WO2007015744A1

WO2007015744A1 - Disubstituted thienyl compounds and their use as pharmaceuticals

Info

Publication number: WO2007015744A1
Application number: PCT/US2006/027333
Authority: WO
Inventors: Ganfeng Cao; Chu-Biao Xue; Rajan Anand; Taisheng Huang; Ling Kong; Joseph Glenn; Hao Feng
Original assignee: Incyte Corp
Current assignee: Incyte Corp
Priority date: 2005-07-21
Filing date: 2006-07-14
Publication date: 2007-02-08
Anticipated expiration: 2008-01-21

Abstract

The present invention relates to modulators of HM74a receptor, and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with HM74a receptor.

Description

DISUBSTITUTED THIENYL COMPOUNDS AND THEIR USE AS PHARMACEUTICALS

FIELD OF THE INVENTION

The present invention relates to modulators of the HM74a receptor, compositions thereof and methods of using the same.

BACKGROUND OF THE INVENTION

Coronary artery disease (or CAD) is the number one cause of death in the United States (Nature Med 2002, 8:1209-1262). The initiation and progression of CAD involves a complex interplay between multiple physiological processes, including inflammation, lipid homeostasis, and insulin resistance/diabetes mellitus. Multiple clinical studies have now shown that the three primary components of plasma lipids, low-density lipoprotein (or LDL), high-density lipoproteins (or HDL), and triglycerides (or TGs), are causally associated with the propensity to develop atherosclerosis and CAD. Along side other risk factors such as positive family history of CAD, elevated body-mass index, hypertension, and insulin resistance/diabetes mellitus, elevated plasma LDL and/or TG-rich lipoproteins and decreased plasma HDL levels have been defined as major cardiovascular risk factors by the National Cholesterol Education Program Adult Treatment Panel m (NCEP ATP III; Am J Cardio 2003, 92: 19i-26i). Accordingly, therapeutic intervention strategies designed to impact these plasma lipid components as well as those that underlie insulin resistance are of great interest to the medical community.

In terms of LDL-lowering, drugs of the statin class are structurally similar to the molecule hydroxymethylglutaryl-coenzyme A (HMG-CoA), a biosynthetic precursor of cholesterol. These drugs are competitive inhibitors of the rate-limiting step of cholesterol biosynthesis catalyzed by HMG-CoA reductase. Mechanistically, the statins lower LDL by upregulating the LDL receptor in the liver as well as by reducing the release of LDL into the circulation. As a monotherapy, the statin class of lipid lowering agents can reduce plasma LDL concentrations by 30-60% and triglycerides by 25%, producing a reduction in the incidence of CAD by 25-60% and the risk of death by 30%. Statins do not have an appreciable effect on HDL. A mechanistically distinct agent, Ezetimibe (Zetia, Merck and Co.), also possesses the ability to reduce plasma LDL, however it functions by inhibiting the absorption of cholesterol by the small intestine via antagonism of the NPClLl receptor (PNAS 2005, 102: 8132-8137). Monotherapy with Ezetimibe typically lowers LDL by 20%, however when co-formulated with a statin, maximal reductions can exceed 60%. As with the statins, however, Ezetimibe has a negligible effect on plasma HDL.

While statins can have a modest impact on circulating triglycerides, PPAR alpha agonists (or fibrates) are far superior in targeting this lipid endpoint. The fibrates function by increasing lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apolipoprotein C-IH (an inhibitor of lipoprotein lipase activity). One such fibrate, Fenofibrate (Tricor, Abort), has been shown in clinical studies to decrease plasma triglyceride levels upwards of 40-60%. Interestingly, the fibrate class of lipid-lowering drugs also has a modest, but significant effect on both LDL (20% reduction) and HDL (10% increase). Currently, the statin class of LDL lowering agents remains the cornerstone of dyslipidemia therapy. Despite the substantial reduction in cardiovascular events that have been achieved with this therapeutic approach, however, the cardio-protection that is afforded to patients by these therapies is still incomplete. It is now clear that therapies that are targeted to increase HDL cholesterol are critical in terms of maximizing patient cardio- protection. The only therapy available to date that has the ability to effectively raise circulating levels of cardioprotective HDL and consequently improve the progression of atherosclerosis in CAD patients is nicotinic acid (niacin or vitamin B₃). Nicotinic acid was first reported to modify lipoprotein profiles in 1955 (Altschul et al. Arch Biochem Biophys 1955, 54: 558-559). Its effects are the most broad-spectrum of any available therapy, effectively raising HDL levels (20-30%) as well as lowering circulating plasma LDL (16%) and triglycerides (38%). The clinical significance of this broad-spectrum activity has been revealed in multiple large clinical studies. In the most recent ARBITER 2 (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2; Taylor et al. Circulation 2004, 110: 3512-3517) study, patients on statin therapy were randomized to either placebo or 1000 mg extended release (ER) niacin (Niaspan, Kos Pharmaceuticals). Patients receiving niacin exhibited a statistically significant decrease in carotid intima-media thickness, a validated surrogate cardiovascular end point. This study also revealed a significantly reduced rate of intima-media thickness progression in subjects without detectable insulin resistance. This study indicates the incomplete cardio-protection that is offered by statin therapy and substantiates the utility of nicotinic acid in reducing overall cardiac risk in low-HDL patients.

While nicotinic acid has been used clinically to modify lipid profiles for over four decades, the mechanism of action of the compound has remained largely obscure. It has long been known that acute nicotinic acid dosing results in a profound decrease in circulating free fatty acids (FFAs). This anti-lipolytic activity was first hypothesized in 1980 to be mediated by a membrane receptor linked to a decrease in intracellular cAMP levels (Aktories et al. FEBS Letters 1980, 115: 11-14). This hypothesis was later confirmed and the implied Gi/₀ GPCR-coupling was verified using pertussis toxin sensitivity studies (Aktories et al. FEBS Letters 1983, 156: 88-92). The identification of specific nicotinic acid binding sites on the surface of adipose and spleen cells confirmed the membrane hypothesis and refined, using modern-day techniques, the G-protein coupling of the receptor itself (Lorenzen et al. MoI Pharm 2001, 59: 349-357). This G-protein mediated, anti-lipolytic activity of nicotinic acid was used for two decades to identify and characterize nicotinic acid analogues in terms of their therapeutic potential. Finally, in 2003, two independent groups simultaneously published the cloning of an orphan Gj_/o-coupled GPCR, HM74a (Wise et al. J Biol Chem 2003, 278: 9869-9874; Tunaru et al. Nat Med 2003, 9: 352-355), which binds to nicotinic acid with high affinity. As predicted, this receptor was shown to be expressed in adipose tissue and spleen, and binds to not only nicotinic acid, but also to the structurally related derivatives that had been previously shown to exhibit adipocyte anti-lipolytic activity. Mice that have been made deficient in the rodent ortholog of HM74a (Puma-g) by homologous recombination resist nicotinic acid-dependent FFA reduction and TG lowering. It is currently hypothesized that the nicotinic acid anti-lipolytic activity is based on the activation of this high affinity GPCR (HM74a), resulting in a decrease in intracellular cAMP and a subsequent attenuation of hormone sensitive lipase (HSL) activity. Decreased adipocyte lipolytic output results in a reduction in circulating FFA and a corresponding reduction in hepatic TGs, very- low density LDL (VLDL), and LDL. The increased levels of HDL arise from an effective reduction of cholesterol ester transfer protein activity due to decreased availability of VLDL acceptor molecules.

Beyond impacting lipid levels and lipoprotein profiles, FFAs play fundamental roles in the regulation of glycemic control. It is now recognized that chronically elevated plasma FFA concentrations cause insulin resistance in muscle and liver, and impair insulin secretion (reviewed in Defronzo et al. Int. J. Clin. Prac. 2004, 58: 9-21). In muscle, acute elevations in plasma FFA concentrations can increase intramyocellular lipid content; this can have direct negative effects on insulin receptor signaling and glucose transport. In liver, increased plasma FFAs lead to accelerated lipid oxidation and acetyl-CoA accumulation, the later of which stimulates the rate-limiting steps for hepatic glucose production. In the pancreas, long- term exposure to elevated FFAs has been shown to impair the beta-cell's ability to secrete insulin in response to glucose. This data has driven the hypothesis that adipose tissue FFA release is a primary driver of the underlying pathologies in type 2 diabetes, and strategies designed to reduce FFAs, for example by agonizing HM74A, may prove effective in improving insulin sensitivity and lowering blood glucose levels in patients with type 2 diabetics/metabolic syndrome

The utility of nicotinic acid as a hypolipidemic/FFA lowering agent is currently limited by four main factors. First, significant doses of nicotinic acid are required to impact FFA release and improve lipid parameters. Immediate release (IR) nicotinic acid is often dosed at 3-9g/day in order to achieve efficacy, and ER nicotinic acid (Niaspan) is typically dosed between l-2g/day. These high doses drive the second issue with nicotinic acid therapy, hepatotoxicity. One of the main metabolic routes for nicotinic acid is the formation of nicotinamide (NAM). Increased levels of NAM have been associated with elevated liver transaminase which can lead to hepatic dysfunction. This toxicity is particularly problematic for sustained release formulations and results in the need to monitor liver enzymes during the initiation of therapy. Third, high doses of nicotinic acid are associated with severe prostaglandin-mediated cutaneous flushing. Virtually all patients experience flushing when on IR-nicotinic acid at or near the T_max of the drug and discontinuation of therapy occurs in 20-50% of individuals. Niaspan, while exhibiting an increased dissolution time, still possesses a flushing frequency of approximately 70%, and this is in spite of the recommended dosing regimen that includes taking Niaspan along with an aspirin after a low- fat snack. Fourth, nicotinic acid therapy often results in FFA rebound, a condition whereby free fatty acid levels are not adequately suppressed throughout the dosing regimen, resulting in a compensatory increase in adipose tissue lipolysis. With immediate release nicotinic acid, this rebound phenomenon is so great that daily FFA AUCs are actually increased after therapy. Such FFA excursions can lead to impaired glycemic control and elevated blood glucose levels, both of which have been shown to occur in some individuals after nicotinic acid therapy. Giving the importance of nicotinic acid in modulating (especially agonizing) HM74a receptor and its limitations, novel small molecules designed to mimic the mechanism of nicotinic acid's action on HM74a offer the possibility of achieving greater HDL, LDL, TG, and FFA efficacy while avoiding adverse effects such as hepatotoxicity and cutaneous flushing. Such therapies are envisoned to have significant impact beyond dyslipidemia to include insulin resistance, hyperglycemia, and associated syndromes by virtue of their ability to more adequately reduce plasma FFA levels during the dosing interval. The present invention is directed to these, as well as other, important ends.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds of Formula I:

I or pharmaceutically acceptable salts or prodrugs thereof, wherein constituent members are defined herein.

The present invention further provides compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating HM74a receptor with a compound of the invention. The present invention further provides methods of agonizing HM74a receptor by contacting the HM74a receptor with a compound of the invention.

The present invention further provides methods of treating diseases associated with HM74a receptor.

The present invention further provides compounds of the invention for use in therapeutic methods of treating diseases associated with HM74a receptor.

