hz); 6.94 (2H, d, J = 10 Hz); 6.88 (1H,); 5.05 (2H, s); 3.92-3.95 (1H, m); 3.75 (3H, s); 2.58 (2H, d, J = 10 Hz); 1.77 (3H, s). Compound 34.11 MS ESI m / e: 353.0 (M-H). 34. 12 RMN A (400MHz) ((CD3) 2SO) d 11.95 (s, lH), 7.49 (d, 2H, J = 8.2 Hz), 7.15 (d, 2H, J = 8.6 Hz), 7.08-7.10 ( m, 2H), 6.91-6.98 (m, 3H), 5.25 (d, 1H, 9.0 Hz), 5.07 (s, 2H), 3.78-3.94 (m, 3H), 2.44-2.59 (m, 2H), 2.26 (s, 3H), 1.55-1.63 (m, 8H), 1.30-1.38 (, 2H), 0.85 (t, 3H, J = 7.3 Hz). [M + l] + calculated for C3? H360: 473.3. Found 473.5. Example 35 The following example illustrates the preparation of 3- [4- (3-methoxy-benzyloxy) -phenyl] -5-methyl-hex-4-enoic acid. Scheme 35.1 of reaction . 1 35.2 Dimethyl acid 2- [l- (4-amino-phenyl) -but-2-ynyl] -malonic acid ester (35.2). "Tin" dihydrate (46 mmol) was added to a solution of compound 35.1 (15.3 mmol, prepared commercially available dimethyl-4-nitrobenzylidene malonate and 1-propynylmagnesium bromide according to the method of Example 33 ) in ethanol (200 ml) The mixture was stirred at 70 ° C. for 17 hours After removing the solvent under reduced pressure, aqueous sodium carbonate solution was added and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over Na 2 SO, concentrated in vacuo, the resulting residue was filtered through a short plug of silica gel, eluting with ethyl acetate.The boiled product was concentrated to obtain compound 35.2 (12.8 mmol). Reaction scheme 35.2 . 2 35.3 Dimethyl ester. 2- (L-. {4 - [(Biphenyl-3-ylmethyl) -amino] -phenyl} - but-2-ynyl) -malonic acid (35.3). A mixture of compound 35.2 (1.0 mmol), 3- (bromomethyl) biphenyl (1.3 mmol) and K2CO3 (2.0 mmol) in DMF (10 mL) was stirred at 90 ° C for 19 hours. After diluting with ethyl acetate, the mixture was washed with aqueous Na 2 CO 3 and then with brine, dried over Na 2 SO 4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate = 2/1) to give compound 35.3. Scheme 35.3 of reaction . 3 35 Acid 3-. { 4 - [(biphenyl-3-ylmethyl) -amino] -phenyl-hex-4-ynoic acid (35). Compound 35 was prepared from compound 35.3 by hydrolysis with base and decarboxylation as described in Example 33. MS ESI m / e: 368 (M-H) NMR A (500 MHz) (DMSO-de) d 7.63-7.66 (2H,); 7.51 (1H, m), 7.34-7.44 (6H, m); 7.05 (2H, d, J = 10 Hz); 6.60 (2H, d, J = 10 Hz); 4.33 (2H, s); 3.79-3.83 (1H, m); 2.44-2.53 (2H, m); 2.09 (lH, s); 1.74 (3H, s). Example 36 following compounds were prepared according to methods described in Example 35.

Table 13 Example 37 This example illustrates preparation of (+/-) 3- (4 - [(4-methoxyphenyl) methoxy] -phenyl) -propanoic acid. Diagram 37.1 of reaction 12. 2 37 Acid (+/-) -3- (4- [(4-methoxyphenyl) methoxy] phenyl) -propanoic acid (37). To a stirred solution of ethyl acetate (100 mL) of 5 - [[4 - [(4-methoxyphenyl) methoxy] phenyl] -methylene] -2,2-dimethyl- [1,3] dioxane-4,6 -dione (200 mg, 0.543 mmol) was added EtOH (4 mL), followed by NaBH (62 mg, 1.63 mmol). reaction mixture was stirred at room temperature for 15 minutes, quenched with water (5 mL), extracted with EtOAc (10 mL). extract was washed with brine, dried over MgSO4, filtered, and concentrated to a white solution. A solution of this white solid in pyridine-water 3: 1 (5 ml) was heated at 100 ° C for 24 hours. reaction mixture was cooled to room temperature and placed in an ice-water bath. Concentrated HCl was carefully added at about pH 2. resulting suspension was extracted with ethyl acetate (10 mL x 3), dried over MgSO, filtered, and concentrated to an off-white solid. Preparative HPLC gave compound 37 as a white solid. MS ESI (neg.) M / e: 285.0 (M - 1). Example 38 This example illustrates preparation of (+/-) - 3- (4 - [(4-methoxyphenyl) methoxy] -phenyl) -3-cyano-propanoic acid.

Acid (+/-) -3- (4 - [(4-methoxyphenyl) methoxy] phenyl) -3-cyano-propanoic acid (38). To a stirred solution in DMF (10 mL) of 2- [4 - [(4-methoxyphenyl) methoxy] phenyl] -acetonitrile (500 mg, 1.97 mmol) was added ethyl bromoacetate (330 μL, 2.96 mmol), followed by K2C03 (20 mg, 5.9 mmol). reaction mixture was stirred at room temperature for 2 hours, poured into ice water (100 mL), filtered, and dried to a white solid. 20 mg of this white solid in THF / 1N NaOH 1: 1 in MeOH (4 mL) was stirred for 5 hours. reaction mixture was concentrated, diluted with water (10 mL), washed with EtOAc (5 mL x 2). aqueous layer was acidified with 3N HCl to pH about 2, extracted with EtOAc (10 mL x 2), dried over MgSO 4, filtered, and concentrated to a white solid. MS ESI (neg.) M / e: 310.0 (M - l).

Example 39 following compounds were prepared by methods described in Example 15 using enantiomer with shortest retention time of chiral HPLC resolution. Table 14 (3S) -3- [4- (3-methyl-benzyloxy) -f-enyl] -hex-4-ynyo acid (39.1). MS-ESI (neg.) M / e: 307.1 (M-H). [a] 20: + 21.26 (c? .188, DMF). (3S) -3- [4- (3-trifluoromethoxy-benzyloxy) -f-enyl] -hex-4-ynoic acid (39.2). MS-ESI (neg.) M / e: 377.0 (M-H). [a] 20: + 18.30 (c? .259, DMF). (3S) -3- [4- (3-Chlorobenzyloxy) -phenyl] -hex-4-ynyo acid (39.3). MS-ESI (neg.) M / e: 327.1 (M-H). [a] 20: + 14.36 (c? .440, DMF). (3S) -3- [4- (2'-Cyano-bifenyl-4-ylmethoxy) -f-enyl] -hex-4-ynoic acid (39.4). MS-ESI (neg.) M / e: 394.1 (M-H). [a] 20: + 16.07 (c? .331, DMF). (3S) -3- [4- (2-Tirf luoromethyl-benzyloxy) -f-enyl] -hex-4-ynoic acid (39.5). MS-ESI (neg.) M / e: 361.1 (M-H). [a] 20: + 12.80 (c? .285, DMF). (3S) -3- [4- (4-Bromobenzyloxy) -f-enyl] -hex-4-ynoic acid (39.6). MS-ESI (neg.) M / e: 371.0, 373.0 (M-H). [] 20: + 19.19 (c .238, DMF), (3S) -3- [4- (4-methoxy-benzyloxy) -f-enyl] -hex-4-ynoic acid (39.7). MS-ESI (neg.) M / e: 323.0 (M-H). [a] 20: + 23.30 (c? .329, DMF). Example 40 following compounds were prepared by methods described in Example 15 using enantiomer with longer retention time of HPLC resolution. Table 15 (3R) -3- [4- (2-Methyl-benzyloxy) -phenyl] -hex-4-ynyoic acid (40.1). NMR A (400 MHz) (acetone-d6) d 7.45 (d, lH, J = 7. 11 Hz); 7.37 (d, 2H, J = 8.58 Hz); 7.26 (d, 1H, J = 1.62 Hz); 7.22-7.27 (, 2H); 7.00 (d, 2H, J = 8.76 Hz); 5.11 (s, 2H); 4.05 (m, 1H); 3.33 (s, 1H); 2.69 (m, 2H); 2.38 (s, 3H); 1. 80 (d, 3H, J = 2.44). MS-ESI (neg.) M / e: 307.1 (M-H). [a] 20: - 19.78 (c? .286, DMF). (3R) -3- [4- (3-Chlorobenzyloxy) -f-enyl] -hex-4-ynyoic acid (40.2). MS-ESI (neg.) M / e: 327.0 (M-H). [a] 20: -20.50 (c? .158, DMF). (3R) -3 - [4- (2'-Cyano-biphenyl-4-ylmethoxy) -phenyl] -hex-4-ynoic acid (40.3). MS-ESI (neg.) M / e: 394.1 (M-H). [a] 20: -25.04 (c? .143, DMF). (3R) -3- [4- (2-Tirf luoromethyl-benzyloxy) -f-enyl] -hex-4-ynoic acid (40.4). MS-ESI (neg.) M / e: 361.0 (M-H). [a] 20: -14.69 (c? .286, DMF). (3R) -3- [4- (4-Methoxy-benzyloxy) -phenyl] -hex-4-ynoic acid (40.5). MS-ESI (neg.) M / e: 323.0 (M-H). [a] 20: -27.20 (c? .324, DMF). Example 41 The following compounds were prepared by the methods similar to those of Example 15. 41. 1 41.2 (3S) -3- [4- (4-methoxy-benzyloxy) -phenyl] -pent-4-ynyoic acid (41.1). MS-ESI (pos.) M / e: 333.1 (M + H). [a] 20: +11.80 (c? .166, DMF). (3R) -3- [4- (4-Methoxy-benzyloxy) -phenyl] -pent-4-ynyoic acid (41.2). MS-ESI (pos.) M / e: 333.1 (M + H). [a] 20: -10.20 (c? .206, DMF). Example 42 Reaction Scheme 42.1 presents a general procedure for the preparation of diaryl ether compounds. Diagram 42.1 of reaction 42. 1 42.2 42.3 Reaction Scheme 42.1, a. ArB (OH) 2, CuO (Ac) 2, Et 3n, DCM, 4A MS, - room temperature, 16h; b. LiOH / THF, MeOH, and water, room temperature, 2h. General procedure for the preparation of diaryl ether compounds: one flask is charged with phenol (1.0 equivalent), Cu (OAc) 2 (1.0 equivalent.), Arylboronic acid (1.0-3.0 equivalent), molecular sieves 4 A powder. The reaction mixture is diluted with CH2C12 to produce a solution of approximately 0.1 M in phenol, and Et3N is added. (5.0 equivalent). After stirring the heterogeneous reaction mixture for 16 hours at 25 ° C under ambient atmosphere, the resulting slurry is filtered and the diaryl ether is isolated from the organic filtrate by flash chromatography. The resulting ester was then hydrolyzed with LiOH (2.0 equivalent) in a 1: 1: 1 mixture of MeOH, THFS and water for 2 hours at 25 ° C. The reaction mixture was acidified with IN HCl, extracted with CH2C12 and concentrated to give the pure acid. 42. 4 3 - [4- (Bifenyl-4-yloxy) -f-enyl] -hex-4-ynoic acid (42.4). MS ESI m / e: 357.0 (M + H). NMR A (500 MHz) CDC13) d 7.60-7.57 (4H, m); 7.46 (2H, dd, J = 8.0, 8.0 Hz); 7.39 (2H, d, J = 8.5 Hz); 7.36 (1H, d, J = 7.3 Hz); 7.09 (2H, d, J = 8.6 Hz); 7.04 (2H, d, J = 8.6 Hz); 4.2-4.1 (1H, m); 2.87 (1H, dd, J = 15.8, 8.6 Hz); 2.77 (1H, dd, J = 15.8, 6.7 Hz); 1.88 (3H, d, J = 2.3 Hz) 42. 5 3- [4- (4-Phenoxy-phenoxy) -phenyl] -hex-4-ynoic acid (42.5). MS ESI m / e: 373.0 (M + H). NMR A (500 MHz) (CDC13) d 7.37-7.32 (5H, m); 7.12 (2H, dd, J = 8.0, 8.0 Hz); 7.03 (2H, d, J = 7.5 Hz); 7.02 (2H, s); 6.97 (2H, d, J = 8.6 Hz); 4.1 (1H, m); 2.85 (1H, dd, J = 15.8, 8.6 Hz); 2.75 (1H, dd, J = 15.8, 6.7 Hz); 1.87 (3H, d, J = 2.3 Hz). 3- [4- (4-Benzyloxy-phenoxy) -phenyl] -hex-4-ynoic acid (42.6). MS ESI m / e: 387.0 (M + H). NMR A (500 MHz) (CDC13) d 7.47 (2H, dd, J = 7.2 Hz); 7.42 (2H, dd, J = 7.5, 7.5 Hz); 7.37 (1H, d, J = 7.3 Hz); 7.33 (2H, d, J = 8.7 Hz); 6.98 (4H, br. S); 6.93 (2H, d, J = 9.7 Hz); 5.07 (2H, s); 4.10 (1H, m); 2.84 (1H, dd, J = 15.7, 8.5 Hz); 2.75 (1H, dd, J = 15.7, 6.7 Hz); 1.86 (3H, d, J = 2.3 Hz).

