WO2010120889A1

WO2010120889A1 - Treatment of metabolic syndrome with cyclic amides

Info

Publication number: WO2010120889A1
Application number: PCT/US2010/031044
Authority: WO
Inventors: James R. Hauske
Original assignee: Ampla Pharmaceuticals Inc.
Priority date: 2009-04-14
Filing date: 2010-04-14
Publication date: 2010-10-21

Abstract

The present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are'as defined in the claims. The present application also relates to the treatment of metabolic syndrome or disorders associated with metabolic syndrome in an affected mammal by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Description

Treatment of Metabolic Syndrome with Cyclic Amides Related Applications

This application claims the benefit of priority to U.S. Provisional Patent Application No. 61/169,108, filed April 14, 2009, which application is hereby incorporated by reference in its entirety.

Background

Obesity

According to the National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994), between one third and one half of men and women in the United States are overweight. In the United States, sixty percent of men and fifty- one percent of women, of the age of 20 or older, are either overweight or obese. In addition, a large percentage of children in the United States are overweight or obese. Obesity is a condition of complex origin. Increasing evidence suggests that obesity is not a simple problem of self-control but is a complex disorder involving appetite regulation and energy metabolism. In addition, obesity is associated with a variety of conditions associated with increased morbidity and mortality in a population. Although the etiology of obesity is not definitively established, genetic, metabolic, biochemical, cultural and psychosocial factors are believed to contribute. In general, obesity has been described as a condition in which excess body fat puts an individual at a health risk.

There is strong evidence that obesity is associated with increased morbidity and mortality. Disease risk, such as cardiovascular disease risk and type 2 diabetes disease risk, increases independently with increased body mass index (BMI). Indeed, this risk has been quantified as a five percent increase in the risk of cardiac disease for females, and a seven percent increase in the risk of cardiac disease for males, for each point of a BMI greater than 24.9 (Kenchaiah et al., N. Engl. J. Med. 347:305, 2002; Massie, N. Engl. J. Med 347:358, 2002). In addition, there is substantial evidence that weight loss in obese persons reduces important disease risk factors. Even a small weight loss, such as 10% of the initial body weight in both overweight and obese adults has been associated with a decrease in risk factors such as hypertension, hyperlipidemia, and hyperglycemia.

Although diet and exercise provide a simple process to decrease weight gain, overweight and obese individuals often cannot sufficiently control these factors to effectively lose weight. Pharmacotherapy is available; several weight loss drugs have been approved by the Food and Drug Administration that can be used as part of a comprehensive weight loss program. However, many of these drugs have serious adverse side effects. When less invasive methods have failed, and the patient is at high risk for obesity related morbidity or mortality, weight loss surgery is an option in carefully selected patients with clinically severe obesity. However, these treatments are high-risk, and suitable for use in only a limited number of patients.

It is not only obese subjects who wish to lose weight. People with weight within the recommended range, for example, in the upper part of the recommended range, may wish to reduce their weight, to bring it closer to the ideal weight. Thus, a need remains for agents that can be used to effect weight loss in overweight and obese subjects. Metabolic Syndrome Metabolic syndrome (also known as "syndrome X," "dysmetabolic syndrome,"

"obesity syndrome," and "Reaven's syndrome") has emerged as a growing problem. For example, metabolic syndrome has become increasingly common in the United States. It is estimated that about 47 million adults in the United States have the syndrome. Metabolic syndrome is generally a constellation of metabolic disorders that all result from, or are associated with, a primary disorder of insulin resistance. Accordingly, the syndrome is sometimes referred to as "insulin resistance syndrome." Insulin resistance is characterized by disorders in which the body cannot use insulin efficiently and the body's tissues do not respond normally to insulin. As a result, insulin levels become elevated in the body's attempt to overcome the resistance to insulin. The elevated insulin levels lead, directly or indirectly, to the other metabolic abnormalities.

Some people are genetically predisposed to insulin resistance, while other people acquire factors that lead to insulin resistance. Acquired factors, such as excess body fat and physical inactivity, can elicit insulin resistance, and more broadly, clinical metabolic syndrome. Because of this relationship between insulin resistance and metabolic syndrome, it is believed that the underlying causes of this syndrome are obesity, physical inactivity and genetic factors. In fact, most people with insulin resistance and metabolic syndrome have central obesity (excessive fat tissue in and around the abdomen). The biologic mechanisms at the molecular level between insulin resistance and metabolic risk factors are not yet fully understood and appear to be complex. Metabolic syndrome is typically characterized by a group of metabolic risk factors that include 1) central obesity; 2) atherogenic dyslipidemia (blood fat disorders comprising mainly high triglycerides ("TG") and low HDL-cholesterol (interchangeably referred to herein as "HDL") that foster plaque buildups in artery walls); 3) raised blood pressure; 4) insulin resistance or glucose intolerance (the body can't properly use insulin or blood sugar); 5) prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood); and 6) a proinflammatory state (e.g., elevated high- sensitivity C-reactive protein in the blood). The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines define metabolic syndrome by the following five clinical parameters: a) a waist circumference greater than 102 cm for men, and greater than 88 cm for women; b) a triglyceride level greater than 150 mg/dl; c) an HDL-cholesterol less than 40 mg/dl for men, and less than 50 mg/dl for women; d) a blood pressure greater than or equal to 130/85 mmHg; and e) a fasting glucose greater than 110 mg/dl.

According to the American Heart Association, however, there are no well- accepted criteria for diagnosing metabolic syndrome. Some guidelines suggest that metabolic syndrome involves four general factors: obesity; diabetes; hypertension; and high lipids. According to the NCEP ATP III guidelines above, the presence of at least three of these factors meets the medical diagnosis of metabolic syndrome.

Although there is no complete agreement on the individual risk or prevalence of each factor, it is known that the syndrome, as generally agreed upon by those skilled in the field, poses a significant health risk to individuals. A person having one factor associated with the syndrome has an increased risk for having one or more of the others. The more factors that are present, the greater the risks to the person's health. When the factors are present as a group, i.e., metabolic syndrome, the risk for cardiovascular disease and premature death is very high.

For example, a person with the metabolic syndrome is at an increased risk of coronary heart disease, other diseases related to plaque buildups in artery walls (e.g., stroke and peripheral vascular disease), prostate cancer, and type 2 diabetes. It is also known that when diabetes occurs, the high risk of cardiovascular complications increases.

Generally, patients suffering from the syndrome are prescribed a change in lifestyle, e.g., an increase in exercise and a change to a healthy diet. The goal of exercise and diet programs is to reduce body weight to within 20% of the "ideal" body weight calculated for age and height.

In some cases, diet and exercise regimens are supplemented with treatments for lipid abnormalities, clotting disorders, and hypertension. For example, patients with the syndrome typically have several disorders of coagulation that make it easier to form blood clots within blood vessels. These blood clots are often a precipitating factor in developing heart attacks. Patients with the syndrome are often placed on daily aspirin therapy to specifically help prevent such clotting events. Furthermore, high blood pressure is present in more than half the people with the syndrome, and in the setting of insulin resistance, high blood pressure is especially important as a risk factor. Some studies have suggested that successfully treating hypertension in patients with diabetes can reduce the risk of death and heart disease by a substantial amount. Additionally, patients have been treated to specifically reduce LDL- cholesterol (interchangeably referred to herein as "LDL") levels, reduce triglyceride levels, and raise HDL levels. Given the increasing prevalence of this syndrome, there remains a need for additional and effective treatments of the syndrome.

Summary of Invention

The present invention provides novel compounds, including purified preparations of those compounds. For instance, the invention provides compounds of formula I or a pharmaceutically acceptable salt thereof:

wherein

X represents hydrogen, optionally substituted lower alkyl (e.g., methyl), or an optionally substituted aryl or heteroaryl ring;

Y represents an optionally substituted aryl, heteroaryl, or heterocyclyl ring; Z represents O, S, NR¹⁶, or C(H)R¹⁷; R¹⁶ represents hydrogen, optionally substituted lower alkyl (e.g., methyl), or an optionally substituted aryl or heteroaryl ring; R¹⁷ represents hydrogen, optionally substituted lower alkyl (e.g., methyl), or an optionally substituted aryl or heteroaryl ring;

W represents

;

R¹ represents hydrogen or optionally substituted lower alkyl;

R² and R³ each independently represent hydrogen or an optionally substituted lower alkyl, or R² and R³ taken together with the carbon to which they are attached form a three- to six-membered cyclic ring; and R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently represent hydrogen or a substituent.

In another aspect, the present invention provides a method of treating obesity, metabolic syndrome or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia) in a mammal comprising administering to a mammal suffering from obesity, metabolic syndrome or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia) a compound of the invention (e.g., a compound of formula I).

In certain embodiments, the disorder associated with metabolic syndrome is diabetes. In preferred embodiments of the methods of the invention, the mammal is a human.

Detailed Description of the Drawings

Figure 1 shows the effects of 7 day administration of compound Ia on overall body weight gain in mice with diet-induced obesity. Figure 2 shows the effects of 7 day administration of compound Ia on insulin content in mice with diet-induced obesity.