The present invention further provides compounds of the invention for use in the preparation of a medicament for use in therapeutic methods of treating diseases associated with HM74a receptor.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds of Formula I:

or pharmaceutically acceptable salts or prodrugs thereof, wherein: ring A is thienyl; Q is COOH or tetrazolyl;

X is CR^laR^2a, NR³, 0, S, SO, or SO₂;

Y is carbocyclyl or heterocyclyl, each optionally substituted by 1, 2 or 3 R⁴; Z is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 R⁵; R¹, R², R^Ia, and R^2a are independently selected from H, C_1-6 alkyl, C_1-6 alkoxy, and C_2- to alkoxyalkyl;

R³ is H or C_1-6 alkyl;

R⁴ and R⁵ are independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, CM haloalkyl, Ci_-4 haloalkoxy, Cy¹, CN, NO₂, 0R^a, SR^a, C(0)R^b, C(0)NR^cR^d, C(O)OR^a, 0C(0)R^b, 0C(0)NR^cR^d, NR^cR^dC(O)NR^cR^d, NR^cR^d, NR^cC(0)R^b, NR^cC(0)0R^a, S(O)R^b, S(0)NR^cR^d, S(O)₂R^b, and S(0)₂NR^cR^d, wherein said C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, 0R^a, SR^a, Cy¹, OCy¹, SCy¹, S(O)₂Cy¹, C(0)R^b, C(0)NR^cR^d, C(O)OR^a, 0C(0)R^b, 0C(0)NR^cR^d NR^cR^d, NR^cC(O)R^b, NR^cC(0)0R^a, S(O)R^b, S(0)NR^cR^d, S(O)₂R^C, and S(0)₂NR^cR^d;

Cy¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, Cj_-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 haloalkyl, CN, NO₂, 0R^a', SR^a>, C(O)R^b>, C(0)NR^c R^d', C(0)0R^a', OC(O)R^b',

0C(0)NR^c'R^d>, NR^c'R^d', NR^c'C(0)R^b', NR^c>C(0)0R^a', S(O)R^b>, S(0)NR^c R^d', S(O)₂R^0', and

S(O)₂NR^c>R^d';

R^a and R^a are independently selected from H, Q_-6 alkyl, Ci_-6 haloalkyl, C_2-6 alkenyl, (Ci_-6 alkoxy)-C_1-6 alkyl, C_2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl;

R^b and R^b are independently selected from H, Ci_-6 alkyl, Ci_-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

R^c and R^c> are independently selected from H, Ci_-6 alkyl, Ci_-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; and R^d and R^d are independently selected from H, C_1-O alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C₂^ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; or R^c and R^d together with the N atom to which they are attached form a A-, 5-, 6- or 7-membered heterocycloalkyl group; or R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6- or

7-membered heterocycloalkyl group.

In some embodiments, Q is COOH. In some embodiments, X is CR^laR^2a or O. In some embodiments, X is CR^laR^2a. In some embodiments, X is CH₂.

In some embodiments, X is O.

In some embodiments, Y is aryl or heteroaryl, each optionally substituted by 1, 2, or 3 R⁴.

In some embodiments, Y is phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by 1 , 2, or 3 R⁴.

In some embodiments, Y is phenyl or a 6-membered heteroaryl, each optionally substituted by 1, 2, or 3 R⁴.

In some embodiments, Y is a 5-membered heteroaryl optionally substituted by 1, 2, or 3 R⁴. In some embodiments:

Y is:

U¹ is N or CH; U² and U³ are independently selected from N and CH;

U⁴ is NH, O, or S; and m, ml, m2, m3, and n are independently selected from 0, 1, 2 or 3.

In some embodiments: Y is:

U¹ is N or CH;

U² and U³ are independently selected from N and CH; U⁴ is NH, O, or S; and m, ml, m2, m3, and n are independently selected from 0, 1, 2 or 3.

In some embodiments, Y is phenyl, pyridyl, thienyl, or l,2,4-oxadiazol-5-yl, each optionally substituted by 1, 2, or 3 R⁴. In some embodiments, Y is phenyl, pyridyl, or l,2,4-oxadiazol-5-yl, each optionally substituted by 1, 2, or 3 R⁴.

In some embodiments, Z is phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by 1, 2, or 3 R⁵.

In some embodiments, Z is phenyl or a 6-membered heteroaryl, each optionally substituted by 1 , 2, or 3 R⁵.

In some embodiments, Z is a 5-membered heteroaryl optionally substituted by 1, 2, or 3 R⁵.

In some embodiments, Z is phenyl, furyl, thienyl, thiazolyl, pyridyl, pyrimidinyl or pyrazinyl, each optionally substituted by 1, 2, or 3 R⁵. In some embodiments, R¹ and R² are independently selected from H and C_1-6 alkyl.

In some embodiments, R¹ and R² are both H.

In some embodiments, R⁴ and R⁵ are independently selected from halo, CN, NO₂, OH, C_1-S alkyl, C_2-6 alkenyl, C₂-₆ alkynyl,

hydroxylalkyl, CM haloalkyl, Q^haloalkoxy, C_1-6 alkoxy, C_2-12 alkoxyalkyl, C_1-6 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, arylalkylsulfonyl, and heteroarylalkylsulfonyl.

In some embodiments, the compounds of the present invention have Formula II:

II wherein Q, X, Y, Z, R¹ and R² are defined herein above. In some embodiments, the compounds of the present invention have Formula HI:

m wherein Q, X, Y, Z, R¹ and R² are defined herein above.

In some embodiments, the compounds of the present invention have Formula IV:

IV wherein Q, X, Y, Z, R¹ and R² are defined herein above.

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.

For example, the term "C_1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

For compounds of the invention in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the

Markush group defined for R. In another example, when an optionally multiple substituent is designated in the form:

then it is understood that substituent R can occur s number of times on the ring, and R can be a different moiety at each occurrence. Further, in the above example, should the variable W be defined to include hydrogens, such as when W is said to be CH₂, NH, etc., any floating substituent such as R in the above example, can replace a hydrogen of the W variable as well as a hydrogen in any other non-variable component of the ring.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

The term "n-membered" where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro- naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n- pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.

As used herein, "alkenyl" refers to an alkyl group having one or more double carbon- carbon bonds. Example alkenyl groups include ethenyl, propenyl, and the like. The term "alkenylenyl" refers to a divalent linking alkenyl group.

As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon- carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. The term "alkynylenyl" refers to a divalent linking alkynyl group.

As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂CI₅, and the like.

As used herein, "carbocyclyl" groups are saturated (i.e., containing no double or triple bonds) or unsaturated (i.e., containing one or more double or triple bonds) cyclic hydrocarbon moieties. Carbocyclyl groups can be mono- , poly- (e.g., 2, 3 or 4 fused rings). Example carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, norbornyl, norpinyl, norcarnyl, adamantyl, phenyl, and the like. Carbocyclyl groups can be aromatic (e.g., "aryl") or non- aromatic (e.g., "cycloalkyl"). In some embodiments, carbocyclyl groups can have from about 3 to about 30 carbon atoms, about 3 to about 20, about 3 to about 10, or about 3 to about 7 ring-forming carbon atoms.

As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.

As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfide Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (can be aryl or heteroaryl) fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like.

As used herein, "heterocyclyl" or "heterocycle" refers to a saturated or unsaturated cyclic hydrocarbon wherein one or more of the ring-forming carbon atoms of the cyclic hydrocarbon is replaced by a heteroatom such as O, S, or N. Heterocyclyl groups can be aromatic (e.g., "heteroaryl") or non-aromatic (e.g., "heterocycloalkyl")- Heterocyclyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Heterocyclyl groups can be characterized as having 3-14 or 3-7 ring-forming atoms. In some embodiments, heterocyclyl groups can contain, in addition to at least one heteroatom, from about 1 to about 13, about 2 to about 10, or about 2 to about 7 carbon atoms and can be attached through a carbon atom or heteroatom. In further embodiments, any ring-forming carbon or heteroatom can be oxidized (e.g., have an oxo or sulfido substituent), or a nitrogen atom can be quaternized. Examples of heterocyclyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like, as well as any of the groups listed below for "heteroaryl" and "heterocycloalkyl." Further example heterocycles include pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 3,6- dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, piperidonyl, 4- piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thia-diazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzo- thiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, methylenedioxyphenyl, moφholinyl, naphthyridinyl, deca-hydroquinolinyl, 2H,6H-l,5,2dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl and isoxazolyl. Further examples of heterocycles include azetidin- 1-yl, 2,5-dihydro-lH-pyrrol-l-yl, piperindin-lyl, piperazin-1-yl, pyrrolidin-1-yl, isoquinol-2- yl, pyridin-1-yl, 3,6-dihydropyridin-l-yl, 2,3-dihydroindol-l-yl, l,3,4,9-tetrahydrocarbolin-2- yl, thieno[2,3-c]pyridin-6-yl, 3,4,10,10a-tetrahydro-lH-pyrazino[l,2-a]indol-2-yl, l,2,4,4a,5,6-hexahydro-pyrazino[l,2-a]quinolin-3-yl, pyrazino[l,2-a]quinolin-3-yl, diazepan- 1-yl, 1 ,4,5,6-tetrahydro-2H-benzo[fJisoquinolin-3-yl, 1 ,4,4a,5,6,10b-hexahydro-2H- benzo[f]isoquinolin-3-yl, 3,3a,8,8a-tetrahydro-lH-2-aza-cyclopenta[a]inden-2-yl, and 2,3,4,7-tetrahydro-lH-azepin-l-yl, azepan-1-yl.

As used herein, "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. As used herein, "heterocycloalkyl" refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems. Example "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (can be aryl or heteroaryl) fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, 4,5,6,7- tetrahydrothieno[2,3-c]pyridinyl, and benzo derivatives of heterocycles such as 1,2,3,4- tetrahydroisoquinyl, indolene and isoindolene groups. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo. As used herein, "alkoxy" refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

As used here, "haloalkoxy" refers to an -O-haloalkyl group. An example haloalkoxy group is OCF₃.

As used herein, "alkoxy alkyl" refers to alkyl substituted by alkoxy. An example alkoxyalkyl group is methoxymethyl.

As used herein, "arylalkyl" refers to alkyl substituted by aryl and "cycloalkylalkyl" refers to alkyl substituted by cycloalkyl. An example arylalkyl group is benzyl, and an example cycloalkylalky is cyclopropylmethyl.

As used herein, "heteroarylalkyl" refers to alkyl substituted by heteroaryl and "heterocycloalkylalkyl" refers to alkyl substituted by heterocycloalkyl. An example heteroarylalkyl group is pyridin-3-yl-methyl, and an example heterocycloalkylalkyl group is piperidin-3-yl-ethyl.

As used herein, "Ci_-6 alkylsulfonyl" refers to (Ci_-6 alkyl)-S(O)₂-. As used herein, "arylsulfonyl" refers to aryl-S(O)₂-. As used herein, "heteroarylsulfonyl" refers to heteroaryl-S(O)₂-.

As used herein, "arylalkylsulfonyl" refers to arylalkyl-S(O)₂-. As used herein, "heteroarylalkylsulfonyl" refers to heteroarylalkyl-S(O)₂-. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a "chiral resolving acid" which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., 5 and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms, such as keto-enol tautomers. Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. The phrase "compounds of the invention" is meant to include not only the free base forms of the compounds disclosed herein but also their pharmaceutically acceptable salts.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds described herein. As used herein, "prodrugs" refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.

In some embodiments, prodrugs of the present invention can include ester compounds of Formula I wherein Q is COOR and R is C_1-6 alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, or heteroarylalkyl, and the like. The COOR esters would be expected to hydrolyze in vivo to form the corresponding acid moiety. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.

Synthesis

The novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.

The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography. Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. The compounds of the invention can be prepared, for example, using the reaction pathways and techniques as described below.

Method A:

X=Br or l

1-3

Scheme 1

As shown in Scheme 1, compounds of formula 1-6 can be prepared using method A. A compound of forumla 1-1, i.e., 3-(4-bromophenyl)propanoic acid or 3-(4- iodoophenyl)propanoic acid, can be converted to a more reactive species such as its corresponding acid chloride 1-2, using a chlorinating reagent such as either thionyl chloride or oxalyl chloride. The acid chloride 1-2 can be coupled with methyl aminothiophenecarboxylate 1-3 to form an amide compound 1-4. Alternatively, compounds of formula 1-4 can be generated by coupling of 1-1 with 1-3 through formation of a mixed anhydride of 1-1 with isobutyl chloroformate followed by using a coupling agent such as EDCI/HOBt. The second aromatic ring (or heteroaromatic ring) at 4-position of the phenyl ring in 1-4 can be introduced by palladium catalyzed Suzuki coupling with a compound of ArB(OH)₂ such as an aryl boronic acid or by Negishi coupling with an organozinc halide compound of ArZnBr(Cl) such as an aryl zinc bromide, wherein Ar can be aryl, heteroaryl or substituted thereof. The ester group on the resulting coupling intermediate 1-5 can be hydrolyzed in the presence of a base such as sodium hydroxide to provide a compound of formula 1-6.