Diagram 42.2 of reaction 42. 10 42.11 Reaction Scheme 42.2. to. TMSCHN2, MeOH, benzene, room temperature, lh; b. K2C03, DMF, room temperature, during. night, - c. LiOH / THF, MeOH, and water, room temperature, 2 h. (S) -3-tert-butoxycarbonylamino-3- acid. { 4- [3- (4-fluoro-phenoxy) -benzyloxy] -phenyl} -propionic (42.11). 3-Boc-amino-3 (4-hydroxyphenyl) -propanoic acid (42.7) (703 mg) was slowly added., 2.5 mmol) in 25 mL of MeOH / benzene (4: 1), 2.5 mL of a 2M solution of trimethylsilyldiazomethane in hexane at 25 ° C. The reaction mixture was stirred for 1 hour and concentrated in vacuo to give the methyl ester. MS ESI m / e: 296.0 (M + H). To a solution of the methyl ester 42.8 (2.5 mmol) and 4-fluorophenoxybenzyl bromide 42.9 (700 mg, 2.5 mmol) in DMF (10 L), K2CO3 (414 mg, 3 mmol) was added and the resulting mixture was stirred during the reaction. night (14 - 16 hours) at 25 ° C. The solution was diluted with water (20 mL) and extracted with EtOAc twice (20 mL). The organic extraction was concentrated and the product was purified by flash chromatography. MS ESI m / e: 518.0 (M + Na). Methyl ester 42.10 (39 mg, 0.08 mmol) was hydrolyzed with LiOH (10 mg, 0.25 mmol) in 1.5 mL of a 1: 1: 1 mixture of MeOH, THF, and water for 2 hours at 25 ° C. The reaction mixture was acidified with 1N HCl, extracted with CH2C12 and concentrated to give the pure acid (42.11). MS ESI m / e: 504.0 (M +? A). RM? A (400 -MHz) "(CDC13) d 8.5 (1H, br. S); 7.34 (1H, dd, J = 8.0, 8.0 Hz); 7.24 (2H, d, J = 8.8 Hz); 7.16 1H, d, J = 7.7 Hz); 7.07-6.98 (5H, m); 6.93 (2H, d, J = 11.7 Hz); 6.92 (1H, d); 5.3 (1H, br. S); 5.03 (2H, s); 3.0-2.8 (2H, m); 2.1-1.9 (1H, m); 1.44 (9H, s). Diagram 42.3 of reaction 42. 10 42.12 Diagram 42.3 of reaction, a. TFA, DCM, room temperature, lh; b. formaldehyde, NaBH (OAc) 3, AcOH, DMF, room temperature overnight; c. LiOH / THF, MeOH, and water, room temperature, 2 h. 3-dimethylamino-3- acid. { 4- [3- (4-fluoro-phenoxy) -benzyloxy] -phenyl} -propionic (42.14). The methyl ester of (S) -3-tert-butoxycarbonylamino-3- acid was treated. { 4- [3- (- fluoro-phenoxy) -benzyloxy] -phenyl} -propionic (42.10) (1.0 g, 2 mmol) with 10 mL of a 10% TFA solution in CH2Cl2 at 25 ° C for 1 hour. The solvent was concentrated in vacuo to give the free amine (42.12). MS ESI m / e: 418.0 (M + Na). The amine (60 mg, 0.15 mmol) was treated with excess formaldehyde (2 equivalent), NaBH (OAc) 3 (85 mg, 0.4 mmol) and catalytic amount of AcOH in DMF overnight (14-16 h) at 25 ° C. C.

The product was purified by inverted phase HPLC. MS ESI m / e: 424.1 (M + H). The methyl ester was hydrolyzed with LiOH (19 mg, 0.45 mmol) in 3 mL of a 1: 1: 1 mixture of MeOH, THF, and water for 2 hours at 25 ° C. The reaction mixture was acidified with 1 HCl, extracted with CH2C12 and concentrated to give the pure acid (42.14) 23 mg). MS ESI m / e: 410.2 (M + H).

RM? A (500 MHz) (CDC13) d 9.46 (1H, br. S.); 7.72 (1H, d, J = 16. 0 Hz); 7.51 (2H, d, J = 8.7 Hz); 7.36 (lH, dd, J = 8.0, 8.0 Hz), 7.17 (2H, d, J = 7.0 Hz), 7.08-6.98 (5H, m); 6.94 (1H, d, J = 8.2 Hz); 6.34 (1H, d, J = 16.0 Hz), 5.10 (2H, s); 3.4-2.9 (2H, m); 2.73 (6H, s); 2.1-1.9 (lH, m) Example 43 Reaction Scheme 43.1 Scheme 43.1 of reaction, a. HN03, HOAc, 80 ° C, 3h; b. SnCl2, EtOAc / EtOH, 70 g. 3h; c. 3-bromobenzaldehyde, DDQ, DMF, room temperature, 2h; d. 4-Trifluoromethylbenzeneboronic acid, Pd (PPh3), DME, Na C03, 80 ° C 14 h; and. LiOH / THF, MeOH, and water, room temperature, 2 h. 3- [2- (4'-Trifluoromethyl-biphenyl-3-yl) -benzooxazol-5-yl] -hex-4-ynoic acid (43.3). The 3- (4-hydroxy-phenyl) -hex-4-ynoic acid methyl ester (1.32 g, 6 mmol) was treated with HN03 (0.30 L, 7.2 mmol) in AcOH (10 mL) at 80 ° C. 3 hours. The solvent was concentrated in vacuo and the 3- (3-nitro-4-hydroxy-phenyl) -hex-4-ynoic acid methyl ester (613 mg, 2.3 mmol) was isolated from flash chromatography. MS ESI m / e: 264.0 (M + H). The nitro group was then reduced with SnCl2 (2.62 g, 11.6 mmol) in EtOH (10 L) and EtOAc (10 mL) at 70 ° C for 3 hours. The reaction mixture was cooled to 25 ° C, washed with saturated aqueous Na 2 CO 3, water, brine, dried over MgSO 4, filtered and concentrated in vacuo. The crude product was then purified by inverted-phase HPLC to give 3- (3-amino-4-hydroxy-phenyl) -hex-4-ynic acid methyl ester (174 mg, 0.74 mmol). MS ESI m / e: 234.0 (M + H). 3- (3-Amino-4-hydroxy-phenyl) -hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol) and 3-bromobenzaldehyde (278 mg, 1.5 mmol) in DMF (3 mL) was treated with DDQ (204 mg, 0.9 mmol) for 2 hours at 25 ° C. The product was purified by inverted phase HPLC. MS ESI m / e: 398.0 (M + H). 3- [2- (3-Bromo-phenyl) -benzooxazol-5-yl] -hex-4-ynoic acid methyl ester (19.6 mg, 0.05 mmol) and trifluorophenylboronic acid (38 mg, 0.2 mmol) in DME (1 mL) and 0.2 mL of 2M solution of aqueous? a2C03 was treated with Pd (PPh3) 4 at 80 ° C for 14 hours. The product was isolated from flash chromatography. MS ESI m / e: 464.0 (M + H). The methyl ester (7.8 mg, 0.017 mmol) was hydrolyzed with LiOH (4 mg, 0.1 mmol) in 1 mL of a 1: 1: 1 mixture of MeOH, THF, and water for 2 hours at 25 ° C. The reaction mixture was acidified with 1N HCl, extracted with CH2C12 and concentrated to give the pure acid (7.6 mg). MS ESI m / e: 450.1 (M + H). RM? TO (500 MHz) (CDC13) d 8.52 (1H, s); 8.30 (1H, d, J = 7.8 Hz); 7. 91 (1H, s); 7.83 (2H, d, J = 8.2 'Hz); 7.82 (1H, s); 7.78 (2H, dd, J = 8.0, 8.0 Hz), 7.67 (1H, dd, J = 7.8, 7.8 Hz), - 7.58 (2H, d, J = 8.4 Hz), 7.46 (1H, dd, J = 8.4 , 1.5 Hz), 4.29 (1H, m); 2.94 (lH, dd, J = 15.8, 8.1 Hz), 2.84 (lH, dd, J = . 8, 6.9 Hz), 1.89 (3H, d, J = 2.3 Hz). Example 44 Reaction Scheme 44.1 44. 1 44.2 Scheme 44.1 of reaction, a. NaOH, EtOH, water, room temperature, 3h (X = Br, Cl). The general procedure for the preparation of aryl benzyl ethers: 3- (4-hydroxy-phenyl) -hex-4-ynoic acid in EtOH (0.4 M) was added to a solution of? AOH 1? (3 equivalent) in water at 25 ° C and stirred for 5 minutes at 70 ° C. ArCH2X (X = Br, Cl, 1 equivalent) in EtOH (0.2M) was added slowly, stirred for 3 hours at 70 ° C. The reaction mixture was acidified with IN HCl and purified from reverse phase HPLC. 44. 3 3- [4- (4-Ethoxy-2-trifluoromethyl-quinolin-6-ylmethoxy) -phenyl] -hex-4-ynoic acid (44.3). MS-ESI m / e: 458.0 (M + H); NMR A (400 MHz) - (DMSO-d6) d 12.6 (1H, br s); 8.31 (1H, s); 8.12 (1H, d, J = 8.7 Hz); 7.95 (lH, dd, J = 8.7, 1.3 Hz), 7.41 (1H, s); 7.31 (2H, d, J = 8.5 Hz), 7.03 (2H, d, J = 8.5 Hz), 5.36 (2H, s); 4.47 (2H, q, J = 8.0 Hz) -, 3.96 (lH, m); 2.62 (2H, d, J = 7.6 Hz), 1.79 (3H, d, J = 1.9 Hz), 1.21 (3H, t, J = 8.0 Hz). 44. 4 3- (4- { 3- [4- (3-Trifluoromethyl-pyridin-2-yl) -piperazine-1-carbonyl] -benzyloxy] -phenyl] -hex-4-ynyl acid MS ESI m / e: 552.0 (M + H); NMR A (400 MHz) (DMSO-de) d 12.5 (lH, br s); 8.57 (lH, d, J = 3.5 Hz); 8.12 (lH, dd, J = 7.9, 1.6 Hz), 7.56-7.48 (3H, m), 7.41 (lH, d, J = 7.5 Hz), 7.30-7.25 (3H, m), 6.98 (2H, d, J = 8.7 Hz), 5.16 (2H, s), 3.95 (1H, m), 3.2 (4H, m), 2.60 (2H, d, J = 7.6 Hz), 2.52 (4H, m), 1.77 (3H, d, J = 2.4 Hz ). 44. 5-3- (4- { 4- [2- (1H-indol-3-yl) -ethylsulfamoyl] -benzyloxy}. Phenyl) -hex-4-ynyl acid. MS ESI m / e: 517.2 (M + H); NMR A (400 MHz) (DMSO-de) d 12.5 (1H, br.s); 10.82 (1H, s); 7.83 (2H, d, J = 8.3 Hz), 7.77 (1H, dd, J = 7.8, 7.8 Hz); 7.39 (1H, d, J = 8.0 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.13 (1H, d, J = 2.2 Hz), 7.06 ( 1H, dd, J = 7.0, 8.0 Hz), 6.97 (2H, d, J = 8.7 Hz), 5.19 (2H, s); 3.95 (1H, m); 3.02 (2H, 5, J = 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 2.61 (2H, d, J = 8.0 Hz), 1.78 (3H, d, J = 2.4 Hz). Example 45 This example illustrates the preparation of the acid (+/-) - 3- [4- (2'-butoxy-5'-methyl-biphenyl-4-ylmethoxy) -phenyl] -3- (4-fluorophenyl) -propionic acid (Four. Five).

Scheme 45.1 of reaction Ethyl 3- (4-fluorophenyl) -3- (4-hydroxyphenyl) -ethyl acrylate (45.1). A solution of lithium hexamethyldisilazide (23.1 L, 1M in THF) was added to a stirred solution of (trimethylsilyl) ethyl acetate (2.53 mL, 13.9 mmol) in THF (15 mL) in 10 minutes at -78 ° C. The reaction mixture was further stirred at this temperature for 20 minutes. A solution of water was slowly added to the reaction mixture. (4-fluorophenyl) - (4-hydroxyphenyl) -methanone (2 g, 9.2 mmol) in THF (30 mL). The reaction mixture was brought to 0 ° C in 5 hours.

The reaction mixture was quenched with saturated ammonium chloride solution, extracted into ethyl acetate and washed with dilute ammonium chloride solution. The organic layer was dried over magnesium sulfate. The solvent was removed under vacuum and the product was purified by flash chromatography on silica gel, giving 45.1 as an oil (1,405 g).

