WO2013068439A1 - 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazepine compounds as dgat1 inhibitors - Google Patents

Abstract

Described herein are compounds of formula (I). The compounds of formula (I) act as DGAT1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.

Description

4 -AMINO- 5 -OXO-7 , 8 -DIHYDROPYRIMIDO [5 , 4 -F] [1 , 4] OXAZEPINE COMPOUNDS AS DGAT1 INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application Serial No. 61/557,483, filed on November 9, 2011, the contents of which are herein incoporated by reference in their entirety.

TECHNICAL FIELD

The present invention is directed to lactam derivative compounds. Specifically, the compounds act as diacylglycerol O-acyltransferase type 1 inhibitors (hereinafter also referred to as "DGAT1"), and can be useful in preventing, treating or acting as a remedial agent for

hyperlipidemia, diabetes mellitus and obesity.

BACKGROUND

Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after meals. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin- dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.

Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipo lysis in adipose tissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat which results in the accumulation of triacylglycerol (TG) in adipose tissue.

In the body there are two TG synthesis pathways, a glycerol phosphate pathway, which is present in most organs and causes de novo TG synthesis, and a monoacylglycerol pathway, which is involved principally in absorption of aliphatic acid from the small intestine. Diacylglycerol acyltransferases (DGATs, EC 2.3.1.20), which are membrane-bound enzymes present in the endoplasmic reticulum, catalyze the final step of the TG synthesis common to the two TG synthesis pathways. The final reaction consists of transferring an acyl group from acyl-coenzyme A to the 3-position of 1 ,2-diacylglycerol to generate TG (Prog. Lipid Res., 43, 134-176, 2004 and Ann. Med., 36, 252-261 , 2004). There are two subtypes of DGATs, DGAT-1 and DGAT-2. There is no significant homology at the generic or amino acid level between the DGAT-1 and DGAT-2, which are encoded by different genes (Proc. Natl. Acad. Sci. USA., 95, 13018-13023, 1998 and JBC, 276, 38870-38876, 2001). DGAT-1 is present in the small intestine, adipose tissue and liver and is believed to be involved in lipid absorption in the small intestine; lipid accumulation in the fat cell; and VLDL secretion and lipid accumulation in the liver (Ann. Med., 36, 252-261, 2004 and JBC, 280, 21506-21514, 2005).

In order to carry out in vivo examination of the physiological function(s) of DGAT-1 and inhibitory activity against DGAT-1, DGAT-1 -knockout (KO) mice deficient in DGAT-1 at the genetic level was produced and analyzed. DGAT1 KO mice show a lack of postprandial rise of plasma TG, suggesting an important role for DGAT1 in the regulation of fat absorption. DGAT1- deficient mice are resistant to high fat diet-induced obesity and have increased sensitivity to insulin and leptin. Moreover, the KO mice are protected against hepatic steatosis and were shown to have decreased levels of tissue TG. In addition, the DGAT1 KO mice have improved glucose metabolism, with lower plasma glucose levels after glucose load or insulin injection. Furthermore, in a hyperinsulinemic-euglycemic clamp study, the DGAT1 KO mice required higher glucose infusion rates relative to the WT controls to maintain euglycemia. (Nature Genetics, 25, 87-90, 2000 and JCI, 109, 1049-1055, 2002). Dgatl KO mice exhibit other post-prandial phenotypes including prolonged release of PYY and GLP-1 as well as delayed gastric emptying (Biochem Biophys Res Commun. 390(3):377-81, 2009). Currently, there is an incomplete understanding of the mechanism or the site of action by which DGAT1 inhibition leads to improvement in these metabolic parameters. Genetic data suggests that inhibition of the intestine DGATl is the prime driver for body weight loss {J Lipid Res. 51:1770-80

2010). Other reports suggest adipose is the main site of action (J. Med Chem 52, 1558-1568, 2009.

From the results, DGAT-1 inhibitors are likely to be therapeutic drugs with efficacy for type 2 diabetes mellitus, obesity, lipidosis, hypertension, fatty liver, arteriosclerosis,

cerebrovascular disorder, coronary artery disease and metabolic syndrome.