Method B:

2-5 2-4

1-3

Scheme 2

As shown in Scheme 2, compounds of formula 2-5 (wherein Ar can be aryl, heteroaryl or substituted version thereof) can be synthesized by method B, starting with 4- bromophenoxyacetic acid 2-1 following a similar reaction sequence to that described in Scheme 1.

X=Br, Cl, or I.

1-3

Scheme 3

Alternatively, compounds of 1-6 can be prepared using Method C described in Scheme

3. Suzuki coupling reaction of 3-[4-(dihydroxyboryl)phenyl]propanoic acid 3-1 with a compound of ArX such as an aryl halide (wherein Ar can be aryl, heteroaryl or the like, and wherein X is halo) provides a propanic acid 3-2. Conversion of the acid 3-2 to a more reactive species such as an acid chloride 3-3 with a chlorinating reagent such as thionyl chloride or oxalyl chloride, followed by coupling with methyl aminothiophenecarboxylate 1- 3 under basic conditions, gives an amide 1-5. Saponification of the ester group on compounds 1-5 in the presence of a base such as sodium hydroxide affords compounds of formula 1-6. Method D:

4-1 4-2 4-3 4-4

1-3

Scheme 4

Compounds of formula 4-7 can be prepared using Method D outlined in Scheme 4. 6- Bromopyridine-3-carbaldehyde 4-2 can be synthesized from 2,5-dibromopyridine 4-1 by selective lithium-halogen exchange at 5-position in a mixed solvent system such as ether/THF followed by an addition of N,N-dimethylformamide. Condensation of this aldehyde with malonic acid at an elevated temperature provides 3-(6-bromopyridin-3- yl)acrylic acid 4-3 which can be converted to a acid 4-4 by a Suzuki coupling reaction with a compound of ArB(OH)₂ such as an aryl boronic acid followed by hydrogenation, wherein Ar can be aryl, heteroaryl or substituted thereof. Compounds of formula 4-7 can be obtained from the resulting acids 4-4 in a similar fashion to that described in Scheme 1.

Method E.^¬

4-1 5-1 5-2 5-3

1-3

Scheme 5

As shown in Scheme 5, a compound of formula 5-6 can be synthesized by method E. 2,5-Dibromopyridine 4-1 is subjected to lithiation (for example, selective lithium-halogen exchange taking place at 2-position) in a solvent such as dichloromethane followed by an addition of N,N-dimethylformamide, to afford 5-bromopyridine-2~carbaldehyde 5-1. Compounds of formula 5-6, wherein Ar can be aryl, heteroaryl or substituted thereof, can be obtained from 5-1 following a similar reaction sequence to that described in scheme 4.

Method F:

Scheme 6

As shown in Scheme 6, Compounds of formula 6-6 can be prepared by using method F. Coupling of methyl aminothiophenecarboxylate 1-3 with benzyloxyacetyl chloride 6-1 followed by hydrogenolysis provides an alcohol 6-2. Nucleophilic substitution of 2-bromo-5- iodopyridine 6-3 with the resulting alcohol 6-2 using a base such as sodium hydride affords an alkoxypyridme intermediate 6-4. Compounds of formula 6-5 can be obtained from the intermediate 6-4 by palladium catalyzed Suzuki coupling with a compound of ArB(OH)₂ such as an aryl boronic acid or by Negishi coupling with an organozinc halide compound ArZnBr(Cl) such as an aryl zinc bromide, wherein Ar can be aryl, heteroaryl or substituted thereof. The ester group on the resulting compound 6-5 can be hydrolyzed in the presence of a base such as sodium hydroxide to provide a compound of formula 1-6. Method G:

7-6 7-5

1-3

Scheme 7

Compounds of formula 7-6 can be prepared by using method G as shown in Scheme 7. 3-Substituted propanoic acid 7-3 can be prepared from the condensation of a compound 7-1 having the formula of ArC(=NH)NHOH, wherein Ar can be aryl, heteroaryl or substituted thereof, with succinic anhydride 7-2. Coupling the acid 7-3 with methyl aminothiophenecarboxylate 1-3 to afford an amide 7-5 can be accomplished by converting the acid to a more reactive species such as an acid chloride 7-4, followed by the addition of methyl aminothiophenecarboxylate 1-3. The ester group on the resulting amide 7-5 can be hydrolyzed in the presence of a base such as sodium hydroxide to affords a compound of formula 7-6. Biology Methods

Compounds of the invention can modulate activity of the HM74a receptor. The term "modulate" is meant to refer to an ability to increase or decrease activity of a receptor. Accordingly, compounds of the invention can be used in methods of modulating HM74a receptor by contacting the receptor with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as full or partial agonists of HM74a receptors. In further embodiments, the compounds of the invention can be used to modulate activity of HM74a receptors in an individual by administering a modulating amount of a compound of the invention. The present invention further provides methods of treating diseases associated with the HM74a receptor, such as dyslipidemia, insulin resistance, hyperglycemia, and others, in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. Example diseases can include any disease, disorder or condition that is directly or indirectly linked to the HM74a receptor, such as diseases, disorders or conditions associated with low expression or low activity of HM74a receptor.

Examples of HM74a receptor-associated diseases include, but are not limited to, dyslipidemia, highly-active anti-retroviral therapy (HAART)-associated lipodystrophy, insulin resistance, diabetes such as type 2 diabetes mellitus, metabolic syndrome, atherosclerosis, coronary heart disease, stroke, obesity, elevated body mass index (BMI), elevated waist circumference, non-alcoholic fatty liver disease, hepatic steatosis, hypertension, and other pathologies, such as those (like many of the aforementioned) associated with elevated plasma FFAs.

As used herein, the term "dyslipidemia" refers to any one or more of the following diseases or conditions: low-HDL cholesterol, elevated cholesterol, elevated LDL cholesterol (including any combination of small, dense LDL, intermediate density lipoproteins, very-low density lipoproteins, and chylomicrons), elevated total cholesterol/HDL ratio, elevated plasma triglycerides, elevated circulating free fatty acid levels, and elevated lipoprotein (a).

In some embodiments, the present invention provides methods of lowering cholesterol level, lowering LDL, lowering total cholesterol/HDL ratio, lowering plasma triglycerides, lowering circulating free fatty acid levels, lowering lipoprotein (a), or raising HDL cholesterol, in a mammal by administering an effective amount of a compound or composition herein to the mammal. As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. In some embodiments, the cell is an adipocyte, a pancreatic cell, a hepatocyte, neuron, or cell comprising the eye.

As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the HM74a receptor with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the HM74a receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the HM74a receptor.

As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and

(3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). Combination Therapies

The compounds of the present invention can be used in combination with other enzyme or receptor modulators. Examples of other enzyme or receptor modulators include, but are not limited to, any one or more of the following: HMG-CoA reductase inhibitors (so- called statins), PPAR alpha agonists or selective modulators, PPAR gamma agonists or selective modulators (both TZD and non-TZD), PPAR delta agonists or selective modulators, PPAR alpha/gamma dual agonists, pan-PPAR agonists or selective modulators, glucocorticoid receptor antagonists or selective modulators, bile acid-binding resins, NPClLl receptor antagonists, cholesterol ester transfer protein inhibitors, apoA-I or synthetic apoA- I/HDL molecules, LXR agonists or selective modulators, FXR agonists or selective modulators, endothelial lipase inhibitors, hepatic lipase inhibitors, SR-BI modulators, estrogen receptor agonists or selective modulators, anabolic steroid or steroid derivatives, insulin or insulin mimetics, sulfonylureas, metformin or other biguanides, DPP-IV inhibitors, PTP-IB modulators, glucose-6-phosphatase inhibitors, Tl-translocase inhibitors, fructose- 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonists, 11-beta-hydroxy steroid dehydrogenase type 1 inhibitors, intestinal lipase inhibitors, neurotransmitter reuptake inhibitor, endocannabinoid receptor antagonist, NPY antagonist, MCH antagonists, MC4R agonists, GLP-I or GLP-I analogues (incretins), GLP-I receptor agonists, thiazide diuretics, beta-adrenergic receptor antagonists, angiotensin II converting enzyme inhibitors, angiotensin II receptor antagonists, calcium channel antagonists, and mineralocorticoid receptor antagonists, or combinations thereof.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral adminstration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose- response curves derived from in vitro or animal model test systems. The compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as antiviral agents, antibodies, immune suppressants, anti-inflammatory agents and the like, as well as any of the aforementioned enzyme or receptor modulators.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spin lable, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the HM74a in tissue samples, including human, and for identifying HM74a ligands by binding of a labeled compound. Accordingly, the present invention includes HM74a assays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to ²H (also written as D for deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³1, ¹²⁴1, ¹²⁵I and ¹³¹I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵1 , ¹³¹1, ³⁵S or will generally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵1, ¹²³1, ¹²⁴1, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful. It is understood that a "radio-labeled " or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of ³H, ¹⁴C, ¹²⁵1 , ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art.

A radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the enzyme. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of HM74a receptor-associated diseases or disorders, such as dyslipidemia, coronary heart disease and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. The compounds of the example section were found to be agonists of HM74a receptor according to one or more of the assays provided herein. EXAMPLES

Example 1

4-{[3-(2'-Methoxybiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic Acid

a) Methyl 4-[3-(4-Bromophenyl)propanoyl]aminothiophene-3-carhoxylate

Method 1: i) To 3-(4-bromophenyl)propanoic acid (5 g, 0.02 mol) in methylene chloride (100 mL) was added oxalyl chloride (9 mL, 0.1 mol). The solution was heated to 40⁰C for 2 h and then concentrated in vacuo to remove the solvent and residual oxalyl chloride (high vacuum) to give 5.4g (100%) crude product 3-(4-bromophenyl)propanoyl chloride, which was used directly for the next step. ii) To 3-(4-bromophenyl)propanoyl chloride (3.0 g, 12 mmol) in methylene chloride (30 mL) was added methyl 4-aminothiophene-3-carboxylate hydrochloride (5 g, 20 mmol) followed by a 2 M solution of sodium bicarbonate in water (12 mL). After being stirred overnight, the reaction mixture was poured into 10 mL water and then extracted with methylene chloride (2 x 20 mL). The organic layers were dried over MgSO₄ and then concentrated in vacuo to afford a brown solid. The crude product was purified via silica gel chromatography to give 1.44 g (98%) of product. LC-MS [M+2] 369.9.

Method 2:

To methyl 4-aminothiophene-3-carboxylate hydrochloride (100 mg, 0.50 mmol) in methylene chloride (5 mL) was added 3-(4-bromophenyl)propanoic acid (124 mg, 0.54 mmol) followed by triethylamine (0.2 mL, 2 mmol), 1-hydroxybenzotriazole (100 mg, 1 mmol) and N-(3-dimethylaminopropyl)-N^l-ethylcarbodiimide hydrochloride (200 mg, 1 mmol). The reaction was stirred for 2 days. The crude product was isolated after a brine wash and a methylene chloride extraction. The solvent was removed in vacuo. The residue was purified via silica gel chromatography to afford 189 mg (99%) of product as a white solid. LC-MS [M+l] 368.05, [M+2] 370.10.

b) Methyl 4-{[3-(2 '-Methoxybiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylate

To methyl 4-{[3-(4-bromophenyl)propanoyI]amino}thiophene-3-carboxylate (337 mg, 0.915 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) was added a 2 M solution of sodium carbonate in water (0.951 mL), (2-methoxyphenyl)boronic acid (152 mg, 0.999 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.1 mmol). The reaction mixture was heated in the microwave for 120 s at 150 ⁰C. The reaction mixture was cooled, filtered and then purified by silica gel chromatography to afford 130 mg (36%) of product as a white solid. LC-MS [M+l] 396.1.

c) 4-{[3-(2 '-Methoxybiphenyl^-ytypropanoylJaminoJthiopheneS-carboxylic Acid

To methyl 4-[3-(2'-methoxybiphenyl-4-yl)propanoyl]aminothiophene-3-carboxylate (130 mg, 0.33 mmol) in methanol (10 mL) was added potassium hydroxide (997 mg, 178 mmol). The mixture was stirred for 2 h and then concentrated in vacuo to remove the solvent. The residue was taken up in 10 mL of water and 10 mL of methylene chloride. The resulting solution was quenched with 12 Ν HCl (adjusting the pH to about 5). The organic layers were separated and dried over MgSO₄ and concentrated in vacuo. The crude product was purified via HPLC to afford a white amorphous powder (20 mg, 20%). LC-MS [M+l] 382.1.

