WO2013139341A1 - Gpr120 receptor modulators - Google Patents

Abstract

There is provided novel 4-fluoro-phenyl-methoxy-benzene carboxylic acid compounds (insert formula I) capable of modulating the G-protein-coupled receptor GPR120, which can be used for controlling insulin levels in vivo and for the treatment of conditions such as type II diabetes, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels. Also claimed are the compounds for use in the treatment of obesity, type II diabetes and metabolic syndrome.

Description

GPR120 receptor modulators

FIELD OF THE INVENTION

The present invention relates to novel compounds capable of modulating the G-protein- coupled receptor GPR120, compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as of diabetes, inflammation, obesity and metabolic diseases.

BACKGROUND OF THE INVENTION

With 350 million diabetics worldwide, a number that has more than doubled since 1980, diabetes is currently the 4th leading cause of death and represents an enormous social and economic burden. Type 2 diabetes (T2D) constitutes 90-95% of the cases is closely associated with obesity and its prevalence is expected to increase at least at the same rate as today. Although lifestyle intervention like a healthy diet and exercise is regarded as the most efficient means to prevent and manage the disease, pharmaceutical intervention is frequently necessary. There is however no cure for T2D and current therapeutics have significant shortcomings.

Activation of GPR120 is reported to result in glucagon-like peptide 1 (GLP-I) secretion (Hirasawa, et al., Nat. Med. 2005, 1 1 , 90-94), increased insulin sensitivity in adipose tissue, decreased lipolysis and decreased inflammation (Oh, et al., Cell 2010, 142, 687-

698). Dysfunctional GPR120 is reported to lead to obesity, which imply that agonists of the receptor can have potential as anti-obesity therapeutics (lchimura, et al., 2012, doi: 10.1038/nature10798). Compounds capable of activation of GPR120 and is thus an interesting target for treatment of type 2 diabetes. Several patent applications claim GPR120 modulators, including W02008066131 , W02008103500, W02008103501 ,

W02009038204, W02009147990, W02010008831 , W02010048207, W02010080537, W02010104195, and W0201 1072132. The present invention comprises a structurally distinct class of GPR120 agonists which includes members with high potency and selectivity over GPR40. The class also comprises dual GPR120/GPR40 agonists. There is currently no cure for T2D. Metformin is one of the oldest but still the drug of choice despite frequent Gl side effects. Sulfonylureas (SUs) are insulin secretagogues commonly used in treatment ofT2D, but have the serious problems that they increase the risk of hypoglycaemia and that they often lead to weight gain. Insulin treatment is also common and carries the same side-effects. Thiazolinedione drugs have also been widely used but concerns over enhanced risk of heart disease have resulted in stringent limitations on their use and calls for their removal from the market. As such, despite the recent approval by regulatory authorities of new classes of anti-diabetic medicines based on either longer duration analogues of GLP-1 or inhibition of degradation of this incretin by DPP-4 inhibitors, new treatments are required urgently. GPR120 agonists may provide improved T2D therapeutics alone, in conjunction with any of the established therapeutics mentioned above, or in conjunction with a new target such as GPR40.

EP1688138A1 discloses compounds that are similar to those of the present invention. Meanwhile, the present inventors have found that selected non-disclosed compounds encompassed by the general formula in EP1688138A1 having a fluoro substiuent in a specific position exhibit superior GRP120 modulation.

SUMMARY OF THE INVENTION

Novel GPR120 compound agonists, methods for their preparation, and related synthetic intermediates and compositions are provided. The novel GPR120 agonists are useful in the treatment of diabetes and other related diseases including metabolic syndrome, dyslipidemia, insulin resistance, and complications of diabetes.

Further provided are methods for treating diseases such as Type II diabetes and other diseases and conditions using one or more of these compounds or compositions, as described in further detail below.

Further, the compounds may be used to stimulate insulin production and stimulate secretion of insulin, glucagon-like peptide 1 (GLP1), and glucose dependent insulinotropic polypeptide (GIP) in a mammal, in particular a human. Additionally, the compounds described herein are useful in lowering blood glucose when administered to a mammal in need of treatment to lower blood glucose.

Further, the compounds of the present invention may be used to treat, counteract or prevent obesity as demonstrated by lchimura et al (Nature; Published online 19

February 2012). Also CNS and autoimmune diseases may be treated with the compounds of the present invention.

The compounds of the present invention are also useful for taste additives in food products. As demonstrated by Cartoni et al (The Journal of Neuroscience, June 23, 2010

• 30(25):8376-8382), Matsumura et al (Neuroscience Letters 450 (2009) 186-190), and Galindo et al (Chem. Senses 37: 123-139, 2012) GPR 120 agonists appear to increase fat taste perception. Specifically the present invention provides compounds represented

wherein n is 1 or 2

R¹ is independently selected from the group consisting of aryl, such as phenyl, substituted aryl, heteroaryl and substituted heteroaryl

R² is independently selected from the group consisting of H, deuterium, halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, oxo, alkoxy, substituted alkoxy, CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, and substituted aryloxy.

Preferably R¹ is independently selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted arylalkyl. Preferably R² is independently selected from the group consisting of hydrogen, (C Cio)alkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C C₁₀)alkoxy, (C₂-C₁₀)heteroalkyl, (C₂- Cio)heteroalkylene, (C₃-Ci₀)cycloalkyl, (C₃-Ci₀)heterocycloalkyl, (C₃-Ci₀)cycloalkylene, (C₃-Cio)heterocycloalkylene, halo, CN , (CrCi₀)haloalkyl, (CrCi₀)perhaloalkyl, (C₂-Ci₀)- alkenyloxy, (C₃-Ci₀)-alkynyloxy, aryloxy, arylalkyloxy, heteroaryloxy, heteroarylalkyloxy, (Ci-C₆)alkyloxy-(Ci-C4)alkyl optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted arylalkyl.

It is also preferred that n is 1.

Preferred compounds of the present invention are selected from the group consisting of:

3-(4-((4-Fluoro-[1 , 1 '-biphenyl]-2-yl)methoxy)phenyl)propanoic acid

3-(4-((4-Fluoro-4'-methyl-[1 , 1 '-biphenyl]-2-yl)methoxy)phenyl)propanoic acid

3-(4-((4-fluoro-4'-methoxy-[1 , 1 '-biphenyl]-2-yl)methoxy)phenyl)propanoic acid

Moreover, the invention provides for the compounds of the present compounds for use, as a medicament, particularly in the treatment of a disease or condition selected from the group consisting of type I or 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, hypertension, cancer, and edema.

In some embodiments, a compound of the present invention comprises a stereomerically pure S-enantiomer. In other embodiments, the compound comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound comprises a mixture of S- and R-enantiomers.

In another aspect, the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent, or excipient, and a compound of any of the embodiments of the invention. According to a preferred embodiment there is provided compounds of the present invention for use as medicaments. In another aspect, the invention provides methods for treating or preventing a disease or condition selected from the group consisting of type I or 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, hypertension, cancer, and edema. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the embodiments. In some such embodiments, the disease or condition is type II diabetes.

In some embodiments, a compound of any of the embodiments is administered with combination with a second therapeutic agent. In some such embodiments, the second therapeutic agent is metformin or is a thiazolidinedione. The second therapeutic agent may be administered before, during, or after administration of the compound of any of the embodiments. In another aspect, the invention provides methods for treating or preventing a disease or condition responsive to the modulation of GPR120. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the embodiments. In another aspect, the invention provides methods for treating or preventing a disease or condition mediated, regulated, or influenced by pancreatic beta-cells. Such methods include administering to a subject in need thereof, a therapeutically effective amount of a compound of any of the embodiments. In another aspect, the invention provides methods for modulating GPR120 function in a cell. Such methods include contacting a cell with a compound of formula any of the embodiments.

In another aspect, the invention provides methods for modulating GPR120 function. Such methods include contacting GPR120 with a compound of any of the embodiments. In another aspect, the invention provides methods for modulating circulating insulin concentration in a subject. Such methods include administering a compound of any of the embodiments to the subject. In some such embodiments, the circulating insulin concentration is increased in the subject after administration whereas in other such embodiments, the circulating insulin concentration is decreased in the subject after administration.

In another aspect, the invention provides the use of a compound of any of the embodiments for treating a disease or condition or for preparing a medicament for treating a disease or condition where the disease or condition is selected from the group consisting of type I or 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. In some such embodiments, the disease or condition is type II diabetes. The compounds of the invention may also be used to prepare medicaments that include a second therapeutic agent such as metformin or a thiazolidinedione.

In another aspect, the invention provides the use of a compound of any of the embodiments for modulating GPR120 or for use in the preparation of a medicament for modulating GPR120.

In another aspect, the invention provides a therapeutic composition that includes a compound of any of the embodiments and a second therapeutic agent such as those described herein, for example, metformin or a thiazolidinedione, as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease or condition mediated by GPR120. In some such embodiments, the disease or condition is type II diabetes. In some embodiments, the compound of any of the embodiments and the second therapeutic agent are provided as a single composition, whereas in other embodiments they are provided separately as parts of a kit. DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons). Examples of alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, and homologs and isomers of, 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, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C₂-C₈ means two to eight carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1 ,4- 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 (i.e. , C₂-C₈ means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 2-propynyl, 3-butynyl, and higher homologs and isomers thereof. The term "alkylene" by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH2CH2CH2CH2-. The two valences may be on any carbon atom of the chain, including on the same carbon, resulting in an alkyl connected by a double bond. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 12 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 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 remainder of the molecule via 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. The alkyl groups of a dialkylamino may be the same or different.

The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, and S may be placed at any position of the heteroalkyl group. Examples include -CH2CH2OCH₃, -CH2CH2NHCH₃,

-CH₂CH₂N(CH3)CH3, -CH₂SCH₂CH₃, -CH₂CH₂S(0)CH₃, -CH₂CH₂S(0)2CH3, and -CH₂CH=N-OCH₃. The atom at the substitution position is always carbon. For example, -OCH₃ or -OCH2CH₃ are not heteroalkyls. Up to two heteroatoms may be consecutive, such as, for example, -CH₂NH-OCH₃. When a prefix such as (C₂-C₈) is used to refer to a heteroalkyl group, the number of carbons (2 to 8, in this example) is meant to include the heteroatoms as well. For example, a C₂-heteroalkyl group is meant to include, for example, -CH₂OH (one carbon atom and one heteroatom replacing a carbon atom) and -

To further illustrate the definition of a heteroalkyl group, where the heteroatom is oxygen, a heteroalkyl group is an, oxyalkyl group. For instance, (C₂-C₈)oxyalkyl is meant to include, for example -CH₂0-CH₃ (a C₃-oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH2CH2CH2CH2OH, and the like, but not

The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2CH2SCH2CH2- and -CH₂SCH₂- CH2NHCH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied. Heteroalkylene groups such as oxymethyl groups (-CH₂0-) may be substituted or unsubstituted. In some embodiments, heteroalkylene groups may be substituted with an alkyl group. For example, the carbon atom of an oxymethylene group may be substituted with a methyl group in a group of formula -CH(CH₃)0-. The terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl" respectively. Thus, the terms "cycloalkyl" and "heterocycloalkyl" are meant to be included in the terms "alkyl" and "heteroalkyl," respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder 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, 4,5- dihydroisoxazol-3-yl, and the like. The term "heterocycloalkyl" includes fully saturated compounds such as piperidine and compounds with partial saturation that are not aromatic. Examples of such groups include, but are not limited to, an imidazoline, oxazoline, or isoxazoline.

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 meant to be included in the terms "alkylene" and "heteroalkylene," respectively.

Additionally, for heterocycloalkylene, one or more heteroatoms can occupy positions at which the heterocycle is attached to the remainder of the molecule. Typically, a cycloalkylene or heterocycloalkylene will have from 3 to 9 atoms forming the ring, more typically, 4 to 7 atoms forming the ring, and even more typically, 5 or 6 atoms will form the cycloalkylene or hetercycloalkylene ring.