Ethyl 3- (4-fluorophenyl) -3- (4-hydroxyphenyl) -propionic acid ester (45.2). A solution of 45.1 (385 mg) in ethanol (12 mL) and ethyl acetate (10 mL) was stirred with 10% Pd in carbon (50 mg) under an atmosphere of hydrogen at room temperature for 3 hours. The reaction mixture was filtered and concentrated to give 45.2 (350 mg). 3- [4- (2'-Butoxy-5'-methyl-biphenyl-4-ylmethoxy) -phenyl] -3- (4-fluorophenyl) -propionic acid ethyl ester (45.3). A mixture of 45.2 (48 mg, 0.166 mmol), 4'-bromomethyl-2-butoxy-5-methyl-biphenyl (67 mg, 0.2 mmol) and cesium carbonate (81 mg, 0.25 mmol) in DMF (2 mL) it was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified with dilute HCl, extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The residue obtained after concentration was flash chromatographed on silica gel to obtain 45.3 (71 mg). Acid (+/-) -3- [4- (2 '-butoxy-5'-methyl-biphenyl-4-ylmethoxy) -phenyl] -3- (4-fluorophenyl) -propionic acid (45). A mixture of 45.3 (56 mg, 0.1 mmol) of NaOH solution (aqueous) (0.31 mL, 0.62 mmol) in THF (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, treated with dilute HCl, and extracted into ethyl acetate. The organic layer was washed with water and concentrated to produce product which was purified by flash chromatography to give "compound 45 (40 mg). RMN A (500 'MHz, CDC13, ppm), d 0.9 (t, 3H), 1.4 (m, 2H), 1.65 (m, 2H), 2.35 (s, 3H), 3.05 (m, 2H), 3.9 (t, 2H), 4.5 (t, 1H), 5.05 (s, 2H), 6.8- 7.5 (m, 15H). MS ESI (neg.) m / e: 511.0 (M-H). EXAMPLE 46 The following compounds were prepared according to analogous methods to those described in Example 45: 3- (4-fluorophenyl) -3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] - propionic (46.1), 3- (4-fluorophenyl) -3- [4- (4-methyl-2-p-tolyl-thiazol-5-ylmethoxy) -phenyl] -propionic acid (46.2) and 3- (4-hydroxy) acid -fluorophenyl) -3-. { 4- [2- (3-trifluoromethyl-phenoxy) -ethoxy] ~ phenyl} ~ propionic (46.3). Starting from (4-hydroxyphenyl) -phenyl-methanone, the following compounds were prepared according to analogous methods to those described in Example 45: 3- [4- (2-methyl-benzyloxy) -phenyl] -3- acid phenylpropionic (46.4), 3- [4- (2'-butoxy-5'-methyl-biphenyl-4-ylmethoxy) -phenyl] -3-phenylpropionic acid (46.5), 3- [4- (4- methyl-2-p-tolyl-thiazol-5-ylmethoxy) -phenyl] -3-phenyl-propionic acid (46.6), 3-phenyl-3- acid. { 4- [2- (3-trifluoromethyl-phenoxy) -ethoxy] -phenyl} -propionic (46.7), 3- [4- (2'-cyano-biphenyl-4-ylmethoxy) -phenyl] -3-phenylpropionic acid (46.8) and 3-phenyl-3- [4- (4'-trifluoromethyl) acid - biphenyl-3-ylmethoxy) -phenyl] -propionic acid (46.9). Starting from (4-hydroxyphenyl) -pyridin-4-yl-methanone, the following compounds were prepared according to analogous methods to those described in Example 45: 3- [4- (2'-butoxy-5'-methyl -biphenyl-4-ylmethoxy) -phenyl] -3-pyridin-4-yl-propionic acid (46.10) and 3-pyridin-4-yl-3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) acid) -phenyl] -propionic (46.11). Example 47 This example illustrates the preparation of the acid (+/-) - 3- (4- [3- (4-chloro-2-methylphenyl) benzyloxy] phenyl) -3- (4-fluorophenyl) -propanoic acid (47). Scheme 47.1 of reaction 45. 2 47.1 47. 2 47 Ethyl 3- (4- (3-iodobenzyloxy) phenyl) -3- (4-fluorophenyl) -propanoate (47.1). Cs2CO3 (4.89 g, 15 mmol) and 1- (bromomethyl) -3-iodobenzene (4.45 g, 15 mmol) were successively added to a solution of dry DMF (20 mL) of 45.2 (2.88 g, 10 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (200 mL), washed with water (100 mL x 2) and brine (100 mL), and dried over Na S0. The solvent was removed under vacuum and the residue was purified by flash chromatography to give compound 47.1 as a colorless oil. MS ESI (pos.) M / e: 505.0 (M + H). 3- (4- [3- (4-chloro-2-methylphenyl) benzyloxy] phenyl) -3- (4-fluorophenyl) -propanoate (47.2). CsF (96 mg, 0.6 mmol), 4-chloro-2-methylphenylboronic acid (102 mg, 0.6 mmol) and Pd (PPh3) (70 mg, 0.06 mmol) were successively added to a solution of dry 1,2-dimethoxyethane ( DME, 2 mL) of 47.1 (108 mg, 0.2 mmol) with stirring under a nitrogen atmosphere. The reaction mixture was stirred at 80 ° C overnight. The solvent was removed under nitrogen flow and the residue was dissolved in CH2Cl2 (2 L) and purified by flash chromatography. Compound 47.2 was obtained as a colorless oil. MS ESI (pos.) M / e 503.0 (M + l). Acid (+/-) - 3-. { 4- [3- (4-chloro-2-methylphenyl) phenyl] methoxy) phenyl} -3- (4-fluorophenyl) -propanoic acid (47). LiOH (48 mg, 2 mmol) was added to a solution of THF-H20 (1/1, 4 mL) of compound 47.2 (104 mg, 0.2 mmol). The reaction mixture was stirred at room temperature overnight. HCl (acid) was added to acidify the mixture at pH 3 at 0 ° C. The mixture was extracted with ethyl acetate (20 mL x 2), washed with water and brine, dried over Na 2 SO 4, and purified by flash chromatography to obtain compound 47 (82 mg) as a colorless oil RM? A (400 MHz) (CDC13) d 2.22 (s, 3H), 3.05 (dd, J = 7.8, 1.1 Hz, 2H), 4.49 (t, J = 8.0 Hz, 1H), 5.09 (s, 2H), 6.92 -7.43 (m, 12H). MS ESI (neg.) M / e 473.0 (M-H). Example 48 The following compounds were prepared according to the methods described in Example 47. Table 16 Example 49 This example illustrates the preparation of (+/-) - 3- (4- (3- (4- (trifluoromethyl) phenyl) encyloxy) phenyl) -4- (dimethylamino) -3-methyl-4-oxobutanoic acid. 49.1 Reaction 49. 1 N-Allil-2 (4-hydroxyphenyl) propanamide (49.1). N, N'-Carbonyldiimidazole (22.65 g, 140 mmol) was added to commercially available 2- (4-hydroxyphenyl) propionic acid (21 g, 127 mmol) in THF (100 mL). Smooth heating and gas emission were observed. The resulting mixture was stirred for 3 hours. Allylamine (10.9 g, 190.5 mmol) and Et3N (19.2 L, 190.5 mmol) were added dropwise, and the mixture was stirred overnight. The reaction was quenched with water (200 mL) and the organic phase was extracted with ethyl acetate (50 mL x 3). The combined organic extracts were dried over MgSO and concentrated in vacuo. The product was purified by flash chromatography (elution with ethyl acetate). Phenol 49.1 was obtained as a white solid. MS ESI m / e: 206 (M-H).

Scheme 49 2 Reaction 49. 2 49.1 49.3 2- (4- (3- (4- (Trifluoromethyl) phenyl) benzyloxy) phenyl) -N-allilpropanamide (49.3). CS2C03 (23.1 g, 71 mmol) was added to a mixture of compound 49.2 (20.33 g, 64.5 mmol) and phenol 49.1 (13.23 g, 64.5 mmol) in DMF (50 mL). The resulting mixture was stirred overnight. The reaction was quenched with water (500 mL). The organic phase was extracted with ethyl acetate (75 mLx3). The combined organic phases were dried over MgSO and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography (10% acetone in dichloromethane) to yield 15.9 g of 49.3 MS ESI m / e: 440 (M-H). 49. 3 49.4 2- (4- (3- (4- (Trifluoromethyl) phenyl) benzyloxy) phenyl) -2-methylpent-4-enonitrile (49.4). The reaction of 3-aza-claisen according to the method of Walters et al. (1991) Tetrahedron Lett. 2: 179-182. Amide 49.3 (15.9 g, 36.2 mmol) and PPh3 (21 g, 80 mmol) were dissolved in anhydrous dichloromethane (160 mL). Et3N (12 g, 119.5 mmol) and CC1 (18.4 g, 119.5 mmol) were added dropwise. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated brine (250 mL). The organic phase was extracted with ethyl acetate (50 mLx3). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (25% ethyl acetate in hexanes) to yield 12.3 g of 49.4. NMR A (400 MHz) (CDC13) d 7.73 (4H, s); 7.70 (1H, s); 7.61-7.51 (3H, m); 7.41 (2H, d, J = 8.9 Hz); 7.05 (2H, d, J = 8.9 Hz); 5.76-5.72 (lH, m), -5.21-5.17 (4H,); 2.71-2.59 (2H, m); 1.72 (3H, s). 49.4 Reaction Scheme 49. 4 49.5 2- (4- (3- (4- (Trifluoromethyl) phenyl) benzyloxy) -phenyl-2-methylpent-4-enoic acid (49.5) 49.4 was added to a mixture of ethylene glycol (8 mL), H20 ( 0.25 mL) and KOH (750 mg) The resulting mixture was heated at 190 ° C for 6 hours, the reaction mixture was cooled to room temperature, the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined residue was dried over MgSO, and concentrated under reduced pressure, The resulting residue was purified by flash chromatography (10% acetone in dichloromethane) to yield 632 mg of 49.5 MS ESI m / e: 441 (MH). Reaction 49. 5 49.6 2- (4- (3- (4- (trifluoromethyl) phenyl) benzyloxy) phenyl) -N, N-diethyl-2-methylpent-4-enamide (49.6). Oxalyl chloride (57.7 mg, 0.45 mmol) was added dropwise to 49.5 (100 mg, 0.23 mmol) in anhydrous dichloromethane (4 mL). The resulting mixture was refluxed in a sealed tube at 50 ° C overnight. The dichloromethane was removed under a stream of N2. Anhydrous ester (2 mL) was added dropwise, followed by diethylamine (50 mg, 0.69 mmol) and Et3N (70 mg, 0.69 mmol). The mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (25% ethyl acetate in hexanes). 82 mg of 49.6 were obtained. MS ESI m / e: 496 (M-H). NMR A (500 MHz) (CDC13) d 7.72 (4H, s); 7.69 (1H, s); 7.6-7.5 (3H, m); 7.14 (2H, d, J = 8.5 Hz); 7.05 (2H, d, J = 8.5 Hz); 5.7-5.6 (1H, m); 5.15 (2H, s "), 5.03-5 (2H, m), 3.5-3.2 (2H, m), 3.0- 2.9 (2H, m), 2.74-2.64 (2H, m), 1.62 (3H, s); 1.13 (3H, s); 0.72 (3H, s). Reaction Scheme 49.6 49. 6 49 Acid (+/-) - 3- (4- (3- (4- (trifluoromethyl) phenyl) -benzyloxy) -phenyl) -4-diethylamino (-3-methyl-4-oxobutanoic acid (49). Oxidation was carried out according to the method of Henry et al (1993) J. Org Chem 58: 4745. A catalytic amount of Os0 was added to a solution of 49.6 (50 mg, 0.1 mmol) in acetone (4). mL), followed by an excess of Jones reagent (0.25 mL) The reaction mixture was stirred at room temperature overnight.The reaction was quenched with water (2 L), and the aqueous phase was extracted with dichloromethane (2M). mLx3) The combined organic extracts were dried over MgSO and were removed under reduced pressure The resulting residue was purified on reverse phase HPLC MS ESI m / e: 514 (MH) Example 50 This example illustrates the preparation of -. {4- [4'- (1, 1-difluoro-ethyl) -biphenyl-3-ylmethoxy] -phenyl} -. N, N-dimethyl-succinamic Reaction Scheme 50.1 49. 2 50.1 [4- (4'-Trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -acetic acid methyl ester (50.1). Compound 49.2 (15.8 g, 50.1 mmol) was added to methyl 4-hydroxyphenylacetate (8.3 g 50 mmol) in DMF (30 mL), followed by Cs2CO3 (17.9 g, 55 mmol). The resulting mixture was stirred overnight. The reaction was quenched with water (300 mL). The organic phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was rinsed with saturated brine, dried over MgSO4, concentrated under reduced pressure. The product (16.3 g) was used in the next step without further purification MS ESI (pos.) M / e: 423 (M + Na).