Example 2 4-{[3-(2'-Ethoxybipheny]-4-yl)propanoyl]amino}thiophene-3-carboxylic Acid

The title compound was synthesized in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene- 3-carboxylate and (2-ethoxyphenyl)boronic acid gave methyl 4-{[3-(4- bromophenyl)propanoyl]amino}thiophene-3-carboxylate in 47% yield. LC-MS [M+l] 410.1

The hydrolysis of methyl 4-{[3-(2'-ethoxybiphenyl-4-yl)propanoyl]amino}thiophene- 3-carboxylate gave 4-{ [S-l^-ethoxybiphenyl^-y^propanoylJaminolthiophene-S-carboxylic acid in 18% yield as a white amorphous powder. LC-MS [M+l] 396.1.

Example 3

4-{[3-(2'-Cyanobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxyIic Acid

The title compound was prepared in a similar fashion as described for Example 1 The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (2-cyanophenyl)boronic acid gave methyl 4-{ [3-(2'-cyanobiphenyl-4- yl)propanoyl]amino}thiophene-3-carboxylate in 28% yield. LC-MS [M+l] 391.15.

The hydrolysis of methyl 4-{[3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene- 3-carboxylate gave 4-{ [3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid in 50% yield as a white amorphous powder. LC-MS [M+l] 377.1.

Example 4 4-{[3-(2',6'-Dimethoxybiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1.

The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-

3-carboxylate and (2,3-dimethoxyphenyl)boronic acid gave methyl 4-{ [3-(2\6'- dimethoxybJphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylate in 32% yield. LC-MS

[M+l] 426.1.

The hydrolysis of methyl 4-{[3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene- 3-carboxylate gave 4-{ [3-(2',6'-dimethoxybiphenyl-4-yl)propanoyl]amino}thiophene-3- carboxylic acid in 28% yield as a white amorphous powder. LC-MS [M+l] 412.2.

Example 5

4-({3-[2'-(Trifluoromethyl)biphenyl-4-yI]propanoyl}amino)thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-

3-carboxylate and (2-trifluoromethylphenyl)boronic acid gave methyl 4-({3-[2'-

(trifluoromethyl)biphenyl-4-yl]propanoyl}amino)thiophene-3-carboxylate in 40% yield. LC-

MS [M+l] 434.1

The hydrolysis of methyl 4-{[3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene- 3-carboxylate gave 4-({3-[2'-(trifluoromethyl)biphenyl-4-yl]propanoyI}amino)thiophene-3- carboxylic acid in 42% yield as a white amorphous powder, LC-MS [M+l] 420.1.

Example 6 4-{[3-(2'-Fluorobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxyIic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (2- fluoromethylphenyl)boronic acid gave methyl 4-{ [3-(2'-fluorobiphenyl-4- yl)propanoyl]amino}thiophene-3-carboxylate in 50% yield. LC-MS [M+l] 384.1.

The hydrolysis of methyl 4-{[3-(2'-fluorobiphenyl-4-yl)propanoyl]amino}thiophene- 3-carboxylate gave 4-{ [3-(2'-fluorobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid in 40% yield as a white amorphous powder. LC-MS [M+l] 370.1.

Example 7

4-{[3-(2'-Chlorobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic Acid

The title compound was synthesized in a similar fashion as described for Example 1.

The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene- 3-carboxylate and (2- chloromethylphenyl)boronic acid gave methyl 4-{[3-(2'- chlorobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylate in 50% yield. LC-MS [M+l]

400.1.

The hydrolysis of methyl 4-{ [3-(2'-chlorobiphenyl-4-yl)propanoyl]amino}thiophene- 3-carboxylate gave 4-{ [3-(2'-chlorobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid in 40% yield as a white amorphous powder. LC-MS [M+l] 386.1.

(

Example 8 4-{[3-(4'-Methoxybiphenyl-4-yI)propanoyl]amino}thiophene-3-carboxyIic Add

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (4'-methoxybiphenyl)boronic acid gave methyl 4-{[3-(4'-methoxybiphenyl- 4-yl)propanoyl]amino }thiophene-3-carboxylate in 99% yield. LC-MS [M+l] 396.1.

The hydrolysis of methyl 4-{[3-(4'-methoxybiphenyl-4- yl)propanoyl]amino}thiophene-3-carboxylate gave 4-{ [3-(4'-methoxybiphenyl-4- yl)propanoyl] amino }tbiophene-3-carboxy lie acid in 9% yield as a white amorphous powder. LC-MS [M+l] 382.1.

Example 9 4-({3-[2'-(Methoxymethyl)biphenyI-4-yI]propanoyI}amino)thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (2- methoxymethylphenyl)boronic acid gave 240 mg (99%) of methyl 4-({3-

[2'-(trifluoromethyl)biphenyl-4-yl]propanoyl}amino)thiophene-3-carboxylate. LC-MS

[M+23] 432.1.

The hydrolysis of 4-({3-[2'-(methoxymethyl)biphenyl-4-yl]propanoyl}amino) thiophene-3-carboxylate gave 4-({3-[2'-(methoxymethyl)biphenyl-4- yl]proρanoyl}amino)thiophene-3-carboxylic acid in 9% yield as a white amorphous powder. LC-MS [M+l] 396.1. Example 10

4-({3-[2'-(Methylsulfonyl)biphenyl-4-yl]propanoyl}amino)thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate (90 mg, 0.24 mmol) and [2-(methylthio)phenyl]boronic acid (45 mg, 0.27 mmol) gave 42 mg (40%) of methyl 4-{[3-(2'-chlorobiphenyl-4-yl)propanoyl]amino}thiophene-3- carboxylate. LC-MS [M+l] 412.0.

To methyl 4-({3-[2'-(methylthio)biphenyl-4-yl]propanoyl}amino)thiophene-3- carboxylate (42 mg, 0.10 mmol) in methanol (4 mL) and water (1 mL) was added Oxone (27 mg, 0.18 mmol). After being stirred for 1 h, the reaction content was poured into EtOAc (10 mL). The organic phase was separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were dried over MgSO₄ and then concentrated in vacuo. The residue was purified via HPLC (2 mg, 5%). LCMS [M+H] 430.1.

Example 11

4-{[3-(3'-Methoxybiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (3-methoxybiphenyl)boronic acid gave methyl 4-{[3-(4'-methoxybiphenyl-4~ yl)propanoyI]amino}thiophene-3-carboxylate in 28% yield. LC-MS [M+l] 396.0.

The hydrolysis of methyl 4-{[3-(3'-methoxybiphenyl-4- yl)propanoyl]amino}thiophene-3-carboxylate gave 4-{ [3-(3'-methoxybiphenyl-4- yl)propanoyl]amino}thiophene-3-carboxylic acid in 60% yield as a white amorphous powder. LC-MS [M+l] 382.1.

Example 12 4-{[3-(4'-Cyanobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4~{[3-(4-bromophenyl)proρanoyl]amino}thiophene-3- carboxylate and (4-cyanophenyl)boronic acid gave methyl 4-{[3-(4'-cyanobiphenyl-4- yl)propanoyl]amino}thiophene-3-carboxylate in 90% yield. LC-MS [M+l] 391.15.

The hydrolysis of methyl 4-{[3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene- 3-carboxylate gave 4-{ [3-(4'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid in 20% yield as a white amorphous powder. LC-MS [M+l] 377.1.

Example 13

4-(3-[4-(2-Furyl)phenyl]propanoylamino)tbiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (2-furyl)boronic acid gave methyl 4-(3-[4-(2- furyl)phenyl]propanoylamino)thiophene-3-carboxylate. The hydrolysis of methyl 4-(3-[4-(2-furyl)phenyl]propanoylamino)thiophene-3- carboxylate gave 4-(3-[4-(2-furyI)phenyl]propanoylamino)thiophene-3-carboxylic acid in 26% yield. LC-MS [M+l] 342.20.

Example 14

4-(3-[4-(2-Thienyl)phenyl3propanoylamino)thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (2-thienyl)boronic acid gave methyl 4-(3-[4-(2- thienyl)phenyl]propanoylamino)thiophene-3-carboxylate.

The hydrolysis of methyl 4-(3-[4-(2-thienyl)phenyl]propanoylamino)thiophene-3- carboxylate gave 4-(3-[4-(2-thienyl)phenyl]propanoylamino)thiophene-3-carboxylic acid in 16% yield. LC-MS [M+l] 358.10.

Example 15

4-{[3-(3'-Cyanobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (3-cyanophenyl)boronic acid gave methyl 4-{[3-(3'-cyanobiphenyl-4- yl)propanoyl]amino}thiophene-3-carboxyIate in 90% yield. LC-MS [M+l] 391.1. The hydrolysis of methyl 4-{[3-(3'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene- 3-carboxylate gave 4-{ [3-(3'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxyUc acid in 10% yield as a white amorphous powder. LC-MS [M+l] 377.1.

Example 16

4-{[3-(2'-Nitrobiphenyl-4-yl)propanoyl]aπiino}thiophene-3-carboxyIic Acid

The title compound was prepared in a similar fashion as described for Example 1. The

Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (2-nitro phenyl)boronic acid gave methyl 4-{[3-(2'-nitrobiphenyl-4- yl)propanoyl]ainino}thiophene-3-carboxylic carboxylate in 80% yield. LC-MS [M+l] 411.1. The hydrolysis of methyl 4-{[3-(2'-nitrobiphenyl-4-yl)propanoyl]amino}thiophene-3- carboxylic carboxylate gave 4-{[3-(2'-nitrobiphenyl-4-yl)propanoyl]amino}thiophene-3- carboxylic acid in 10% yield as a white amorphous powder. LC-MS [M+l] 397.1.

Example 17

4-({3-[2'-(Trifluoromethoxy)biphenyl-4-yl]propanoyI}amino)thiophene-3-carboxylic

Acid

^{The title} compound was prepared in a similar fashion as described for Example 1. The

Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (2- trifluoromethoxy)boronic acid gave 100 mg (80%) of methyl 4-({3-[2'-

(trifluoromethoxy)biphenyl-4-yl]propanoyl }ammo)thiophene-3-carboxylate. LC-MS [M+l] 450.0. The hydrolysis of methyl 4-({3-[2'-(trifluoromethoxy)biphenyl-4- yl]propanoyl }amrno)thiophene-3-carboxylate gave 4-({3-[2'-(txifluoromethoxy)biρhenyl-4- yl]propanoyl}amino)thiophene-3-carboxylic acid in 10% yield as a white amorphous powder. LC-MS [M+l] 436.1.

Example 18

4-({3-[4-(3-Thienyl)phenyl]propanoyl}amino)thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3- carboxylate and (3-thienyl)boronic acid gave methyl 4-(3-[4-(3- thienyl)phenyl]propanoylamino)thiophene-3-carboxylate in 90% yield. LC-MS [M+l] 372.0. The hydrolysis of methyl 4-(3-[4-(3-thienyl)phenyl]proρanoylamino)thiophene-3- carboxylate gave 4-(3-[4-(3-thienyl)phenyl]propanoylamino)thiophene-3-carboxylic acid in 10% yield. LC-MS [M+l] 358.1.