The terms "bicycloalkyl" and "heterobicycloalkyl" by themselves or in combination with other terms, represent, unless otherwise stated, bicyclic versions of "cycloalkyl" and "heterocycloalkyl" respectively. Examples of bicycloalkyl include norbornyl, decalinyl, bicyclo[2.2.2]octyl, and other structures described by the bicyclo[X.Y.Z]alkyl nomenclature,

The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl", are meant to include alkyl substituted with halogen atoms which can be the same or different, in a number ranging from one to (2m + 1), where m is the total number of carbon atoms in the alkyl group. For example, the term "halo(CrC₄)alkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one 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 otherwise stated, 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(CrC₄)alkyl", is meant to include trifluoromethyl, pentachloroethyl, 1 ,1 , 1-trifluoro-2-bromo-2-chloroethyl, and the like.

The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon ring. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl and 4-pyridazinyl.

The term "fused aryl" means, unless otherwise stated, an aryl which is fused with another cyclic aromatic or non-aromatic ring. The term "fused heteroaryl" means, unless otherwise stated, a heteroaryl which is fused with another cyclic aromatic or non- aromatic ring. Examples of fused aryl and fused heteroaryl groups include 1-naphthyl, 2- naphthyl, 4-biphenyl, dibenzofuryl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, benzooxadiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 H-indazolyl, carbazolyl, 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 group which is unsubstituted or substituted. Preferably, the term "heteroaryl" refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, furyl, thienyl (thiophenyl), pyridyl, or pyrimidyl which is substituted or unsubstituted. Preferably, the term "fused aryl refers to naphthyl, indanyl, indenyl, or quinolyl. Preferably, the term "fused heteroaryl" refers to quinolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, triazolyl, tetrazolyl, or quinoxalinyl group which is unsubstituted or substituted.

Each of the above terms (e.g., "alkyl," "heteroalkyi," "aryl" and "heteroaryl") is meant 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 term "substituent", which may be present on alkyl or heteroalkyi radicals, as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl, or on other groups indicated as "optionally substituted", can be a variety of groups selected from: -OR', =0, =NR\ =N-OR\ -NR'R", -SR', halogen, -OC(0)R\ -C(0)R', -C0₂R', -CONR'R", - OC(0)NR'R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR'-S0₂NR"R"', -NR"C0₂R', -NH- C(NH₂)=NH, -NR'C(NH₂)=NH, -NH-C(NH₂)=NR', -SiR'R"R"', -S(0)R', -S0₂R', -S0₂NR R", -NR"S0₂R, -CN, -(C₂-C₅)alkynyl, -(C₂-C₅)alkenyl, and -N0₂, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred. Other suitable substituents include aryl and heteroaryl groups. R', R" and R'" each independently refer to hydrogen, unsubstituted (d-C₆)alkyl and (C₂- C₆)heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted (CrC₄)-alkyl, (Ci-C₄)-alkoxy or (C C₄)-thioalkoxy groups, halo(C C₄)alkyl, or aryl-(Ci-C₄)alkyl groups. 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 meant to include 1-pyrrolidinyl and 4-morpholinyl.

Typically, an alkyl or heteroalkyi group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention.

More preferably, an alkyl or heteroalkyi radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyi radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant 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', -NR'S0₂NR"R'", -S(0)R', -S0₂R', -S0₂NR'R", -NR"S0₂R, -CN, -(C₂-C₅)alkynyl, -(C₂-C₅)alkenyl and -N0₂, where R' and R" are as defined above.

Further preferred substituents are selected from: -OR', =0, -NR'R", halogen, -OC(0)R', - C0₂R', -CONR'R", -OC(0)NR'R", -NR"C(0)R', -NR'C0₂R", -NR'-S0₂NR"R"', -S0₂R', -S0₂NR'R", -NR"S0₂R, -CN, -(C₂-C₅)alkynyl, -(C₂-C₅)alkenyl, and -N0₂. Similarly, substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, -OR', -OC(0)R', -NR'R", -SR', -R', -CN, -N0₂, -C0₂R', -CONR'R", -C(0)R', -OC(0)NR'R", -NR"C(0)R', -NR"C(0)₂R', -NR'-C(0)NR"R"', -NH-C(NH₂)=NH, -NR'C(NH₂)=NH, -NHC(NH₂)=NR', -S(0)R', -S(0)₂R', -S(0)₂NR'R", -N₃, -CH(Ph)₂, perfluoro(CrC₄)alkoxy, and perfluoro(Ci-C₄)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are independently selected from hydrogen, (C C₄)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C C₄)alkyl, (unsubstituted aryl)oxy-(C C₄)alkyl, -C₂-C₅)alkynyl, and -(C₂-C₅)alkenyl. As used herein, the term "benzo-fused cycloalkane ring" is meant to include bicyclic structures in which benzene is fused with a cycloalkane (or cycloheteroalkane).

As used herein, the term "heterobenzo-fused (C₅-C₈)cycloalkane ring" has the same meaning as "benzo-fused (C₅-C₈)cycloalkane ring" except the benzene of the benzo- fused (C₅-C₈)cycloalkane ring is replaced with a six-membered heteroaryl ring comprising 1 or 2 nitrogen (N) atoms. The (C₅-C₈)cycloalkane of benzo-fused (C₅- C₈)cycloalkane rings and heterobenzo-fused (C₅-C₈)cycloalkane ring may include only carbon atoms, but may also include one or more heteroatoms. Such heteroatoms typically are selected from O, N, or S.

As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).

The term "pharmaceutically acceptable salt" is meant to include a salt of the active compound which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on 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 such compound with a sufficient amount of the desired base, either neat 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 such 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 like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.

Also included are salts of amino acids such as arginine and the like, and salts of organic acids like 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 may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form 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 parent form of the compound for the purposes of the invention.

In addition to salt forms, the invention provides compounds which 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 enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.

The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely 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 then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one 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 greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed.

Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-lnterscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L , Stereochemistry of Carbon

Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (EX. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). In one aspect, a class of compounds that modulates GPR120 is described herein.

Depending on the biological environment (e.g., cell type, pathological condition of the subject, etc.), these compounds can modulate, e.g., activate or inhibit, the actions of GPR120. By modulating GPR120, the compounds find use as therapeutic agents capable of regulating insulin levels in a subject.

The compounds find use as therapeutic agents for modulating diseases and conditions responsive to modulation of GPR120 and/or mediated by GPR120 and/or mediated by pancreatic beta-cells. As noted above, examples of such 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 so forth). While the compounds of the invention are believed to exert their effects by interacting with GPR120, the mechanism of action by which the compounds act is not a limiting embodiment of the invention.

Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein. 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 which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

By "pharmaceutically acceptable" it is meant that the carrier, excipient, or diluent is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof. Composition formulation may improve one or more pharmacokinetic properties (e.g., oral bioavailability, membrane permeability) of a compound of the invention (herein referred to 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 bringing the active ingredient into association with the carrier which constitutes one or more accessory 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, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. 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, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable 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 agents, for example starch, gelatin or acacia, 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 or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256, 108, 4, 160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; 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 polyoxy-ethylene 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 fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty 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.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol.

Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture 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 may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said 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. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may 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-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may 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 liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the invention are employed. As used herein, topical application is also meant 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.

In another aspect, the invention provides methods of 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, comprising administering to 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 disease or condition responsive to the modulation of GPR120 comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.

In some embodiments, 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.

In certain embodiments, a cell to be contacted can be made to express or overexpress GPR120, for example, by expressing GPR120 from heterologous nucleic acid introduced into the cell or, as another example, by upregulating the expression of GPR120 from nucleic acid endogenous to the cell.

Depending on the disease to be treated and the subject's condition, the compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal, local) routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. The invention also contemplates administration of the compounds of the invention in a depot formulation, in which the active ingredient is released over a defined time period.

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 GPR120, an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range, the dosage may be

0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. The compounds of the invention can be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which 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. Such other agents, or drugs, may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such 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.

The compounds of the invention may be used in combination with a second therapeutic agent such as those described herein. Thus, in some embodiments, therapeutic compositions are provided that include a compound of the invention and a second therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a subject with a disease or condition mediated by GPR120. in some embodiments, therapeutic compositions are provided that include a compound of the invention and a second therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the prophylactic treatment of a subject at risk for a disease or condition mediated by GPR120. In some such embodiments, the components are provided as a single composition. In other embodiments, the compound and the second therapeutic agent are provided separately as parts of a kit.

Examples of other therapeutic agents that may 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 HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), vitamin B₃ (also known as nicotinic acid, or niacin), vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate and benzafibrate), probucol, nitroglycerin, and inhibitors of cholesterol absorption (e.g., beta- sitosterol and acylCoA-cholesterol acyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthase inhibitors, squalene epoxidase inhibitors and squalene synthetase inhibitors; (b) antithrombotic agents, such as thrombolytic agents (e.g., streptokinase, alteplase, anistreplase and reteplase), heparin, hirudin and warfarin derivatives, beta-blockers (e.g., atenolol), beta-adrenergic agonists (e.g., isoproterenol), ACE inhibitors and vasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride, nitroglycerin and enaloprilat); and (c) anti-diabetic agents such as insulin and insulin mimetics, sulfonylureas (e.g., glyburide, meglinatide), biguanides, e.g., metformin (GLUCOPHAGE®), glucosidase inhibitors (acarbose), insulin sensitizers, e.g., thiazolidinone compounds, rosiglitazone (Avandia), troglitazone (Rezulin), ciglitazone, pioglitazone (ACTOS®) and englitazone, DPP-IV inhibitors, e.g., vildagliptin (Galvus®), sitagliptin (Januvia), and GLP-I analogs, e.g. exenatide (Byetta). In some embodiments, a compound of the invention may be administered along with a DPP-IV inhibitor or a GLP-I analog.

The weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Combinations of a compound of the invention and other active ingredients will generally also 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 circulating insulin concentration in a subject, comprising administering a compound or composition of the invention.

"Compound" and "compounds" as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds specificed by the generic and subgeneric formulae, such as a pharmaceutically acceptable salt. Unless specified otherwise, the term further includes the isotopes, racemates, stereoisomers, and tautomers of the compound or compounds.

"Racemates" refers to a mixture of enantiomers.

"Solvate" or "solvates" of a compound refer to those compounds, where compounds are as defined herein, that are bound to a stoichiometric or non- stoichiometric amount of a solvent. Solvates of a compound includes solvates of all forms of the compound such as the oxide, ester, prodrug, or pharmaceutically acceptable salt of the disclosed generic and subgeneric formulae. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans. The present invention provides solvates of the compounds disclosed herein.

"Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds of this invention may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

"Tautomer" refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

"Prodrug" refers to any derivative of a compound of the embodiments that is capable of directly or indirectly providing a compound of the embodiments or an active metabolite or residue thereof when administered to a patient. Prodrugs of a compound of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications may be cleaved in vivo to release the parent compound, or an active metabolite. For example, prodrugs include compounds wherein a hydroxy, amino, or sulfhydryl group in a compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of the embodiments when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment

(e.g., the brain or lymphatic system) relative to the parent species. Prodrugs include ester, amide, and carbamate (e.g., N, N-dimethylaminocarbonyl) forms of hydroxy functional groups of compounds of the invention. Examples of ester prodrugs include formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate derivatives. An general overview of prodrugs is provided in T Higuchi and V Stella, Pro-drugs as Novel

Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and includes, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium. When the molecule contains a basic functionality, acid addition salts of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, oxalic acid, 4-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. Salts can also be formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts are suitable for administration in a patient and possess desirable pharmacological properties. Suitable salts further include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.

Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-0-C(0)-.

It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to -substituted aryl-(substituted aryl) -substituted aryl. Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

The terms "optional" or "optionally" as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocyclyl group optionally mono- or di- substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is mono- or disubstituted with an alkyl group and situations where the heterocyclyl group is not substituted with the alkyl group.