SUMMARY OF THE INVENTION

A compound of formula (I):

I or pharmaceutically acceptable salts thereof, wherein X and R¹ are further described below. The compounds described herein are DGAT-1 inhibitors, which are useful in the treatment of type 2 diabetes mellitus, obesity, lipidosis, hypertension, fatty liver, arteriosclerosis, cerebrovascular disorder, coronary artery disease and metabolic syndrome, particularly, obesity and diabetes.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

Described herein are compounds of A compound of formula (I):

or pharmaceutically acceptable salts thereof, wherein X is selected from the group consisting of - NH-, -NR²-, -S-, -SO- and -SO²-; R¹ is selected from the group consisting of hydrogen, Ci-Ci₀alkyl, C₃-C₆cycloalkyl, aryl, Ci- C₆alkylaryl, heterocycle, Ci-C₆alkyl-0-aryl and Ci-C₆alkylheterocycle;

wherein any alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C₆halogen-substitutedalkyl, C₃-C₆cycloalkyl, Ci-C₆alkoxy, - NH0₂Ci-C₆alkyl, -COOH, NHCOOCi-C₆alkyl, NR²COOCi-C₆alkyl, S0₂N(Ci-C₆alkyl)₂ and - OH,

wherein any aryl or heterocycle are unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C₆alkoxy and Ci-Cehalogen-substitutedalkyl; and

-R² is selected from the group consisting of Ci-Ci₀alkyl.

In certain embodiments, formula I can have the following stereochemistry:

I-a

In certain embodiments of the compounds described herein, X is selected from the group consisting of-NH-, -NR²-, -S-, -SO- and -SO²-. In some embodiments, X is -NH- or -NR²-. In other embodiments, X is -S-, -SO- or -SO²-. In still other embodiments, X is -NH-. In yet other embodiments, X is -NR²-. In certain embodiments, X is -S-. In other embodiments, X is -SO-. In yet other embodiments, X is -SO²-.

In certain embodiments of the compounds described herein, R¹ is selected from the group consisting of hydrogen, Ci-Ci₀alkyl, C₃-C₆cycloalkyl, aryl, Ci-C₆alkylaryl, heterocycle, Ci- C₆alkyl-0-aryl and Ci-Cealkylheterocycle.

In certain embodiments of the compounds described herein R¹ is hydrogen. In certain embodiments R¹ is Ci-Cioalkyl. In any of the embodiments described herein the alkyl can be branched or straight. Suitable alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 ,2-dimethylpropyl, 1- ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1- ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2-methylpropyl and 1 -ethyl- 1- methylpropyl. In certain embodiments of the compounds described herein R¹ is C3-C₆cycloalkyl.

Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R¹ is aryl. In other embodiments, R¹ is Ci-C₆alkylaryl. In still other embodiments, R¹ is Ci-C₆alkyl-0-aryl. Suitable aryls include, but are not limited to, phenyl and napthyl.

In certain embodiments, R¹ is heterocycle. In other embodiments, R¹ is Ci- C₆alkylheterocycle. Suitable heterocylces include, but are not limited to, pyridine, pyrrolidinone, pyrrolidine, pyrimidine, pyrazole, pyrazine, oxolane, oxane and indazole.

In any of the alkyls described herein, the alkyl can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C₆halogen- substitutedalkyl, C₃-C₆cycloalkyl, Ci-C₆alkoxy, -NH0₂Ci-C₆alkyl, -COOH, NR²COOCi-C₆alkyl, S0₂N(Ci-C₆alkyl)₂ and -OH. In certain embodiments, the alkyl is unsubstituted.

In other embodiments the alkyl is substituted with one or more halogens. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine and iodine. In other embodiments the alkyl is substituted with one or more Ci-C₆halogen-substituted alkyls. Suitable halogen-substituted alkyls include, but are not limited to, trifluoromethyl. In other embodiments the alkyl is substituted with one or more cycloakyls. Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In other embodiments the alkyl is substituted with one or more Ci-C₆alkoxys. Suitable alkoxys include methoxy, ethoxy, butoxy and propoxy.

In other embodiments the alkyl is substituted with one or more -OH groups. In other embodiments the alkyl is substituted with one or more -COOH groups.

In still other embodiments the alkyl is substituted with one or more -NH0₂Ci-C₆alkyl groups. In still other embodiments, the alkyl is substituted with one or more, NR²COOCi-C₆alkyl groups. In yet another embodiment, the alkyl can be substituted with one or more S0₂N(Ci- C₆alkyl)₂ groups.