Detailed Description of the Invention

The present invention provides certain novel compounds, including purified preparations of those compounds. For instance, the invention provides compounds of formula I or a pharmaceutically acceptable salt thereof:

(D wherein

Y represents an optionally substituted aryl, heteroaryl, or heterocyclyl ring;

Z represents O, S, NR¹⁶, or C(H)R¹⁷;

R¹⁶ represents hydrogen, optionally substituted lower alkyl (e.g., methyl), or an optionally substituted aryl or heteroaryl ring; R¹⁷ represents hydrogen, optionally substituted lower alkyl (e.g., methyl), or an optionally substituted aryl or heteroaryl ring;

W represents

;

R¹ represents hydrogen or optionally substituted lower alkyl;

R² and R³ each independently represent hydrogen or an optionally substituted lower alkyl, or R² and R³ taken together with the carbon to which they are attached form a three- to six-membered cyclic ring; and

R⁴, R⁵, RR⁶⁶,, RR⁷⁷,, RR⁸⁸,, RR⁹⁹,, RR¹¹⁰⁰,, RR¹¹¹¹,, RR¹¹², R¹³, R¹⁴, and R¹⁵ each independently represent hydrogen or a substituent. In certain embodiments, X represents an optionally substituted aryl or heteroaryl ring. In certain embodiments, X represents hydrogen.

In certain embodiments, X represents an optionally substituted phenyl ring. In certain such embodiments, X is optionally substituted with optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted amido, optionally substituted acylamino, cyano, or nitro. In certain embodiments, Y represents an aryl or heteroaryl ring. In certain such embodiments, Y represents an optionally substituted phenyl ring. In certain such embodiments, Y is optionally substituted with optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted amido, optionally substituted acylamino, cyano, nitro, or two adjacent substituents together represent -OCH₂O- forming a heterocycle with the carbons to which they are attached. In certain embodiments, Y represents a phenyl ring optionally substituted with optionally substituted lower alkyl, such as trifluoromethyl, halogen, or two adjacent substituents together represent -OCH O- forming a heterocycle with the carbons to which they are attached. In certain embodiments wherein Y represents a heteroaryl or heterocyclyl ring, Y is selected from benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof. In certain such embodiments, Y is selected from benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof. For example, in certain embodiments, Y is selected from benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazolyl, pyridopyridinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof. In certain embodiments, Z represents C(H)R¹⁷.

In certain embodiments, R¹⁷ represents an optionally substituted aryl or heteroaryl ring. In certain embodiments, R¹⁷ represents hydrogen.

In certain embodiments, R¹⁷ represents an optionally substituted phenyl ring. In certain such embodiments, R¹⁷ is optionally substituted with optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted amido, optionally substituted acylamino, cyano, or nitro.

In certain embodiments, W represents

In certain embodiments, R⁴, R⁵, R⁶, R⁷, and R⁸ each independently represent hydrogen, optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted aminoalkyl, such as an optionally substituted tertiary aminoalkyl, optionally substituted amido, optionally substituted acylamino, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, such as an optionally substituted nitrogen-containing heterocyclyl (e.g., morpholine, piperidine, piperazine, or pyrrolidine), optionally substituted heterocyclylalkyl, such as an optionally substituted nitrogen-containing heterocyclylalkyl, optionally substituted aryl, cyano, or nitro. In certain embodiments, one of R⁴, R⁵, R⁶, R⁷, and R⁸ represents optionally substituted lower alkyl, such as isobutyl, and the others each represent hydrogen. In certain embodiments, one of R⁴, R⁵, R⁶, R⁷, and R⁸ represents optionally substituted carbocyclylalkyl and the others each represent hydrogen. For example, in certain embodiments, R⁶ represents optionally substituted carbocyclylalkyl and R⁴, R⁵, R⁷, and R⁸ each represent hydrogen. In certain such embodiments, the optionally

substituted carbocyclylalkyl is selected

O or N(OR²¹), wherein R²¹ represents hydrogen or optionally substituted alkyl; R¹⁸ represents optionally substituted alkyl, aryl, heteroaryl, or heterocyclyl; R¹⁹ represents hydrogen or optionally substituted alkyl, aryl, heteroaryl, or heterocyclyl; R²⁰ represents hydrogen or optionally substituted alkyl; and R²¹ represents optionally substituted alkyl, aryl, heteroaryl, or heterocyclyl. In certain embodiments wherein R¹⁸ represents optionally substituted heteroaryl or heterocyclyl, R¹⁸ is selected from optionally substituted benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof. For example, R¹⁸ may be selected from optionally substituted thienyl, furanyl, oxazolyl, oxadiazolyl, benzothiophenyl, isoquinolyl, thiazolyl, pyridyl, pyrimidyl, benzothiazolyl, and benzoxazolyl.

In certain embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently represent hydrogen, optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted aminoalkyl, such as an optionally substituted tertiary aminoalkyl, optionally substituted amido, optionally substituted acylamino, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, such as an optionally substituted nitrogen-containing heterocyclyl (e.g., morpholine, piperidine, piperazine, or pyrrolidine), optionally substituted heterocyclylalkyl, such as an optionally substituted nitrogen-containing heterocyclylalkyl, optionally substituted aryl, cyano, or nitro. In certain embodiments, R¹ represents hydrogen. In certain embodiments, R¹ represents methyl.

In certain embodiments, R² is hydrogen and R³ is an optionally substituted lower alkyl, such as methyl. In certain embodiments, R² and R³ taken together with the carbon to which they are attached form a cyclopropane or cyclobutane ring. In certain embodiments, Z represents C(H)R¹⁷, R¹⁷ represents hydrogen, R¹ represents lower alkyl, such as methyl, and X represents hydrogen. In certain embodiments, Z represents C(H)R¹⁷, R¹⁷ represents hydrogen, R¹ represents hydrogen, and X represents optionally substituted aryl or heteroaryl ring, such as optionally substituted phenyl.

In certain embodiments, Z represents C(H)R¹⁷, R¹⁷ represents optionally substituted aryl or heteroaryl ring, such as optionally substituted phenyl, R¹ represents hydrogen, and X represents hydrogen.

In certain embodiments, a compound of formula I has the structure 1,

uch as a structure Ia,

Further exemplary compounds of formula I include:

(9), and

(10).

In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, or 40% ee, or 50% ee, or 60% ee, or 70% ee, or 80% ee, or 90% ee, or even 95% or greater ee. In certain embodiments, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than 30% de, or 40% de, or 50% de, or 60% de, or 70% de, or 80% de, or 90% de, or even 95% or greater de.

The present invention also relates to a method of treating obesity in a mammal. The invention further relates to a method of minimizing metabolic risk factors associated with obesity, such as hypertension, diabetes and dyslipidemia. In one embodiment, the methods comprise administering to a mammal in need of such treatment an effective anti-obesity dose of a compound of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof). In preferred embodiments of the methods of the invention, the mammal is a human.

In another aspect, the present invention provides a method of treating or preventing metabolic syndrome or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia) in a mammal comprising administering to a mammal suffering from metabolic syndrome or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia) an effective dose of a compound of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof). In certain embodiments, the disorder associated with metabolic syndrome is diabetes.

In preferred embodiments of the methods of the invention, the mammal is a human.

In certain embodiments, the present invention relates to methods of treatment with a compound of formula I, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula I). An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.

In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diasteriomer of a compound (e.g., of formula I). A diasteriomerically enriched mixture may comprise, for example, at least 60 mol percent of one diasteriomer, or more preferably at least 75, 90, 95, or even 99 mol percent. Compounds suitable for use in methods of the invention include any compound of the invention as set forth above (e.g., a compound represented by formula I, or a pharmaceutically acceptable salt thereof).

One aspect of the present invention provides a pharmaceutical composition suitable for use in a human patient, or for veterinary use, comprising an effective amount of a compound of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable carriers. In certain embodiments, the pharmaceutical compositions may be for use in treating or preventing obesity, metabolic syndrome, or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia)n. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient, or for veterinary use. In certain embodiments, the pharmaceutical preparation comprises an effective amount of a compound of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof).

Compounds of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof) may be used in the manufacture of medicaments for the treatment of any diseases disclosed herein.

As used herein, the term "obesity" includes both excess body weight and excess adipose tissue mass in an animal. An obese individual is one having a body mass index of > 30 kg/m². While the animal is typically a human, the invention also encompasses the treatment of non-human mammals. The treatment of obesity, as provided in methods of the present invention, contemplates not only the treatment of individuals who are defined as "obese", but also the treatment of individuals with weight gain that if left untreated may lead to the development of obesity.

The term "healthcare providers" refers to individuals or organizations that provide healthcare services to a person, community, etc. Examples of "healthcare providers" include doctors, hospitals, continuing care retirement communities, skilled nursing facilities, subacute care facilities, clinics, multispecialty clinics, freestanding ambulatory centers, home health agencies, and HMO's.

The term "hydrate" as used herein, refers to a compound formed by the association of water with the parent compound. The term "metabolite" is intended to encompass compounds that are produced by metabolism of the parent compound under normal physiological conditions. For example, an N-methyl group may be cleaved to produce the corresponding N- desmethyl metabolite, or an amide may be cleaved to the corresponding carboxylic acid and amine. Preferred metabolites of the present invention include those that exhibit activity suitable for the treatment of obesity, metabolic syndrome, or a disorder associated with metabolic syndrome.

As used herein, a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

The term "solvate" as used herein, refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of the solute, such as with molecules or ions of a compound of the invention).

The term "treating" includes prophylactic and/or therapeutic treatments. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-. The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-. The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.

Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF₃, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF₃, -CN, and the like.

The term "C_x__y" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term "C_x__yalkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms "C₂-_yalkenyl" and "C₂-_yalkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term "alkylamino", as used herein, refers to an amino group substituted with at least one alkyl group.