Turning next to the compositions of the invention, the term "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, and possesses acceptable toxicities. Acceptable carriers or excipients include those that are acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier or excipient" as used in the specification and claims includes both one and more than one such carrier or excipient.

With reference to the methods of the present invention, the following terms are used with the noted meanings:

The terms "treating" or "treatment" of a disease includes inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

A preferred embodiment of the invention is treatment of a disease that consists of relieving the disease.

The term "diagnosing" refers to determining the presence or absence of a particular disease or condition. Additionally, the term refers to determining the level or severity of a particular disease or condition, as well as monitoring of the disease or condition to determine its response to a particular therapeutic regimen.

The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. "A therapeutically effective amount" includes the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

The term "mammal" includes, without limitation, humans, domestic animals (e.g., dogs or cats), farm animals (cows, horses, or pigs), and laboratory animals (mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, or monkeys).

The term "insulin resistance" can be defined generally as a disorder of glucose metabolism. More specifically, insulin resistance can be defined as the diminished ability of insulin to exert its biological action across a broad range of concentrations producing less than the expected biologic effect (see, e.g., Reaven GM, J. Basic & Clin. Phys. &

Pharm. (1998) 9:387-406 and Flie J, Ann. Rev. Med. (1983) 34: 145-60). Insulin resistant persons have a diminished ability to properly metabolize glucose and respond poorly, if at all, to insulin therapy. Manifestations of insulin resistance include insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver.

Insulin resistance can cause or contribute to polycystic ovarian syndrome, impaired glucose tolerance, gestational diabetes, metabolic syndrome, hypertension, obesity, atherosclerosis and a variety of other disorders. Eventually, the insulin resistant individuals can progress to a point where a diabetic state is reached.

The term "diabetes mellitus" or "diabetes" means a disease or condition that is generally characterized by metabolic defects in production and utilization of glucose that result in the failure to maintain appropriate blood sugar levels in the body. The result of these defects is elevated blood glucose, referred to as "hyperglycemia." Two major forms of diabetes are Type I diabetes and Type II diabetes. As described above, Type I diabetes is generally the result of an absolute deficiency of insulin, the hormone that regulates glucose utilization. Type II diabetes often occurs in the face of normal, or even elevated levels of insulin and can result from the inability of tissues to respond appropriately to insulin. Most Type II diabetic patients are insulin resistant and have a relative deficiency of insulin, in that insulin secretion can not compensate for the resistance of peripheral tissues to respond to insulin. In addition, many Type II diabetics are obese. Other types of disorders of glucose homeostasis include impaired glucose tolerance, which is a metabolic stage intermediate between normal glucose homeostasis and diabetes, and gestational diabetes mellitus, which is glucose intolerance in pregnancy in women with no previous history of Type I or Type II diabetes.

The term "metabolic syndrome" refers to a cluster of metabolic abnormalities including abdominal obesity, insulin resistance, glucose intolerance, diabetes, hypertension and dyslipidemia. These abnormalities are known to be associated with an increased risk of vascular events.

The term "abdominal obesity" is defined by a cutoff point of waist circumference > 102 cm in men and > 80 cm in women, as recommended by the third report of the national cholesterol education program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (NCEP/ATP Panel III).

The guidelines for diagnosis of Type II diabetes, impaired glucose tolerance, and gestational diabetes have been outlined by the American Diabetes Association (see, e.g., The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care, (1999) Vol. 2 (Suppl 1):S5-19).

The term "secretagogue" means a substance or compound that stimulates secretion. For example, an insulin secretagogue is a substance or compound that stimulates secretion of insulin.

The term "symptom" of diabetes, includes, but is not limited to, polyuria, polydipsia, and polyphagia, as used herein, incorporating their common usage. For example, "polyuria" means the passage of a large volume of urine during a given period; "polydipsia" means chronic, excessive thirst; and "polyphagia" means excessive eating. Other symptoms of diabetes include, e.g., increased susceptibility to certain infections (especially fungal and staphylococcal infections), nausea, and ketoacidosis (enhanced production of ketone bodies in the blood).

The term "complication" of diabetes includes, but is not limited to, microvascular complications and macrovascular complications. Microvascular complications are those complications that generally result in small blood vessel damage. These complications include, e.g., retinopathy (the impairment or loss of vision due to blood vessel damage in the eyes); neuropathy (nerve damage and foot problems due to blood vessel damage to the nervous system); and nephropathy (kidney disease due to blood vessel damage in the kidneys). Macrovascular complications are those complications that generally result from large blood vessel damage. These complications include, e.g., cardiovascular disease and peripheral vascular disease. Cardiovascular disease refers to diseases of blood vessels of the heart. See, e.g., Kaplan RM, et al., "Cardiovascular diseases" in Health and Human Behavior, pp. 206-242 (McGraw-Hill, New York 1993). Cardiovascular disease is generally one of several forms, including, e.g., hypertension

(also referred to as high blood pressure), coronary heart disease, stroke, and rheumatic heart disease. Peripheral vascular disease refers to diseases of any of the blood vessels outside of the heart. It is often a narrowing of the blood vessels that carry blood to leg and arm muscles.

The term "atherosclerosis" encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis" and "atherosclerotic disease".

The term "antihyperlipidemic" refers to the lowering of excessive lipid concentrations in blood to desired levels.

The term "modulate" or "modulating" refers to the treating, prevention, suppression, enhancement, or induction of a function or condition. For example, compounds can modulate Type II diabetes by increasing insulin in a human, thereby suppressing hyperglycemia. Compounds can also modulate GPR120 by acting as GPR120 agonists.

[0130] The term "triglyceride(s)" ("TGs"), as used herein, incorporates its common usage. TGs consist of three fatty acid molecules esterified to a glycerol molecule. TGs serve to store fatty acids that are used by muscle cells for energy production or are taken up and stored in adipose tissue. Because cholesterol and TGs are water insoluble, they must be packaged in special molecular complexes known as "lipoproteins" in order to be transported in the plasma. Lipoproteins can accumulate in the plasma due to overproduction and/or deficient removal. There are at least five distinct lipoproteins differing in size, composition, density, and function. In the cells of the small intestine, dietary lipids are packaged into large lipoprotein complexes called "chylomicrons", which have a high TG and low- cholesterol content. In the liver, TG and cholesterol esters are packaged and released into plasma as TG-rich lipoprotein called very low density lipoprotein ("VLDL"), whose primary function is the endogenous transport of TGs made in the liver or released by adipose tissue. Through enzymatic action, VLDL can be either reduced and taken up by the liver, or transformed into intermediate density lipoprotein ("IDL"). IDL, is in turn, either taken up by the liver, or is further modified to form low density lipoprotein ("LDL"). LDL is either taken up and broken down by the liver, or is taken up by extrahepatic tissue. High density lipoprotein ("HDL") helps remove cholesterol from peripheral tissues in a process called reverse cholesterol transport.

The term "dyslipidemia" refers to abnormal levels of lipoproteins in blood plasma including both depressed and/or elevated levels of lipoproteins (e.g., elevated levels of LDL and/or VLDL, and depressed levels of HDL). The term "hyperlipidemia" includes, but is not limited to, the following:

(1) Familial Hyperchylomicronemia, a rare genetic disorder that causes a deficiency in an enzyme, LP lipase, that breaks down fat molecules. The LP lipase deficiency can cause the accumulation of large quantities of fat or lipoproteins in the blood;

(2) Familial Hypercholesterolemia, a relatively common genetic disorder caused where the underlying defect is a series of mutations in the LDL receptor gene that result in malfunctioning LDL receptors and/or absence of the LDL receptors. This brings about ineffective clearance of LDL by the LDL receptors resulting in elevated LDL and total cholesterol levels in the plasma;

(3) Familial Combined Hyperlipidemia, also known as multiple lipoprotein-type hyperlipidemia is an inherited disorder where patients and their affected first- degree relatives can at various times manifest high cholesterol and high triglycerides. Levels of HDL cholesterol are often moderately decreased;

(4) Familial Defective Apolipoprotein B-100 is a relatively common autosomal dominant genetic abnormality. The defect is caused by a single nucleotide mutation that produces a substitution of glutamine for arginine, which can cause reduced affinity of LDL particles for the LDL receptor. Consequently, this can cause high plasma LDL and total cholesterol levels;

(5) Familial Dysbetaliproteinemia, also referred to as Type III Hyperlipoproteinemia, is an uncommon inherited disorder resulting in moderate to severe elevations of serum TG and cholesterol levels with abnormal apolipoprotein E function. HDL levels are usually normal; and (6) Familial Hypertriglyceridemia, is a common inherited disorder in which the concentration of plasma VLDL is elevated. This can cause mild to moderately elevated TG levels (and usually not cholesterol levels) and can often be associated with low plasma HDL levels.

Risk factors for hyperlipidemia include, but are not limited to, the following: (1) disease risk factors, such as a history of Type I diabetes, Type I I diabetes, Cushing's syndrome, hypothyroidism and certain types of renal failure; (2) drug risk factors, which include, birth control pills; hormones, such as estrogen, and corticosteroids; certain diuretics; and various [beta]-blockers; (3) dietary risk factors include dietary fat intake per total calories greater than 40%; saturated fat intake per total calories greater than 10%; cholesterol intake greater than 300 mg per day; habitual and excessive alcohol use; and obesity.

The terms "obese" and "obesity" refers to, according to the World Health Organization, a Body Mass Index ("BMI") greater than 27.8 kg/m2 for men and 27.3 kg/m2 for women

(BMI equals weight (kg)/height (m2)). Obesity is linked to a variety of medical conditions including diabetes and hyperlipidemia. Obesity is also a known risk factor for the development of Type II diabetes (see, e.g., Barrett-Conner E, Epidemol. Rev. (1989) 1 1 : 172-181 ; and Knowler, et al., Am. J. CUn. Nutr. (1991) 53: 1543-1551).

The term "pancreas" refers to a gland organ in the digestive and endocrine system of vertebrates, including mammals. The pancreas secretes both digestive enzymes and hormones such as insulin, GLP-1 and GIP, as well as other hormones. The term "islet" or "islet of Langerhans" refers to endocrine cells of the pancreas that are grouped together in islets and secrete insulin and other hormones.

The term "beta cell" refers to cells found in the islet of Langerhans that secrete insulin, amylin, and other hormones.

The term "endocrine cell" refers to cells that secrete hormones into the blood stream. Endocrine cells are found various glands and organ systems of the body including the pancreas, intestines, and other organs.

The term "L cell" refers to gut endocrine cells that produce GLP-I. [0141] The term "K cell" refers to gut endocrine cells that produce GIP.

The term "incretin" refers to a group of hormones that increases insulin secretion in response to food intake. Incretins include GLP-I and GIP.

The term "insulin" refers to a polypeptide hormone that regulates glucose metabolism. Insulin binds to insulin receptors in insulin sensitive cells and mediates glucose uptake. Insulin is used to treat Type I diabetes and may be used to treat Type II diabetes.

The term "GLP-1 " or "glucagon-like peptide" is a peptide hormone primarily produced by L cells. GLP-1 increases insulin secretion, decreases glucagon secretion, increases beta cell mass and insulin gene expression, inhibits acid secretion and gastric emptying in the stomach, and decreases food intake by increasing satiety.

The term "GIP" or "gastric inhibitory peptide" or "glucose dependent insulinotropic polypeptide" refers to a peptide hormone produced primarily by K cells. GIP stimulates insulin secretion. GIP also has significant effects on lipid metabolism. The term "cAMP" or "cyclic AMP" or "cyclic adenosine monophosphate" refers to an intracellular signalling molecule involved in many biological processes, including glucose and lipid metabolism.

The term "agonist" refers to a compound that binds to a receptor and triggers a response in a cell. An agonist mimics the effect of an endogenous ligand, a hormone for example, and produces a physiological response similar to that produced by the endogenous ligand.