Example 19

4-[(3-Biphenyl-4-ylpropanoyl)amino]thiophene-3-carboxylic Acid

a) 4-{[3-(4-Bromophenyl)propanoyl]amiiιo}thiophene-3-carboxylic Acid

To methyl 4-{[3-(4-bromophenyl)propanoyl]amino}thiophene-3-carboxylate (189 mg, 0.513 mmol) in methanol (5 niL) was added potassium hydroxide pellets (516 mg, 9.2 mmol). The reaction was stirred at room temperature for 2 h and quenched with 1 N HCl till pH=6. The cloudy mixture was extracted with 2 x 20 mL EtOAC. The organic layers were combined, dried with brine and then over MgSO₄, and concentrated in vacuo. The crude product was then purified via HPLC to afford an amorphous white powder (50 mg, 30%), LC-MS [M+l] 355.1.

b) 4-[(3-Biphenyl-4-ylpropanoyl)amino]thiophene-3-carboxylic Acid

To 4-{[3-(4-bromoρhenyl)propanoyl]amino}thiophene-3-carboxylic acid (28 mg, 0.079 mmol) in N,N-dimethylformamide (2 mL) was added 2 M of sodium carbonate in water (0.08 mL), phenylboronic acid (10.1 mg, 0.083 mmol) and tetxakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol). The reaction was heated in microwave for 120 s at 150 ⁰C. After cooling to room temperature, the mixture was filtered and then purified via HPLC to afford the product (10 mg, 40%). LC-MS [M+l] 352.1.

Example 20

3-t3-(2'-Methoxybiphenyl-4-yl)propanoyl]aminothiophene-2-carboxyIic Acid

a) Methyl 3-[3-(4-Bromophenyl)pwpanoyl]aminothiophene-2-carboxylate.

3-(4-Bromophenyl)propanoic acid (1.00 g, 4.36 mmol) was dissolved in acetonitrile (15 mL). To the mixture was added 4-methylmorpholine (1.0 mL, 9.1 mmol) and then isobutyl chloroformate (0.6 mL, 5 mmol). To the above mixture, a solution of methyl 3- aminothiophene-2-carboxylate (0.68 g, 4.3 mmol) in acetonitrile (5 mL) was added. The mixture was stirred at room temperature for 1 h and concentrated. The residue was purified with CombiFlash to give 940 mg (60%) of product as a white powder. LC-MS [M+l] 368.00.

b) 3-[3-(2'-Methoxybiphenyl-4-yl)propanoyl]aminothiophene-2-carboxylic Acid.

To methyl 3-[3-(4-bromophenyl)propanoyl]aminothiophene-2-carboxylate (100 mg, 0.3 mmol) in N,N-dimethylformamide (2.0 mL) was added a 2 M solution of sodium carbonate in water (0.3 mL), (2-methoxyphenyl)boronic acid (45 mg, 0.3 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20 mg, 0.024 mmol) .The reaction was heated in a microwave for 120 s at 150 ⁰C. LC-MS indicated the coupling product 396.10 (M+l), as well as some hydrolyzed product 382.15. The reaction content was then concentrated to dryness, and then a 3 M solution of KOH in methanol (5 mL) was added. The mixture was then heated at 60 ⁰C for 15 min. LC-MS indicated completion of the reaction. The reaction mixture was then concentrated to dryness, and 5 mL DMSO and 0.5 mL of TFA were carefully added. The acidic solution was then filtered and purified by prep HPLC to give 24 mg (20%) of product. LC-MS [M+H] 382.20.

Example 21

3-{[3-(2'-CyanobiphenyI-4-yl)propanoyl]amino}thiophene-2-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 3-[3-(4-bromophenyl)propanoyl]aminothiophene-2- carboxylate and (2- cyanomethoxy)boronic acid gave methyl 3-{[3-(2'-cyanobiphenyl-4- yl)propanoyl]amino}thiophene-2-carboxylate in 99.4% yield. The hydrolysis of methyl 3-{[3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-

2-carboxylate gave 3-{ [3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-2-carboxylic acid in 80% yield as a white amorphous powder. LC-MS [M+l] 377.1.

Example 22 3-{[3-(3'-Cyanobiphenyl-4-yl)propanoyl]amino}thiophene-2-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 3-[3-(4-bromophenyl)propanoyl]aminothiophene-2- carboxylate and (3- cyanomethoxy)boronic acid gave methyl 3-{[3-(3'-cyanobiphenyl-4- yl)propanoyl]amino}thiophene-2-carboxylate in 90% yield. LC-MS [M+l] 391.1.

The hydrolysis of methyl 3-{[3-(3'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene- 2-carboxylate gave 3-{[3-(3'-cyanobiphenyl-4-yl)propanoyl] amino }thiophene-2-carboxylic acid in 10 % yield as a white amorphous powder. LC-MS [M+l] 377.0.

Example 23

3-[3-(2',6'-Dimethoxybiphenyl-4-yl)propanoyl]aminothiophene-2-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 20. The Suzuki coupling reaction of methyl 3-[3-(4-bromophenyl)propanoyl]aminothiophene-2- carboxylate and (2,6-dimethoxyphenyl)boronic acid gave methyl 3-[3-(2',6'- dimethoxybiphenyl-4-yl)propanoyl]aminothiophene-2-carboxylate. { LC-MS [M+l] 426.20}. The hydrolysis of methyl 3-[3-(2',6'-dimethoxybiphenyl-4-yl)propanoyl]aminothiophene-2- carboxylate gave 3-[3-(2',6'-dimethoxybiphenyl-4-yl)propanoyl]aminothiophene-2-carboxylic acid in 30% yield. LC-MS [M+l] 412.10.

Example 24 3-[(3-Biphenyl-4-ylpropanoyl)amino]thiophene-2-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 20. The Suzuki coupling reaction of methyl 3-[3-(4-bromophenyl)propanoyl]aminothiophene-2- carboxylate and phenylboronic acid gave methyl 3-[(3-biphenyl-4- ylpropanoyl)amino]thiophene-2-carboxylate. {LC-MS [M+l] 366.10} The hydrolysis of methyl 3-[(3-biphenyl-4-ylpropanoyl)amino]thiophene-2-carboxylate_J gave 3-[(3-biphenyl-4- ylpropanoyl)amino]thiophene-2-carboxylic acid in 20% yield. LC-MS [M+l] 352.20.

Example 25 3-{[3-(2'-Ethoxybiphenyl-4-yI)propanoyI]amino}thiophene-2-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 1. The Suzuki coupling reaction of methyl 3-[3-(4-bromophenyl)propanoyl]aminothiophene-2- carboxylate and (2-ethoxyphenyl)boronic acid gave methyl 3-{[3-(2'-ethoxybiphenyl-4- yI)propanoyl]amino}thiophene-2-carboxylate in 30% yield. LC-MS [M+l] 410.1.

The hydrolysis of methyl 3-{[3-(2'-ethoxybiphenyl-4-yl)propanoyI]amino}thiophene- 2-carboxylate gave 3-{ [S-φ'-ethoxybiphenyM-yOpropanoyltøminoJthiophene^-carboxylic acid in 50% yield as a white amorphous powder. LC-MS [M+l] 396.1.

Example 26

3-{[3-(4'-Cyanobiphenyl-4-yl)propanoyl]amino}thiophene-2-carboxylic Acid

Suzuki coupling reaction of methyl 3-[3-(4-bromophenyl)propanoyl]aminothiophene-2- carboxylate and (4- cyanophenyl)boronic acid gave methyl 3-{[3-(4'-cyanobiphenyl-4- yl)propanoyl]amino}thiophene-2-carboxylate in 90% yield. LC-MS [M+l] 391.1.

The hydrolysis of methyl 3-{[3-(4'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene- 2-carboxylate gave 3-{[3-(4'-cyanobiρhenyl-4-yl)propanoyl] amino }thiophene-2-carboxylic acid in 20% yield as a white amorphous powder. LC-MS [M+l] 377.1.

Example 27

2-[3-(2'-Methoxybiphenyl-4-yl)propanoyl]aminothiophene-3-carboxylic Acid

a) Methyl 2-[3-(4-Bromophenyl)propanoyl]aminothiophene-3-carboxylate.

To a mixture of methyl 2-aminothiophene-3-carboxylate (1.7 g, 0.011 mol) and 3-(4- bromophenyl)propanoic acid (2.08 g, 9.08 mmol) in methylene chloride (10.0 mL) was added 1-hydroxybenzotriazole (1.8 g, 13 mmol), N-(3-dimethylaminopropyi)-N- ethylcarbodiimide hydrochloride (2.6 g, 14 mmol) and triethylamine (5.0 mL, 36 mmol). The resulting mixture was stirred at room temperature overnight and diluted with methylene chloride. The solution was washed with 1 Ν NaOH, brine, dried over MgSO₄, filtered and concentrated. The residue was purified with Combiflash (0-5% ethyl acetate in hexanes) to give 1.03 g (38%) of product. LC-MS [M+l] 369.15.

b) 2-[3-(2 '-Methoxybiphenyl^-yljpropanoylJaminothiophene-S-carboxylic Acid.

To methyl 2-[3-(4-bromophenyl)propanoyl]aminothiophene-3-carboxylate (100 mg, 0.3 mmol) in Ν,Ν-dimethylformamide (2.0 mL) was added a 2 M solution of sodium carbonate in water (0.3 mL), (2-methoxyphenyl)boronic acid (45 mg, 0.30 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20 mg, 0.024 mmol). The reaction was heated in the microwave for 120 s at 150 ⁰C. LC-MS indicated the coupling product 396.10 (M+l). The reaction content was then concentrated to dryness, and then 5 mL of KOH in methanol (3 M) was added, the solution was heated at 60 ⁰C for 15 min. LC-MS indicated the completion of the reaction. The reaction mixture was then concentrated to dryness, and 5 mL of DMSO and 0.5 mL of TFA was carefully added. The resulting solution was filtered and purified by prep HPLC to give 32.8 mg (30%) of product. LC-MS [M+l] 382.20.

Example 28 2-[3-(2',6'-Dimethoxybiphenyl-4-yI)propanoyI]aminothiophene-3-carboxyIic Acid

The title compound was prepared in a similar fashion as described for example 27. The Suzuki coupling reaction of Methyl 3-[3-(4-bromophenyl)propanoyl]aminothiophene-2- carboxylate and 2,6-dimethoxyphenylboronic acid gave methyl 2-[3-(2',6'- dimethoxybiphenyl-4-yl)propanoyI]aminotbiophene-3-carboxylate. The hydrolysis of methyl 2-[3-(2',6'-dimethoxybiphenyl-4-yl)propanoyl]aminothiophene-3-carboxylate, gave 2-[3- (2',6'-dimethoxybiphenyl-4-yl)propanoyl]aminothiophene-3-carboxylic acid in 40% yield. LC-MS [M+l] 412.20.