The term "alkylthio", as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term "amide", as used herein, refers to a group

wherein R⁹ and R¹⁰ each independently represent a hydrogen or hydrocarbyl group, or R⁹ and R¹⁰ taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by

wherein R⁹, R¹⁰, and R¹⁰ each independently represent a hydrogen or a hydrocarbyl group, or R⁹ and R¹⁰ taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term "aminoalkyl", as used herein, refers to an alkyl group substituted with an amino group.

The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group.

The term "aryl" as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term "carbamate" is art-recognized and refers to a group

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R⁹ and R¹⁰ taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms "carbocycle", "carbocyclyl", and "carbocyclic", as used herein, refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon. Preferably a carbocycle ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms. The term "carbocyclylalkyl", as used herein, refers to an alkyl group substituted with a carbocycle group.

The term "carbonate" is art-recognized and refers to a group -OCO₂-R⁹, wherein R⁹ represents a hydrocarbyl group.

The term "carboxy", as used herein, refers to a group represented by the formula -CO₂H.

The term "ester", as used herein, refers to a group -C(O)OR⁹ wherein R⁹ represents a hydrocarbyl group.

The term "ether", as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O- heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

The terms "halo" and "halogen" as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

The terms "hetaralkyl" and "heteroaralkyl", as used herein, refers to an alkyl group substituted with a hetaryl group.

The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.

Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10- membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term "heterocyclylalkyl", as used herein, refers to an alkyl group substituted with a heterocycle group.

The term "hydrocarbyl", as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof. The term "hydroxyalkyl", as used herein, refers to an alkyl group substituted with a hydroxy group.

The term "lower" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A "lower alkyl", for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

The terms "polycyclyl", "polycycle", and "polycyclic" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

The term "sulfate" is art-recognized and refers to the group -OSO₃H, or a pharmaceutically acceptable salt thereof.

The term "sulfonamide" is art-recognized and refers to the group represented by the general formulae

wherein R and R independently represents hydrogen or hydrocarbyl, such as alkyl, oorr RR⁹⁹ aanndd RR¹¹⁰⁰ ttaakkeenn ttooggeetthheerr wwiitthh tthhee iinntteerrvveenniini g atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term "sulfoxide" is art-recognized and refers to the group -S(O)-R⁹, wherein R⁹ represents a hydrocarbyl.

The term "sulfonate" is art-recognized and refers to the group SO₃H, or a pharmaceutically acceptable salt thereof.

The term "sulfone" is art-recognized and refers to the group -S(O)₂-R⁹, wherein R⁹ represents a hydrocarbyl.

The term "thioalkyl", as used herein, refers to an alkyl group substituted with a thiol group. The term "thioester", as used herein, refers to a group -C(O)SR⁹ or -SC(O)R⁹ wherein R⁹ represents a hydrocarbyl.

The term "thioether", as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

The term "urea" is art-recognized and may be represented by the general formula

R⁹ R⁹ wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R⁹ taken together with R¹⁰ and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

Methods of preparing substantially isomerically pure compounds are known in the art. If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts may be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Alternatively, enantiomerically enriched mixtures and pure enantiomeric compounds can be prepared by using synthetic intermediates that are enantiomerically pure in combination with reactions that either leave the stereochemistry at a chiral center unchanged or result in its complete inversion. Techniques for inverting or leaving unchanged a particular stereocenter, and those for resolving mixtures of stereoisomers are well known in the art, and it is well within the ability of one of skill in the art to choose an appropriate method for a particular situation. See, generally, Furniss et al. (eds.), Vogel's Encyclopedia of Practical Organic Chemistry 5^th Ed., Longman Scientific and Technical Ltd., Essex, 1991, pp. 809-816; and Heller, Ace. Chem. Res. 23: 128 (1990).

The amount of active agent(s) (e.g., a compound of the invention, such as a compound of formula I) administered can vary with the patient, the route of administration and the result sought. Optimum dosing regimens for particular patients can be readily determined by one skilled in the art.

Compounds of the invention may be administered to an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an individual, the compound of the invention can be administered as a pharmaceutical composition containing, for example, the compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, the aqueous solution is pyrogen free, or substantially pyrogen free, or has low enough pyrogen activity. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, sprinkle capsule, granule, powder, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The term "low enough pyrogen activity", with reference to a pharmaceutical preparation, refers to a preparation that does not contain a pyrogen in an amount that would lead to an adverse effect (e.g., irritation, fever, inflammation, diarrhea, respiratory distress, endotoxic shock, etc.) in a subject to which the preparation has been administered. For example, the term is meant to encompass preparations that are free of, or substantially free of, an endotoxin such as, for example, a lipopoly saccharide (LPS).

A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize or to increase the absorption of a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which consist of phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. 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 judgment, 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 phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

A pharmaceutical composition (preparation) containing a compound of the invention can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, boluses, powders, granules, pastes for application to the tongue); sublingually; anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramusclularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments a compound of the invention may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein. The most preferred route of administration is the oral route. The formulations of the present invention may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsuled matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly( anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

The addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration.

Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977).

Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.

In certain embodiments, a compound of the present invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.

In certain embodiments, a compound of the present invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof) may be administered conjointly with another treatment for diabetes including, but not limited to, sulfonyl ureas (e.g., chlorpropamide, tolbutamide, glyburide, glipizide, or glimepiride), medications that decrease the amount of glucose produced by the liver (e.g., metformin), meglitinides (e.g., repaglinide or nateglinide), medications that decrease the absorption of carbohydrates from the intestine (e.g., alpha glucosidase inhibitors such as acarbose), medications that effect glycemic control (e.g., pramlintide or exenatide), DPP-IV inhibitors (e.g., sitagliptin), insulin treatment, or combinations of the above. In certain embodiments, a compound of the present invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof) may be administered conjointly with another treatment for obesity including, but not limited to, orlistat, sibutramine, phendimetrazine, phentermine, diethylpropion, benzphetamine, mazindol, dextroamphetamine, rimonabant, cetilistat, GT 389-255, APD356, pramlintide/AC137, PYY3-36, AC 162352/PYY3-36, oxyntomodulin, TM 30338, AOD 9604, oleoyl-estrone, bromocriptine, ephedrine, leptin, pseudoephedrine, or pharmaceutically acceptable salts thereof.

It is contemplated that a compound of the present invention will be administered to a subject (e.g., a mammal, preferably a human) in a therapeutically effective amount (dose). By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect (e.g., treatment of obesity, metabolic syndrome, or a disorder associated with metabolic syndrome, such as obesity, diabetes, hypertension, and hyperlipidemia). It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et αl. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814- 1882, herein incorporated by reference).

As used herein, compounds of the invention (e.g., compounds of formula I, or a pharmaceutically acceptable salt thereof) include the pharmaceutically acceptable salts of compounds of the invention. The compounds of the invention, including their pharmaceutically acceptable salts, can also exist as various solvates, such as with water (e.g., a hydrate, such as a hemihydrate, monohydrate, dihydrate, trihydrate, or tetrahydrate), methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Suitable solvents and procedures for the preparation of solvates and hydrates can generally be selected by a skilled artisan. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. The term "pharmaceutically acceptable salts" includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, trifluoroacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzensulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are the salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs form the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. The present invention provides a kit comprising: a) one or more single dosage forms each comprising a dose of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; and b) instructions for administering the single dosage forms for the treatment of obesity, metabolic syndrome, or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia). In certain embodiments, the invention relates to a method for conducting a pharmaceutical business, by manufacturing a formulation or kit as described herein, and marketing to healthcare providers the benefits of using the formulation or kit in the treatment of obesity, metabolic syndrome, or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia).

In certain embodiments, the invention provides a method for conducting a pharmaceutical business, by providing a distribution network for selling a formulation or kit as described herein, and providing instruction material to patients or physicians for using the formulation to treat obesity, metabolic syndrome, or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia).

In certain embodiments, the present invention relates to a method for conducting a pharmaceutical business, by providing a distribution network for selling a formulation or kit as described herein, and providing instruction material to patients or physicians for using the formulation to treat obesity, metabolic syndrome, or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia).

In certain embodiments, the invention comprises a method for conducting a pharmaceutical business, by determining an appropriate formulation and dosage of a compound of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof) to be administered in the treatment of obesity, metabolic syndrome, or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia), conducting therapeutic profiling of identified formulations for efficacy and toxicity in animals, and providing a distribution network for selling an identified preparation as having an acceptable therapeutic profile. In certain embodiments, the method further includes providing a sales group for marketing the preparation to healthcare providers.

In certain embodiments, the invention relates to a method for conducting a pharmaceutical business by determining an appropriate formulation and dosage of a compound of the invention (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof) to be administered in the treatment of obesity, metabolic syndrome, or a disorder associated with metabolic syndrome (e.g., obesity, diabetes, hypertension, and hyperlipidemia), and licensing, to a third party, the rights for further development and sale of the formulation.

Exemplification

Example 1: Binding Assays for Compounds of the Invention A FLIPR assay was conducted to monitor agonist and antagonist selectivity for compounds of the invention against the CBl, GLP-I, MCHRl, OXl, SST5, Y2, and Y4 receptors. Percentage activation and percentage inhibition values were determined for each compound on each of the GPCRs listed above. Agonist selectivity was determined upon initial addition of compounds followed by 10 minute incubation at 25 ⁰C. Following compound incubation, reference agonists were added at EC80 to determine percentage inhibition.

Assay Design:

Agonist percentage activation determinations were obtained by assaying sample compounds and referencing the Emax control for each of the GPCRs profiled. Antagonist percentage inhibition determinations were obtained by assaying sample compounds and referencing the control EC80 wells for each of the GPCRs profiled.