The term "partial agonist" refers to a compound that binds to a receptor and triggers a partial response in a cell. A partial agonist produces only a partial physiological response of the endogenous ligand.

EXAMPLES

GENERAL

All commercial available starting materials and solvents were used without further purification, unless otherwise stated. THF was freshly distilled from sodium/benzophenone. Acetone and A/,A/-diisopropylethyl amine (DIPEA) were dried over 4A sieves. Purification by flash chromatography was carried out using silica gel 60 (0.040-0.063 mm, Merck). ¹ H and ¹³C NMR spectra were calibrated relative to TMS internal standard or residual solvent peak. Reactions were routinely monitored by TLC using Merck silica gel F254 plates. Melting points were measured on a Buchi melting point apparatus and are uncorrected. Purity was determined by HPLC and confirmed by NMR. All test compounds were of >95% purity. HPLC analysis was performed using a Dionex 120 C18 column (5μ, 4.6x150 mm); flow: 1 mL/min; 10% acetonitrile in water (0-1 min), 10-100% acetonitrile in water (1-10 min), 100% acetonitrile (11-15 min), with both solvents containing 0.05 % TFA as modifier; UV detection at 254 nm. High-resolution mass spectra (HRMS) were obtained on a Thermo Finnigan TSQ 700 using electrospray ionization (ESI), Bruker micrOTOF-Q II (ESI) or an lonSpec 4.7 T Ultima FTMS using DHB matrix (MALDI). Electron ionization mass spectra were obtained on a Thermo Finnigan SSQ 710 (El).

GENERAL PROCEDURE A: WILLIAMSON ETHER SYNTHESIS

A mixture of benzyl chloride (1 equiv.), phenol (1.1 equiv.), potassium carbonate (2.0 equiv.), potassium iodide (0.5 equiv.) and anhydrous acetone (5 mL/mmol) was heated at reflux under nitrogen until consumption of benzyl chloride. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and residue was purified by flash chromatography. GENERAL PROCEDURE B: SUZUKI COUPLING

A mixture of aryl halide (1.0 equiv.), boronic acid (1.1 equiv.), potassium carbonate (1.2 equiv.), acetonitrile (6.4 mL/mmol), water (2.1 mL/mmol) and tetrakis(triphenyl)palladium(0) (5 mol%) was taken in a round bottom flask under argon atmosphere. The reaction mixture was evacuated and backfilled with argon three times and then heated at 75 °C until complete consumption of aryl halide. The reaction was cooled to room temperature, concentrated in vacuo, added water and extracted with EtOAc. The organic phases were combined, washed with brine, dried over Na₂S0₄, concentrated under vacuum and purified by flash chromatography.

GENERAL PROCEDURE C: ESTER HYDROLYSIS

The ester (1 equiv) dissolved in THF (~5 mL/mmol ester) was added LiOH^«H₂0 (2-3 equiv) in H₂0 (~2 mL/mmol ester). The reaction was stirred at room temperature until complete consumption of the starting material as indicated by TLC, typically after 2-4 hours. The reaction was concentrated in vacuo, diluted with water, acidified with 1 M HCI until pH <1 at 0 °C and extracted with EtOAc. The combined extracts were washed with brine, dried over Na₂S0₄ and concentrated under vacuum.

Methyl 3-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)propanoate (1 ). Following general procedure A, 2-bromo-5-fluorobenzyl chloride (331 mg, 1.48 mmol) was coupled with and methyl 3-(4-hydroxyphenyl)propanoate (280 mg, 1.55 mmol) to give 478 mg (88%) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 1 :9): f?_f = 0.43 (EtOAc: petroleum ether, 1 :4); ¹ H NMR (400 MHz, CDCI₃) δ 7.52 (dd, J = 8.7, 5.2 Hz, 1 H), 7.31 (dd, J = 9.4, 3.1 Hz, 1 H), 7.14 (d, J = 8.6 Hz, 2H), 6.94-6.87 (m, 3H), 5.06 (s, 2H), 3.67 (s, 3H), 2.90 (t, J = 7.8 Hz, 2H), 2.61 (t, J = 7.8 Hz, 2H); ¹³C NMR (101 MHz, CDCIs) δ 173.4, 163.5, 161.0, 156.7, 138.8, 133.7, 133.7, 133.5, 129.4, 1 16.2, 1 16.0, 115.9, 1 15.7, 1 15.6, 1 14.9, 68.9, 51.6, 35.9, 30.1 ; ESI-MS calcd for Ci₇H₁₆BrF0₃Na (M + Na⁺) 389.0165, found: 389.0175.

Methyl 3-(4-((4-fluoro-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoate (2a).

Following general procedure B, 1 (129 mg, 0.35 mmol) was coupled with phenylboronic acid (54 mg, 0.44 mmol) to give 99 mg (77%) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1:9): R_f = 0.42 (Si0₂, EtOAc: petroleum ether, 1:4); ¹H NMR (400 MHz, CDCI₃) δ 7.44-7.30 (m, 6H), 7.30-7.26 (m, 1H), 7.10- 7.04 (m, 3H), 6.76 (d, J= 8.6 Hz, 2H), 4.89 (s, 2H), 3.65 (s, 3H), 2.87 (t, J= 7.8 Hz, 2H), 2.58 (t, J= 7.8 Hz, 2H); ¹³C NMR (101 MHz, CDCI₃) δ 173.3, 163.5, 161.1, 156.8, 139.5, 137.2, 137.2, 136.7, 136.6, 133.1, 131.6, 131.5, 129.2, 129.1, 128.4, 127.4, 115.4, 115.1, 114.8, 114.8, 114.6, 67.5, 51.5, 35.9, 30.0; ESI-MS calcd for C2₃H₂iF0₃Na (M +

Na⁺) 387.1372, found: 387.1343.

3-(4-((4-Fluoro-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid (2b). Following general procedure C, 1 (91 mg, 0.25 mmol) was hydrolyzed to give 82 mg (94%) of a thick syrup: ¹H NMR (400 MHz, CDCI₃) δ 7.43-7.30 (m, 1H), 7.29-7.23 (m, 1H), 7.10- 7.03 (m, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 4.89 (s, 1 H), 2.87 (t, J = 7.7 Hz, 1 H), 2.62 (t, J = 7.7 Hz, 1H); ¹³C NMR (101 MHz, CDCI₃) δ 178.9, 178.8, 163.5, 161.1, 156.9, 139.5, 137.2, 137.2, 136.7, 136.6, 132.7, 131.6, 131.5, 129.2, 129.1, 128.4, 127.4, 115.4, 115.1, 114.9, 114.8, 114.6, 67.5, 35.7, 29.7; HRMS calcd for C₂₂H₁₉F0₃Na (M + Na⁺)

373.1210, found 373.1221.

Methyl 3-(4-((4-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoate (3a). Following general procedure B, 1 (97 mg, 0.26 mmol) was coupled with p- tolylboronic acid (43 mg, 0.32 mmol) to give 83 mg (83%) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1:9): f?_f = 0.43 (Si0₂, EtOAc: petroleum ether, 1:4); ¹H NMR (400 MHz, CDCI₃) δ 7.34 (dd, J= 9.7, 2.7 Hz, 1H), 7.26 (dd, J= 8.3, 5.9 Hz, 1H), 7.21 (s, 4H), 7.10-7.02 (m, 3H), 6.80-6.73 (m, 2H), 4.89 (s, 2H), 3.66 (s, 3H), 2.87 (t, J = 7.8 Hz, 2H), 2.58 (t, J = 7.8 Hz, 2H), 2.39 (s, 3H); ¹³C NMR (101 MHz,

CDCIs) δ 173.3, 163.4, 161.0, 156.8, 137.2, 137.2, 136.7, 136.68, 136.5, 133.0, 131.6, 131.5, 129.2, 129.1, 129.0, 115.3, 115.1, 114.9, 114.8, 114.6, 67.6, 51.6, 35.9, 30.1, 21.1; ESI-MS calcd forC₂2H24F0₃ (M⁺) 379.1704, found: 379.1683.

3-(4-((4-Fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid (3b).

Following general procedure C, 3a (75 mg, 0.20 mmol) was hydrolyzed to give 68 mg (94%) of a thick syrup: ¹H NMR (400 MHz, CDCI₃) δ 7.34 (dd, J= 9.7, 2.7 Hz, 1H), 7.28- 7.24 (m, 1H), 7.21 (s, 4H), 7.11-7.02 (m, 3H), 6.78 (d, J= 8.6 Hz, 2H), 4.89 (s, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 2.39 (s, 3H); ¹³C NMR (101 MHz, CDCI₃) δ

178.0, 163.5, 161.0, 156.9, 137.2, 137.2, 136.7, 136.6, 136.6, 132.7, 131.6, 131.5, 129.2, 129.1, 129.0, 115.3, 115.1, 114.9, 114.8, 114.6, 67.6, 35.6, 29.7, 21.1; HRMS calcd for C2₃H₂iF0₃Na (M + Na⁺) 387.1367, found 387.1349.

Methyl 3-(4-((4-fluoro-4'-methoxy-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoate (4a). Following general procedure B, 1 (85 mg, 0.23 mmol) was coupled with 4- methoxyphenylboronic acid (35 mg, 0.25 mmol) to give 61 mg (67 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1:9); f?_f = 0.41 (EtOAc: petroleum ether, 1:2): ¹H NMR (400 MHz, CDCI₃) δ 7.33 (dd, J = 9.7, 2.7 Hz,

1H), 7.28 - 7.23 (m, 4H), 7.10 - 7.02 (m, 3H), 6.96 - 6.91 (m, 2H), 6.80 - 6.75 (m, 2H), 4.88 (s, 2H), 3.84 (s, 3H), 3.66 (s, 3H), 2.87 (t, J= 7.8 Hz, 2H), 2.58 (t, J= 7.8 Hz, 2H); ¹³C NMR (101 MHz, CDCI₃) δ 173.5, 163.5, 161.1, 159.2, 157.0, 137.2, 137.1, 136.9, 136.8, 133.2, 132.0, 131.8, 131.7, 130.4, 129.4, 115.6, 115.3, 115.0, 114.8, 114.0, 67.8, 55.5, 51.7, 36.1, 30.2.

3-(4-((4-fluoro-4'-methoxy-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid (4b).

Following general procedure C, 4b (20 mg, 0.051 mmol) was hydrolyzed to give 18 mg (95 %) of a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.41 - 7.30 (m, 4H), 7.24 (td, J = 8.5, 3.0 Hz, 1H), 7.13 - 7.08 (m, 2H), 7.01 - 6.95 (m, 2H), 6.82 - 6.75 (m, 2H), 4.92 (d, J = 8.0 Hz, 2H), 3.78 (s, 3H), 2.73 (t, J = 7.5 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 174.1, 162.5, 160.1, 158.7, 156.3, 137.3, 136.7, 136.6, 133.4, 131.9, 131.9, 131.1, 130.18, 129.2, 115.6, 115.3, 115.0, 114.8, 114.5, 113.8, 67.1, 55.1, 35.8, 29.6; ESI-MS calcd forC2₃H₂iF0₄ (M+Na⁺) 403.1316, found: 403.1305.

Methyl 3-(4-((4-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoate (5a). Following general procedure B, 1 (85 mg, 0.23 mmol) was coupled with m- tolylboronic acid (35 mg, 0.25 mmol) to give 64 mg (73 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1:9); R_f = 0.50 (EtOAc:petroleum ether, 1:2): ¹H NMR (400 MHz, CDCI₃) δ 7.34 (dd, J = 9.7, 2.7 Hz, 1H), 7.31 - 7.24 (m, 3H), 7.19 - 7.02 (m, 6H), 6.80 - 6.74 (m, 2H), 4.89 (s, 2H), 3.65 (s, 3H), 2.87 (t, J = 7.8 Hz, 2H), 2.58 (t, J= 7.8 Hz, 2H), 2.35 (s, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 173.5, 163.7,

161.2, 157.0, 139.6, 138.2, 136.9, 136.8, 133.2, 131.7, 131.6, 130.1, 129.4, 128.4,

128.3, 126.3, 115.5, 115.3, 115.1, 114.9, 114.7, 67.8, 51.7, 36.1, 31.1, 30.2, 21.6.