Example 29

2-[(Biphenyl-4-yloxy)acetyI]aminothiophene-3-carboxylic Acid

a) Methyl 2-[(4-Bromophenoxy)acetyl]aminothiophene-3-carboxylate

To a stirred solution of (4-bromophenoxy)acetic acid (5.0 g, 0.022 mol) in dry methylene chloride (80 mL) at 0 ⁰C was added catalytic amount of DMF (5 drops) followed by oxalyl chloride (5.5 mL, 0.065 mol). The resulting yellow solution was stirred at room temperature for 1 h and concentrated under reduced pressure to give the desired acid chloride as a yellow solid which was used directly for next step of reaction. Methyl 2- aminothiophene-3-carboxyIate (3.4 g, 0.022 mol) and a 1.0 M solution of sodium bicarbonate in water (30 niL) were sequentially added to a solution of the acid chloride in methylene chloride. The mixture was stirred at room temperature overnight. To the reaction mixture methylene chloride (100 mL) and water (80 mL) were added. The organic layer was separated and the aqueous layer was extracted with methylene chloride (2 x 100 mL). The combined organic solution was dried, filtered and concentrated to give 7.4 g (92%) of product as a yellowish solid. LC-MS 369.9 (M+l).

b) 2-[(Biphenyl-4-yloxy)acetyl]aminothiophene-3-carboxylicAcid

Methyl 2-[(4-bromophenoxy)acetyl]aminothiophene-3-carboxylate (100 mg, 0.27 mmol and phenylboronic acid (36 mg, 0.30 mmol) were dissolved in DMF (1.0 mL) before adding a 2 M solution of sodium carbonate in water (0.3 mL) and polymer-bound tetrakis(triphenylphosphine) palladium (0.5 mmol/g loading; 50 mg, 0.03 mmol). The mixture was irradiated using microwave for 1 min at 150 ⁰C and filtered into a scintillation vial through a short pad of silica gel. The pad was washed with additional DMF (3 mL). Water (1.0 mL) and potassium hydroxide (0.152 g, 2.7 mmol) were added to the filtrate. The resulting mixture was stirred overnight (20 h) at room temperature and acidified with 3 N HCl. Purification by prep-HPLC gave 3 mg (3.1%) of product as a white powder. LC-MS [M+l] 354.10.

Example 30

2-([(2'-Methoxybiphenyl-4-yl)oxy]acetylamino)thiophene-3-carboxyIic Acid

The title compound was prepared in a similar manner as described for Example 29. LC-MS [M+l] 384.10.

Example 31 2-{[3-(4-Pyridin-2-ylphenyl)propanoyl]amino}thiophene-3-carboxylic Acid

a) 3-(4-Pyridin-2-ylphenyl)propanoic Acid.

3-[4-(Dihydroxyboryl)phenyl]propanoic acid (0.388 g, 2.00 mmol), 2-bromopyridine (0.21 mL, 2.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.104 mmol) were mixed in acetonitrile (10.0 mL) and a 0.4 M solution of sodium carbonate in water (10.0 mL). The reaction mixture was heated in a microwave for 1000 seconds at 150 ⁰C. LC-MS indicated the reaction was complete. LC-MS (M+l) 228.0. The reaction mixture was then concentrated to dryness and used directly for next step.

b) 3-(4-Pyridin-2 -ylphenyl)propanoyl Chloride

To 3-(4-pyridin-2-ylρhenyl)propanoic acid (470 mg, 2.1 mmol) in methylene chloride (10 mL) was added oxalyl chloride (0.87 mL, 10 mmol). The reaction was heated to 40 ⁰C for 2 h. A piperidine quench showed the conversion to acid chloride. The solvent was removed in vacuo and the crude product was used in the next reaction (510 mg , 99%).

c) Methyl 2-{[3-(4~Pyridin-2-ylphenyl)propanoyl]amino}thiophene-3-carboxylate

To 3-(4-pyridin-2-ylphenyl)propanoyl chloride (510 mg, 2.1 xnmol) in methylene chloride (10 mL) was added methyl 4-aminothiophene-3-carboxylate hydrochloride (422 mg, 2.18 mmol) followed by a 2 M solution of sodium bicarbonate in water (2 mL). The reaction was stirred overnight. To the reaction mixture was added water (10 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude product was purified via combiflash. The purified material was mainly the desired product (97 mg, 99%). LC-MS [M+l], 367.1.

d) 2-{[3-(4-Pyridin-2-ylphenyl)propanoyl]amino}thiophene-3-carboxylic Acid

To methyl 2-{ [3-(4-pyridin-2-ylphenyl)propanoyl]amino}thiophene-3-carboxylate (97 mg, 0.26 mmol) in methanol (10 mL) was added potassium hydroxide (1.00 g, 17.8 mmol). The reaction mixture was stirred at room temperature for 2 h. Methanol was removed in vacuo. The residue was diluted with water (10 mL) and the pH was adjusted to 3 using concentrated HCl. The resulting solution was extracted with EtOAc (2 x 10 mL). The organic layers were combined and the solvent removed in vacuo. The residue was then purified via HPLC (9 mg, 10%). LC-MS [M+H] 353.1

Example 32

2-{[3-(4-Pyridin-2-ylphenyl)propanoyl]amino}thiophene-3-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 31. Methyl 2-{ [3-(4-pyridin-2-ylphenyl)propanoyl]amino}thiophene-3-carboxylate (LC-MS [M+l] 367.1) was obtained in 50% yield by coupling of methyl 2-aminothiophene-3- carboxylate with 3-[(4-pyridin-2-yl)phenyl]propanoyl chloride. The hydrolysis of methyl 2- { [3-(4-pyridin-2-ylphenyl)propanoyl]amino }thiophene-3-carboxylate gave 2-{ [3~(4-pyridin- 2-ylphenyl)propanoyl]amino}thiophene-3-carboxylic acid in 10% yield. LC-MS [M+l] 353.1.

Example 33 3-{[3-(4-Pyridin-2-ylphenyl)propanoyl]amino}thiophene-2-carboxylic Acid

The title compound was prepared in a similar fashion as described for Example 31.

Methyl 3-{ [3-(4-pyridin-2-ylphenyl)propanoyl]amino}thiophene-2-carboxylate (LC-MS [M+l] 367.1) was obtained in 60% yield and the hydrolysis of methyl 3-{ [3-(4-pyridin-2- ylphenyl)ρropanoyl]amino}thiophene-2-carboxylate gave 3-{ [3-(4-pyridin-2- ylphenyl)propanoyl]amino}thiophene-2carboxylic acid in 20% yield. LC-MS [M+l] 353.1.

Example 34

3-{[3-(4-Pyrimidin-2-ylphenyI)propanoyl]amino}thiophene-2-carboxylic Acid

This compound was prepared in a similar fashion as described for Example 31. LC- MS [M+l] 354.1.

Example 35 4-{[3-(4-Pyrazin-2-ylphenyl)propanoyl]amino}thiophene-3-carboxylic Acid

Example 36

4-{[3-(4-Pyridin-3-ylphenyl)propanoyI]amino}thiophene-3-carboxylic Acid

This compound was prepared in a similar fashion as described for Example 31. LC- MS [M+l] 353.1.

Example 37 2-({3-[4-(l,3-Thiazol-2-yI)phenyI]propanoyl}amino)thiophene-3-carboxylic Acid

This compound was prepared in a similar fashion as described for Example 31. LC- MS [M+l] 359.1.

Example 38 4-({3-[6-(2-Methoxyphenyl)pyridin-3-yl]propanoyl}amino)thiophene-3-carboxylic Acid

a) ό-Bromo-pyridineS-carbaldehyde.

2,5-Dibromopyridine (10.0 g, 0.0422 mol) was dissolved in the mixture solvent of ether (150.0 mL) and tetrahydrofuran (100.0 mL). The resulting solution was cooled to -78

⁰C, and ra-butyllithium (1.60 M in hexane, 26.4 mL) was added slowly. The reaction mixture was stirred at -78 ⁰C for another 30 min before N,N-dimethylformamide (6.5 mL, 0.084 mol) was added slowly. The mixture was stirred at -78 ⁰C for 1 hr and then warmed up to -30⁰C over 30 min. LC-MS showed no starting material. The reaction was quenched with water. The organic phase was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified with 10%EtOAC/Hexane on silica gel to afford the desired product as a white solid (2.4 g, 30%). LC-MS,[M+1] 186.2;

188.2.

b) (2E)-3-(6-Bromopyridin-3~yl)acrylic Acid

A mixture of 6-bromo-pyridine-3-carbaldehyde (2.3 g, 0.012 mol), malonic acid (2.8 g, 0.027 mol), pyridine (7 mL, 0.09 mol) and piperidine (0.1 mL, 0.001 mol) was heated at 100 ⁰C for one hour. The mixture was cooled to room temperature and filtered. The obtained precipitates were washed with water, dried under reduced pressure to give the desired product

(1.9 g, 67%). LC-MS [M+l] 228.0; 230.0.

c) (2E)-3-(6-Phenylpyridin-3-yl)acrylic Acid.

(2Z)-3-(6-Bromopyridin-3-yl)acrylic acid (0.15 g, 0.66 mmol) and phenylboronic acid (0.10 g, 0.86 mmol) were dissolved in N,N-dimethylformamide (2 mL). The solution was then degassed with N₂ for 5 min, and to the solution were added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1)

(50 mg, 0.06 mmol) and a 2.00 M solution of sodium carbonate in water (1 mL) under N₂.

The reaction mixture was microwave-irradiated at 120 ⁰C for 20 min. After cooling down to room temperature, 10 mL of water and 10 mL of EtOAc were added. The organic phase was separated and the aqueous layer was extracted with methylene chloride. The resulting aqueous solution was acidified to pH=3 and then evaporated under reduced pressure to afford the desired product (100 mg, 70%). LC-MS [M+l] 226.3.

d) 3-(6-Phenylpyridin-3-yl)propanoic Acid

To a solution of (2E)-3-(6-phenylpyridin-3-yl)acrylic acid (200 mg, 0.888 mmol) in

DMF (5.0 mL) was added 10% palladium on activated carbon (wet, 10 mg) at room temperature. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 15 min. LC-MS showed that the starting material disappeared completely. The mixture was passed through a Celite pad. The filterate was evaporated under reduced pressure to give the desired product (199mg, 100%). LC-MS [M+l] 228.2.

e) 4-({3-[6-{2-Methoxyphenyl)pyήdin-3-yl]propanoyl}amino)thiophene-3~carboxylic Acid.

To a one-neck round-bottom flask were added 3-[6-(2-methoxyphenyl)pyridin-3- yl]propanoic acid (0.050 g, 0.19 mmol) and thionyl chloride (2.0 mL, 27 mmol). After being stirred at 80 ⁰C for 1 h, the solvent was removed under reduced pressure and the residue was dissolved in methylene chloride (2.0 mL). To the resulting solution were added methyl 4- aminothiophene-3-carboxylate (40 mg, 0.25 mmol) and a 1.0 M solution of sodium bicarbonate in water (2.0 mL). After being stirred overnight, the mixture was diluted with 5 mL of methylene chloride and 5 mL of water. The organic phase was separated and the aqueous layer was extracted with methylene chloride. The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and evaporated. The residue was then dissolved in TBDF (6 mL) and MeOH (3 mL). To the resulting solution were added LiOHJH₂O (20 mg) and water (1 mL). The mixture was stirred at room temperature for 1 h. The organic solvents were removed under reduced pressure. The residue was acidified to pH=3, and then purified using prep-HPLC to give the desired product (25 mg, 20%). LC-MS [M+l] 383.1.

Example 39

2-({3-[6-(2-Methoxyphenyl)pyridin-3-yl]propanoyl}amino)thiophene-3-carboxylic Acid

This compound was prepared by procedures analogous to those of Example 38. LC-

MS [M+l] 383.1.

Example 40

3-({3-[6-(2-Methoxyphenyl)pyridin-3-yl]propanoyl}amino)thiophene-2-carboxylic Acid

This compound was prepared by procedures analogous to those of Example 38. LC- MS [M+l] 383.1.