The protocol design is as follows:

Unless specified otherwise, all sample compounds were diluted in 100% anhydrous DMSO including all serial dilutions. Occasionally sample compounds were provided in a different solvent, in this case all master stock dilutions were performed in the specified diluent. All control wells contained identical solvent final concentrations as sample compound wells. Sample compounds were transferred from a master stock solution into a daughter plate that was used in the assay. Each sample compound was diluted into assay buffer (Ix HBSS with 2OmM HEPES) at an appropriate concentration to obtain final concentrations. Calcium Flux Assay Agonist Assay Format:

All sample compounds were plated at lμM in duplicate for assaying against all GPCRs. Concentrations described here reflect final compound concentrations during the antagonist assay. Due to the nature of the assay, the compound concentration during the agonist assay was 1.25 μM. These steps were taken toa ssure the compound concentation was 1.0 μM during the antagonist assay. Reference agonists were handled as mentioned above serving as assay control. These reference agonists were handled as described above for both EMax and EC80 control wells. Assay was read for 180 seconds using the FLIPRTETRA. (This assay run added sample compounds and reference agonist to respective rows.) At the completion of the first "Single Addition" assay run, assay plate was removed from the FLIPRTetra and placed at 25 ⁰C for 10 minutes. Antagonist Assay Format:

Using the EC50 values determined previously, stimulated all pre-incubated sample compound and reference antagonist (if applicable) wells with EC80 of reference agonist. Read for 90 seconds using the FLIPRTETRA. (This assay added reference agonist to respective wells — then fluorescence measurements were collected to calculate percentage inhibition.) Data Processing: All plates were subjected to appropriate baseline corrections. Once baseline corrections were processed, maximum fluorescence values were exported and data manipulated to calculate percentage activation, percentage inhibition, Z', EC50, and IC50. Percentage activation data was calculated using Emax as 100% control. Percentage inhibition was calculated using EC80 as 0% inhibition. Ligands Used:

GPCR Target Reference Ligand CBl CP-55,940 GLP-I Glucagon QC Criteria:

The QC criterium for percent effect validation was thatduplicates must be <30% divergent. If this QC condition failed, that concentration was removed from curve fitting. If two or more concentrations with the dose response failed, the entire compound curve for that compound was repeated on a different assay plate.

The QC criterium for Z' Statistic was that it must be >0.5. If this QC condition failed, all data collected from that particular GPCR was repeated.

The QC criterium for Signal-to-Noise (SfN) was that it must be >5. If this QC condition failed, all data collected from that particular GPCR was repeated. The QC criterium for R2 was that it must be >0.90. If this QC condition failed, all data collected from that particular GPCR was repeated.

The QC criterium for EC50 Value for reference agonist(s) was that it must be within 5-fold of historic EC50 value. If this QC condition failed, all data collected from that particular GPCR was repeated. A percent activation of greater than 15% in the agonist assays was considered significant.

The QC criterium for IC50 Value for reference antagonist(s) was that it must be within 10-fold of historic EC50 value. If this QCcondition failed, all data collected from that particular GPCR was repeated. A percent activation of greater than 50% in the antagonist assays was considered significant. Negative values in these assays with an absolute value of greater than 15 may be indicative of allosteric potentiation.

Tables 1 and 2 shows the results of these binding assays for several compounds of the invention. Table 1:

Table 2:

Example 2: Synthesis of compounds of the invention

Proton and carbon NMR spectra were obtained on a Bruker AC 300 spectrometer at 300 MHz and 75 MHz, respectively. Proton spectra were referenced to tetramethylsilane as an internal standard. Melting points were obtained on a Mel- Temp II apparatus and are uncorrected. HPLC analyses were obtained using a Sunfire Cl 8 5μm Analytical Column and an Alltech Alltima Cl 8 Analytical Column Method A (Table 2) with UV detection using standard solvent programs on a Shimadzu Prominence HPLC system. Table 2: HPLC (Method A)

Alltech Altima Cl 8 Rocket Column

A = Water with 0.05% v/v Trifluoroacetic Acid

B = Acetonitrile with 0.05% v/v Trifluoroacetic Acid

UV Detection at 254 nm and 230 nm Scheme 1

Preparation of (S)-l-(Ter/-butoxycarbonyl)piperidine-3-carboxylic acid

(102). To a stirred mixture of (5^r)-piperidine-3-carboxylic acid (101, 4.00 g, 31.0 mmol) in THF (76 rnL) and water (76 rnL) was added BoC₂O (9.50 g, 43.4 mmol) and NaHCO₃ (3.64 g, 43.4 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was diluted with water (20 mL) and ether (20 mL). The aqueous layer was adjusted to pH 2 with concentrated HCl (12 N) and was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were then washed with brine (80 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to afford 102 (6.79 g, 95%) as a clear oil: ¹U NMR (300 MHz, CDCl₃) δ 4.12 (d, /= 7.2 Hz, IH), 3.88 (d, /= 13.5 Hz, IH), 3.05 (t, /= 11.1 Hz, IH), 2.91- 2.82 (m, IH), 2.54-2.45 (m, IH), 2.08 (d, / = 3.9 Hz, IH), 1.76-1.60 (m, IH), 1.59- 1.23 (m, HH)

Preparation of (S)-Tert-buty\ 3-[(methoxymethyl)carbamoyl]piperidine- 1-carboxylate (103). (S)-l-(re^butoxycarbonyl)piperidine-3-carboxylic acid (102, 6.79 g, 29.62 mmol), iV,0-dimethylhydroxylamine (3.62 g, 37.0 mmol), EDC-HCl (7.10 g, 37.0 mmol) and iV,iV-diisopropylethylamine (12.9 mL, 74.0 mmol) were dissolved in dichloromethane (109 mL) and the reaction was stirred overnight at room temperature under nitrogen. The reaction mixture was then diluted with ethyl acetate, washed with 5% aq. HCl (2 x 40 mL), saturated NaHCO₃ (100 mL), brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to afford 103 (9.73 g, >100% crude) as a yellow oil: ¹U NMR (300 MHz, CDCl₃) δ 4.16-4.09 (m, 2H), 3.81 (s, 3H), 3.24 (s, 3H), 2.91-2.66 (m, 3H), 1.93 (d, /= 12.6 Hz, IH), 1.75-1.59 (m, 3H), 1,51 (s, 9H).

Preparation of (S)-7Vr/-butyl-3-benzoylpiperidine-l-carboxylate (104). (S)-Te rt-buty\ 3-[(methoxymethyl)carbamoyl]piperidine-l-carboxylate (103, 9.73 g, 35.7 mmol) was dissolved in anhydrous THF (144 mL) and cooled to -10 ⁰C. Phenylmagnesium bromide solution in THF (72 mL of 1.0 M, 71.5 mmol) was then added dropwise to the solution under nitrogen and was stirred for 15 min. The reaction mixture was then warmed up to room temperature and was stirred for 2 h. Aqueous HCl (5%, 72 mL) was added slowly to quench the reaction and was stirred for 15 min. The mixture was then extracted with ether (3 x 200 mL). The combined organic layers were then washed with saturated NaHCO₃ (100 mL), brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to afford 104 (10.0 g, 97%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, /= 4.8 Hz, 2H), 7.56 (t, / = 5.1 Hz, IH), 7.48 (t, / = 4.8 Hz, 2H), 4.11 (d, / = 14.1 Hz, IH), 3.45-3.37 (m, IH), 2.92 (t, /= 7.0 Hz, IH), 2.72 (t, /= 9.0 Hz, IH), 2.01 (d, /= 1.5 Hz, IH), 1.80-1.54 (m, 3H), 1.42 (s, 9H).

Preparation of (S)-Ter/-butyl-3-[(S)-hydroxyphenylmethyl]piperidine-l- carboxylate (107). A solution of (S)-tert-buty\ 3-benzoylpiperidine-l-carboxylate (104, 3.00 g, 10.4 mmol) in anhydrous toluene (35 mL) was cooled to -78 ⁰C under nitrogen and (i?)-2-methyl-CBS-oxazaborolidine (1.0 M in toluene, 5.2 mL, 5.2 mmol) was added slowly. After 10 min of stirring, catecholborane (1.0 M, 31.1 mL, 31.1 mmol) was added slowly. The reaction mixture was then stirred for 2 h and was transferred into the freezer (-14 ⁰C) to be left overnight. The mixture was cooled to 0 ⁰C and water was added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aqueous NaOH (2 x 50 mL), water (2 x 50 mL), 5% aq. HCl (2 x 25 mL), brine (2 x 50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, 0-20% EtOAc in hexanes gradient) provided 107 (0.669 g, 22%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.30 (m, 5H), 4.50 (s, IH), 3.89 (d, / = 7.2 Hz, IH), 2.69 (t, / = 9.6 Hz, IH), 2.55 (/ = 10.5 Hz, IH), 2.04- 1.98 (br s, IH), 1.83 (d, / = 7.5 Hz, 2H), 1.81-1.68 (m, 2H), 1.52-1.33 (m, 10H). Preparation of (S)-Tert-butyl-3-[(R)-phenyl-4-

(trifluoromethylphenoxy)methyl]piperidine-l-carboxylate (109). To a solution of (5^r)-fert-butyl-3-[(5^r)-hydroxyphenylmethyl]piperidine-l-carboxylate (107, 0.150 g, 0.515 mmol) in anhydrous DMSO (3 mL) at 0 ⁰C was added sodium hydride (0.031 g, 0.772 mmol, 60% in mineral oil). The reaction mixture was then heated at 55 ⁰C for 1 h to form the sodium alkoxide. To the alkoxide was added dropwise l-chloro-4- (trifluoromethyl)benzene (108, 0.1 mL, 0.772 mmol) and the reaction mixture was heated at 95 ⁰C for 2 h. The reaction mixture was cooled and extracted with ethyl acetate (3 x 50 mL). The organic layers were then washed with water (2 x 15 mL), and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, 0-20% EtOAc in hexanes gradient) provided 109 (0.133 g, 59%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 7.41 (d, /= 8.7 Hz, 2H), 7.36-7.24 (m, 5H), 6.87 (d, / = 8.4 Hz, 2H), 4.98 (d, /= 5.7 Hz, IH), 3.93 (d, /= 13.2 Hz, IH), 2.76-2.66 (m, 2H), 2.04-1.94 (m, 2H), 1.71-1.65 (m, IH), 1.51-1.40 (m, 12H). Preparation of (S)-3-[(fl)-Phenyl(4- trifluoromethylphenoxy)methyl]piperidine (110). To a solution of (5^r)-fert-butyl-3- [(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine-l-carboxylate (109, 0.133 g, 0.305 mmol) in CH₂Cl₂ (5 mL) was added trifluoroacetic acid (1 mL) and reaction mixture was left to stir at room temperature for 1 h. This was then concentrated under vacuum to provide 110 (0.103 g, 100%) as a brown oil. This material was used for the final coupling reaction without further purification.