3-(4-((4-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid (5b).

Following general procedure C, 5a (20 mg, 0.053 mmol) was hydrolyzed to give 19 mg (98 %) of a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (br. s, 1H), 7.31 (m, 7H), 7.10 (d, J= 8.1 Hz, 2H), 6.78 (d, J= 8.3 Hz, 2H), 4.89 (s, 2H), 2.74 (dd, J= 19.1, 7.6 Hz,

2H), 2.58 - 2.41 (m, 2H), 2.28 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 172.2, 162.6, 160.2, 156.2, 138.8, 137.8, 137.5, 136.7, 136.6, 133.4, 132.9, 131.8, 129.7, 129.2, 128.2, 128.1, 126.0, 115.7, 115.5, 114.8, 114.5, 67.1, 35.3, 29.4, 20.9; ESI-MS calcd for C2₃H21FO₃ (M+Na⁺) 387.1367, found: 387.1378.

Ethyl 3-(4-(5-fluoro-2-methoxybenzyloxy)phenyl)propanoate (6a). Following general procedure A, 2-(chloromethyl)-4-fluoro-1-methoxybenzene (300 mg, 1.72 mmol) was coupled with ethyl 3-(4-hydroxyphenyl)propanoate (368 mg, 1.89 mmol) to give 485 mg (85%) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 1:19):

¹H NMR (400 MHz, CDCI₃) δ 7.20 (dd, J = 9.0, 3.1 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.99-6.86 (m, 1H), 6.80 (dd, J= 9.0, 4.3 Hz, 1H), 5.05 (s, 1H), 4.12 (q, J= 7.1 Hz, 1H), 3.83 (s, 1H), 2.89 (t, J= 7.8 Hz, 1H), 2.58 (t, J= 7.8 Hz, 1H), 1.23 (t, J= 7.1 Hz, 1H); ¹³C NMR (101 MHz, CDCI₃) δ 173.0, 158.4, 157.1, 156.0, 152.6 (d, J = 2.0 Hz), 133.0, 129.3, 127.5 (d, J= 7.3 Hz), 115.1, 114.8 (d, J = 5.4 Hz), 114.4, 114.2, 110.9 (d, J= 8.1

Hz), 64.5, 60.4, 55.9, 36.2, 30.2, 14.2.

3-(4-(5-fluoro-2-methoxybenzyloxy)phenyl)propanoic acid (6b). Following general procedure C, 6a (15 mg, 0.36 mmol) was hydrolyzed to give 50 mg (91%) of a white solid: mp 96-97 °C; ¹H NMR (400 MHz, CDCI₃) δ 10.50 (s, 1H), 10.48 (s, 1H), 9.43 (t, J = 576.8 Hz, 2H), 8.94 (dd, J= 1125.0, 58.3 Hz, 2H), 7.20 (dt, J= 13.6, 6.8 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.99 - 6.87 (m, 3H), 6.81 (dd, J = 9.0, 4.3 Hz, 1 H), 5.06 (s, 2H), 3.84 (s, 3H), 2.91 (t, J = 7.7 Hz, 2H), 2.66 (t, J = 7.7 Hz, 2H); ¹³C NMR (101 MHz, CDCI₃): δ 177.6, 158.4, 157.2, 156.0, 152.6, 132.6, 129.3 , 127.4 (d, J = 7.4 Hz), 1 15.0 (d, J = 24.7 Hz), 1 14.7 - 1 14.6 (m), 1 14.4, 1 14.2, 1 10.9 (d, J = 8.2 Hz), 64.5, 55.9, 35.6, 29.8, 1.0; HRMS calcd for Ci₇H₁₇FN0₄Na (M + Na⁺) 327.1003, found: 327.101 1.

Ethyl 4-(4-((2-bromo-5-fluorobenzyl)oxy)phenyl)butanoate (7). Following general procedure A, 1-bromo-2-(bromomethyl)-4-fluorobenzene (340 mg, 1.6 mmol) was coupled with ethyl 4-(4-hydroxyphenyl)butanoate (437 mg, 1.6 mmol) to give 549 mg (85

%) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 1 :9); f?_f = 0.57 (EtOAc: petroleum ether, 1 :2): ¹ H NMR (400 MHz, CDCI₃) δ 7.52 (dd, J = 8.6, 6.0 Hz, 1 H), 7.34 (dd, J = 8.2, 2.6 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 2H), 7.05 (td, J = 8.4, 2.6 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 5.06 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.92 (p, J = 7.5 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR

(101 MHz, CDCIs) δ 173.7, 163.3, 160.8, 156.8, 134.4, 132.6, 130.3, 130.2, 129.7, 122.6, 122.5, 120.2, 119.9, 114.9, 1 14.7, 69.1 , 60.4, 34.4, 33.8, 26.9, 14.4.

Ethyl 4-(4-((4-fluoro-[1 ,1'biphenyl]-2-yl)methoxy)phenyl)butanoate (8a). Following general procedure B, 7 (100 mg, 0.25 mmol) was coupled with phenylboronic acid (34 mg, 0.28 mmol) to give 79 mg (79 %) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 1 :9); R_f = 0.55 (EtOAc: petroleum ether, 1 :2): ¹ H NMR (400 MHz, CDCI₃) δ 7.57 (dd, J = 8.5, 5.9 Hz, 1 H), 7.45 - 7.32 (m, 5H), 7.13 - 7.01 (m, 4H), 6.80 - 6.74 (m, 2H), 4.85 (s, 2H), 4.1 1 (q, J = 7.1 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.29 (t, J =

7.5 Hz, 2H), 1.95 - 1.85 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 173.7, 156.9, 144.2, 144.1 , 139.6, 134.1 , 131.6, 131.5, 130.3, 129.5, 129.1 , 128.6, 127.9, 1 17.0, 1 16.8, 114.9, 114.8, 1 14.6, 67.7, 60.4, 34.4, 33.8, 26.9, 14.4.

Ethyl 4-(4-((4-fluoro-[1 ,1 'biphenyl]-2-yl)methoxy)phenyl)butanoic acid (8b).

Following general procedure C, 8a (68 mg, 0.17 mmol) was hydrolyzed to give 59 mg (93 %) of a white solid; R, = 0.10 (EtOAc:petroleum ether, 1 :2): mp 92-94 °C; ¹ H NMR (400 MHz, DMSO-de) δ 12.02 (s, 1 H), 7.64 (dd, J = 8.5, 6.1 Hz, 1 H), 7.46 - 7.36 (m, 5H),

7.27 (td, J = 8.6, 2.7 Hz, 1 H), 7.18 (dd, J = 9.8, 2.7 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 4.86 (s, 2H), 2.49 - 2.47 (m, 2H), 2.17 (t, J = 7.4 Hz, 2H), 1.77 - 1.69 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 174.3, 162.8, 160.4, 156.3, 144.0, 143.9, 138.8, 133.8, 132.2, 132.1 , 130.4, 130.3, 129.2, 128.8, 128.4, 127.8, 1 16.5, 1 16.3, 1 14.5, 114.3, 67.0, 33.5, 33.0, 26.5; ESI-MS calcd for C2₃H21 FO₃ (M+Na⁺)

387.1367, found: 387.1359.

Ethyl 4-(4-((4-fluoro-4'-methyl-[1 ,1 '-biphenyl]-2-yl)methoxy)phenyl)butanoate (9a). Following general procedure B, 7 (100 mg, 0.25 mmol) was coupled with p-tolylboronic acid (38 mg, 0.28 mmol) to give 86 mg (83 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1 :9); R_f = 0.63 (EtOAc: petroleum ether, 1 :2): ¹ H NMR (400 MHz, CDCI₃) δ 7.56 (dd, J = 8.4, 5.9 Hz, 1 H), 7.27 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.10 - 7.01 (m, 4H), 6.79 (t, J = 5.7 Hz, 2H), 4.86 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.38 (s, 3H), 2.29 (t, J = 7.5 Hz, 2H),

1.90 (p, J = 7.5 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 173.7, 163.6, 161.1 , 157.0, 144.2, 144.1 , 137.7, 136.6, 134.0, 131.5, 131.4, 130.3, 129.5, 129.3, 129.0, 1 17.0, 116.8, 114.9, 114.6, 1 14.3, 67.7, 60.4, 34.4, 33.8, 26.9, 21.3, 14.4.

4-(4-((4-fluoro-4'methyl-[1 ,1 '-biphenyl]-2-yl)methoxy)phenyl)butanoic acid (9b).

Following general procedure C, 9a (78 mg, 0.19 mmol) was hydrolyzed to give 73 mg (100 %) of a white solid: mp 86-87 °C; ¹ H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1 H), 7.62 (dd, J = 8.5, 6.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2H), 7.27 - 7.20 (m, 3H), 7.14 (dd, J =

9.9, 2.7 Hz, 1 H), 7.06 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.85 (s, 2H), 2.49 (d, J = 7.8 Hz, 2H), 2.32 (s, 3H), 2.18 (t, J = 7.4 Hz, 2H), 1.78 - 1.69 (m, 2H); ¹³C NMR (101 MHz, DMSO-de) δ 174.3, 162.8, 160.4, 156.3, 143.9, 137.2, 135.9, 133.9, 132.2, 132.1 , 130.3, 129.2, 129.0, 128.8, 1 16.4, 1 16.2, 114.5, 1 14.3, 1 14.1 , 67.0, 33.5, 33.0, 26.5, 20.7; ESI-MS calcd fo^^sFOs (M+Na⁺) 401.1523, found: 401.1513.

Ethyl 4-(4-((4-fluoro-4'-methoxy-[1 ,1 '-biphenyl]-2-yl)methoxy)phenyl)butanoate (10a). Following general procedure B, 7 (100 mg, 0.25 mmol) was coupled with (4- methoxyphenyl)boronic acid (42 mg, 0.28 mmol) to give 65 mg (61 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1 :9); f?_f = 0.48 (EtOAc: petroleum ether, 1 :2): ¹ H NMR (400 MHz, CDCI₃) δ 7.57 (dd, J = 8.5, 5.9 Hz, 1 H), 7.45 - 7.32 (m, 5H), 7.13 - 7.01 (m, 4H), 6.80 - 6.74 (m, 2H), 4.85 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.95 - 1.85 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 173.7, 156.9, 144.2, 144.1 , 139.6,

134.1 , 131.6, 131.5, 130.3, 129.5, 129.1 , 128.6, 127.9, 1 17.0, 1 16.8, 1 14.9, 1 14.8, 1 14.6, 67.7, 60.4, 34.4, 33.8, 26.9, 14.4.

4-(4-((4-fluoro-4'-methoxy-[1 ,1 '-biphenyl]-2-yl)methoxy)phenyl)butanoic acid (10b). Following general procedure C, 10a (51 mg, 0.12 mmol) was hydrolyzed to give 47 mg (98 %) of a white solid: mp 151-152 °C; ¹ H NMR (400 MHz, DMSO-d₆) δ 7.60 (dd, J= 8.3, 6.3 Hz, 1H), 7.37 (d, J= 8.5 Hz, 2H), 7.21 (td, J= 8.5, 2.6 Hz, 1H), 7.13 (dd, J = 9.9, 2.5 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.85 (s, 2H), 3.76 (s, 3H), 2.44 (t, J = 7.6 Hz, 2H), 1.88 (t, J= 7.3 Hz, 2H), 1.71 - 1.61 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 176.8, 162.8, 160.3, 158.9, 156.0, 143.6, 135.2, 132.2, 132.1, 131.0, 130.4, 130.3, 130.1, 129.2, 116.4, 116.2, 114.4,

114.0, 113.8, 67.0, 55.1, 37.8, 34.5, 28.5; ESI-MS calcd for C24H2₃FO4 (M+Na⁺) 417.1473, found: 417.1488.