Diagram 50.2 of Reaction 50. 1 50.2 1-methyl ester of 2-tert-butyl ester. { 4- [4'-trifluoromethyl-biphenyl-3-ylmethoxy] -phenyl} -succinic (50.2). Compound 50.1 (4 g, 10 mmol) in THF (12 mL) was added dropwise to LDA in THF (1M, 12 mL) at -78 ° C. The resulting mixture was stirred for 30 minutes before tert-butyl bromoacetate (2.15 g, 11 mmol) in THF (2 mL) was added over 10 minutes. The reaction mixture was stirred for 2 hours at -78 ° C and allowed to slowly warm to 0 ° C. The reaction was quenched with saturated aqueous NH4C1 (20 mL). The organic phase was extracted with ethyl acetate (25 mLx3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (50% ethyl acetate in hexanes) to yield 3.3 g of 50.2. MS ESI (pos.) M / e: 537 (M + Na). NMR A (400 MHz) (CDCl 3) d 7.72 (4H, s); 7.68 (1H, s); 7.58-7.49. (3H, m); 7.25-7.24 (2H,); 6.98-6.97 (2H, m); 5.14 (2H, s); 4.04-4.0 (1H, m); 3.7 (3H, s); 3.1 (1H, m); 2.63 (1H, m); 1.42 (9H, s).

Diagram 50.3 of Reaction - ~ 50.2 50.3 2- Tertiary butyl ester. { 4- [4'-trifluoromethyl-biphenyl-3-ylmethoxy] -phenyl} -succinic (50.3). Lithium hydroxide (121 mg, 5 mmol) was added to a solution of 50.2 in MeOH / THF / H20 (1: 1, 90 mL). The resulting mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure. The reaction mixture was extracted with dichloromethane (10 mL x 3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (50% ethyl acetate in hexanes) to yield the acid 50.3 (860 mg). MS ESI (pos.) M / e: 523 (M + Na). RM? A (400MHz ('(CDC13) d 7.72 (4H, s), 7.67 (1H, s), 7.59-7.47 (3H,), 7.29-7.25 (2H,), 6.98-6.97 (2H, m), 5.14 ( 2H, s), 4.04-4.0 (1H, m), 3.1-3.053 (1H, m), 2.64.2.60 (1H, m), 1.4 (9H, s).

Reaction scheme 50.4 50. 3 50.4-tert-butyl ester - 3-acid. { 4- [4'-trifluoromethyl-biphenyl-3-ylmethoxy] -phenyl} -N, N-dimethyl-succinamic (50.4). A solution of compound 50.3 (50 mg, 0.1 mmol) in dichloromethane (2 mL) was treated with 1-hydroxybenzotriazole (15 mg, "0.11 mmol) and EDC (21 mg, 0.11 mmol) sequentially.The resulting mixture was stirred for 1 hour. one hour, before dimethylamine (9 mg, 0.2 mmol) was added dropwise, the reaction was quenched 30 minutes later with water (5 mL), the reaction mixture was extracted with dichloromethane (2 mL x 3). they were combined, dried over MgSO4 and concentrated under reduced pressure to yield amide 50.4 (48 mg) The product was used in the next step without further purification MS ESI (pos.) m / e: 527 (M +).

Reaction scheme 50.5 50. 4 50 Acid (+/-) -3. { 4- ['-trifluoromethyl-biphenyl-3-yl-ethoxy] -phenyl} -N, N-dimethyl-succinamic (50). The 50.4 'ester (48 mg, 0.09 mmol) was dissolved in a dichloromethane / TFA solution (3: 1, 2 L). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the product was purified on reverse phase HPLC to yield acid 50 (30 mg). MS ESI (pos.) M / e: 472 (M + H). NMR A (400MHZ) (CDC13) d 7.72 (4H, s); 7.67 (1H, s); 7.59-7.28 (3H, m); 7.2 (2H, d, J = 8.6 Hz); 7.0 (2H, d, J = 8-6 Hz); 5.13 (2H, s); 4.24-4.21 (1H,); 3.20-3.13 (1H, m); 3.0 (3H, s); 2.95 (3H, s); 2.76-2-71 (1H, m).

Example 51 This example illustrates the preparation of 3- (4-methyl-thiazol-2-yl) -3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -propionic acid.

Diagram 51.1 of Reaction 50. 3 51.1 3- [4- (4'-Trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -succinnamic acid tert-butyl ester - (51.1). Sequentially, 1-hydroxybenzotriazole (225 mg, 1.65 mmol) and EDC (315 mg, 1.65 mmol) were added sequentially to compound 50.3 (750-mg, 1.5 mmol) in dichloromethane (25 mL). The resulting mixture was stirred for 1 hour before ammonium hydroxide (25% in water, 630 mg, 4.5 mmol) was added dropwise. The reaction was quenched after 30 minutes with water (10 mL). The reaction mixture was extracted with dichloromethane (10 mL x 3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The product was purified by flash chromatography (50% ethyl acetate in hexanes) to yield 51.1 (720 mg) as a white solid. MS ESI (pos.) M / e: 500 (M + H). NMR A (400MHz) (CDC13) d 7.72 (4H, s); 7.68 (1H, s); 7.57-7.48 (3H, m); 7.29-7.25 (2H, m); 7.0-6.97 (2H, d, J = 6.8 Hz); 5.14 (2H, s) -; 3.91-3.88 (1H, m); 3.19-3.13 (1H, m); 2.60-2.55 (1H, m); 1.4 (9H, s).

Diagram 51.2 of Reaction 51. 1 51.2 3-Thiocarbamoyl-3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -propionic acid tert-butyl ester (51.2). Lawesson's reagent (81 mg, 0.2 mmol) was added to a solution of compound 51.1 (50 mg, 0.1 mmol) in THF (2 mL). The resulting mixture was stirred at room temperature for 6 hours. The reaction was quenched with water (5 mL). The reaction mixture was extracted with dichloromethane (3 mL × 3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The product was purified by flash chromatography (50% ethyl acetate in hexanes) to yield compound 51.2 (40 mg) as a clear film. MS ESI (pos. M / e: 516 (M + H).) NMR A (400 MHz) (CDC13) d 7.72 (4H, s); 7.67 (1H, s); 7.51-7.48 (3H, m); 7.31 -7.28 (2H, m); 7.0-6.97 (2H, m); 5.14 (2H, s); 4.25-4.22 (lH, m); 3.51-3.46 (lH, m); 2.78-2.72 (1H, m);; 1.38 (9H, s).

Diagram 51.3 of Reaction 51. 2 51.3 Ethyl 3- (4-methyl-thiazol-2-yl) -3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -propanoate (51.3). A solution of 51.2 (100 mg, 0.19 mmol) in EtOH (3 mL) was treated with chloroacetone (88 mg, 0.95 mmol). The resulting mixture was refluxed for 5 hours. Aqueous HCl (6N, 25 μL) was added in the above reaction mixture and the reaction was heated at 50 ° C overnight. The solvent was removed under reduced pressure. The product was purified by flash chromatography (50% ethyl acetate in hexanes) to yield 51.3 (50 mg). MS ESI (pos.) M / e 526 (M + H). Diagram 51.4 of Reaction 51. 3 51 Acid (+/-) -3- (4-Methyl-thiazol-2-yl) -3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -propionic acid (51). Compound 51.3 (50 mg, 0.1 mmol) was dissolved in MeOH / THF / H20 (1: 1: 1, 3 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH = 4 and extracted with dichloromethane (3 mLx3). The product was purified on reverse phase HPLC to yield compound 51 (40 mg). MS ESI (pos.) M / e: 498 (M + H). NMR A (400 MHz) (DMSO) d 792 (2H, d, J = 8.7 Hz); 7.84 (3H, d, J = 8.8 Hz); 7.71 (lH, t, J = 5.1 Hz); 7.54 (2H d, J = 7Hz); 7.29 (2H, d, J = 8.7 Hz), 7.09 (1H, s); 7.01 (2 H, d, J = 8.7 Hz); 5.18 (2H, s); 4.66 (1H, m); 3.2 (1H, m); 2.93 (1H, m); 2.33 (3H, s). Example 52 This example illustrates the preparation of (+/-) - 3- (4- ((4-methyl-2-p-tolylthiazol-5-yl) methoxy) phenyl) -3- (thiophen-2-yl) acid propionic Diagram 52.1 of Reaction 1. 1 52.1 2, 2-Dimethyl-5- [4- (tetrahydro-pyran-2-yloxy) benzylidene] - [1,3] dioxane-4,6-dione (52.1). The protection of phenol with dihydropyran was carried out based on the method given in Miyashita et al. (1997) J. Org. Chem. 42: 3272. Compound 1.1 (500 g, 2 mol) was dissolved in dichloromethane (4 L). 3-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followed by PPTS (5 g, 20 mmol). The reaction mixture was heated to gentle reflux (3.5 h). HPLC showed approximately 90% completion of the reaction. The reaction was concentrated under reduced pressure to approximately 2 liters of volume. 1 L of acetone was added, and 2 L of solvent were removed under reduced pressure. 1 L of acetone was added and 1 L of solvent was removed under reduced pressure. 0.5 L of acetone was added and 0.5 L of solvent was removed under reduced pressure. The resulting thick slurry of very fine light yellow crystals was filtered and rinsed sequentially with 2 portions of 500 mL of acetone. The product was dried in a vacuum oven at 50 ° C until no additional solvent was collected in the traps. The compound 52.1 (528 g) was obtained as fine pale yellow crystals. NMR A (400 MHz) (DMSO-de) d 8.29 (s, 1H); 8.18 (d, 2H, J = 8.9 Hz); 7.13 (d, 2H, J = 8.9 Hz); 5.67 (m, 1H); 3.70 (m, 1H); 3.60 (m, 1H); 1.9-1.5 (m, 12H). MS ESI (pos.) M / e: 355.1 (M + Na).

Reaction Scheme-52.2 52. 1 52.2 3- (4-hydroxyphenyl) -3- (thiophen-2-yl) propanoate of (+/-) -methyl (52.2). A 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and was placed in a bath of water at room temperature. Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask together with anhydrous THF (150 mL). After purging with nitrogen for 30 minutes, a solution of thiophen-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added per cannula. After the addition was complete, the reaction mixture was stirred for 1.5 hours and quenched with aqueous NH C1 (1M, 100 mL) was diluted with ethyl acetate (100 mL). The aqueous layer was acidified to pH about 2 with concentrated HCl and extracted with ethyl acetate (150 mL x 2). The extract was washed with brine and concentrated. The residue was dissolved in 100 mL of DMF-water 10: 1 heated at 100 ° C for 8 hours. The reaction was cooled and diluted with 500 mL of water and extracted with ethyl acetate (150 mL x 3). The organic layer was dried with MgSO 4, filtered, and concentrated on a rotary evaporator. The residue was dissolved in MeOH (200 mL) and 5 drops of concentrated H2SO4 were added and the solution was refluxed for 24 hours. The solution was concentrated to a residue on a rotary evaporator and purified using flash column chromatography with 30% ethyl acetate / hexanes as the eluent. The fractions were combined and concentrated to give 2.69 g (10.3 mmol) of 52.2 as a viscous oil. Diagram 52.3 of Reaction 52. 2 52 Acid (+/-) -3- (4- ((4-methyl-2-p-tolylthiazol-5-yl) methoxy) phenyl) -3- (thiophen-2-yl) propanoic acid (52). Thiazole chloride 3.1 (108 mg, 0.457 mmol) and phenol 52.2 (100 mg, 0.381 mmol) were dissolved in DMF (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50 ° C for 16 hours and diluted with water (15 L) and methylene chloride (15 mL). The organic layer was washed with water, dried with MgSO, filtered and concentrated. The residue was purified by column chromatography (silica gel, 33% to 66% ethyl acetate in hexanes). The eluate containing the desired compound was concentrated dissolved in a solution of THF / MeOH / 2N LiOH (aqueous) (1: 1: 1) (2 mL). The mixture was stirred at room temperature for 90 minutes, and the solution was poured into HCl (aqueous) 0.65 N (2 mL). The aqueous phase was extracted with dichloromethane (3 x 10 mL) and the combined organic phases were dried over Na2SO4. After filtration and drying, 156 mg (0.323 mmol) of carboxylic acid 52 was obtained. (400 MHz) (CDC1) d 7.77 (d, 2H, J = 8.1 Hz), 7.23-7.30 (m, 5H), 6.89-6.97 (m, 4H), 5.24 (s, 2H, 4.58 (t, 1H, J = 7.8 Hz), 3.02 (m, 1H), 2.92 (, 1H), 2.40 (s, 3H), 2.33 (s, 3H) Example 53 This example illustrates the preparation of acid (+/-) - 3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -3- (thiazol-2-yl) -propionic Scheme 53.1 Reaction 52. 1 53.1 3- (4-hydroxyphenyl) -3- (thiazol-2-yl) propanoate of (+/-) Methyl (53.1). A 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and placed in a water bath at room temperature. Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask together with anhydrous THF (150 mL). After purging with nitrogen for 30 minutes, a solution of thiozol-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula. After the addition was completed, the reaction mixture was stirred for 1.5 hours, cooled with NH 4 Cl (1M, 100 mL) was diluted with ethyl acetate (100 mL). The aqueous layer was acidified to pH about 2 with concentrated HCl and extracted with ethyl acetate (150 mL x 2). The extract was washed with brine and concentrated. The residue was dissolved in 100 mL of DMF-water 10: 1 and heated at 100 ° C for 8 hours. The reaction was cooled and diluted with 500 mL of water and extracted with ethyl acetate (150 mL x 3). The organic layer was dried over MgSO4, filtered and concentrated in a rotary evaporator. The residue was dissolved in MeOH (200 mL) and 5 drops of concentrated H2SO4 were added and the solution was refluxed for 24 hours. The solution was concentrated to a residue on a rotary evaporator and purified using flash column chromatography with 50% ethyl acetate / hexanes as eluent. The fractions were combined and concentrated to give 1.90 g (7.25 mmol) of 53.1 as a viscous oil.