General Procedure for the Preparation of Amides 2a, 4a, and 5a. To a suspension of (S)-3-[(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (110, 0.100 g, 1.0 equiv) and carboxylic acids (111-113, 1.0 equiv) in CH₂Cl₂ (5 niL) was added EDC*HC1 (1.5 equiv), 1-hydroxybenzotriazole (1.5 equiv) and triethylamine (2.0 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with CH₂Cl₂ (5 mL), washed with water (5 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, 4:1 hexanes/EtOAc) provided the carboxylic amides 2a, 4a, and 5a.

Preparation of (S)-2-(4-Isobutylphenyl)-l-[(S)-3-(fl)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (2a). The reaction of (5^r)-3-[(R)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (110, 103 mg, 0.307 mmol) and (5^r)-(+)-ibuprofen (111, 64 mg, 0.307 mmol) following the general procedure gave 2a (115 mg, 72%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.38 (m, 5H), 7.35-7.21 (m, 2H), 7.19-7.04 (m, 2H), 6.98 (d, /= 8.0 Hz, IH), 6.85 (d, / = 8.6 Hz, 2H), 6.70 (d, J = 1.9 Hz, IH), 5.03 (d, / = 4.9 Hz, IH), 4.72-4.59 (m, IH), 3.86-3.79 (m, IH), 3.53 (d, / = 14.3 Hz, 0.5H), 3.35 (q, / = 6.8 Hz, 0.5H), 2.86 (t, / = 10.7 Hz, 0.5H), 2.55 (t, /= 11.5 Hz, 0.5H), 2.42 (d, / = 7.1 Hz, 2H), 2.39-2.21 (m, IH), 2.04-1.68 (m, 3H), 1.41 (d, / = 6.6 Hz, 2H), 1.31 (d, / = 6.8 Hz, 2H), 1.26 (s, IH), 0.91-0.85 (m, 6H), 0.57-0.53 (m, IH); ESI, m/z 546 [M + Na]⁺.

Mixture of Diastereomers

Preparation of 2-(3-Isobutylphenyl)-l-[(S)-3-(fl)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (4a). The reaction of (S)-3-[(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (110, 107 mg, 0.319 mmol) and 2-(3-isobutylphenyl)propanoic acid (112, 66 mg, 0.319 mmol) following the general procedure gave 4a (70 mg, 42%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, / = 8.5 Hz, 2H), 7.33-7.22 (m, 5H), 7.19-6.61 (m, 6H), 5.02 (dd, / = 4.5 Hz, / = 19.8 Hz, 0.5H), 4.75-4.63 (m, IH), 4.40 (d, / = 12.3 Hz, 0.2H), 3.88-3.70 (m, 2H), 3.58 (d, /= 13.5 Hz, 0.2H), 3.40 (d, / = 6.8 Hz, 0.2H), 2.97-2.24 (m, 4H), 2.03 (br s, 0.5H), 1.87-1.74 (m, 2H), 1.66-1.53 (m, 2H), 1.49- 1.05 (m, 5H), 0.85 (d, / = 6.6 Hz, 6H); ESI, m/z 524 [M + H]⁺.

Pure Diastereomer 1

Preparation of 2-(3-Isobutylphenyl)-l-[(S)-3-(fl)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (4a, pure diastereomer #1). The reaction of (S)-3- [(i?)-phenyl(4- trifluoromethylphenoxy)methyl]piperidine (110, 107 mg, 0.319 mmol) and 2-(3- isobutylphenyl)propanoic acid (112, 66 mg, 0.319 mmol) following the general procedure gave 4a, pure diastereomer #1 (26 mg, 15%) as a hygroscopic white solid: ¹U NMR (300 MHz, CDCl₃) δ 7.42-7.38 (m, 3H), 7.34-7.12 (m, 5H), 7.09- 6.96 (m, 2H), 6.84 (d, / = 8.6 Hz, 2H), 6.70 (s, 0.4H), 6.61 (d, / = 7.4 Hz, 0.4H), 5.05 (d, / = 4.6 Hz, IH), 4.75-4.61 (m, IH), 3.83-3.75 (m, IH) 3.60-3.11 (m, IH), 2.85 (t, /= 11.0 Hz, IH), 2.59-2.24 (m, 4H), 2.08-1.74 (m, 2H), 1.49-1.23 (m, 6H), 0.85 (d, /= 17.5 Hz, 6H); ESI, m/z 524 [M + H]⁺.

Pure Diastereomer 2

Preparation of 2-(3-Isobutylphenyl)-l-[(S)-3-(fl)-phenyl(4- trifluoromethylphenoxy)methyl)piperidin-l-yl]propan-l-one (4a, pure diastereomer #2). The reaction of (5)-3-[(/?)-phenyl(4- trifluoromethylphenoxy) methyl] piperidine (110, 107 mg, 0.319 mmol) and 2-(3- isobutylphenyl) propanoic acid (112, 66 mg, 0.319 mmol) following the general procedure gave 4a, pure diastereomer #2 (5.6 mg, 3%) as a hygroscopic white solid: ¹U NMR (300 MHz, CDCl₃) δ 7.41 (d, / = 8.5 Hz, 2H), 7.36-7.15 (m, 4H), 7.10-6.74 (m, 7H), 4.98 (d, / = 5.7 Hz, 0.5H), 4.66-4.63 (m, IH), 4.41 (d, / = 13.0 Hz, 0.5H), 3.88-3.70 (m, 2H), 2.93 (t, /= 13.0 Hz, IH), 2.76-2.66 (m, IH), 2.55-2.41 (m, 2H), 2.03-1.72 (m, 2H), 1.67-1.02 (m, 7H), 0.87 (d, / = 4.9 Hz, 6H); ESI, m/z 524 [M + H]⁺.

Preparation of 2-(2-Isobutylphenyl)-l-[(S)-3-(fl)-phenyl(4- trifluoromethylphenoxy) methylpiperidin-l-yl]propan-l-one (5a). The reaction of (S)-3-[(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (110, 100 mg, 0.298 mmol) and 2-(2-isobutylphenyl)propanoic acid (113, 62 mg, 0.298 mmol) following the general procedure gave 5a (100 mg, 64%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, / = 8.6 Hz, 2H), 7.31-7.23 (m, 4H), 7.18-7.13 (m, 4H), 6.89-6.84 (m, 2H), 6.73 (d, /= 8.5 Hz, IH), 5.04-4.36 (m, 2H), 4.04-3.89 (m, IH), 3.59-3.50 (m, IH), 2.96 (t, /= 11.8 Hz, IH), 2.86-2.26 (m, 3H), 2.05-1.50 (m, 5H), 1.46 (d, / = 3.1 Hz, 3H), 1.26 (s, IH), 0.93 (d, / = 6.7 Hz, 6H); ESI, m/z 524 [M + H]⁺.

General Procedure for the Preparation of Amides 2b, 4b, and 5b. To a suspension of (S)-3-[(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (117, 0.100 g, 1.0 equiv) and carboxylic acids (111-113, 1.0 equiv) in CH₂Cl₂ (5 niL) was added EDC*HC1 (1.5 equiv), 1-hydroxybenzotriazole (1.5 equiv) and triethylamine (2.0 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with CH₂Cl₂ (5 mL), washed with water (5 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, 4:1 hexanes/EtOAc) provided the carboxylic amides 2b, 4b, and 5b.

Preparation of (S)-2-(4-Isobutylphenyl)-l-[(S)-3-(S)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (2b). The reaction of (S)-3-[(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (117, 144 mg, 0.429 mmol) and (5^r)-(+)-ibuprofen (111, 89 mg, 0.429 mmol) following the general procedure gave 2b (122 mg, 23%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.24 (m, 7H), 7.16-7.05 (m, 2H), 7.01-6.83 (m, 4H), 5.06 (d, /= 12.7 Hz, 0.5H), 4.82 (m, IH), 4.62 (d, /= 13.0 Hz, 0.5H), 4.11 (d, / = 13.4 Hz, 0.5H), 3.85-3.80 (m, IH), 3.67 (q, /= 6.8 Hz, 0.5H), 2.82 (t, / = 11.4 Hz, 0.5H), 2.59-2.38 (m, 3.5H), 1.99-1.55 (m, 3H), 1.44-1.12 (m, 6H), 0.85 (d, /= 5.3 Hz, 6H); ESI, m/z 546 [M + Na]⁺.