Ethyl 4-(4-((4.fluoro-4'(methylthio)-[1,1'-biphenyl]-2-yl)methoxy)phenyl)butanoate (11a).

Following general procedure B, 7 (100 mg, 0.28 mmol) was coupled with (4- (methylthio)phenyl)boronic acid (47 mg, 0.28 mmol) to give 62 mg (55 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1:9); R_f = 0.52 (EtOAc: petroleum ether, 1:2); ¹H NMR (400 MHz, CDCI₃) δ 7.56 (dd, J = 8.5, 5.9 Hz, 1H), 7.33-7.26 (m, 4H), 7.11 -7.01 (m, 4H), 6.79 (t, J =5.1 Hz, 2H), 4.84 (s, 2H), 4.12

(q, J= 7.1 Hz, 2H), 2.58 (t, J= 7.6 Hz, 2H), 2.51 (s, 3H), 2.30 (t, J= 7.5 Hz, 2H), 1.91 (p, J = 7.5 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 173.7, 163.6, 161.2, 156.9, 143.7, 143.6, 138.5, 136.2, 136.2, 134.1, 131.8, 131.7, 130.2, 130.2, 129.5, 126.3, 116.9, 116.7, 114.9, 114.8, 114.5, 67.7, 60.4, 34.4, 33.8, 26.9, 15.7, 14.4.

4-(4-((4-fluoro-4'-(methylthio)-[1,1'-biphenyl]-2-yl)methoxy)phenyl)butanoic acid (11b).

Following general procedure C, 11a (53 mg, 0.12 mmol) was hydrolyzed to give 49 mg (98 %) of a white solid; mp 135-136 °C; R_f = 0.10 (EtOAc: petroleum ether, 1:2); ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 7.63 (dd, J = 8.5, 6.1 Hz,

1H), 7.39 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.25 (td, J = 8.6, 2.8 Hz, 1H), 7.16 (dd, J = 9.9, 2.7 Hz, 1H), 7.06 (d, J= 8.5 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.87 (s, 2H), 2.51 (d, J = 4.7 Hz, 2H), 2.49 (s, 3H), 2.18 (t, J = 7.4 Hz, 2H), 1 .78 - 1 .69 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 174.3, 162.8, 160.4,

156.3, 143.4, 143.3, 138.2, 135.2, 135.1 , 133.9, 132.3, 132.2, 130.3, 130.3,

129.4, 129.2, 125.6, 1 16.4, 1 16.2, 1 14.6, 1 14.4, 1 14.2, 67.0, 33.5, 33.0, 26.5, 14.4; HRMS calcd for C₂4H₂3F0₃Na (M + Na⁺) 433.1244 found 433.1263.

Ethyl 3-(4-((5-fluoro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)oxy) phenyl) propanoate (A). To a solution of ethyl 3-(4-((2-bromo-5- fluorobenzyl)oxy)phenyl)propanoate (1.14 g, 3.0 mmol) and bis(pinacolato)diboron (0.87 g, 3.4 mmol) in anhydrous dioxane (14 ml_) was added potassium acetate (0.88 g, 8.97 mmol) and PdCI₂(dppf)2 (80 mg, 0.11 mmol). The mixture was evacuated and back filled with nitrogen (3 times) and heated at 80 °C overnight. The reaction mixture was cooled to ambient temperature, concentrated in vacuo, diluted with ethyl acetate and filtered through celite pad. The filtrate was concentrated in vacuo to give 0.89 g (69%) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 1 :9): ¹ H NMR (400 MHz, CDCIs) δ 7.84 (dd, J = 8.2, 6.6 Hz, 1 H), 7.28 (dd, J = 10.5, 2.4 Hz, 1 H), 7.14 - 7.09 (m, 2H), 6.97 (td, J = 8.4, 2.5 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2H), 5.33 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.89 (t, J = 7.8 Hz, 2H), 2.58 (t, J = 7.8 Hz, 2H), 1.31 (s, 12H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 165.1 (d, J_F = 250.6 Hz), 157.3, 147.6, 138.4, 132.6, 129.4, 114.9, 114.0 (d, J_F = 21.9 Hz), 1 13.65 (d, J_F = 20.2 Hz). 83.9, 68.6, 60.4, 36.3, 30.2, 24.9, 14.4.

Ethyl 3-(4-((5-fluoro-2-(pyridin-2-yl)benzyl)oxy)phenyl)propanoate (12a). Following general procedure B, A (100 mg, 0.23 mmol) was coupled with 2-iodopyridine (53 mg, 0.26 mmol) to give 61 mg (69 %) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 1 :3): ¹ H NMR (400 MHz, CDCI₃) δ 8.67 (dd, J = 4.8, 0.6 Hz, 1 H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.41 (dd, J = 9.9, 2.6 Hz, 1H), 7.25 (ddd, J = 7.2, 5.0, 0.8 Hz, 1H), 7.12 - 7.04 (m, 3H), 6.79 (d, J = 8.6 Hz, 2H), 5.18 (s, 2H), 4.11 (q, J= 7.1 Hz, 2H), 2.86 (t, J= 7.8 Hz, 2H), 2.56 (t, J= 7.8 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 173.0, 163.0 (d, J_F = 247.7 Hz), 158.1, 156.9, 149.2, 138.3, 136.7, 135.3, 133.1, 131.5, 129.2, 123.8, 122.1, 115.2 (d, J_F = 22.8 Hz),

114.8, 114.6 (d, J_F = 21.5 Hz), 67.6, 60.3, 36.2, 30.2, 14.2.

3-(4-((5-Fluoro-2-(pyridin-2-yl)benzyl)oxy)phenyl)propanoic acid (12b). Following general procedure C, 12a (50 mg, 0.13 mmol) was hydrolyzed to give 44 mg (95 %) of a white solid: mp 142-144 °C; ¹H NMR (400 MHz, CDCI₃) δ 8.69 (dd, J= 4.9, 0.7 Hz, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1 H), 7.50 - 7.44 (m, 2H), 7.40 (dd, J = 9.8, 2.6 Hz, 1 H), 7.31 - 7.27 (m, 1H), 7.13-7.04 (m, 3H), 6.82-6.75 (m, 2H), 5.14 (s, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.61 (t, J = 7.7 Hz, 2H); ¹³C NMR (101 MHz, CDCI₃) δ 177.4, 163.0 (d, J_F = 247.8 Hz), 157.9, 156.9, 149.0, 138.1, 136.9, 135.1, 132.7, 131.5, 129.2, 123.9, 122.2, 115.30

(d, J_F = 22.8 Hz), 114.9, 114.7 (d, J_F = 21.5 Hz), 67.5, 35.6, 29.8; HRMS calcd for C₂iH₁₈FN0₃Na (M + Na⁺) 374.1163, found: 374.1176.

Ethyl 3-(4-((5-fluoro-2-(pyridin-3-yl)benzyl)oxy)phenyl)propanoate (13a). Following general procedure B, A (100 mg, 0.23 mmol) was coupled with 3-iodopyridine (53 mg, 0.26 mmol) to give 68 mg (77 %) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 1:1): ¹H NMR (400 MHz, CDCI₃) δ 8.61 (dd, J= 4.7, 1.4 Hz, 2H), 7.69 (dt, J= 7.8, 1.9 Hz, 1H), 7.39-7.25 (m, 3H), 7.15-7.10 (m, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.77 (t, J = 5.7 Hz, 2H), 4.85 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.87 (t, J = 7.8

Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 162.7 (d, J_F = 247.9 Hz), 156.6, 149.8, 148.9, 137.1, 136.5, 135.2, 133.8, 133.5, 131.9, 129.3, 123.2, 116.1 (d, J_F = 22.4 Hz), 115.28 (d, J_F= 21.4 Hz), 114.8, 67.5, 60.4, 36.1, 30.1, 14.2.

3-(4-((5-Fluoro-2-(pyridin-3-yl)benzyl)oxy)phenyl)propanoic acid (13b). Following general procedure C, 13a (60 mg, 0.16 mmol) was hydrolyzed to give 51 mg (92 %) of a white solid: mp 105-108 °C; ¹ H NMR (400 MHz, CDCI₃) δ 8.68 - 8.52 (m, 2H), 7.72 (d, J

= 7.9 Hz, 1 H), 7.37 (dt, J = 6.5, 3.3 Hz, 2H), 7.31 - 7.26 (m, 1 H), 7.14 (dd, J = 8.3, 2.7 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 4.84 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.62 (t, J = 7.7 Hz, 2H); ¹³C NMR (101 MHz, CDCI₃) δ 176.8, 162.8 (d, J_F = 248.2 Hz), 156.6, 149.1 , 148.1 , 137.1 , 133.4, 131.9, 129.4, 123.5, 1 16.3 (d, J_F = 22.4 Hz), 1 15.4 (d, J_F = 21.4 Hz), 1 14.9, 67.6, 35.8, 29.9; HRMS calcd for C₂i H₁₉FN0₃ (M + +) 352.1343, found: 352.1363.

Ethyl 3-(4-((5-fluoro-2-(pyridin-4-yl)benzyl)oxy)phenyl)propanoate (14a). Following general procedure B, A (100 mg, 0.23 mmol) was coupled with 4-bromopyridine hydrochloride (50 mg, 0.26 mmol) to give 62 mg (70 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 2:3): ¹ H NMR (400 MHz, CDCI₃) δ 8.64 (dd, J = 4.5, 1.6 Hz, 2H), 7.37 (dd, J = 9.5, 2.6 Hz, 1 H), 7.31 - 7.26 (m, 3H), 7.14 (dd, J = 8.3, 2.7 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 2H), 6.80 - 6.74 (m, 2H), 4.86 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 162.9 (d, J_F = 248.5 Hz), 136.6, 134.8, 133.5,

131.3, 129.4, 124.1 , 1 16.3 (d, J_F = 22.4 Hz), 115.4 (d, J_F = 21.4 Hz), 1 14.8, 67.4, 60.4, 36.1 , 30.1 , 14.2.

3-(4-((5-Fluoro-2-(pyridin-4-yl)benzyl)oxy)phenyl)propanoic acid (14b). Following general procedure C, 14a (56 mg, 0.15 mmol) was hydrolyzed to give 48 mg (92 %) of a white solid: mp 171-173 °C; ¹ H NMR (400 MHz, DMSO-d₆) δ 12.09 (br. s, 1 H), 8.61 (dd, J = 4.5, 1.5 Hz, 2H), 7.49 (dd, J = 9.9, 2.7 Hz, 1 H), 7.44 (dt, J = 7.6, 4.1 Hz, 4H), 7.34 (td, J = 8.5, 2.7 Hz, 1 H), 7.10 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 3H), 4.96 (s, 2H),

2.73 (t, J = 7.6 Hz, 3H), 2.47 (t, J = 7.6 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 173.7, 161.9 (d, J_F = 245.6 Hz), 156.0, 149.5, 146.6, 136.8, 134.9, 133.3, 131.7, 129.1 , 123.9, 1 16.0 (d, J_F = 22.4 Hz), 1 15.3 (d, J_F = 21.2 Hz), 114.5, 66.8, 35.4, 29.4, HRMS calcd for C₂i H₁₉FN0₃ (M + H⁺) 352.1343, found: 352.1378.

Ethyl 3-(4-((5-fluoro-2-(5-methylpyridin-2-yl)benzyl)oxy)phenyl)propanoate (15a).