In certain embodiments of the compounds described herein, any aryl and heterocycle are unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-Cealkoxy and Ci-Cehalogen-substitutedalkyl. In certain embodiments, any aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C₆alkoxy and Ci-Cehalogen-substitutedalkyl. Suitable halogens, Ci-C₆alkoxys and Ci-C₆halogen-substituted alkyls are described above. In other embodiments, any heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C₆alkoxy and Ci-C₆halogen-substitutedalkyl. Suitable halogens, Ci-C₆alkoxys and Ci-C₆halogen-substituted alkyls are described above.

In some embodiments, the aryl is substituted with one or more halogens. In other embodiments, the aryl is substituted with one or more halogen-substituted alkyls. In yet another embodiment, the aryl is substituted with one or more alkoxys. In some embodiments, the heterocycle is substituted with one or more halogens. In other embodiments, the heterocycle is substituted with one or more halogen-substituted alkyls. In yet another embodiment, the heterocycle is substituted with one or more alkoxys.

In certain embodiments of the compounds described herein, R² is Ci-C₆alkyl. Suitable alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 ,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1 , 1- dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1-ethylbutyl, 1,1 ,2- trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2-methylpropyl and 1 -ethyl- 1-methylpropyl.

Definitions

The term "halogen" includes "halogen", fluorine, chlorine, bromine and iodine.

The term "Ci-C _loalkyl" encompasses straight alkyl having a carbon number of 1 to 10 and branched alkyl having a carbon number of 3 to 10. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1 ,2- dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1 , 1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 2- ethylbutyl, 1-ethylbutyl, 1,1 ,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2-methylpropyl and 1 -ethyl- 1 -methylpropyl, and the like.

The term "halogen-substitutedCi-C₆ alkyl" encompasses Ci-C₆alkyl with the hydrogen atoms thereof being partially or completely substituted with halogen, examples thereof including fluoromethyl, difluoromethyl, trifluoromethyl and the like. Examples of "aryl" include phenyl, naphthyl, tolyl, and the like.

The term "heterocycles" includes heteroaryls and hetercycloalkyls. "Heteroaryls" are 5- or 6-membered monocyclic or 8- to 14-membered polycyclic hetero aromatic cyclic group containing at least one, preferably from 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a part of the ring-constitutive members; and concretely, for example, it includes a pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a tetrazolyl group, a pyridazinyl group, a pyrazinyl group, a furyl group, a thienyl group, an indolyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group, an indazolyl group, a purinyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a

naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, a pyrido[3,2-b]pyridyl group and the like. "Heterocycloalkyls" are 5- or 6-membered monocyclic or 8- to 14-membered polycyclic heteronon-aromatic cyclic group containing at least one, preferably from 1 to 5 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a part of the ring-constitutive members. Cycloheteroalkyls include an aziridine ring, pyrrolidine ring, piperidine ring, tetrahydropyran ring (or xane), tetrahydrofuran ring (or oxolane ring), dioxane ring, morpholine ring and the like.

The term "cycloalkyl" includes a monocyclic or polycyclic, saturated or partially- unsaturated carbocyclic group having from 3 to 10, preferably from 3 to 8 carbon atoms, concretely, for example, a cyclopropyl group, a cyclobutenyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a bicyclohexyl group, an adamantyl group and the like.

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate

(embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine,

triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

The compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefmic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline Intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. It will be understood that, as used herein, references to the compounds of the structural formulas described herein are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

Solvates, and in particular, the hydrates of the compounds of the structural formulas described herein are included in the present invention as well.

Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.

In the compounds of the formulas described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium (iH) and deuterium (¾). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic formula can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically- enriched reagents and/or Intermediates. Methods of Treatment

Also encompassed by the present invention are methods of treating DGAT1 -related diseases. The compounds described herein are effective in preventing or treating various

DGAT1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compound of the invention is especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety.

One aspect of the invention described herein provides a method for the treatment and control of obesity or metabolic syndrome, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having the formulas described herein or a pharmaceutically acceptable salt thereof. For example, the compounds described herein are useful for treating or preventing obesity by administering to a subject in need thereof a composition comprising a compound of formula I.