Diastereomer 1

Preparation of 2-(3-Isobutylphenyl)-l-[(S)-3-(S)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (4b, diastereomer

#1). The reaction of (S)-3- [(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (117, 73 mg, 0.218 mmol) and 2-(3-isobutylphenyl)propanoic acid (112, 45 mg, 0.218 mmol) following the general procedure gave 4b, diastereomer #1 (15 mg, 13%) as a hygroscopic white solid: ¹U NMR (300 MHz, CDCl₃) δ 7.44-7.22 (m, 6H), 7.19- 6.94 (m, 4H), 6.89-6.84 (m, 3H), 5.08 (d, / = 12.1 Hz, 0.5H), 4.79 (t, / = 7.7 Hz, IH), 4.65 (d, /= 12.8 Hz, 0.5H), 4.19 (d, / = 13.5 Hz, 0.5H), 3.86-3.81 (m, IH), 3.69 (q, / = 6.7 Hz, 0.5H), 2.81 (t, /= 11.3 Hz, 0.5H), 2.54-2.34 (m, 4H), 1.99-1.67 (m, 3H), 1.56-1.02 (m, 6H), 0.88-0.77 (m, 6H); APCI, m/z 524 [M + H]⁺.

Diastereomer 2

#2). The reaction of (S)-3- [(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (117, 73 mg, 0.218 mmol) and 2-(3-isobutylphenyl)propanoic acid (112, 45 mg, 0.218 mmol) following the general procedure gave 4b, diastereomer #2 (4 mg, 3%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.44-7.21 (m, 7H), 7.08- 7.00 (m, 4H), 6.89-6.83 (m, 2H), 4.81-4.66 (m, IH), 4.46-4.37 (m, IH), 4.15-4.09 (m, IH), 3.89-3.68 (m, IH), 3.07-2.74 (m, 2H), 2.47-2.43 (m, IH), 1.87-1.71 (m, IH), 1.47-1.11 (m, 9H), 0.87 (d, /= 5.1 Hz, 6H); APCI, m/z 524 [M + H]⁺.

Mixture of Diastereomers

Preparation of 2-(3-Isobutylphenyl)-l-[(S)-3-(S)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (4b). The reaction of (S)-3-[(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (117, 73 mg, 0.218 mmol) and 2-(3-isobutylphenyl)propanoic acid (112, 45 mg, 0.218 mmol) following the general procedure gave 4b (20 mg, 17%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.44-7.28 (m, 7H), 7.07-6.93 (m, 4H), 6.89-6.83 (m, 2H), 5.09- 4.63 (m, IH), 4.40 (d, / = 12.9 Hz, 0.4H), 4.22-4.09 (m, 0.6H), 3.89-3.68 (m, IH), 3.07-2.71 (m, 2H), 2.53-2.34 (m, 2H), 2.07-1.72 (m, 2H), 1.63 (s, IH), 1.44-1.02 (m, 7H), 0.95-0.77 (m, 6H); APCI, m/z 524 [M + H]⁺.

Diastereomer 1

Preparation of 2-(2-Isobutylphenyl)-l-[(S)-3-(S)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (5b, diastereomer

#1). The reaction of (S)-3- [(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (117, 146 mg, 0.435 mmol) and 2-(2-isobutylphenyl)propanoic acid (113, 90 mg,

0.435 mmol) following the general procedure gave 5b, diastereomer #1 (18 mg, 8%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, /= 8.7 Hz, 2H), 7.35-7.05 (m, 9H), 6.89-6.81 (m, 2H), 5.07 (d, / = 12.3 Hz, 0.5H), 4.84-4.71 (m, IH), 4.08-3.99 (m, IH), 3.58 (d, / = 10.7 Hz, 0.5H), 2.82-2.19 (m, 4H), 2.04-1.88 (m, 2H), 1.39-1.02 (m, 8H), 0.97-0.86 (m, 6H); APCI, m/z 524 [M + H]⁺.

Diastereomer 2

Preparation of 2-(2-Isobutylphenyl)-l-[(S)-3-(S)-phenyl(4- trifluoromethylphenoxy) methylpiperidin-l-yl]propan-l-one (5b, diastereomer

#2). The reaction of (S)-3- [(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (117, 146 mg, 0.435 mmol) and 2-(2-isobutylphenyl)propanoic acid (113, 90 mg, 0.435 mmol) following the general procedure gave 5b, diastereomer #2 (22 mg, 9%) as a hygroscopic white solid: ¹U NMR (300 MHz, CDCl₃) δ 7.41 (d, /= 8.6 Hz, 2H), 7.34-7.14 (m, 8H), 7.03 (d, /= 5.6 Hz, IH), 6.91-6.81 (m, 2H), 4.84-4.38 (m, 2H), 4.01 (t, /= 6.5 Hz, IH), 3.81 (d, /= 13.1 Hz, 0.5H), 3.48 (d, / = 14.8 Hz, 0.5H), 2.99-2.39 (m, 4H), 2.05-1.85 (m, 2H), 1.47-1.02 (m, 7H), 0.95 (d, / = 6.5 Hz, 6H); APCI, m/z 524 [M + H]⁺.

Mixture of Diastereomers

Preparation of 2-(2-Isobutylphenyl)-l-[(S)-3-(S)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (5b). The reaction of (S)-3-[(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (117, 146 mg, 0.435 mmol) and 2-(2-isobutylphenyl)propanoic acid (113, 90 mg, 0.435 mmol) following the general procedure gave 5b (82 mg, 36%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.38 (m, 2H), 7.32-7.02 (m, 9H), 6.91-6.82 (m, 2H), 5.10- 4.38 (m, 2H), 4.10-3.46 (m, 2H), 3.03-2.33 (m, 4H), 2.08-1.51 (m, 3H), 1.39-1.02 (m, 7H), 0.88 (d, / = 3.5 Hz, 6H); APCI, m/z 524 [M + H]⁺.

Scheme 3

Preparation of (/?)-l-(Ter/-butoxycarbonyl)piperidine-3-carboxylic acid (120). To a stirred mixture of (i?)-piperidine-3-carboxylic acid (119, 4.00 g, 31.0 mmol) in THF (76 rnL) and water (76 mL) was added BoC₂O (9.50 g, 43.36 mmol) and NaHCO₃ (3.64 g, 43.4 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was diluted with water (20 mL) and ether (20 mL). The aqueous layer was adjusted to pH 2 with concentrated HCl (12 N) and was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were then washed with brine (80 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to afford 120 (6.7 g, 95%) as a clear oil: ¹U NMR (300 MHz, CDCl₃) δ 4.13 (d, /= 6.0 Hz, IH), 3.91 (d, /= 13.5 Hz, IH), 3.05 (m, IH), 2.91-2.82 (m, IH), 2.54-2.45 (m, IH), 2.08 (d, / = 3.9 Hz, IH), 1.76-1.60 (m, 2H), 1.52 (m, IH), 1.45 (s, 9H). Preparation of (R )-Ter/-butyl-3-[(methoxymethyl)carbamoyl]piperidine- 1-carboxylate (121). (i?)-l-(rert-butoxycarbonyl)piperidine-3-carboxylic acid (120, 6.7 g, 29.6 mmol), iV,0-dimethylhydroxylamine (3.62 g, 37.0 mmol), EDC-HCl (7.10 g, 37.0 mmol) and iV,iV-diisopropylethylamine (12.9 mL, 74.0 mmol) were dissolved in dichloromethane (109 mL) and the reaction was stirred overnight at room temperature under nitrogen. The reaction mixture was then diluted with ethyl acetate, washed with 5% aq. HCl (2 x 40 mL), saturated NaHCO₃ (100 mL), brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to afford 121 (9.0 g crude) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 4.16-4.09 (m, 2H), 3.81 (s, 3H), 3.24 (s, 3H), 2.91-2.66 (m, 3H), 1.93 (d, / = 12.6 Hz, IH), 1.75-1.59 (m, 3H), 1,51 (s, 9H).

Preparation of (R )-7Vr/-butyl-3-benzoylpiperidine-l-carboxylate (122). (R)-Te rt-buty\ 3-(methoxymethylcarbamoyl)piperidine-l-carboxylate (121, 9.7 g, 35.73 mmol) was dissolved in anhydrous THF (144 mL) and cooled to -10 ⁰C. Phenylmagnesium bromide solution in THF (72 mL of 1.0 M, 72.1 mmol) was then added dropwise to the solution under nitrogen and was stirred for 15 minutes. The reaction mixture was then warmed up to room temperature and was stirred for 2 h. Aqueous HCl (5%, 72 mL) was added slowly to quench the reaction and was stirred for 15 minutes. The mixture was then extracted with ether (3 x 200 mL). The combined organic layers were then washed with saturated NaHCO₃ (100 mL), brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to afford 122 (10.0 g, 97%) as a clear oil: ¹U NMR (300 MHz, CDCl₃) δ 8.00 (d, / = 4.8 Hz, 2H), 7.60 (m, IH), 7.45 (m, 2H), 4.28-4.08 (m, 2H), 3.42-3.37 (m, IH), 2.92 (m, IH), 2.72 (t, / = 9.0 Hz, IH), 2.01 (d, / = 1.5 Hz, IH), 1.80-1.54 (m, 3H), 1.42 (s, 9H). Preparation of (/?)-Ter/-butyl-3-[(/?)-hydroxyphenylmethyl]piperidine-l- carboxylate (123). A solution of (i?)-tert-butyl-3-benzoylpiperidine-l-carboxylate (122, 3.00 g, 10.4 mmol) in anhydrous toluene (35 mL) was cooled to -78 ⁰C under nitrogen and (i?)-2-methyl-CBS-oxazaborolidine (1.0 M in toluene, 5.2 mL, 5.2 mmol) was added slowly. After 10 min of stirring, catecholborane (1.0 M, 31.1 mL, 31.1 mmol) was added slowly. The reaction mixture was then stirred for 2 h and was transferred into the freezer (-14 ⁰C) to be left overnight. The mixture was cooled to 0 ⁰C and water as added dropwise to quench the reaction. The reaction mixture was diluted with ether, washed with 5% aqueous NaOH (2 x 50 mL), water (2 x 50 mL), 5% aqueous HCl (2 x 25 niL), brine (2 x 50 rnL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, 0-20% EtOAc in hexanes gradient) provided 123 (0.70 g, 22%) as a white solid: ¹U NMR (300 MHz, CDCl₃) δ 7.38-7.30 (m, 5H), 4.50 (s, IH), 3.89 (d, / = 7.2 Hz, IH), 2.69 (t, / = 9.6 Hz, IH), 2.55 (/ = 10.5 Hz, IH), 2.04- 1.98 (br s, IH), 1.83 (d, / = 7.5 Hz, 2H), 1.81-1.68 (m, 2H), 1.52-1.33 (m, 10H).