Following general procedure B, A (100 mg, 0.23 mmol) was coupled with 2-bromo-5- methylpyridine (44 mg, 0.26 mmol) to give 65 mg (71 %) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 3:7): ¹ H NMR (400 MHz, CDCI₃) δ 8.52 -

8.47 (m, 1 H), 7.55 (dd, J = 8.0, 1.7 Hz, 1 H), 7.42 (ddd, J = 12.6, 9.2, 4.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1 H), 7.10 - 7.04 (m, 3H), 6.79 (d, J = 8.6 Hz, 2H), 5.15 (s, 2H), 4.10 (t, J = 7.1 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.56 (t, J = 7.8 Hz, 2H), 2.38 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 173, 162.9 (d, J_F = 247.3 Hz), 156.9, 155.2, 149.6, 138.1 , 138.0, 137.2, 135.2, 133.0, 131.7, 131.4 (d, J_F = 8.3 Hz), 129.2, 123.3,

1 15.4, 1 15.1 (d, J_F = 22.8 Hz), 1 14.9, 1 14.5 (d, J_F = 21.4 Hz), 67.5, 60.4, 36.18, 30.1 , 18.2, 14.2.

3-(4-((5-Fluoro-2-(5-methylpyridin-2-yl)benzyl)oxy)phenyl)propanoic acid (15b).

Following general procedure C, 15a (60 mg, 0.15 mmol) was hydrolyzed to give 51 mg (91 %) of a white solid: mp 110-112 °C; ¹ H NMR (400 MHz, CDCI₃) δ 8.55 - 8.51 (m, 1 H), 7.58 (dd, J = 8.0, 1.7 Hz, 1 H), 7.45 - 7.33 (m, 3H), 7.11 - 7.03 (m, 3H), 6.77 (d, J = 8.6 Hz, 2H), 5.08 (s, 2H), 2.85 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 7.7 Hz, 2H), 2.38 (s, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 177.8, 162.9 (d, J_F = 247.6 Hz), 156.9, 154.8, 149.2, 137.9, 137.7, 134.8, 132.8, 132.0, 131.5, 129.2, 123.7, 1 15.3 (d, J_F = 22.8 Hz), 1 14.9, 1 14.7 (d, J_F = 21.5 Hz), 67.5, 35.9, 29.9, 18.2; HRMS calcd for C₂₂H₂oFN0₃Na (M + Na⁺)

388.1319, found: 388.1333.

Ethyl 3-(4-((4,4'-difluoro-[1 ,1 '-biphenyl]-2-yl)methoxy)phenyl)propanoate (16a).

Following general procedure B, ethyl 3-(4-((2-bromo-5- fluorobenzyl)oxy)phenyl)propanoate (150 mg, 0.39 mmol) was coupled with (4- fluorophenyl)boronic acid (61 mg, 0.43 mmol) to give 130 mg (83 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1 :9): ¹ H NMR (400 MHz, CDCIs) δ 7.38 - 7.20 (m, 4H), 7.13 - 7.02 (m, 5H), 6.76 (d, J = 8.6 Hz, 2H), 4.84 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 162.4 (d, J_F = 246.7 Hz), 162.35 (d, J_F = 246.8 Hz), 156.8, 136.8, 136.7, 135.98 (d, JF= 95.2 Hz), 135.95 (d, J_F = 95.3 Hz), 133.3, 131.68 (d, J_F = 8.0 Hz), 130.8, 130.8, 129.4, 115.69 (d, J_F = 22.3 Hz), 1 15.38 (d, J_F = 21.4 Hz), 1 14.95 (d, J_F = 21.3 Hz), 67.6, 60.4, 36.2, 30.1 , 14.3.

3-(4-((4,4'-Difluoro-[1 ,1 '-biphenyl]-2-yl)methoxy)phenyl)propanoic acid (16b).

Following general procedure C, 16a (138 mg, 0.35 mmol) was hydrolyzed to give 114 mg (89 %) of a colorless gummy mass: ¹ H NMR (400 MHz, CDCI₃) δ 7.38 - 7.18 (m, 4H), 7.12 - 7.00 (m, 5H), 6.77 (d, J = 8.5 Hz, 2H), 4.84 (s, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.62 (t, J = 7.7 Hz, 2H); ¹³C NMR (101 MHz, CDCI₃) δ 179.3, 162.4 (d, J_F = 246.8Hz), 156.9, 136.7 (d, J_F = 7.5 Hz), 136.4 (d, J_F = 3.2 Hz), 135.5 (d, J_F = 3.4 Hz), 132.9, 131.7 (d, J_F= 8.0 Hz), 130.8 (d, J_F= 8.1 Hz), 129.3, 115.7 (d, J_F = 22.3 Hz), 115.4 (d, J_F = 21 Hz), 114.92, 114.9 (d, J_F = 21.2 Hz), 67.6, 35.8, 29.7; HRMS calcd for C₂2H₁₈F₂0₃Na + Na⁺) 391.1116, found: 391.1101.

Ethyl 3-(4-((4'-chloro-4-fluoro-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoate (17a). Following general procedure B, ethyl 3-(4-((2-bromo-5- fluorobenzyl)oxy)phenyl)propanoate (150 mg, 0.39 mmol) was coupled with (4- chlorophenyl)boronic acid (68 mg, 0.43 mmol) to give 136 mg (84 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1:9): ¹H NMR (400 MHz,

CDCIs) 57.39-7.31 (m, 1H), 7.30-7.21 (m, 1H), 7.12-7.04 (m, 1H), 6.77 (d, J = 8.6 Hz, 1H), 4.84 (s, 1H), 4.11 (q, J= 7.1 Hz, 1H), 2.88 (t, J= 7.8 Hz, 1H), 2.57 (t, J= 7.8 Hz, 1H), 1.22 (t, J = 7.1 Hz, 1H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 162.5 (d, J_F = 247.0 Hz), 156.7, 136.6 (d, J_F = 7.5 Hz), 136.6, 136.2 (d, J_F = 3.3 Hz), 133.7, 133.4, 131.6 (d, J_F = 8.1 Hz), 130.5, 129.4, 128.6,115.8 (d, J_F = 22.3 Hz), 115.1 (d, J_F = 21.2

Hz), 114.8, 67.5, 60.4, 36.2, 30.2, 14.3.

3-(4-((4'-Chloro-4-fluoro-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid (17b). Following general procedure C, 17a (90 mg, 0.22 mmol) was hydrolyzed to give 81 mg

(97 %) of an amorphous solid: ¹H NMR (400 MHz, CDCI₃) δ 7.40 - 7.31 (m, 3H), 7.30 - 7.22 (m, 3H), 7.13 - 7.03 (m, 3H), 6.77 (d, J = 8.6 Hz, 2H), 4.84 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H): ¹³C NMR (101 MHz, CDCI₃) δ 177.9, 162.5 (d, J_F = 247.1 Hz), 156.8, 137.9, 136.7, 136.6, 136.6 (d, J_F= 7.5 Hz), 133.7, 132.9, 131.5 (d, J_F = 8.1 Hz), 130.5, 129.3, 128.6, 115.8 (d, J_F = 22.3 Hz), 115.0 (d, J_F = 21.4 Hz), 114.967.6,

35.6, 29.7; HRMS calcd for CzaH^CIFOsNa (M + Na⁺) 407.0821, found: 407.0801.

Ethyl 3-(4-((4'-cyano-4-fluoro-[1 ,1 '-biphenyl]-2-yl)methoxy)phenyl)propanoate (18a). Following general procedure B, A (100 mg, 0.23 mmol) was coupled with 4- bromobenzonitrile (45 mg, 0.25 mmol) to give 65 mg (69%) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 1 :9): ¹ H NMR (400 MHz, CDCI₃) δ 7.71 -

7.66 (m, 2H), 7.50 - 7.44 (m, 2H), 7.36 (dd, J = 9.5, 2.7 Hz, 1 H), 7.29 - 7.24 (m, 1 H), 7.15 - 7.07 (m, 3H), 6.78 - 6.72 (m, 2H), 4.82 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCIs) δ 172.9, 162.8 (d, J_F = 248.4 Hz), 156.6, 144.4, 136.6 (d, J_F = 7.6 Hz), 135.8, 133.6, 132.2, 131.5 (d, J_F = 8.2 Hz),, 129.9, 129.4, 118.6, 116.4 (d, J_F = 22.4 Hz), 1 15.4

(d, J_F = 21.4 Hz), 1 14.8, 11 1.5, 67.5, 60.4, 36.1 , 30.1 , 14.2.

3 3-(4-((4'-Cyano-4-fluoro-[1 ,1 '-biphenyl]-2-yl)methoxy)phenyl)propanoic acid (18b). Following general procedure C, 18a (59 mg, 0.15 mmol) was hydrolyzed to give

49 mg (89 %) of a colorless amorphous solid: ¹ H NMR (400 MHz, CDCI₃) δ 7.71 - 7.66 (m, 2H), 7.50 - 7.44 (m, 2H), 7.36 (dd, J = 9.4, 2.7 Hz, 1 H), 7.29 - 7.24 (m, 1 H), 7.15 - 7.07 (m, 3H), 6.78 - 6.73 (m, 2H), 4.82 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H); ¹³C NMR (101 MHz, CDCI₃) δ 178.7, 162.8 (d, J_F = 248.4 Hz), 156.7, 144.4, 136.6 (d, J_F = 7.6 Hz), 135.8, 133.2, 132.2, 131.5 (d, J_F = 8.2 Hz), 129.9, 129.4, 1 18.6,

1 16.4 (d, J_F = 22.4 Hz), 1 15.4 (d, J_F = 21.4 Hz), 1 14.8, 1 11.5, 67.5, 35.8, 29.7; HRMS calcd for C₂₃H₁₈FN0₃Na (M + Na⁺) 398.1 163, found: 398.1151.

Ethyl 3-(4-((2-(5-chloropyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)propanoate (19a).

Following general procedure B, A (100 mg, 0.23 mmol) was coupled with 2-chloro-5- iodopyridine (59 mg, 0.25 mmol) to give 66 mg (68 %) of a colorless oil after flash chromatography (Si0₂, EtOAc: petroleum ether, 3:7): ¹ H NMR (400 MHz, CDCI₃) δ 8.41 -

8.36 (m, 1 H), 7.67 (dd, J = 8.2, 2.5 Hz, 1 H), 7.36 (ddd, J = 5.2, 4.2, 1 .6 Hz, 2H), 7.27 (dd, J = 8.4, 5.7 Hz, 1 H), 7.17 - 7.07 (m, 3H), 6.81 - 6.73 (m, 2H), 4.82 (s, 2H), 4.12 (q, J = 7.2 Hz, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 7.8 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 162.9 (d, J_F = 248.7 Hz), 156.5, 150.8, 149.5, 139.3, 137.1 (d, J_F = 7.6 Hz), 134.2, 133.6, 132.6 (d, J_F = 3.3 Hz), 131.9 (d, J_F = 8.2 Hz),

129.4, 123.9, 1 16.7 (d, J_F = 22.4 Hz), 1 15.6 (d, J_F = 21.4 Hz), 1 14.8, 67.5, 60.4, 36.1 , 30.1 , 14.2.

3-(4-((2-(5-Chloropyridin-3-yl)-5-fluorobenzyl)oxy)phenyl)propanoic acid (19b).

Following general procedure C, 19a (52 mg, 0.13 mmol) was hydrolyzed to give 46 mg (95 %) of an amorphous off white solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.40 (d, J = 2.5 Hz, 1 H), 7.68 (dd, J = 8.2, 2.5 Hz, 1 H), 7.36 (dd, J = 8.7, 3.6 Hz, 2H), 7.29 - 7.23 (m, 1 H), 7.17 - 7.08 (m, 3H), 6.81 - 6.74 (m, 2H), 4.82 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H); ¹³C NMR (101 MHz, CDCI₃) δ 178.4, 162.9 (d, J_F = 248.8 Hz), 156.6,

150.7, 149.5, 139.4, 137.0 (d, J_F = 7.7 Hz), 134.3, 133.3, 132.6, 131 .9 (d, J_F = 8.2 Hz)„ 129.4, 123.9, 1 16.7 (d, J_F = 22.4 Hz), 1 15.6 (d, J_F = 21.4 Hz), 1 14.9, 67.6, 35.8, 29.8; HRMS calcd for C₂i H₁₇CIFN0₃Na (M + Na⁺) 408.0773, found: 408.0757.