Scheme 53.2 of Reaction 53. 1 53 Acid (+/-) - 3- [4- ('-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -3- (thiazol-2-yl) -propionic acid (53). Benzyl chloride 2.3 (123 mg, 0.456 mmol) and phenol 53.1 (100 mg, 0.380 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50 ° C for 16 hours, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% ethyl acetate to 70% hexanes). The eluate containing the desired compound was concentrated and dissolved in a solution of THF / MeOH / 2N LiOH (aCuisine) (1: 1: 1) (2 mL). The mixture was stirred at room temperature for 90 minutes, and the solution was poured into HCl (aqueous) 0.65 N (2 mL). The aqueous phase was extracted with dichloromethane (3 x 10 mL) and the combined organic phases were dried over? A2S0. After filtration and drying, 150 mg (0.311 (mmol) of carboxylic acid 53 were obtained. NMR A (400 MHz) (CDC13) d 7.47-7.77 (m, 9H), 7.24-7.27 (m, 3H), 6.99 -7.00 (m, 2H), 5.14 (s, 2H), 4.78 (dd, 1H, J = 6.8, 4.4 Hz), 3.47 (dd, 1H, J = 12.8, 6.8 Hz), 3.09 (dd, 1H, J = 12.8, 4.4 Hz) Example 54 This example illustrates the preparation of (+/-) -3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] -3- (3-methylthiophen) acid. -2-il) -propionic Scheme 54.1 of Reaction 52. 1 54.1 3- (4-hydroxyphenyl) -3- (3-methylthiophen-2-yl) -propanoate of (+/-) - methyl (54.1). A 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and placed in a water bath at room temperature. Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask together with anhydrous THF (150 mL). After purging with nitrogen for 30 minutes, a solution of 3-methylthiophen-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula. After the addition was completed, the reaction mixture was stirred for 1.5 h, quenched with aqueous NH 4 Cl (1 M, 100 mL) and diluted with ethyl acetate (100 mL). The aqueous layer was acidified to pH of about 2 with concentrated HCl and extracted with ethyl acetate (150 mL x 2). The extract was washed with brine and concentrated. The residue was dissolved in 100 mL of DMF-water 10: 1 and heated at 100 ° C for 8 hours. The reaction mixture was cooled and diluted with 500 mL of water and extracted with ethyl acetate (150 mL x 3). The combined organic layers were dried with MgSO4, filtered and concentrated in a rotary evaporator. The residue was dissolved in MeOH (200 mL ") and added with 5 drops of concentrated H2SO4 and the solution was refluxed for 24 hours.The solution was concentrated to a residue in a rotary evaporator and purified using Instantaneous column with 30% ethyl acetate / hexanes as the eluent The fractions were combined and concentrated to give 2.33 g (7.25 mmol) of 54.1 as a viscous oil Scheme 54.2 Reaction 54. 1 54 Acid (+/-) -3- [4- (4-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl) -3- (3-methylthiophen-2-yl) propionic acid (54). Benzyl chloride 2.3 (113 mg, 0.434 mmol) and phenol 54.1 (100 mg, 0.362 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50 ° C for 16 hours, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% ethyl acetate 60% in hexanes). The eluate containing the desired compound was concentrated and dissolved in a THF / MeOH / 2N LiOH solution (aqueous) (1: 1: 1) (2 mL). The mixture was stirred at room temperature for 90 minutes, the solution was poured into HCl (aqueous) 0.65 N (2 mL). The aqueous phase was extracted with dichloromethane (3 x 10 mL) and the combined organic phases were dried over Na2SO4. After filtration and drying, 154 mg (0.311 mmol) of carboxylic acid 54 were obtained. RM. TO (400 MHz) (CDC13) d 7.43-7.70 (m, 8H), 7.21 (d, 2H, J = 8.6 Hz), 7.05 (d, 1H, J = 5.0 Hz), 6.92 (d, 2H, J = 8.6 Hz), 6.76 (d, 1H, 5.0 Hz), 5.09 (s, 2H), 4.74 (t, 1H, J = 7.8 Hz), 3.05 (d, 2H, J = 7.8 Hz), 2.15 (s, 3H). Example 55 This example illustrates the preparation of 3- (4-hydroxyphenyl) -3- (lH-pyrrol-1-yl) propanoate Scheme 55.1 of Reaction or / = \,? H2 G? H0AC = \ XH? X¿- / ^ VA ^ -C02H + MeoX ° AoMe heating * "H °? I- / ^ / O V-C02H 55.1 3- (4-hydroxyphenyl) -3- (lH-pyrrol- 1- il) propanoic (55.1) At 100 ° C, 2,5-dimethoxytetrahydrofuran (8.5 mmol) was added to a mixture of 3-amino-3- (4-hydroxyphenyl) propanoic acid (7.7 mmol) and sodium acetate. (46 mmol) in acetic acid (34 mL) After stirring for 1 hour, the acetic acid was removed under reduced pressure, the residue was extracted with ethyl acetate (300 mL), the organic layer was washed with brine and dried over anhydrous Na2SO and concentrated The residue was purified by column chromatography (10% methanol in dichloromethane) to compound 55.1 LC-MS (neg.) m / e: 230.2 MH) Scheme 55.2 Reaction 3- (4-hydroxyphenyl) -3- (lH-pyrrol-1-yl) propanoate of (+/-) -methyl (55). Trimethylsilyldiazomethane (8 mL, 2M in diethyl ether, 16 mmol) was added to a solution of compound 55.1 (7 mmol) in methanol (25 mL). After 10 minutes, the solvent was removed to yield the methyl compound. MS ESI (pos.) M / e: 246.1 (M + H). Example 56 The following compounds were prepared from compound 55 according to the methods described in Example 18.

Table 17 Compound 56.1 MS ESI (neg.) M / e: 431 (M-H). NMR A (500MHz) (DMSO-d6) d 12.3 (1H, s); 7.81 (2H, d, J = 8 Hz); 7.30 (4H, m); 6.99 (2H, d, J = 9 Hz); 6.92 (2H, m); 5.98 (2H, m); 5.56 (1H, t, J = 8Hz), 5.29 (2H, s); 3.18 (2H, m); 2.44 (3H, s); 2.38 (3H, s). Compound 56.2 MS ESI (neg.) M / e: 464 (M-H). NMR A (500MHz) (DMSO-de) d 7.92 (2H, m); 7.84 (3H,); 7.72 (1H, d, J = 8 Hz); 7.53 (2H, m); 7.26 (2H, d, J = 9 Hz); 7.00 (2H, d, J = 9 Hz), 6.91 (2H, m); 5.55 (1H, d, J = 8 Hz); 5.19 (2H, s); 3. 16 (2H, m). Compound 56.3. MS ESI (neg.) M / e: 396 (M-H). NMR A (500MHz) (DMSO-de) d 12.37 (1H, s); 7.65-7.77 (4H, m); 7.41-7.51 (5H, m); 67.27 (2H, m); 7.01 (2H, d, J = 5 Hz)); 6.92 (2H, m); 5.99 (2H, m), 5.56 (lH,); 5.18 (2H, s), 3.21 (2H, m). Compound 56.4 MS ESI (neg.) M / e: 350 (M-H). NMR A (500MHz) (DMSO-de) d 12.4 (1H, s); 7.30-7.34 (1H, t, J = 8Hz); 7.26 (2H, d J = 9Hz); 7.01 (2H, m); 6.96 (2H, J = 9Hz)); 6.90-6.92 (3H, m); 5.98 (2H, m), 5.55 (1H, t, J = 8 Hz); 5.07 (2H, s); 3.78 (3H, s); 3.21 (2H, m). Compound 56.5 MS ESI (neg.) M / e: 364 (M-H). NMR A (500MHz) (DMSO-d6) d 7.24-7.31 (3H, m); 6.99 (2H, m); 6.88 (3H, m); 5.97 (2H, s); 5.55 (lH, m); 5.06 (2H, s), 4.04 (2H, q, J = 7 Hz); 3.16 (2H, m); 1.34 (3H, t, J = 7Hz). Compound 56.6. MS ESI (neg.) M / e: 412 (M-H). NMR-A (500MHz) (DMSO-d6) d 7.40-7.43 (3H, m); 7.16-7.26 (4H, m); 7.08 (1H, s); 7.03 (2H, d, J = 8 Hz)); 6.90-6.97 (5H, m); 5.98 (2H, s), 5.54 (1H, t, J = 8 Hz); 5.09 (2H, s); 3.17 (2H, m). Compound 56.7. MS ESI (neg.) M / e: 396 (M-H). NMR A (500MHz) (DMSO-de) d 7.70-7.71 '(4H, m); 7.41-7.55 (4H,); 7.39 (1H, m); 7.25 (2H, d, J = 8 Hz)); 6.98 (2H, d, J = 9 Hz); 6.89 (2H, s); 5.97 (2H, s); d, J = 8 Hz); 5:55 (1H, t, J = 8 Hz); 5.12 (2H, s); 3.10 (2H, m) Compound 56.8. MS ESI (neg.) M / e: 421 (M-H). NMR A (500MHz) (DMSO-de) d 8.19 (1H, s); 8.05 (1H, d, J = 8 Hz); 7.87 (1H, d, J = 8 Hz); 7.80 (2H, d, J = 8 Hz); 7.71 (1H, t, J = 8 Hz); 7.56 (2H, d, J = 8 Hz); 7.26 (2H, d, J = 8 Hz); 6.90 (2H, d, J = 8 Hz); 5.98 (2H, m); 5.55 (2H, t, J = 8 Hz)); 5.17 (2H, s); 3.13 (2H, m). Compound 56.9. MS ESI (neg.) M / e: 421 (M-H). RMN A (500MHz) (DMSO-de) d 7.99 (lH, d, J = 8 Hz), 7.84 / 1H, t, J = 8 Hz); 7.68 (1H, d, J = 8 Hz); 7.58-7.64 (5H, m); 7.17 (2H, d, J = 8 Hz); 6.96 (2H, d, J = 8 Hz); 6.81 (2H, m); 5.95 (2H, m); 5.55 (1H, t, J = 7 Hz); 5.18 (2H, s); 2.73 (2H, d, J = 7 Hz). Example 57 The following compounds were prepared according to the methods described in Examples 55 and 56. Table 18 R; r == v N ^ ° i? A CO? H Compound 57.1. MS ESI (neg.) M / e: 431 (M-H). NMR A (500MHz) (DMSO-de) d 7.81 (2H, m); 7.28-7.32 (4H, m); 7.00 (2H, d, J = 8 Hz); 6.92 (2H, s); 5.99 (2H, s); 5.57 (1H, m); 5.30 (2H, s); 3.23 (2H, m); 2.44 (3H, s); 2.38 (3H, s). Compound 57.2. MS ESI (neg.) M / e: 464 (M-H). RMN A (500MHz) (DMSO-de) d 793 (2H, d, J = 8 Hz) _; 7.83-7.86 (3H, m); 7.72 (1H, d, J = 8 Hz); 7.56 (2H, m); 7.27 (2H, d, J = 9 Hz); 7.01 (2H, d, J = 9 Hz); 6.91 (2H, "m), 5.98 (2H, s), 5.55 (1H, d, J = 8 Hz), 3.14 (2H, m), Compound 57.3 MS ESI (neg.) M / e: 396 (MH RMN A (500MHz) (CDC13) d 7.63-776 (4H, m); 7.39-7.59 (5H, m); 7.15 (2H, d, J = 8 Hz); 6.77 (2H, s); 6.19 (2H, s); 5.64 (1H, s); 5.13 (2H, s); 3.22-3.26 (2H, m). Compound 57.4. MS ESI (neg.) M / e: 350 (M-H). NMR A (500MHz) (DMSO-de) d 7.33 (1H, t, J = 8 Hz); 7.25 (2H, d, J = 8 Hz); 7.01 (2H, m); 6.95 (2H, d, J = 9 Hz); 6.90 (3H, m); 5.98 (2H, s); 5.55 (1H, t, H = 8 Hz); 5.07 (2H, s); 3.78 (3H, s); 3.16 (2H, m). Compound 57.5. MS ESI (neg.) M / e: 412 (M-H). NMR A (500MHz) (DMSO-de) d 7.40-7-43 (3H, m); 7.24-7.26 (3H, m); 7.20 (1H, m); 7.10 (1H, s); 7.03 (2H, d, J = 9 Hz); 6.90-6.93 (5H,); 5.98 (2H, m); 5.55 (1H, m); 5.10 (2H, s), 3.18 (2 H, m). Compound 57.6. MS ESI (neg.) M / e: 412 (M-H). RMN A (500MHz) (DMSO-de) d 7.99 (1H, d, J = 8 Hz); 7.81 (1H, m); 7.68 (1H, d, J = 8 Hz); 7.61-7.65- (5H, m); 6.92 (2H, m); 5.99 (2H, s); 5.56 (1H, t, J = 8 Hz); 5.20 (2H, s); 3.19 (2H, m) - .. Example 58 This example illustrates the preparation of (+/-) - 3- (-4- (benzyloxy) phenyl) -3- (1H-pyrazol-1-yl) propanoic acid ( 58.3). Diagram 58.1 of Reaction 58. 1 1- (4- (Benzyloxy) benzyl) -iH-pyrazole (58.1). After a mixture of pyrazole (7.73 mmol) and potassium hydroxide (7.73 mmol) in DMF (35 mL) was stirred at room temperature for 30 minutes, a solution of 1- (benzyloxy) -4- was added dropwise. (chloromethyl) benzene (6.44 mmol) in DMF (7 mL). The reaction mixture was stirred at room temperature overnight and the product was obtained from a normal aqueous treatment. Column chromatography (ethyl acetate / hexane 1: 2) of the residue afforded compound 58.1 as a white solid LC-MS ESI (pos.) M / e: 265 (M + H); NMR A (500 MHz) (DMSO-d6) d 7.79 (1H, m); 7.46 (3H, m); 7.40 (2H, m); 7.36 (1H, m); 7.21 (2H, d, J = 9 Hz)); 5.27 (2H, s); 5.11 (2H,).