Preparation of (R)-Tert-butyl-3-[(R)-phenyl(4-

(trifluoromethylphenoxy)methyl]piperidine-l-carboxylate (124). To a solution of (i?)-fer?-butyl-3-[(i?)-hydroxyphenylmethyl]piperidine-l-carboxylate (107, 0.150 g, 0.515 mmol) in anhydrous DMSO (3 mL) at 0 ⁰C was added sodium hydride (0.031 g, 0.772 mmol, 60% in mineral oil). The reaction mixture was then heated at 55 ⁰C for 1 h to form the sodium alkoxide. To the alkoxide was added dropwise l-chloro-4- (trifluoromethyl)benzene (108, 0.10 mL, 0.772 mmol) and the reaction mixture was heated at 95 ⁰C for 2 h. The reaction mixture was cooled and extracted with ethyl acetate (3 x 50 mL). The organic layers were then washed with water (2 x 15 mL), and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, 0-20% EtOAc in hexanes gradient) provided 124 (0.133 g, 59%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 7.42 (d, /= 8.7 Hz, 2H), 7.36-7.24 (m, 5H), 6.85 (d, / = 8.4 Hz, 2H), 4.99 (d, /= 5.7 Hz, IH), 3.95 (d, /= 13.2 Hz, IH), 2.76-2.65 (m, 2H), 2.03-1.94 (m, 2H), 1.71-1.65 (m, IH), 1.51-1.40 (m, 12H).

Preparation of (fl)-3-[(fl)-Phenyl(4- trifluoromethylphenoxy)methyl]piperidine (125). To a solution of (R)-tert-buty\-3- [(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine-l-carboxylate (124, 0.10 g, 0.205 mmol) in CH₂Cl₂ (5 mL) was added trifluoroacetic acid (1 mL) and reaction mixture was left to stir at room temperature for 1 h. The mixture was concentrated under vacuum to provide 125 as a brown oil. This material was used for the final coupling reaction without further purification.

General Procedure for the Preparation of Amides 2c, 4c, and 5c. To a suspension of (i?)-3-[(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (125, 0.100 g, 1.0 equiv) and carboxylic acids (111-113, 1.1 equiv) in CH₂Cl₂ (5 mL) was added EDC*HC1 (1.5 equiv), 1-hydroxybenzotriazole (1.5 equiv) and triethylamine (2.0 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with CH₂Cl₂ (5 rnL), washed with water (5 rnL) and brine (10 rnL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, 4:1 hexanes/EtOAc) provided the carboxylic amides 2c, 4c, and 5c.

Preparation of (5)-2-(4-Isobutylphenyl)-l-[(R)-3-(R)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (2c). The reaction of (i?)-3-[(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (125, 50 mg, 0.15 mmol) and (5^r)-(+)-ibuprofen (111, 37 mg, 0.18 mmol) following the general procedure gave 2c (35 mg, 45%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.38 (m, 2H), 7.38-7.29 (m, 4H), 7.19-7.03 (m, 5H), 6.99-6.75 (m, 2H), 4.98 (d, /= 4.9 Hz, IH), 4.96-4.24 (m, 2H), 3.84-3.64 (m, 2H), 2.03-1.60 (m, 5H), 1.55- 1.22 (m, 5H), 0.93-0.92 (m, 2H), 0.91-0.89 (m, 6H); ESI, m/z 546 [M + Na]⁺.

Preparation of 2-(3-Isobutylphenyl)-l-[(fl)-3-(fl)-phenyl(4- trifluoromethyphenoxy)methylpiperidin-l-yl]propan-l-one (4c). The reaction of (i?)-3-[(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (125, 50 mg, 0.15 mmol) and 2-(3-isobutylphenyl)propanoic acid (112, 37 mg, 0.18 mmol) following the general procedure gave 4c (39 mg, 50%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.44-7.28 (m, 7H), 7.07-6.93 (m, 4H), 6.89-6.83 (m, 2H), 5.09 (m, IH), 4.40 (m, IH), 3.89-3.68 (m, 3H), 3.07-2.71 (m, 2H), 2.53-2.34 (m, 2H), 2.07-1.72 (m, 2H), 1.44-1.02 (m, 6H), 0.95-0.77 (m, 6H); ESI, m/z 546 [M + Na]⁺.

Preparation of 2-(2-Isobutylphenyl)-l-[(fl)-3-(fl)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (5c). The reaction of (i?)-3-[(i?)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (125, 50 mg, 0.15 mmol) and 2-(2-isobutylphenyl)propanoic acid (113, 37 mg, 0.18 mmol) following the general procedure gave 5c (41 mg, 52%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.41 (d, / = 8.6 Hz, 2H), 7.38-7.29 (m, 5H), 7.18-7.12 (m, 4H), 6.86-6.83 (d, /= 8.5 Hz, 2H), 5.04-4.36 (m, 2H), 4.04-3.89 (m, IH), 3.59-3.50 (m, IH), 2.96 (m, IH), 2.86-2.26 (m, 3H), 2.05-1.50 (m, 5H), 1.46 (d, / = 3.1 Hz, 3H), 1.26 (s, IH), 0.93 (m, 6H); ESI, m/z 546 [M + Na]⁺.

Scheme 4

General Procedure for the Preparation of Amides 2d, 4d, and 5d. To a suspension of (i?)-3-[(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (128, 0.100 g, 1.0 equiv) and carboxylic acids (111-113, 1.1 equiv) in CH₂Cl₂ (5 niL) was added EDC*HC1 (1.5 equiv), 1-hydroxybenzotriazole (1.5 equiv) and triethylamine (2.0 equiv). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with CH₂Cl₂ (5 mL), washed with water (5 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, 4:1 hexanes/EtOAc) provided the carboxylic amides 2d, 4d, and 5d.

Preparation of (S)-2-(4-Isobutylphenyl)-l-[(fl)-3-(S)-phenyl(4- trifluoromethylphenoxy)methyl)piperidin-l-yl]propan-l-one (2d). The reaction of (i?)-3-[(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (128, 50 mg, 0.15 mmol) and (5^r)-(+)-ibuprofen (111, 37 mg, 0.18 mmol) following the general procedure gave 2d (60 mg, 77%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.44 (d, /= 8.6 Hz, 2H), 7.38-7.29 (m, 4H), 7.19-7.03 (m, 5H), 6.99-6.75 (m, 2H), 4.98 (d, / = 4.9 Hz, 0.5H), 4.66 (d, /= 4.9 Hz, IH), 4.64 (d, / = 4.4 Hz, 0.5 H), 3.86-3.61 (m, 2H), 2.88-2.52 (m, IH), 2.52-2.37 (m, 2H), 1.90-1.41 (m, 3H), 1.32-1.08 (m, 7H), 0.91-0.89 (m, 6H); ESI, m/z 546 [M + Na]⁺.

Pure Diastereomer 1

Preparation of 2-(3-Isobutylphenyl)-l-[(fl)-3-(S)-phenyl(4- (trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (4d, diastereomer

#1). The reaction of (i?)-3-[(S)-phenyl(4-(trifluoromethylphenoxy)methyl]piperidine (128, 70 mg, 0.20 mmol) and 2-(3-isobutylphenyl)propanoic acid (112, 45 mg, 0.22 mmol) following the general procedure gave 4d, diastereomer #1 (8.1 mg, 7.1%) as a hygroscopic white solid: ¹U NMR (300 MHz, CDCl₃) δ 7.40 (d, /= 8.7 Hz, 2H), 7.35-7.05 (m, 9H), 6.89-6.81 (m, 2H), 5.07 (d, / = 12.3 Hz, 0.5H), 4.84-4.71 (m, IH), 4.08-3.99 (m, IH), 3.58 (d, / = 10.7 Hz, 0.5H), 2.89-2.04 (m, 4H), 2.04-1.88 (m, 2H), 1.39-1.02 (m, 7H), 0.97-0.86 (m, 6H); ESI, m/z 546 [M + Na]⁺.