Ethyl 3-(4-((5-fluoro-2-(6-methoxypyridin-3-yl)benzyl)oxy)phenyl)propanoate (20a).

Following general procedure B, A (200 mg, 0.47 mmol) was coupled with 5-bromo-2- methoxypyridine (92 mg, 0.49 mmol) to give 151 mg (79 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 1:3): ¹H NMR (400 MHz, CDCI₃) δ 8.13

(dd, J= 2.4, 0.6 Hz, 1H), 7.57 (dd, J= 8.5, 2.5 Hz, 1H), 7.35 (dd, J= 9.6, 2.7 Hz, 1H), 7.25-7.21 (m, 1H), 7.08 (dq, J = 4.4, 3.0 Hz, 3H), 6.78 (ddd, J= 5.7, 4.9, 1.7 Hz, 3H), 4.86 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 2.87 (t, J = 7.8 Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 1.22 (t, J= 7.1, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 163.6, 162.9 (d, J_F= 123.6 Hz), 156.7, 146.6, 139.4, 137.9 (d, J_F = 7.6 Hz), 133.8, 133.7, 133.4, 131.8 (d,

J_F= 8.1 Hz), 129.3, 128.3, 115.9 (d, J_F = 22.4 Hz), 115.1 (d, J_F = 21.3 Hz), 114.8, 110.5, 67.6, 60.4, 53.6, 36.2, 30.1, 14.2.

3-(4-((5-Fluoro-2-(6-methoxypyridin-3-yl)benzyl)oxy)phenyl)propanoic acid (20b).

Following general procedure C, 20a (130 mg, 0.32 mmol) was hydrolyzed to give 117 mg (97 %) of an amorphous off white solid: ¹H NMR (400 MHz, CDCI₃) δ 8.16 -8.11 (m, 1H), 7.58 (dd, J = 8.5, 2.5 Hz, 1H), 7.35 (dd, J = 9.6, 2.7 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.11 - 7.05 (m, 3H), 6.81 - 6.75 (m, 3H), 4.86 (s, 2H), 3.96 (s, 3H), 2.88 (t, J = 7.7 Hz, 2H), 2.62 (t, J = 7.7 Hz, 2H).; ¹³C NMR (101 MHz, CDCI₃) δ 178.4, 163.6, 162.6 (d, J_F =

247.2 Hz), 156.8, 146.5, 139.6, 137.1 (d, J_F = 7.6 Hz), 133.7, 133.7, 133.1, 131.9 (d, J_F = 8.1 Hz), 129.3, 128.4, 115.9 (d, J_F = 22.4 Hz), 115.2(d, J_F= 21.3 Hz), 114.9, 110.6, 67.6, 53.7, 35.8, 29.8; HRMS calcd for C₂iH₁₇CIFN0₃Na (M + Na⁺) 408.0773, found: 408.0757.

Ethyl 3-(4-((5-fluoro-2-(6-methylpyridin-3-yl)benzyl)oxy)phenyl)propanoate (21a).

Following general procedure B, A (100 mg, 0.23 mmol) was coupled with 5-bromo-2- methylpyridine (42 mg, 0.24 mmol) to give 66 mg (72 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 2:3): ¹ H NMR (400 MHz, CDCI₃) δ 8.49

(d, J = 1.9 Hz, 1 H), 7.57 (dd, J = 7.9, 2.3 Hz, 1 H), 7.36 (dd, J = 9.6, 2.7 Hz, 1 H), 7.26 (dd, J = 8.5, 5.6 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 1 H), 7.13 - 7.06 (m, 3H), 6.80 - 6.74 (m, 2H), 4.85 (s, 2H), 4.1 1 (q, J = 7.1 Hz, 2H), 2.87 (t, J = 7.7 Hz, 2H), 2.62 - 2.53 (m, 5H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 162.7 (d, J_F = 247.5 Hz), 157.7, 156.7, 148.9, 137.1 (d, J_F = 7.5 Hz), 136.8, 133.8 (d, J_F = 3.3 Hz), 133.4, 132.2,

131.8 (d, J_F = 8.1 Hz), 129.3, 122.8, 1 16.0 (d, J_F = 22.4 Hz), 1 15.2 (d, J_F = 21.3 Hz), 1 14.8, 67.5, 60.4, 36.1 , 30.1 , 24.2, 14.2.

3-(4-((5-Fluoro-2-(6-methylpyridin-3-yl)benzyl)oxy)phenyl)propanoic acid (21 b).

Following general procedure C, 21 a (61 mg, 0.16 mmol) was hydrolyzed to give 50 mg (88 %) of an amorphous white solid: ¹ H NMR (400 MHz, DMSO) δ 1 1.95 (br. s, 1 H), 8.46 (d, J = 1.8 Hz, 1 H), 7.72 (dd, J = 8.0, 2.4 Hz, 1 H), 7.46 (dd, J = 9.9, 2.7 Hz, 1 H), 7.40 (dd, J = 8.5, 5.8 Hz, 1 H), 7.31 (dd, J = 9.6, 6.7 Hz, 2H), 7.1 1 (d, J = 8.7 Hz, 2H), 6.83 - 6.75 (m, 2H), 4.90 (s, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.46 (t, J = 7.5 Hz, 2H); ¹³C NMR

(101 MHz, DMSO) δ 173.8, 161.7 (d, J_F = 244.8 Hz), 157.0, 156.1 , 148.4, 137.1 (d, J_F = 7.7 Hz), 136.6, 134.3 (d, J_F= 3.1 Hz), 133.4, 132.2 (d, J_F = 8.2 Hz), 131.7, 129.2, 122.6, 1 16.0 (d, J_F = 22.2 Hz), 1 15.2 (d, J_F = 21.1 Hz), 1 14.5, 67.0, 35.5, 29.5, 23.7; HRMS calcd for C₂₂H₂i FN0₃Na (M + Na⁺) 366.1500, found: 366.1484.

Ethyl 3-(4-((5-fluoro-2-(6-fluoropyridin-3-yl)benzyl)oxy)phenyl)propanoate (22a).

Following general procedure B, A (100 mg, 0.23 mmol) was coupled with 5-bromo-2- fluoropyridine (43 mg, 0.25 mmol) to give 66 mg (72 %) of a colorless oil after flash chromatography (Si0₂, EtOAc:petroleum ether, 2:3): ¹H NMR (400 MHz, CDCI₃) δ 8.21

(d, J = 2.5 Hz, 1 H), 7.83 - 7.77 (m, 1 H), 7.36 (dd, J = 9.4, 2.7 Hz, 1 H), 7.30 - 7.23 (m, 1H), 7.16 - 7.07 (m, 3H), 6.96 (dd, J = 8.4, 2.9 Hz, 1H), 6.80 - 6.74 (m, 2H), 4.81 (s, 2H), 4.16-4.07 (m, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.23 (t, J= 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCI₃) δ 172.9, 163.1 (d, J_F = 240.1 Hz), 162.8 (d, J_F = 248.3 Hz), 156.5, 147.5 (d, J_F = 14.7 Hz), 141.8 (d, J_F = 8.0 Hz), 137.1 (d, J_F= 7.6 Hz),

133.6, 133.2 (d, J_F = 4.7 Hz), 132.8, 131.9 (d, J_F = 8.2 Hz), 129.4, 116.5 (d, J_F = 22.4 Hz), 115.5 (d, J_F = 21.4 Hz), 114.8, 109.2 (d, J_F = 37.4 Hz), 67.6, 60.4, 36.1, 30.1, 14.2.

3-(4-((5-Fluoro-2-(6-fluoropyridin-3-yl)benzyl)oxy)phenyl)propanoic acid (22b).

Following general procedure C, 22a (60 mg, 0.15 mmol) was hydrolyzed to give 46 mg (82 %) of colorless gummy solid: ¹H NMR (400 MHz, CDCI₃) δ 8.21 (d, J = 2.5 Hz, 1H), 7.80 (ddd, J= 8.3, 7.8, 2.5 Hz, 1H), 7.36 (dd, J = 9.4, 2.7 Hz, 1H), 7.30-7.23 (m, 1H), 7.16 - 7.06 (m, 3H), 6.96 (dd, J = 8.3, 2.7 Hz, 1H), 6.80 - 6.73 (m, 2H), 4.81 (s, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H; ¹³C NMR (101 MHz, CDCI₃) δ 178.6,

163.1 (d, J_F = 240.6 Hz), 162.8 (d, J_F = 248.4 Hz), 156.6, 147.4 (d, J_F= 14.4 Hz), 141.9, 137.1 (d, J_F= 7.6 Hz), 133.2, 133.2, 132.7 (d, J_F= 3.3 Hz), 131.9 (d, J_F = 8.2 Hz), 129.4, 116.5 (d, J_F= 22.4 Hz), 115.5 (d, J_F= 21.4 Hz), 114.8, 109.2 (d, J_F= 37.1 Hz), 67.6, 35.8, 29.7; HRMS calcd for C₂iH₁₇F₂N0₃Na (M + Na⁺) 392.1069, found: 392.1059. BIOLOGICAL ASSAYS

BRET p-arrestin 2 interaction assay (see Table 1 )

The BRET assay was performed as described previously (Jenkins, et al., Biochem. J. 2010, 432, 451-459). Briefly, plasmids encoding either GPR120 or FFA1 fused at their C-terminal to enhance yellow fluorescent protein were co-transfected into HEK 293 cells with a plasmid encoding β-arrestin 2 fused to Renilla luciferase. Cells were distributed into white 96 well plates 24 h post-transfection, then maintained in culture for another 24 h prior to their use. To conduct the assay cells were first washed in Hank's Balanced Salt Solution then the Renilla luciferase substrate coelenterazine h (5 μΜ) and the ligand of interest were added. Cells were incubated at 37° C for either 5 min (GPR120) or 30 min (FFA1) before luminescence at 535 and 475 nm was measured using a Pherastar FS. The ratio of luminescence at 535/475 nm was then used to calculate the BRET response.

Table 1

*EC₅₀ = 10-100 μΜ **EC₅₀= 1-10 μΜ *** ECso <1 μΜ

Claims

1. Compound according to formula (I):

wherein n is 1 or 2

R¹ is independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl

R² is independently selected from the group consisting of H, deuterium, halo, alkyl, substituted alkyl, cycloalkyi, substituted cycloalkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, oxo, alkoxy, substituted alkoxy, CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, and substituted aryloxy.

2. The compound of claim 1 , wherein n is 1.

3. The compound of claim 1 or 2, wherein R¹ is aryl or substituted aryl.

4. The compound of any one of claims 1-3, wherein R¹ is a phenyl group optionally substituted in the para-position.

4b. The compound of any one of claims 1-3, wherein R¹ is an optionally substituted 3- pyridyl group.

4c. The compound of any one of claims 1-3, wherein R¹ is an alkoxy group.

5. The compound of any one of the preceding claims, wherein R² is H or F.

6. A compound of claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:

3-(4-((4-Fluoro-[1 , 1 '-biphenyl]-2-yl)methoxy)phenyl)propanoic acid

3-(4-((4-Fluoro-4'-methyl-[1 , 1 '-biphenyl]-2-yl)methoxy)phenyl)propanoic acid

3-(4-((4-fluoro-4'-methoxy-[1 , 1 '-biphenyl]-2-yl)methoxy)phenyl)propanoic acid

7. Compound according to formula (I) for use in the treatment of a disease or condition selected from the group consisting of obesity, Type II diabetes and metabolic syndrome:

wherein n is 1 or 2

R¹ is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyi, substituted cycloalkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl and substituted heteroaryl

R² is independently selected from the group consisting of H, deuterium, halo, alkyl, substituted alkyl, cycloalkyi, substituted cycloalkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, oxo, alkoxy, substituted alkoxy, CN, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, and substituted aryloxy.

8. The compound of claim 7, wherein n is 1.

9. The compound of claim 7 or 8, wherein R¹ is aryl or substituted aryl.

10. The compound of any one of claims 7-9, wherein R¹ is a phenyl group optionally substituted in the para-position.