Methods of treating or preventing obesity and conditions associated with obesity refer to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of an obese subject or to reduce or maintain the body weight of an individual at risk of becoming obese. One outcome of treatment may be reducing the body weight of an obese subject relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention. Another outcome of treatment may be preventing body weight, regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy and preventing weight gain from cessation of smoking. Another outcome of treatment may be decreasing the occurrence of and/or the severity of obesity-related diseases. Yet another outcome of treatment may be decreasing the risk of developing diabetes in an overweight or obese subject. The treatment may suitably result in a reduction in food or calorie intake by the subject, including a reduction in total food intake, or a reduction of intake of specific components of the diet such as carbohydrates or fats; and/or the inhibition of nutrient absorption; and/or the inhibition of the reduction of metabolic rate; and in weight reduction in patients in need thereof. The treatment may also result in an alteration of metabolic rate, such as an increase in metabolic rate, rather than or in addition to an inhibition of the reduction of metabolic rate; and/or in minimization of the metabolic resistance that normally results from weight loss.

Prevention of obesity and obesity-related disorders refers to the administration of the pharmaceutical formulations described herein to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention may be reducing the body weight of a subject at risk of obesity relative to that subject's body weight immediately before the administration of the compounds or combinations of the present invention. Another outcome of prevention may be preventing body weight regain of body weight previously lost as a result of diet, exercise, or pharmacotherapy. Another outcome of prevention may be preventing obesity from occurring if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Another outcome of prevention may be decreasing the occurrence and/or severity of obesity-related disorders if the treatment is administered prior to the onset of obesity in a subject at risk of obesity. Moreover, if treatment is commenced in already obese subjects, such treatment may prevent the occurrence, progression or severity of obesity-related disorders, such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovary disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.

Another aspect of the invention that is of interest relates to a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat hyperglycemia, diabetes or insulin resistance.

More particularly, another aspect of the invention that is of interest relates to a method of treating type 2 diabetes in a mammalian patient in need of such treatment comprising

administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat type 2 diabetes.

Yet another aspect of the invention that is of interest relates to a method of treating non- insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with the formulas described herein or a pharmaceutically acceptable salt thereof in an amount that is effective to treat non-insulin dependent diabetes mellitus.

The present invention is also directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating various DGAT1 -related diseases, such as metabolic diseases such as obesity, diabetes, hormone secretion disorder, hyperlipemia, gout, fatty liver, and the like; circulatory diseases such as angina pectoris, acute/congestive cardiac insufficiency, myocardial infarction, coronary arteriosclerosis, hypertension, nephropathy, electrolyte abnormality, and the like; central and peripheral nervous system diseases such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit/hyperactivity disorder, dysmnesia, somnipathy, cognitive impairment, dyskinesia, dysesthesia, dysosmia, morphine resistance, drug dependence, alcohol dependence, and the like; reproductive system diseases such as infertility, premature delivery, sexual dysfunction, and the like; and other conditions including digestive diseases, respiratory diseases, cancer, and chromatosis. The compounds described herein are especially useful as a preventive or a remedy for obesity, diabetes, fatty liver, bulimia, depression, or anxiety. For example, the present invention is directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating obesity, diabetes, hormone secretion disorder, hyperlipemia, gout and fatty liver.

Additionally, the present invention is directed to the use of a compound of structural formula I in the manufacture of a medicament for use in treating diabetes.

Pharmaceutical Compositions

Compounds of the invention may be administered orally or parenterally. As formulated into a dosage form suitable for the administration route, the compound of the invention can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases.

In clinical use of the compound of the invention, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form, and may then be administered. By "pharmaceutically acceptable" it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As such additives, various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose,

carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate,

hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.

Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as syrups, elixirs, injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations. The liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use. Especially for injections, if desired, the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto.

The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition. The compositions may further contain any other therapeutically-effective compounds. In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the

range of the intended remedial effect. In general, when orally administered, the dose may be from

0.001 to 50 mg/kg of body weight/day, and it may be administered at a time or in several times.

The dose is preferably from about 0.01 to about 25 mg/kg/day, more preferably from about 0.05 to about 10 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg, preferably 0.01 , 0.05, 0.1, 0.2,

0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 and 1,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response.