Mixture of Diastereomer

Preparation of 2-(3-(Isobutylphenyl)-l-[(fl)-3-(S)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (4d). The reaction of (R)-3-[(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (128, 70 mg, 0.20 mmol) and 2-(3-isobutylphenyl)propanoic acid (112, 45 mg, 0.20 mmol) following the general procedure gave 4d (63 mg, 57%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.30 (m, 7H), 7.29-7.01 (m, 4H), 6.98-6.80 (m, 2H), 5.05- 4.97 (m, 2H), 4.75-4.38 (m, 2H), 4.15-4.09 (m, IH), 3.89-3.68 (m, 5H), 2.47-2.43 (m, IH), 1.47-1.11 (m, 6H), 0.97-0.86 (m, 6H); ESI, m/z 546 [M + Na]⁺.

Preparation of 2-(2-Isobutylphenyl)-l-[(fl)-3-(S)-phenyl(4- trifluoromethylphenoxy)methylpiperidin-l-yl]propan-l-one (5d). The reaction of (i?)-3-[(S)-phenyl(4-trifluoromethylphenoxy)methyl]piperidine (128, 60mg, 0.179 mmol) and 2-(2-isobutylphenyl)propanoic acid (113, 40 mg, 0.18 mmol) following the general procedure gave 5d (54 mg, 58%) as a hygroscopic white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.41 (d, / = 8.7 Hz, 2H), 7.31-7.12 (m, 9H), 6.89-6.81 (m, 2H), 5.03-4.55 (m, 2H), 4.00-3.58 (m, 2H), 2.95-2.51 (m, 3H), 2.49-2.37 (m, IH), 2.03- 1.99 (m, 4H), 1.96-1.63 (m, 5H), 0.97-0.86 (m, 6H); ESI, m/z 546 [M + Na]⁺.

Example 3: Effect of Compound Ia on the Body Weight and Insulin Content of Male C57BL/6J Mice Which Exhibit Diet Induced Obesity

Sixty-five C57BL/6J mice (4-6 weeks of age) were provided with free access to a high fat diet (D12451 45% of Kcal derived from fat; Research Diets, New Jersey, USA) for 14 weeks. Animals were maintained on a normal phase 12 h light-dark cycle (lights on 07:00). During this time body weight was recorded weekly. Animals were then singly housed in polypropylene cages for a further three week period and placed on reverse phase lighting (lights off for 8 h from 09:30 - 17:30 h) during which time the room was illuminated by red light. During the third week, animals underwent daily handling (animals were handled as if to be dosed but are actually not weighed or dosed). Animals were then dosed with vehicle orally once daily for a 7 day baseline period. Body weight and food and water intake was recorded daily. On day -2 during this baseline period (after the completion of dosing on that day), a blood sample (approx. 40 μL) was taken from the lateral tail vein using lithium heparin coated collection tubes (Sarstedt CB300LH). The sample was spun in a cooled centrifuge (4 ⁰C) and the plasma fraction collected and frozen. The sample was subsequently assayed for glucose and insulin content. Towards the end of the baseline treatment, animals were weighed and allocated into treatment groups matched, as closely as possible, for body weight and baseline glucose and insulin. Excess animals were set aside as spares and did not progress to the dosing phase of this particular study. The criteria for withdrawing the animals included general condition, the body weight response to baseline dosing (e.g., poor condition, excessive weight loss), and outlying plasma insulin and glucose values. Animals then either proceeded directly to the treatment study below, or if used in multiple treatment studies, animals proceeded through a seven day treatment study (e.g., with another test compound) followed by a seven day washout cycle before entering the treatment study below.

For the treatment study, mice were dosed once daily for six days with vehicle, compound Ia at 75, 100, or 150 mg/kg, or rimonabant, used as a control. All treatments were dosed orally by gavage. Dosing solutions were prepared in a vehicle of 1% methyl cellulose in de-ionised water using a mortar and pestle and were sonicated if deemed necessary. Drugs were made up fresh each day immediately prior to dosing and were administered using a dose volume of 3 ml/kg. Drug doses were expressed as free base. During the baseline and treatment period food intake, water intake and body weight were recorded daily. At the completion of dosing, animals were examined and any overt behaviour was recorded. Dosing began at approximately 08:45 each day.

On day six, all the mice were fasted at 16:00. On day seven the mice underwent an oral glucose tolerance test (OGTT). Each animal was dosed with vehicle or test compound and 60 minutes later were dosed with D-glucose (2 g/kg po). A baseline blood sample was taken immediately before the glucose load and further blood samples were taken 15, 30 and 60 minutes post glucose administration. All blood samples (approximately 30 μL, with the exception of the baseline samples which were slightly larger) were taken from the tail vein. Blood samples were taken into lithium heparinised tubes (Sarstedt Microvette CB300) and plasma separated by centrifugation. Plasma samples were frozen at -80 ⁰C and subsequently assayed for glucose and insulin content using commercially available kits and reagents; area under the curve (AUC) was calculated, and a log transform was used for insulin. Food was re-presented subsequent to the OGTT and final readings were taken on the morning of day eight.

Figure 1 shows the effects of seven day administration of compound Ia administered orally at 75, 100, and 150 mg/kg on the overall body weight gain in the mice with diet-induced obesity. Body weights in figure 1 are expressed as adjusted means (n=10), and the standard errors of the mean (SEMs) were calculated from the residuals of the statistical model. Body weight was analysed by ANCOVA with body weight on day one as covariate. Multiple comparisons against the vehicle group were performed by Williams' test for compound Ia and by multiple t-test for rimonabant. Significances in Figure 1 are denoted by *p<0.05, **P<0.01, and ***P<0.001. Figure 1 shows a dose-dependent increase in weight loss for compound Ia as compared to vehicle, with statistically significant results observed at each dose. Specifically, when dosed orally at 150 mg/kg, compound Ia demonstrated approximately a 200% increase in weight loss as compared to vehicle.

Figure 2 shows the effects of seven-day administration of compound Ia administered orally at 75, 100, and 150 mg/kg on insulin content in the mice with diet-induced obesity. Means (n=10) were adjusted for differences between the treatment groups in body weight on day 1 and in plasma insulin on day -2. Analysis was by robust regression and included treatment as a factor and day 1 body weight and log(day -2 insulin) as covariates. SEMs were calculated from the residuals of the statistical models. Multiple comparisons against vehicle were by Williams' tests for compound Ia and the multiple t-test for rimonabant. Significances in Figure 2 are denoted by *p<0.05, **P<0.01, and ***P<0.001. Figure 2 shows a statistically significant decrease in insulin as compared to vehicle upon treatment with compound Ia at 75, 100, or 150 mg/kg. Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents

While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

Claims:

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

(I) wherein

X represents hydrogen, optionally substituted lower alkyl, or an optionally substituted aryl or heteroaryl ring;

Y represents an optionally substituted aryl, heteroaryl, or heterocyclyl ring; Z represents O, S, NR¹⁶, or C(H)R¹⁷; R¹⁶ represents hydrogen, optionally substituted lower alkyl, or an optionally substituted aryl or heteroaryl ring;

R¹⁷ rep irreesseennttss hhyyddrrooggeenn,, ooppttiioonnaallllyy ssuubbssttiiituted lower alkyl, or an optionally substituted aryl or heteroaryl ring;

W represents

R¹ represents hydrogen or optionally substituted lower alkyl;

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently represent hydrogen or a substituent.

2. The compound of claim 1, wherein X represents an optionally substituted aryl or heteroaryl ring.

3. The compound of claim 2, wherein X represents an optionally substituted phenyl or thiophene.

4. The compound of any of claims 1-3, wherein X is optionally substituted with optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted amido, optionally substituted acylamino, cyano, or nitro.

5. The compound of claim 1, wherein X represent hydrogen.

6. The compound of any of claims 1-5, wherein Y represents an optionally substituted phenyl.

7. The compound any of claims 1-6, wherein Y is optionally substituted with optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted amido, optionally substituted acylamino, cyano, nitro, or two adjacent substituents together represent -OCH₂O- forming a heterocycle with the carbons to which they are attached.

8. The compound of any of claims 1-7, wherein Z represents C(H)R¹⁷.

9. The compound of claim 8, wherein R¹⁷ represents an optionally substituted aryl or heteroaryl ring.

10. The compound of claim 9, wherein R¹⁷ represents an optionally substituted phenyl.

11. The compound of claim 9 or 10, wherein R¹⁷ is optionally substituted with optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted amido, optionally substituted acylamino, cyano, or nitro.

12. The compound of any of claims 1-11, wherein R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ each independently represent hydrogen, optionally substituted lower alkyl, halogen, hydroxyl, carboxyl, optionally substituted ester, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted thioester, optionally substituted thioacyl, optionally substituted thioether, optionally substituted alkoxyl, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted amido, optionally substituted acylamino, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, cyano, or nitro.

13. The compound of any of claims 1-12, wherein W represents

14. The compound of any of claims 1-13, wherein R¹ represents hydrogen or optionally substituted lower alkyl.

15. The compound of claim 14, wherein R¹ represents methyl.

16. The compound of any of claims 1-15, wherein R² is hydrogen and R³ is an optionally substituted lower alkyl.

17. The compound of any of claims 1-15, wherein R² and R³ taken together with the carbon to which they are attached form a cyclopropane or cyclobutane ring.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of claims 1-17.

19. A method of treating obesity, metabolic syndrome, or a disorder associated with metabolic syndrome in a mammal, comprising administering to a mammal suffering from obesity, metabolic syndrome, or a disorder associated with metabolic syndrome, a compound of any of claims 1-18.

20. The method of claim 19, wherein the disorder associated with metabolic syndrome is selected from obesity, diabetes, hypertension, or hyperlipidemia.

21. The method of claim 20, wherein the disorder associated with metabolic syndrome is diabetes.

22. The method of any of claims 19-21, wherein said mammal is a human.