Example 41 2-({3-[S-(2-Fluoropheny^])pyridin-2-yl]propanoyl}amino)thiophene-3-carboxylic Acid

a) 5-Bromopyridine-2-carbaldehyde

^OHCYΛ

A solution of 2,5-dibromopyridine (9.48g, 40 mmol) in methylene chloride (100 mL) was cooled to -78 ⁰C , and π-butyllithium (1.60 M in hexane, 25.0 mL, 40 mmol ) was then added to the solution. After stirring at -78 ⁰C for 30 min, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The mixture was allowed to slowly warm up to room temperature and stirring was continued for one more hour at room temperature. The reaction was quenched by addition of aqueous NH₄Cl. Ethyl acetate was used to extract the product, and the extracts were dried, filtered and concentrated to give 8.50g (74.2%) of crude product, which was used directly for next step.

b) (2E)-3-(5-Bromopyridin-2-yl)acrylic Acid

A mixture of 5-bromopyridine-2-carbaldehyde (3.0 g, 16 mmol), malonic acid (5.0 g,

48 mmol), pyridine (10.0 mL, 124 mmol) and piperidine (0.2 mL, 2 mmol) was heated at 100 ⁰C for 3 h. After cooling to room temperature, the solid formed was collected by filtration, washed with water, and dried to give 1.2g (54%) of product. LC-MS [M] 228.0.

c) 3-[5-(2-Fluorophenyl)pyridin-2-yl]propanoic Acid

3-[5-(2-Huorophenyl)pyridin-2-yl]propanoic acid was synthesized in a similar fashion as described in procedures c and d of Example 38. LC-MS [M+l] 246.1.

d) 4-(3-[5-(2~Fluorophenyl)pyridin-2-yl]propanoylamino)thiophene-3-carboxylicAcid The title compound was synthesized in a similar fashion to that described in step e) of

Example 38. LC-MS [M+l] 371.0.

Example 42 3-[({[5-(3-Methoxyphenyl)pyridin-2-yI]oxy}acetyl)amino]thiophene-2-carboxyIic Acid

a) Methyl 3-(Glycoloylamino)thiophene-2-carboxylate.

A mixture of methyl 2-aminothiophene-3-carboxylate (2.2 g, 14 mmol), benzyloxyacetyl chloride (2.2 niL, 14 mmol), methylene chloride (20 mL), and a 3.0 M solution of sodium bicarbonate in water (20.0 mL) was stirred at room temperature overnight. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was then dissolved in MeOH (10 mL). To the solution was added Pd/C (50 mg). The mixture was stirred at room temperature under H₂ at 50 psi for 5 h. The mixture was poured through a celite pad. The filterate was evaporated under reduced pressure to provide the desired product (2.5 g, 86%). LC-MS [M+l]=216.2.

b) 3-({[(5-Iodopyridin-2-yl)oxy]acetylJamino)thiophene-2-carboxylic Acid.

To a solution of 2-bromo-5-iodopyridine (0.66 g, 2.3 mmol) in DMF (5 mL) at -10 ⁰C was added sodium hydride (0.46 g, 12 mmol). Methyl 3-(glycoloylamino)thiophene-2- carboxylate (0.5 g, 2 mmol) was added in portions. After being stirred at 50⁰C overnight, the pH of the mixture was adjusted to 5 by addition of HCl. EtOAc was used to extract the product. The combined extracts were washed with brine, dried, filtered, and evaporated under reduced pressure to afford the desired product which was purified on silica gel with 20%EtOAc/Hexane (120 mg, 21%). LC-MS [M+l] 404.9.

c) 3-[({[5-(3-Methoxyphenyl)pyridin~2-yl]oxy}acetyl)amino]thiophene-2-carboxylic Acid.

3-({[(5-Iodopyridin-2-yl)oxy]acetyl}amino)thiophene-2-carboxyIic acid (30 mg, 0.07 mmol) and (3-methoxyphenyl)boronic acid (11 mg, 0.074 mmol) were dissolved in N,N- dimethylformamide (1 mL) and toluene (1 mL). After being degassed with N₂ for 2 min, [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(π) complex with dichloromethane (1:1) (3 mg, 0.004 mmol) and a 2.00 M solution of sodium carbonate in water (1 mL) were added to the solution under N₂. The reaction mixture was microwave-irradiated at 140 ⁰C for 40 min. The reaction mixture was diluted by addition of 5 mL of toluene and 5 mL of water. The organic phase was separated and the aqueous layer was extracted with methylene chloride. The aqueous solution was acidified to pH=3 and evaporated under reduced pressure to give the crude desired product which was purified using Prep-HPLC to give the desired product (11 mg, 33%). LC-MS [M+l] 385.4.

Example 43 3-[({[5-(2-Methoxyphenyl)pyridin-2-yl]oxy}acetyl)amino]thiophene-2-carboxylic Acid

This compound was prepared by procedures analogous to those of Example 42. LC- MS [M+l] 385.0.

Example 44

3-[({[5-(2-Fluoroxyphenyl)pyridin-2-yl]oxy}acetyl)amino]thiophene-2-carboxylic Acid

This compound was prepared by procedures analogous to those of Example 42. LC- MS [M+l] 373.1.

Example 45 3-{[({5-[2-(Trifluoromethyl)phenyl]pyridin-2-yl}oxy)acetyl]amino}thiophene-2- carboxylic Acid

This compound was prepared by procedures analogous to those of Example 42. LC-

MS [M+l] 422.9.

Example 46 3-({[(5-Phenylpyridin-2-yI)oxy]acetyI}amino)thiophene-2-carboxylic Acid

This compound was prepared by procedures analogous to those of Example 42. LC- MS [M+l] 355.1.

Example 47

3-[({[5-(2-Cyanophenyl)pyridin-2-yl]oxy}acetyl)amino]thiophene-2-carboxylic Add

This compound was prepared by procedures analogous to those of Example 42. LC- MS [M+H] 380.0.

Example 48

4-[3-(3-Phenyl-l,2,4-oxadiazol-5-yl)propanoyl]aminothiophene-3-carboxylic Add

a) 3-(3-Phenyl-l,2,4-oxadiazol-5-yl)propanoicAcid

To N'-hydroxybenzenecarboximidamide (1.00 g, 7.34 mmol) in 1,4-dioxane (4 mL, 50 mmol) was added succinic anhydride (735 mg, 7.34 mmol). The reaction was heated to 200 °C for 600 s. After cooling to room temperature, the reaction mixture was purified via Combi-flash. to give the desired product (1.4 g, 87%).

b) Methyl 4-[3-(3-Phenyl-l,2,4-oxadiazol-5-yl)propanoyl]aminothiophene-3- carboxylate

To 3-(3-phenyl-l,2,4-oxadiazol-5-yl)propanoyl chloride (prepared from 3-(3-ρhenyl- l,2,4-oxadiazol-5-yl)propanoic acid according to the procedure described in sample 29) (100 mg, 0.4 mmol) in methylene chloride (10 mL) was added methyl 4-aminothiophene-3- carboxylate (69.7 mg, 0.444 mmol) and a 2 M solution of sodium bicarbonate in water (0-4 mL). After being stirred overnight, the reaction content was poured into water (10 mL) water. The resulting solution was extracted with methylene chloride (2 x 10 mL). The organic layers were combined, dried and concentrated in vacuo. The crude product was directly used in the next reaction.

c) 4-[3-(3-Phenyl-l, 2,4-oxadiazol-5-yl)propanoyl]aminothiophene-3-carboxylic Acid.

To methyl 4-[3-(3-phenyl-l,2,4-oxadiazol-5-yl)propanoyl]aminothiophene-3- carboxylate (150 mg, 0.42 mmol) in methanol (10 mL) was added potassium hydroxide (1 g, 20 mmol). After being stirred for 2 h, the solvent was removed in vacuo. The residue was taken up in water (10 mL) and the pH was adjusted to 3 using concentrated HCl. The aqueous layer was extracted with EtOAc (2 x 10 mL). The organic layers were combined and the solvent removed in vacuo. The residue was purified via HPLC to give 43 mg (30%) of desired product. LC-MS [M+1J 344.1.

Example 49

2-({3-[3-(4-Methoxyphenyl)-l,2,4-oxadiazol-5-yl]propanoyl}amino)thiophene-3- carboxylic acid

This compound was prepared by procedures analogous to those of Example 48. LC- MS [M+H] 374.0.

Example 50

4-({3-t5-(2-Methoxyphenyl)-2-thienyI]propanoyl}amino)thiophene-3-carboxylic add

The title compound was synthesized starting from 2,5-dibromothiophene in a similar fashion to that described in Examples 38 and 41. LC-MS [M+l] 388.1.

Example A

GTPγS recruitment assay

Membranes were prepared from HEK293 cells transiently transfected with human

HM74a and G_α0 protein. Assays were performed in 384-well format in a volume of 50 μL per assay point. Serial dilutions of compounds were prepared in the assay buffer (20 niM HEPES pH. 7.4, 100 mM NaCl, 10 mM MgCl₂, 10 mg/L saponin and 10 μM GDP) and mixed with membranes (2 μg per assay point) and ³⁵S GTPγS (Amersham, 0.3 nM) in the assay buffer.

The mixtures were incubated at room temperature for 30 min and wheat germ agglutinin SPA beads (Amersham) (0.2 mg per assay point) in the assay buffer were added. After 30 min incubation with agitation, plates were centrifuged at 1500 g for 5 min and bound ³⁵S GTPyS was determined by counting on a TopCount scintillation counter. An active compound according to this assay has an ECs₀ of about 50 μM or less.

Example B Nicotinic acid displacement assay

Membranes were prepared from HEK293 cells transiently transfected with the human HM74a and G_α0 protein. Wheat germ agglutinin SPA beads (Amersham) were weighed and suspended in the assay buffer (50 mM Tris-HCl, pH. 7.5, 1 mM MgCl₂ and 0.02% CHAPS). The beads were mixed with membrane (75 μg membrane/mg beads) at room temperature for 1 hr. The beads were spun down and washed once with buffer and then resuspended in buffer at 5 mg beads/ml. 2OnM of ³H nicotinic acid was added to the beads and then mixed with compounds at (total vol. of 50 μL). Nonspecific binding was determined by the inclusion of 100 μM nicotinic acid. The binding mixtures were incubated at room temperature for overnight with agitation. Plates were centrifuged at 1500 g for 5 min and bound ³H nicotinic acid was determined by counting on a TopCount scintillation counter. An active compound according to this assay has an IC₅₀ of about 50 μM or less.

Example C FLIPR assay

HEK293e cells transfected with human HM74a and G_αi₆ DNA were seeded the day before the assay at 50,000 cells/well in 384-well plates. Cells were washed once with IX HBSS and incubated with FLIPR Calcium 3 (Molecular Devices) dye in IX HBSS buffer containing 3 mM probenecid at 37 ⁰C and 5% CO₂ for 60 min. Compounds were added to the cell plate and fluorescence changes due to G_αi<₅-mediated intracellular calcium response were measured. An active compound according to this assay has an EC₅₀ of about 50 μM or less.

Example D cAMP assay CHO cells stably transfected with human HM74a are seeded at 7,500 cells/well in a

96-well plate in HAMS F12 medium with 10 % FBS. The plate is incubated overnight at 37 ⁰C and 5 % CO₂. The test compounds are prepared in a stimulation buffer containing IX HANKS, 20 mM HEPES, 5 μM forskolin, and 0.25 mM IBMX. The media from the cell plate is removed before adding 30 μL of the test compounds. After 30 minute incubation at 37 ⁰C and 5 % CO₂, the cAMP level is assayed using HitHunter cAMP XS assay kit (DiscoverX, CA). IC5₀ determinations are based on compound inhibition relative to DMSO controls. An active compound according to this assay has an IC₅₀ of about 100 μM or less. Example E

Adipocyte lipolysis assay

Preadipocytes purchased from Zen Bio are plated at 8.7 X 10 ⁴ cells/well in 96-well plates, differentiated for 14 days and than mature adipocytes are assayed during days 15 through 21. Adipocyte maturation is assessed by the presence of rounded cells with large lipid droplets in the cytoplasm. Following maturation, cells are washed and incubated overnight with IBMX (100 μM) and various concentrations of compound diluted in assay buffer containing a final DMSO concentration of 0.1%. After overnight culture, the glycerol concentration in the supernatants is determined with the Lipolysis Assay Kit purchased from

Zen-Bio. Absorbance at 540 nm is directly proportional to the glycerol concentration in the sample. ICso determinations are based on compound inhibition relative to DMSO controls.