Diagram 58.2 of Reaction 58. 1 58.2 1- (4- (Benzyloxy) phenyl) but-3-enyl) -lH-pyrazole (58.2). To a solution of compound 58.1 (3.41 mmol) in THF (30 mL) at -78 ° C was added dropwise n-butyllithium in hexanes (3.75 mmol). The mixture was stirred for 10 minutes followed by the addition of allyl bromide (3.75 mmol). The reaction mixture was allowed to warm to room temperature overnight, quenched by the addition of. Water. After extraction with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO and concentrated under reduced pressure. Column chromatography (ethyl acetate / hexane 1: 3) of the residue afforded compound 58.2 as a white solid. LC-MC ESI (pos.) M / e: 305 (M + H). Scheme 58.3 of Reaction 58. 2 58.3 3- (4-Benzyloxy) phenyl) -3- (1H-pyrazole-1-iDpropanoic acid (58.3) A solution of KMnO (1.68 mmol) in water (19 mL) was added dropwise to a mixture of compound 58.2 (1.08 mmol), NaI04 (2.2 mmol), acetone (6 mL), and acetic acid (6 mL). After stirring at room temperature for 1 hour, ethylene glycol (2 mL) was added and stirred for an additional 1 hour. Mn02 was removed by filtration through silica gel (eluting with methanol: dichloromethane 1: 9). After concentration under reduced pressure, the residue was purified by column chromatography (methanol: dichloromethane 1: 9), yielding compound 58.3 (243 mg, 0.75 mmol). LC-MS ESI (pos.) M / e: 323 (M + H). Diagram 58.4 of Reaction 3- (4- (benzyloxy) phenyl) -3- (1H-pyrazol-1-yl) methyl propanoate (58.4). Compound 58.3 was esterified in a manner similar to the method analyzed with respect to Reaction Scheme 55.2. Diagram 58.5 of Reaction 58. 4 58 3- (4-hydroxyphenyl) -3- (lH-pyrazo-1-I) propanoate of (+/-) -methyl (58). A mixture of compound 58.4 (0.37 mmol) and a small amount of Pd-C in methanol (8 mL) was stirred at room temperature under a hydrogen atmosphere for 20 minutes. After filtration and concentration, the residue was purified by column chromatography. Compound 58 (81 mg, 0.33 mmol) was obtained. LC-MS ESI (pos.) M / e: 247 (M + H). Example 59 The following compounds were prepared from compound 58 according to the methods described in Example 18. Table 19 Compound 59.1. MS ESI (neg.) M / e: 321 (M-H). NMR A (500MHz) (DMSO-de) d 7.84 (1H, d, J = 2Hz); 7.40-7.50 (5H,); 7.35 (1H, m); 7.27 (2H, d, J = 9 Hz); 6.97 (2H, d, J = 9 Hz); 6.24 (1H, s); 5.79 (1H, m); 5.06 (2H, s); 3.3 (1H, m); 3.12 (1H, m). Compound 59.2. MS ESI (neg.) M / e: 397 (M-H). RMN A (500MHz) (DMSO-de) d 7.85 (1H, s); 7.64-7.77 (4H, m); 7.41-7.50 (6H, m); 7.29 (2H, d, J = 8 Hz); 7.01 (2H, d, J = 9 Hz); 6.24 (1H, s); 5.80 (1H, m); 5.18 (2H, s); 3.3 (lH, m); 3.12 (lH, m). Compound 59.3. ESI MS (neg.m / e: 465 (MH) .A (500MHz) NMR (DMSO-de) d 7.93 (2H, d, J = 8 Hz), 7.85 (4H, m), 7.73 (1H, d, J = 7 Hz), 7.54 (2H, m), 7.29 (1H, s), 7.28 (2H, m), 7.00 (2H, m), 6.23 (1H, s), 5.80 (1H, m), 5.20 ( 2H, s), 3.3 (1H,), 3.14 (1H, m), Compound 59.4 MS ESI (neg.) M / e: 479 (MH). (500MHz) (DMSO-de) d 7.92 (2H, m); 7.82-7.86 (3H, m); 7.72 (1H, m); 7.52-7.56 (2H, m); 7.36 (1H, s); 7.20 (2H, d, J = 9 Hz); 6. 99 (2H, d, J = 9 Hz); 6.02 (1H, m); 5.69 (1H, m); 5.14 (2H, s); 3.3 (1H,); 2.98 (1H, m); 2.24 (3H, s). Compound 59.5. MS ESI (neg.) M / e: 411 (M-H). NMR A (500MHz) (DMSO-de) d 7.63-7.73 (4H, m); 7.36-7.52 (6H, m); 7.20 (2H, d, J = 8 Hz); 6.99 (2H, d, J = 8 Hz); 6.01 (1H, s); 5.70 (1H, m); 5.17 (2H, s); 3.3 (1H, m) M 2.99 (1H, m); 2.24 (3H, s). Compound 59.6. MS ESI (neg.). m / e: 479 (M-H). RMN A (500MHz) (DMSO-de) d 7.93 (2H, m); 7.84 (3H, m); 7.71 (2H, m); 7.55 (2H, m); 7.26 (2H, d, J = 9 Hz); 7.00 (2H, d, J = 9 Hz), 6.00 (1H, s); 5.69 (1H, m); 5.19 (2H, s); 3.3 (lH, m); 3.05 (1H, m); 2.15 (3H, s). Compound 59.7. MS ESI (neg.) M / e: 411 (M-H). RM? (500MHz) (DMSO-de) d 7.64-7.74 (5H, m); 7.39-7.52 (5H, m); 7.26 (2H, d J = 9 Hz); 6.99 (2H, d, J = '9 Hz); 5.99 (lH, s); 5X68 (1H, m); 5.17 (2H, s); 3.3 (lH, m); 3.06 (1H, m); 2.15 (3H, s).