Combination Therapy

The compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of formula I. When a compound of formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I is preferred. However, the combination therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I.

Examples of other active ingredients that may be administered in combination with a compound of formula I and either administered separately or in the same pharmaceutical composition, include, but are not limited to:

(1) dipeptidyl peptidase-IV (DPP-4) inhibitors;

(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/γ Ddual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), such as those disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO 2004/020408, and WO 2004/066963, and (4) PPARy□ partial agonists; (ii) biguanides, such as metfomiin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

(3) insulin or insulin analogs, such as insulin lispro, insulin detemir, insulin glargine, insulin glulisine, and inhalable formulations of each thereof;

(4) leptin and leptin derivatives and agonists;

(5) amylin and amylin analogs, such as pramlintide;

(6) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;

(7) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);

(8) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO 99/01423, WO

00/39088, and WO 00/69810;

(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists, such as exenatide, liraglutide, taspoglutide, AVE0010, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof;

(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl Co A: cholesterol acyltransferase inhibitors, such as avasimibe;

(11) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof;

MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists;

(12) antiobesity compounds;

(13) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti- inflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;

(14) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;

(15) glucokinase activators (GKAs), such as LY2599506; (16) inhibitors of 11 β-hydroxysteroid dehydrogenase type 1, such as those disclosed in U.S. Patent No. 6,730,690; WO 03/104207; and WO 04/058741;

(17) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-0859;

(18) inhibitors of fructose 1,6-bisphosphatase, such as those disclosed in U.S. Patent Nos.

6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476;

(19) inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);

(20) AMP-activated Protein Kinase (AMPK) activators;

(21) agonists of the G-protein-coupled receptors: GPR-109, GPR-119, and GPR-40;

(22) SSTR3 antagonists, such as those disclosed in WO 2009/011836;

(23) neuromedin U receptor agonists, such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS);

(24) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);

(25) GPR-105 antagonists, such as those disclosed in WO 2009/000087;

(26) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various iso forms, such as SGLT-1; SGLT-2, such as dapagliflozin, canagliflozin and remogliflozin and those described in WO2010/023594 such as PF-04971729; and SGLT-3;

(27) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-

2);

(28) inhibitors of fatty acid synthase;

(29) inhibitors of acetyl-CoA carboxylase- 1 and 2 (ACC-1 and

ACC-2);

(30) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

(31) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M- BAR); and

(32) bromocriptine mesylate and rapid-release formulations thereof.

Dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I include, but are not limited to, sitagliptin (disclosed in US Patent No. 6,699,871), vildagliptin, saxagliptin, alogliptin, denagliptin, carmegliptin, dutogliptin, melogliptin, linagliptin, and pharmaceutically acceptable salts thereof, and fixed-dose combinations of these compounds with metformin hydrochloride, pioglitazone, rosiglitazone, simvastatin, atorvastatin, or a sulfonylurea.

Other dipeptidyl peptidase-IV (DPP-4) inhibitors that can be used in combination with compounds of formula I include, but are not limited to:

(2i?,3^,5i?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran-3-amine; (2i?,3^,5i?)-5-(l-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)-2-(2,4,5- trifluorophenyl)tetrahydro-2H-pyran-3-amine;

(2i?,3S,5i?)-2-(2,5-difluorophenyl)tetrahyd

tetrahydro-2H-pyran-3-amine;

(3i?)-4-[(3i?)-3-amino-4-(2,4,5-trifluoropheny

one;

4-[(3i?)-3-amino-4-(2,5-difluorophenyl)butanoyl]hexahydro- 1 -methyl-2H- 1 ,4-diazepin-2-one

hydrochloride; and

(3i?)-4 (3i?)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-hexahydro-3-(2,2,2-trifluoroe

diazepin-2-one; and

pharmaceutically acceptable salts thereof.