An active compound according to this assay has an IC_5O of about 10 μM or less.

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A compound of Formula I:

I or pharmaceutically acceptable salt or prodrug thereof, wherein: ring A is thienyl;

Q is COOH or tetrazolyl;

X is CR^laR^2a, NR³, 0, S, SO, or SO₂;

Y is carbocyclyl or heterocyclyl, each optionally substituted by 1, 2 or 3 R⁴;

Z is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 R⁵;

R¹, R², R^la, and R^2a are independently selected from H, Q_-6 alkyl, Ci^alkoxy, and C_2- io alkoxyalkyl;

R³ is H or C_1-6 alkyl;

R⁴ and R⁵ are independently selected from halo, C_1-6 alkyl, C_2-6 alkenyl, C₂.₆ alkynyl, Ci_-4 haloalkyl, Ci₄ haloalkoxy, Cy¹, CN, NO₂, 0R^a, SR^a, C(0)R^b, C(0)NR^cR^d, C(0)0R^a, OC(O)R^b, 0C(0)NR^cR^d, NR^cR^dC(0)NR^cR^d, NR^cR^d, NR^cC(0)R^b, NR^cC(O)OR^a, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d, wherein said Ci_-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, 0R^a, SR^a, Cy¹, OCy¹, SCy¹, S(O)₂Cy¹, C(0)R^b, C(0)NR^cR^d, C(0)0R^a, 0C(0)R^b, 0C(0)NR^cR^d, NR^cR^d, NR^cC(0)R^b, NR^cC(O)OR^a, S(O)R^b, S(O)NR^cR^d, S(O)₂R⁰, and S(0)₂NR^cR^d;

Cy¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 halo, C₁₄ alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_w haloalkyl, CN, NO₂, OR^a', SR^a', C(0)R^b>, C(0)NR°R^d', C(O)OR^3', 0C(0)R^b>, 0C(0)NR^c R^d>, NR^c R^d', NR^c'C(0)R^b>, NR^c'C(0)0R^a>, S(O)R^b', S(0)NR^c'R^d>, S(O)₂R^0', or S(O)₂NR^c>R^d';

R^a and R^a are independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, (Ci-6 alkoxy)-Ci.6 alkyl, C_2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl;

R^b and R^b are independently selected from H, Ci_-6 alkyl, Ci_-6 haloalkyl, C_2-6 alkenyl, C₂-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; R^c and R^c are independently selected from H, Ci_-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C₂-β alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; and

R^d and R^d are independently selected from H, Ci_-6 alkyl, Q-O haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; or R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group; or R^c and R^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.

2. The compound of claim 1 , wherein Q is COOH.

3. The compound of claim 1, wherein X is CR^laR^2a or O.

4. The compound of claim 1 , wherein X is CR^laR^2a.

5. The compound of claim 1, wherein X is CH₂.

6. The compound of claim 1, wherein X is O.

7. The compound of claim 1, wherein Y is aryl or heteroaryl, each optionally substituted by 1, 2, or 3 R⁴.

8. The compound of claim 1, wherein Y is phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by 1, 2, or 3 R⁴.

9. The compound of claim 1, wherein Y is phenyl or a 6-membered heteroaryl, each optionally substituted by 1, 2, or 3 R⁴.

10. The compound of claim 1, wherein Y is a 5-membered heteroaryl optionally substituted by 1, 2, or 3 R⁴.

11. The compound of claim 1 , wherein: Y is:

U¹ is N or CH;

U² and U³ are independently selected from N and CH;

U⁴Is NH, O, or S; and m, ml, m2, m3, and n are independently selected from 0, 1, 2 and 3.

12. The compound of claim 1, wherein Y is phenyl, pyridyl, thienyl, or l,2,4-oxadiazol-5- yl, each optionally substituted by 1, 2, or 3 R⁴.

13. The compound of claim 1, wherein Z is phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by 1, 2, or 3 R⁵.

14. The compound of claim 1, wherein Z is phenyl or a 6-membered heteroaryl, each optionally substituted by 1, 2, or 3 R⁵.

15. The compound of claim 1, wherein Z is a 5-membered heteroaryl optionally substituted by 1, 2, or 3 R⁵.

16. The compound of claim 1, wherein Z is phenyl, furyl, thienyl, thiazolyl, pyridyl, pyrimidinyl or pyrazinyl, each optionally substituted by 1, 2, or 3 R⁵.

17. The compound of claim 1, wherein R¹ and R² are independently selected from H or Qus alkyl.

18. The compound of claim 1 , wherein R¹ and R² are both H.

19. The compound of claim 1, wherein R and R⁵ are independently selected from halo, CN, NO₂, OH, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci_-6 hydroxylalkyl, Cj_-4 haloalkyl, Ci_-4 haloalkoxy, C_1-6 alkoxy, C_2-12 alkoxyalkyl, Cj_-6 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, arylalkylsulfonyl, and heteroarylalkylsulfonyl.

20. The compound of claim 1, wherein said compound has Formula II:

II.

21. The compound of claim 1 , wherein said compound has Formula IH:

πi.

22. The compound of claim 1, wherein said compound has Formula IV:

W.

23. A compound of claim I selected from:

4-{[3-(2'-methoxybiphenyl-4-yl)proρanoyl]amino}thiophene-3-carboxylic acid;

4-{ [3-(2'-ethoxybiρhenyl-4-yl)propanoyl]amino }thiophene-3-carboxylic acid;

4-{[3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid;

4-{[3-(2',6'-dimethoxybiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid;

4-({ 3-[2'-(trifluoromethyl)biphenyl-4-yl]propanoyl } amino)thiophene-3-carboxylic acid;

4- { [3-(2'-fluorobiphenyl-4-yl)propanoyl]amino } thiophene-3-carboxylic acid;

4-{ [3-(2'-chlorobiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid;

4- { [3-(4'-methoxybiphenyl-4-yl)propanoyl]amino } thiophene-3-carboxylic acid;

4-({3-[2'-(methoxymethyl)biphenyl-4-yl]propanoyl}amino)thiophene-3-carboxylic acid; 4-({3-[2'-(methylsulfonyl)biphenyl-4-yl]propanoyl}amino)thiophene-3-carboxylic acid;

4-{ [3-(3'-methoxybiphenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid;

4-{[3-(4'-cyanobiρhenyl-4-yl)propanoyl]amino}thiophene-3-carboxylic acid;

4-(3-[4-(2-furyl)phenyl]propanoylamino)thiophene-3-carboxylic acid;

4-(3-[4-(2-thienyl)phenyl]propanoylamino)thiophene-3-carboxylic acid;

4-{[3-(3'-cyanobiphenyl-4-yl)propanoyl]aπuno}thiophene-3-carboxylic acid;

4-{ [3-(2'-nitrobiphenyl-4-yl)propanoyl]amiiio Jthiophene-3-carboxylic acid;

4-({3-[2'-(trifluoromethoxy)biphenyl-4-yl]propanoyl}amino)thiophene-3-carboxylic acid;

4-({3-[4-(3-thienyl)phenyl]propanoyl}amino)thiophene-3-carboxylic acid;

4-[(3-biphenyl-4-ylpropanoyl)amino]thiophene-3-carboxylic acid;

S-tS^'-methoxybiphenyl^-y^propanoyllaminothiophene^-carboxylic acid ;

3-{[3-(2'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-2-carboxylic acid;

3-{[3-(3'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-2-carboxylic acid;

3-[3-(2',6'-dimethoxybiphenyl-4-yl)propanoyl]aminothiophene-2-carboxylic acid;

3-[(3-biphenyl-4-ylpropanoyl)amino]thiophene-2-carboxylic acid;

3-{[3-(2'-ethoxybiphenyl-4-yl)propanoyl]amino}thiophene-2-carboxylic acid;

3-{[3-(4'-cyanobiphenyl-4-yl)propanoyl]amino}thiophene-2-carboxylic acid;

2-[3-(2'-methoxybiphenyl-4-yl)propanoyl]aminothiophene-3-carboxylic acid;

2-[3-(2',6'-dimethoxybiphenyl-4-yl)propanoyl]aminothiophene-3-carboxylic acid;

2-[(biphenyl-4-yloxy)acetyl]aminothiophene-3-carboxylic acid ;

2-([(2'-methoxybiphenyl-4-yl)oxy]acetylamino)thioρhene-3-carboxylic acid;

2- { [3-(4-ρyridin-2-ylphenyl)propanoyl]amino }thioρhene-3-carboxylic acid;

2- { [3-(4-pyridin-2-ylphenyl)propanoyl]amino }thiophene-3-carboxylic acid;

3-{ [3-(4-pyridin-2-ylphenyl)propanoyl]amino }thiophene-2-carboxylic acid;

3-{ [3-(4-pyrimidin-2-ylphenyl)propanoyl]amjno}thiophene-2-carboxylic acid ;

4-{ [3-(4-pyrazin-2-ylphenyl)propanoyl]amino}thiophene-3-carboxylic acid ;

4-{ [3-(4-pyridin-3-ylphenyl)propanoyl]amino}thioρhene-3-carboxylic acid ;

2-({3-[4-(l,3-thiazol-2-yl)phenyl]propanoyl}amino)thiophene-3-carboxylic acid ;

4-({ 3-[6-(2-methoxyphenyl)pyridin-3-yl]propanoyl } amino)thiophene-3-carboxylic acid; 2-({3-[6-(2-methoxyphenyl)pyridin-3-yl]propanoyl}amino)thiophene-3-carboxylic acid;

3-({3-[6-(2-methoxyphenyl)pyridin-3-yl]propanoyl}amino)thiophene-2-carboxylic acid;

2-( { 3-[5-(2-fluorophenyl)pyridin-2-yl]propanoyl }amino)thiophene-3-carboxylic acid;

3-[({[5-(3-methoxyphenyl)ρyridin-2-yl]oxy}acetyl)amino]thiophene-2-caτboxylic acid;

3-[({ [5-(2-methoxyphenyl)ρyridin-2-yl3oxy}acetyl)ammo]thiophene-2-carboxylic acid;

3-[({[5-(2-fluoroxyphenyl)ρyridin-2-yl]oxy}acetyl)amino]thiophene-2-carboxylic acid;

3-{[({5-[2-(trifluoromethyl)phenyl]pyridm-2-yl}oxy)acetyl]amino}thiophene-2- carboxylic acid;

3-({[(5-phenylpyridin-2-yl)oxy]acetyl}amino)thiophene-2-carboxylic acid;

3-[({[5-(2-cyanophenyl)pyridin-2-yl]oxy}acetyl)amino]thiophene-2-carboxylic acid; and

4-[3-(3-phenyl-l,2,4-oxadiazol-5-yl)propanoyl]aminothiophene-3-carboxylic acid,

2-({3-[3-(4-meihoxyphenyl)-l,2,4-oxadiazol-5-yl]propanoyl}amino)thiophene-3- carboxylic acid; and

4-({3-[5-(2-methoxyphenyl)-2-thienyl]propanoyl}amino)thiophene-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.

24. A composition comprising a compound of any one of claims 1 to 23, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. A method of modulating HM74a receptor comprising contacting said HM74a receptor with a compound of any one of claims 1 to 23, or pharmaceutically acceptable salt thereof.

26. The method of claim 25 wherein said modulating is agonizing.

27. A method of treating a disease in a patient, wherein said disease is associated with HM74a receptor, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 23, or pharmaceutically acceptable salt thereof.

28. The method of claim 27 wherein said disease is associated with elevated plasma FFAs.

29. The method of claim 27 wherein said disease is dyslipidemia, highly-active anti- retroviral therapy (HAART)-associated lipodystrophy, insulin resistance, diabetes, metabolic syndrome, atherosclerosis, coronary heart disease, stroke, obesity, elevated body mass index (BMI), elevated waist circumference, non-alcoholic fatty liver disease, hepatic steatosis, or hypertension.