Example 60 This example illustrates the preparation of ethyl 3- (4-hydroxyphenyl) -3- (5-methyloxazol-2-yl) propanoate. Diagram 60.1 of Reaction 60. 1 2- (4- (Benzyloxy) phenyl) -? - (prop-2-ynyl) acetamide (60.1). A mixture of 4- (benzyloxy) phenylacetic acid (20.7 mmol), 1-hydroxybenzotriazole hydrate (37 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (37 mmol), propargylamine (20.7 mmol) and α-methylmorpholine (62 mmol) in DMF (60 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (400 L), washed with IN HCl, water, saturated NaOC3 solution, brine and dried over Na2SO4. After removing the solvent under reduced pressure, the residue was triturated with dichloromethane. Compound 60.1 was obtained as a white solid after filtration and drying. LC-MS ESI (pos.) M / e: 280 (M + H). Diagram 60.2 of Reaction 60. 1 60.2 2- (4-Benzyloxy) benzyl) -5-methyloxazole (60.2). A mixture of compound 60.1 (10.1 mmol), AuCl3 (1 mmol) in dichloromethane (100 mL) was stirred at room temperature overnight. Additional dichloromethane (100 L) was added and the reaction mixture was washed with NaHCO 3 solution and saturated brine. After drying over α2S04 and concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate-hexanes 1: 2) to obtain compound 60.2. LC-MS ESI (pos.) M / e: 280 (M + H). Diagram 60.3 of Reaction 60. 2 60.3 Ethyl 3- (4- (benzyloxy) phenyl) -3- (5-methyloxazol-2-yl) propanoate (60.3). Compound 60.3 was obtained from compound 60.2 according to the method of Example 58. Reaction Scheme 60.4 60. 3 60 3- (Hydroxyphenyl) -3- (5-methyloxazol-2-yl) propanoate of (+/-) - ethyl (60). Compound 60 was obtained from compound 60.3 according to the method of Example 58. Example 61 The following compounds were prepared from compound 60 according to the methods described in Example 18. Table 20 Compound 61.1 MS ESI (neg.) M / e: 336 (M-H). RMN A (500MHz) (DMSO-de) d 7.41-7.46 (4H, m), 7.36 (1H, m); 7.17 (2H, d, J = 9 Hz); 6.97 (2H, d, J = Hz); 6.73 (1H, s); 5.09 (2H, s); 4.44 (1H, m); 3.08 (1H, m); 2.71 (1H, m); 2.22 (3H, s). Compound 61.2 MS ESI (neg.) M / e: 480 (M-H). RMN A (500MHz) (DMSO-de) d 7.91-7.93 (2H, m); 7.82-7.85 (3H, m); 7.72 (2H, d, J = Hz); 7.54 (2H, m); 7.18 (2H, d, J = 8 Hz); 6.99 (2H, d, J = 8 Hz); 6.72 (1H, s); 5.17 (2H, s); 4.44 (1H, m); 3. 08 (1H, m); 2.74 (1H,); 2.21 (3H, s). Compound 61.3 MS ESI (neg.) M / e: 447 (M-H). RMN A (500MHz) (DMSO-de) d 7.80 (2H, d, J = 8 Hz); 7.30 (2H, d, J = 8 Hz); 7.19 (2H, d, J = 8 Hz); 7.00 (2H, d, J = 8 Hz); 6.73 (1H, s); 5.27 (2H, s); 4.44 (1H, m); 3.10 (1H, m); 2.73 (1H, m); 2. 43 (3H, s); 2.34 (3H, s); 2.21 (3H, s). Compound 61.4 MS ESI (neg.) M / e: 366 (M-H). NMR A (500MHz) (DMSO-de) d 7.32 (1H, t, J = 8 Hz); 7.16 (2H, d, J = 8 Hz); 7.00 (2H, m); 6.96 (2H, m); 6.89 (1H, m); 6.72 (1H, s); . 05 (2H, s); 4.42 (1H, m); 3.76 (3H, s); 3.06 (1H, m); 2.76 (1H, m); 2.21 (3H, s). Compound 61.5 MS ESI (neg.) M / e: 500 (M-H). RM? TO (500MHz) (DMSO-de) d 7.50 (2H, d, J = 8 Hz); 7.44 (2H, d, J = 8 Hz); 7.11-7.18 (4H, m); 6.97 (3H, m); 6.71 (1H, s); 5.10 (2H, s); 4.43 (1H, m); 3.93 (2H, t, J = 7 Hz); 3.06 (1H, m); 2.70 (1 HOUR, ); 2.20 (3H, s), 1.61 (2H, m); 1.36 (2H, m); 0.86 (3H, t, J = 7 Hz). Example 62 This example illustrates the preparation of 3- (4- (3- (4- (trifluoromethyl) phenyl) benzyloxy) phenyl) -3- (isoxazol-5-yl) propanoic acid (62). Diagram 62.1 of Reaction - (4,4 { Dietoxy-l- (4- (tetrahydro-2 H -pyran-2-yloxy) phenyl) but-2-ynyl) -2,2-dimethyl-l, 3-dioxane-4, 6-dione (62.1). The proprietary aldehyde-diethyl acetal (5 g, 39 mmol) was cooled in anhydrous THF (65 mL) at -5 ° C and treated with ethylmagnesium bromide (39 mmol in 14 mL of anhydrous THF) dropwise over 10 minutes. After 45 minutes, the Grignard reagent solution was added to compound 52.1 in anhydrous THF (50 mL). After stirring for 1 hour, the reaction was quenched with saturated NH4C1 (aqueous) (20 mL) was diluted with hexanes (100 mL). After vigorous mixing, the layers were separated and the organic layer was discarded. The aqueous layer was acidified and extracted twice with diethyl ester. The combined organic layers were washed with saturated brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was used immediately without further purification MS ESI (pos.) M / e: 478.3 (M + NH) +. Diagram 62.2 of Reaction 62. 1 62.2 6,6-Dietoxy-3- (4- (tetrahydro-2H-pyran-2-yloxy) phenyl) ethyl hex-4-inocide (62.1). Ethanolysis and decarboxylation were carried out according to the method of Example 16. Ester 62.2 was obtained as a light yellow oil (8 g) - Reaction Scheme 62.3 62. 2 62.3 Ethyl 3- (4-hydroxyphenyl) -3- (isoxazol-5-yl) propanoate (62.3). Compound 62.2 (1 g, 2.5 mmol) and hydroxylamine hydrochloride (0.43 g, 6.2 mmol) were dissolved in a mixture of ethanol (10 mL) and water (1 mL). After refluxing for 2 hours, the reaction mixture was diluted with 200 mL of water and extracted with diethyl ether (2 x 100 mL). The combined organic layers were washed with saturated brine, dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol in eluent of dichloromethane). Compound 62.3 was obtained as a thick oil (0.38 g). NMR A (500MHz) (CDC13) d 8.14 (d, J = 1.5 Hz, 1H); 7.12 (d, J = 8.5 Hz, 2H); 6.77 (d, J = 8.5, 2H); 5.98 (d, J = 1.0 Hz, 1H); 5.30 (s, 1H); 4.64 (t, J = 8.0 Hz, 1H); 4.06 (m, 2H); 3.15 (dd, J = 16, 7.5 Hz, 1H); 2.95 (dd, J = 16, 8.0 Hz, 1H); 1.17 (t, J = 7.2 Hz, 3H). Diagram 62.4 of Reaction 62. 3 62.4 ethyl 3- (4- (3- (4- (trifluoromethyl) phenyl) benzyloxy) phenyl) -3- (isoxazol-5-yl) propanoate (62.4). Compound 62.3 was rented according to the procedure of Example 2. LC-MS ESI (pos.) M / e: 496.1 (M + H). NMR A (500MHz) (CDC13) d 8.14 (s, 1H); 7.70 (s, 4H); 7.66 (s, 1H); 7.56 (d, J = 7.5 Hz, lH); 7.50-7.45 (m, 2H); 7.22 (d, J = 8.5 Hz, 2H); 6.96 (d, J = 8.5, 2H); 5.99 (s, lH); 5.12 (s, 2H); 4.67 (t, J = 7.7 Hz, 1H); 4.08 (m, 2H); 3.16 (dd, J = 16, 7.5 Hz, 1H); 2.95 (dd, J = 16, 8.0 Hz, 1H); 1.17 (t, J = 7.2 Hz, 3H). Diagram 62.5 of Reaction 62. 4 62 Acid (+/-) -3- (4- (3- (4- (trifluoromethyl) phenyl) -benzyloxy) phenyl) -3- (isoxazol-5-yl) propanoic .. (62). Compound 62.4 was dissolved in glacial acetic acid (1 mL) and water (0.3 mL) and heated at 95 ° C for 16 hours. HCl 1N (0.1 mL) was added and the reaction mixture was heated for another 16 hours. The reaction mixture was poured into deionized water (50 mL) and extracted twice with diethyl ether. The combined organic layers were washed with saturated brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol in eluent of dichloromethane). Compound 62 was obtained with a thick oil (26 mg). LC-MS ESI (pos.) M / e: 468.1 (M + H). NMR A (500MHz) (CDC13) d 8.14 (S, 1H); 7.70 (s, 4H) '; 7.66 (s, lH); 7.56 (d, J = 7.5 Hz, 1H); 7.50-7.45 (m, 2H); 7.22 (d, J = 8.5 Hz); 6.96 (d, J = 8.5, 2H); 5.99 (s, 1H); 5.12 (s, 2H); 4.67 (t, J = 7.7 Hz, 1H); 4.08 (ra, 2H); 3.16 (dd, J = 16, 7.5 Hz, 1H); 2.95 (dd, J = 16, 8.0 Hz, 1H); 1.17 (t, J = 7.2 Hz, 3H). Example 63 This example illustrates the preparation of 3- [4- (2 '-butoxy-5' -methyl-biphenyl-4-ylmethoxy) -phenyl] -3- (1-methyl-1H-pyrazol-5-yl) acid. ) propionic acid and 3- [4- (2'-butoxy-5 '-methyl-biphenyl-4-ylmethoxy) -phenyl] -3- (l-methyl-lH-pyrazol-3-yl) propionic acid. Diagram 63.1 of Reaction 3- (4-hydroxyphenyl) -3- (1-methyl-1H-pyrazol-5-yl) -propanoic acid ethyl ester (63.1) and 3- (4-hydroxyphenyl) -3- (1-methyl-1H-pyrazole-3) -yl) ethyl propanoate (63.2). Compound 62.2 was dissolved in absolute ethanol (6 mL). A solution of methylhydrazine (173 mg, 3.7 mmol) in 6N HCl (aqueous) (0.6 mL) was added and the reaction mixture was heated to reflux. After 2 hours, the reaction mixture was diluted with 200 mL of water, neutralized with saturated aqueous aHC03 and extracted with diethyl ether (2 x 100 mL). The combined organic layers were washed with saturated brine, dried over MgSO, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol in dichloromethane). Compounds 63.1 and 63.2 were obtained as an inseparable mixture in a ratio of approximately 4: 5 by NMR A LC-MS ESI (pos.) M / e: 275.2 (M + H). Diagram 63.2 of Reaction 3- [4- (2'-Butoxy-5'-methyl-biphenyl-4-ylmethoxy) -phenyl] -3- (l-methyl-lH-pyrazol-5-yl) -propanoic acid ethyl ester (63.3) and 3- [4- (2'-Butoxy-5'-methyl-biphenyl-4-ylmethoxy) phenyl] -3- (1-methyl-1H-pyrazol-3-yl) ethyl clothingnoate (63.4). The mixture of 63.1 and 63.2 was alkylated with 4- (2-butoxy-5-methyl) phenyl) benzyl bromide according to the method of Example 2. The separation of 63.3 and 63.4 can be achieved by flash chromatography (silica gel, 3% acetone in dichloromethane).

Scheme 63 3 Reaction 63. 3 63.5 Acid (+/-) -3- [4- (2 '-butoxy-5' -methyl-biphenyl-4-ylmethoxy) -phenyl] -3- (l-methyl-lH-pyrazol-5-yl ) propionic (63.5). A 25 mL pear-shaped flask was charged with ethanol (1 mL), compound 63.3 (20 mg, 0.04 mmol), and 2N NaOH (acuoSO) (2 mL, 4.0 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was acidified to a pH of 3 with HCl 1 N and extracted with ethyl acetate (2 x 10 mL). The combined extracts were washed with brine and concentrated. The resulting residue was purified by preparative TLC (30% acetone in dichloromethane) to yield compound 63.5 (4.0 mg). RM? TO (400 MHz) (CDC13) d 7.55 (d, 2H, J = 2 Hz); 7.42 (d, 2H, J = 2 Hz); 7.29 (m, lH); 7.19-7.08 (m, 4H): 6.95-6.86 (m, 3H); 5.98 (s, 1 HOUR); 5.05 (s, 2H); 4.46 (m, 1H); 3.94 (s, 3H); 3.31 (m, 1H); 3.01 (m, 1H); 2.33 (s, 3H); 1.67 (m, 3H); 1.40 (m, 3H); 0.90 (t, 3H, J = 6 Hz). MS ESI (neg.) M / e 497.2 (M-H).

Diagram 63.4 of Reaction 63. 4 63.6 Acid (+/-) - 3- [4- (2'-Butoxy-5'-methyl-biphenyl-4-ylmethoxy) -phenyl] -3- (l-methyl-lH-pyrazol-3-yl) propionic (63.6). The hydrolysis of 63.4 was carried out as described above. MS ESI (neg.) M / e: 497.2 (M-H). Example 64 The foing compounds were prepared from compounds 63.1 and 63.2 according to the methods described in Example 63. 64. 1 Acid (+/-) - 3- (1-methyl-1H-pyrazol-3-yl) -3- (4- ((4-methyl-2-p-tolylthiazol-5-yl) methoxy) phenyl) propanoic acid (64.1) NMR A (400MHz) (CDC13) d 7.84 (m, 2H); 7.12 (m, 5H); 6.89 (m, 2H); 5.92 (s, 1H); 5.13 (s, 2H); 4.46 (q, lH, J = 6 Hz); 3.88 (s, 3H); 3.23 (m, 1H, 2.98 (m, 1H), 2.50 (s, 3H), 2.39 (s, 3H), MS ESI (neg.) M / e: 446.2 (M-H). 64. 2 Acid (+/-) -3- (l-methyl-lH-pyrazol-5-yl) -3- (4- ((4-methyl-2-p-tolylthiazol-5-yl) methoxy) phenyl) propanoic acid ( 64.2). MS ESI (neg.) M / e: 446.2 (M-H). 64. 3 Acid (+/-) -3- (1-methyl-1H-pyrazol-3-yl) -3- [4- (4'-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl-propionic acid (64.3). NMR A (400MHz) (CDC13) d 7.69-7.46 (m, 8H); 7.26-6.92 (m, 5H); 5.96 (s, 1H); 5.01 (s, 2H); 4.47 (m, 1H); 3.91 (s, 3H); 3.25 (m, 1H); 2.99 (m, 1H). MS ESI (neg.) M / e: 479.2 (M-H). 64. 4 (+/-) -3- (1-methyl-1H-pyrazol-5-yl) -3- [4- [4 '-trifluoromethyl-biphenyl-3-ylmethoxy) -phenyl] propionic acid (64.4). NMR A (400MHz) (CHCl 3 ~ d 3) d 7.85-7-44 (m, 8H); 7.06 (d, 2H, J = 6 Hz); 6.92 (s, 1H); 5.10 (s, 2H); 4.46 (m, 1H); 3.71 (s, 3H); 3.05 (m, 1H); 2.96 (m, 1H). MS ESI (neg.) M / e: 479.2 (M-H). Example 65. Cell-based Aequorin Assay A cell-based aequorin assay can be used to characterize the modulating activity of the compounds in the GPR40 signaling pathway. In an example assay, CHO cells were transfected into 15 cm dishes containing 14 million cells with 5 μg of the GPR40 expression vector and 5 μg of the Aequoriña expression vector (Euroscreen) using Lipofectamine 2000 (Invitrogen). After 17-24 hours post-transfection, the cells are washed with phosphate-buffered saline (PBS) and detached from the tissue culture box with 2 mL of trypsin (0.25% (w / w)). Trypsin is stopped with 28 mL of Hanks buffered saline solution containing 20 mM Hepes (H / HBSS) and 0.01% fatty acid-free bovine serum albumin (BSA) or 0.625% fatty acid-free human serum albumin (HSA). Colantrancina is added at 1 μg / mL and the cells are incubated for 2 hours at room temperature. The cells are mixed gently every 15 minutes. The compounds are dissolved in dimethyl sulfoxide for the preparation of concentrated solutions mM. The compounds are eluted in H / HBSS containing either 0.01% SA or 0.625% HSA. Serial dilutions of the test compounds are prepared to determine the dose response. Aequorin luminescence measurements are made using a EG & G Berthold 96-well luminometer and the response is measured for a 20 second interval after the cells and compounds are mixed. The area under the curve of 2-20 seconds is plotted to determine the response to the dose. The EC50 (effective concentration to reach 50% maximum response) of the dose response plot is determined. Table 21 represents representative data (EC50 values) obtained from the example compounds of the invention for the relative activation of human GPR40. The stereoisomers in Table 21 are as specified, ie, S-enantiomers or R-enantiomers, and if not specified, are mixtures of S-enantiomers and R-enantiomers. further, the present invention provides the S-enantiomers, the R-enantiomers and mixtures of both S-enantiomers and R-enantiomers including racemates of each compound prepared according to the synthesis methods described herein or adapted with the minor modifications necessary of these methods. Example 66: Insulin Secretion Test C57 / B16 mice were euthanized with carbon dioxide gas. The pancreatic bile duct was attached to the duodenum and then cannulated. H / HBSS containing 0.75 mg / ml collagenase XI (Sigma) in the pancreas through the cannula was then infused. The pancreas was cut and then incubated at 37 ° C for 13 minutes to complete the enzymatic digestion. The collagenase digestion was stopped in H / HBSS containing 1% BSA and washed once in the same buffer. The islets were purified using density gradient centrifugation using Histopaque (Sigma) and collected by hand under a stereoscopic microscope. The islets are grown overnight in the middle of the Roswell Park Memorial Institute (RMPI) containing 10% fetal bovine serum and 50 uM beta-mercaptoethanol. After the culture during the night, the islets are incubated in the middle Modified Dulbecco's Eagle (DMEM) containing 2.8 mM glucose for one hour. For the determination of insulin secretion, the islets are incubated in DMEM containing 12.5 mM glucose and the test compounds for one hour. The insulin released in the culture medium of the islets is measured using an insulin ELISA. All publications and patent applications cited in this specification are incorporated herein by reference as if each publication or individual patent application was individually and individually indicated to be incorporated by reference. Although the above invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art in view of the teachings of this invention that certain changes and modifications may be made thereto. without departing from the spirit or scope of the appended claims.

It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (60)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compound in accordance with the claim (I): Q-L1-P-L2-MX-L3-AI or a solvate or pharmaceutically acceptable prodrug thereof, characterized in that Q is hydrogen, aryl, heteroaryl, (Ci-Ce) alkyl or (C2-C6) heteroalkyl; L1 is a bond, (C? -C4) alkylene, (C2-C4) heteroalkylene, O, S (0) m, N (RX), C (0) - (C5-C7) heterocycloalkylene, (C? -C ) alkylene-S02N (R2), (Ci-C4) alkylene-? (R2) S0 or C (0) N (R2); P is an aromatic ring, a heteroaromatic ring, (C3-C8) heterocycloalkylene or (C3-C8) cycloalkylene; L2 is a bond, (A-e) alkylene, (C2_ C6) heteroalkylene, O, S (0) m,? ÍR1), C (0) N (R2), S02N (R2), (Ci- C4) alkylene-C (0) N (R2), (C? C4) alkylene-N (R2) C (O), (C2-C4) alkenylene-C (0) N (R2), (C2-C) alkenylene-N (R2) C (O), (C? ~ C4) alkylene-S02N (R2), ° (C? -C4) alky1 ene-N (R2) S02, (C2-C4) alkenylene-S02N (R2) or (C2-C) alkenylene-N (R2) S02; M is an aromatic ring, a heteroaromatic ring, (Cs-Cs) cycloalkylene, aryl (C 1 -C 4) alkylene or heteroaryl? (Ci- C) alkylene; X is CRA4, N (R5), 0 or S (0) n; L3 is a bond, (C1-C5) alkylene or (C2-C5) heteroalkylene, with the proviso that L3 is not a bond when L2 is a bond; A is -C02H, tetrazol-5-yl, -S03H, -P03H2, -S02? H2, - (0)? HS02CH3, -CHO, -C (0) R6, -C (0)? HR6, -C ( 0) NHOR7, thiazolidinodion-yl, hydroxyphenyl or pyridyl; R1 is (Ci-e) alkyl or aryl (C? -C3) (C2_6) alkyl heteroalkyl; R2 is hydrogen, (Ci-Ce) alkyl or (C2_ Ce) heteroalkyl; R3 is cyano, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) alkynyl , -? R8R9, -C (O) NR10R1: L, -? R12C (0) R13 or -? R12S (0) pR13; R4 is hydrogen, cyano, aryl, heteroaryl, (Ci-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl; optionally R3 and R4 combine to form a 3, 4, 5, 6 or 7 member ring containing from zero to three heteroatoms selected from N, O and S; R5 is hydrogen, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or (C3-C8) cycloalkyl; R6 is heteroaryl; R7 is hydrogen or (C1-C5) alkyl; R8 and R9 are independently hydrogen, (Cx-C5) alkyl, oxy (C1-C5) alkyl or carboxy (C1-C5) alkyl; optionally, R8 and R9 combine to form a 4, 5, 6 or 7 member ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, 0 and S; R10, R11 and R12 are independently selected from hydrogen, aryl, heteroaryl, (C? -C8) alkyl, (C2-C8) heteroalkyl, (C3-C8) cycloalkyl and (Cs-Cs) heterocycloalkyl, optionally, R10 and R11 combine to form a 4, 5, 6 or 7 member ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S; R13 is aryl, heteroaryl, (Ci-Cs) alkyl, (C2-C8) heteroalkyl, (C3-C8) cycloalkyl or (Cs-Cs) heterocycloalkyl; the subscripts m and n are independently 0, l or 2; and the subscript p is 1 or 2; and wherein the compound is different from 3- (4- (4-methoxybenzyloxy) phenyl) pen-4-inoic acid; β-ethenyl-4-phenylmethoxy-benzenepropanoic acid; 4- (2-quinolinylmethoxy) -β- [4- (2-quinolinylmethoxy) phenyl] -benzenepropanoic acid; N- [4- (benzoylamino) phenyl] -? - phenyl-glycine; 3- (4- (isopentyloxy) -benzamido) -3-phenylpropanoate; 3- (4-isobutoxybenzamido) -3-phenylpropanoate; (R) -2- ((IR, 4R) -4- isopropylcyclohexanecarboxamido) -3-phenylpropanoic acid; (R) -3- (4- (benzyloxy) phenyl) -2- (tert-butoxycarbonyl) propanoic acid; 3- (4-chlorophenyl) -2- (furan-2-carboxamido) propanoic acid; 3- (3,4-dimethoxyphenyl) -3- (furan-2-carboxamido) -propanoic acid; 3- (4-chlorobenzamido) -3- (4- (dimethylamino) phenyl) -propanoic acid; 3- (2- (2- (3, 4-dimethylphenoxy) ethylthio) -lH-benzo [d] imidazol-1-yl) propanoic acid; acid { 2-bromo-4- [(3,4-dichloro-phenyl) -hydrazonomethyl] -6-ethoxy-phenoxy} -acetic; 2- (4- (2- (2- (4-chlorophenyl) furan-5-carboxyamy) ethyl) -phenoxy) -2-methylpropanoic acid; 5- (3- (3, 4-dimethoxyphenyl) -5- (2-fluorophenyl) -4,5-dihydropyrazol-1-yl) -5-oxopentanoic acid, 2- (2- (3- (3,4- -dihydro-2H-benzo [b] [1,4] dioxepin-7-yl) -2-methyl-4-oxo-4H-chromen-7-yloxy) acetamido) acetic acid; 3- (4'-bromo-biphenyl-4-yl) -4-phenyl-butyric acid; 3- (4'-bromo-biphenyl-4-yl) -3-phenylsulfanyl-propionic acid; 3- (5- (2-Chloro-6-fluoro-4- (trifluoromethyl) phenoxy) -2,4-dinitrophenyl) -propanoic acid; 3- (3- (2-Chloro-4- (trifluoromethyl) phenoxy) -phenyl) propanoic acid; 3- (4- (4-methoxybenzyloxy) phenyl) pen-4-inoic; 3- (4- (4-methoxybenzyloxy) phenyl) -5- (trimethylsilyl) pen-4-ynoic acid; ß, ß-dimethyl-4 - [[[4-methyl-2- [4- (trifluoromethyl) phenyl] -5-thiazolyl] methyl] thio] -benzenepropanoic acid; β-amino-4- [(4-bromo-2,5-dihydro-2-methyl-5-oxo-1-phenyl-1H-pyrazol-3-yl) methoxy] -3-methoxy-benzenepropanoic acid; or salts thereof. Compound according to claim 1, characterized in that when P and M are benzene, at least two of L2, X and L3 are different from CH2. Compound according to claim 1, characterized in that when Q is aryl or heteroaryl, L1 is a bond, M is a monocyclic aromatic ring, X is N (R5), 0 or S (0) n, and A contains a carbonyl group, then P is not a 1,2-azole ring. 4. Compound according to claim 1, characterized in that when Q is aryl, L1 is a bond, M is an aromatic ring, X is CR3R4, O or S (0) n and A_ contains a carbonyl group, then P is different from furan or thiophene. Compound according to claim 1, characterized in that P is selected from the group consisting of benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline. 6. Compound according to claim 1, characterized in that P is selected from the group consisting of benzene, naphthalene, pyrrole, pyrrazine, pyridine, pyrimidine, pyridazine, purine, indole, carboline, isoquinoline, quinoxaline and quinoline. Compound according to claim 1, characterized in that P is an aromatic ring, X is CR3R4, M is benzene and X is for a l? , L3 is methylene, A is -C02H, R3 is cyano, aryl, heteroaryl, (A-Cs) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or -NR8R9, L1 is a bond, L2 is oxymethylene or thiomethylene, and R 4 is hydrogen. Compound according to claim 1, characterized in that A is -C02H, tetrazol-5-yl, -C (0) NHS02CH3 or -C (0) NHR6. 9. Compound according to claim 1, characterized in that R3 is cyano, aryl, heteroaryl, (Cj.-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or -? R8R9. 10. Compound in accordance with the claim 9, characterized in that R4 is hydrogen. 11. Compound in accordance with the claim I, characterized in that M is an aromatic ring, a heteroaromatic ring or (C5-C8) cycloalkylene. 12. Compound in accordance with the claim II, characterized in that R3 is cyano, aryl, heteroaryl, (Ci-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or - R8R9. 13. Compound according to claim 12, characterized in that A is -C02H or tetrazol-5-yl. 14. Compound according to claim 12, characterized in that A is -C02H. 15. Compound according to claim 14, characterized in that X is CR3R4 or N (R5). 16. Compound according to claim 15, characterized in that L3 is (C1-C5) alkylene or (C? C5) heteroalkylene. 17. Compound according to claim 16, characterized in that P is an aromatic ring or heteroaromatic ring. 18. Compound in accordance with the claim 1, characterized in that P is an aromatic ring or heteroaromatic ring. 19. Compound according to claim 18, characterized in that X is CR3R4 or N (R5). 20. Compound in accordance with the claim -21, characterized in that L3 is (C1-C5) alkylene. 21. Compound according to claim 20, characterized in that A is -C02H. 22. Compound according to claim 21, characterized in that R3 is cyano, aryl, heteroaryl, (Ci- C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or - R8R9. 23. Compound according to claim 22, characterized in that M is benzene or a heteroaromatic ring. 24. Compound according to claim 23, characterized in that R4 is hydrogen. 25. Compound in accordance with the claim 23, characterized in that L1 is a bond, 0 or NA1) and L2 is (C2-C6) heteroalkylene. 26. Compound in accordance with the claim 24, characterized in that L1 is a bond and L2 is (C2-C6) heteroalkylene. 27. Compound according to claim 19, characterized in that M is benzene and X is for a L2. 28. Compound in accordance with the claim 27, characterized in that L3 is methylene. 29. Compound in accordance with the claim 28, characterized in that A is -C02H. Compound according to claim 29, characterized in that R3 is cyano, aryl, heteroaryl, (L-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or - R8R9. 31. Compound in accordance with the claim 30, characterized in that L1 is a bond and L2 is oxymethylene or thiomethylene. 32. Compound in accordance with the claim 31, characterized in that R4 is hydrogen. 33. Compound according to claim 1, characterized in that Q is aryl. 34. Compound according to claim 1, characterized in that L1 is a bond and L2 is oxymethylene or thiomethylene. 35. Compound according to claim 1, characterized in that P is an aromatic ring or a heteroaromatic ring and A is -C02H. 36. Compound in accordance with the claim 1, characterized in that P is an aromatic ring or a heteroaromatic ring and X is CR3R4 or N (R5). 37. Compound according to claim 1, characterized in that A is -C02H and X is CR3R4 or? (R5). 38. Compound in accordance with the claim 36, characterized in that X is CR3R4 and R3 is cyanoaryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or -NR8R9. 39. Compound according to claim 37, characterized in that X is CR3R4 and R3 is cyanoaryl, heteroaryl, (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl or -NR8R9. 40. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier, diluent or excipient and the compound according to claim 1. 41. Use of a compound according to claim 1, in the preparation of a medicament for the treatment of a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, - hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. 42. Use according to claim 41, wherein the disease or condition is type II diabetes. 43. Use according to claim 1 in the preparation of a medicament for treating a disease or condition responsive to the modulation of GPR40. 44. Use according to claim 43, wherein the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia , dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. 45. Use according to any of claims 41-44, wherein the compound is formulated to be administered orally, partially or topically. 46. Pharmaceutical composition, characterized in that it comprises: the compound according to claim 1 and a second therapeutic agent as a combined preparation for use in the treatment of a disease or condition mediated by GPR40. 47. Composition according to claim 46, characterized in that the second therapeutic agent is a metformin or a thiazolidinedione. 48. Use of a compound according to claim 1 to modulate the function of GPR40 in a cell. 49. Use of a compound according to claim 1 in the preparation of a medicament for modulating the concentration of circulating insulin in a subject. 50. Use according to claim 49, wherein the medicament increases the insulin concentration. 51. Use according to claim 49, wherein the medicament decreases the insulin concentration. 52. Use of a compound according to claim 1, for the treatment of a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia , hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. 53. Use according to claim 52, wherein this disease or condition is type II diabetes. 54. Use according to claim 1 for treating a disease or condition responsive to the modulation of GPR40. 55. Use according to claim 54, wherein the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. 56. Use of a compound according to claim 1 for treating type II diabetes in combination with a second therapeutic agent. • 57. Use in accordance with claim 56, wherein the second therapeutic agent is a metformin or a thiazolidinedione. 5-8. Use of a compound according to claim 1 for modulating the concentration of insulin in circulation in a subject. 59. Use of a compound according to claim 58, wherein the concentration of insulin is increased. 60. Use of a compound according to claim 58, wherein the "concentration of insulin" is decreased. 5 0 '5