Antiobesity compounds that can be combined with compounds of formula I include topiramate; zonisamide; naltrexone; phentermine; bupropion; the combination of bupropion and naltrexone; the combination of bupropion and zonisamide; the combination of topiramate and phentermine; fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such as orlistat and cetilistat; melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentrating hormone (MCH) receptor antagonists; neuropeptide Yi or Y5 antagonists (such as MK-0557); CB1 receptor inverse agonists and antagonists (such as rimonabant and taranabant); β3 adrenergic receptor agonists; ghrelin antagonists; bombesin receptor agonists (such as bombesin receptor subtype-3 agonists); and 5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin. For a review of anti-obesity compounds that can be combined with compounds of the present invention, see S. Chaki et al., "Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity,"

Expert Opin. Ther. Patents, 1 1 : 1677-1692 (2001); D. Spanswick and K. Lee, "Emerging antiobesity drugs," Expert Opin. Emerging Drugs, 8: 217-237 (2003); J.A. Fernandez-Lopez, et al,

"Pharmacological Approaches for the Treatment of Obesity," Drugs, 62: 915-944 (2002); and K.M. Gadde, et al, "Combination pharmaceutical therapies for obesity," Exp. Opin. Pharmacother., 10: 921- 925 (2009).

Glucagon receptor antagonists that can be used in combination with the compounds of formula I include, but are not limited to:

N-[4-((\S)- 1 - {3-(3,5-dichlorophenyl)-5-[6-(trifiuoromethoxy)-2-naphthyl]- lH-pyrazol- 1 - yl}ethyl)benzoyl]-P-alanine;

N-[4-((lR)- 1 - {3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]- lH-pyrazol- 1 - yl}ethyl)benzoyl]-P-alanine;

N-(4- { 1 -[3-(2,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)- lH-pyrazol- 1 -yl]ethyl}benzoyl)-P- alanine; N-(4- {(liS)- 1 -[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)- IH-pyrazol- 1 -yl] ethyl} benzoyl)- β-alanine;

N-(4-{(lS)-l-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-lH-indol-3-yl)methyl]butyl}benzoy alanine; and

N-(4-{(lS)-l-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-yl)methyl]butyl}benzoyl)- -alanine; and

pharmaceutically acceptable salts thereof.

Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can be used in combination with the compounds of formula I include, but are not limited to:

[5-(5- {4-[2-(trifiuoromethyl)phenoxy]piperidin- 1 -yl} - 1 ,3,4-thiadiazol-2 -yl)-2H-tetrazol-2- yl] acetic acid;

(2 - {4-[2-(trifiuoromethyl)phenoxy]piperidin- 1 -yl} -2,5'-bi- 1 ,3-thiazol-4-yl)acetic acid;

(5- {3-[4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl]isoxazol-5-yl} -2H-tetrazol-2-yl)acetic acid;

(3- {3-[4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl]- 1 ,2,4-oxadiazol-5-yl} - lH-pyrrol- 1 -yl)acetic acid;

(5- {5-[4-(2-bromo-5-fluorophenoxy)piperidin- 1 -yl]pyrazin-2-yl} -2H-tetrazol-2-yl)acetic acid; and (5- {2-[4-(5-bromo-2-chlorophenoxy)piperidin- 1 -yl]pyrimidin-5-yl} -2H-tetrazol-2-yl)acetic acid; and pharmaceutically acceptable salts thereof.

Glucokinase activators that can be used in combination with the compounds of formula I, but are not limited to:

3 -(6-ethanesulfonylpyridin-3 -yloxy)-5 -(2-hydroxy- 1 -methyl-ethoxy)-N-( 1 -methyl- 1 H-pyrazol-3 - yl)benzamide;

5 -(2-hydroxy- 1 -methyl-ethoxy)-3 -(6-methanesulfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H-pyrazol-3 - yl)benzamide;

5 -( 1 -hydroxymethyl-propoxy)-3 -(6-methanesulfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H-pyrazol-3 - yl)benzamide;

3 -(6-methanesulfonylpyridin-3 -yloxy)-5 -( 1 -methoxymethyl-propoxy)-N-( 1 -methyl- 1 H-pyrazol-3 - yl)benzamide;

5 -isopropoxy-3 -(6-methanesulfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H-pyrazol-3 -yl)benzamide; 5 -(2-fluoro- 1 -fluoromethyl-ethoxy)-3 -(6-methanesulfonylpyridin-3 -yloxy)-N-( 1 -methyl- 1 H- pyrazol-3 -yl)benzamide;

3-( {4-[2-(dimethylamino)ethoxy]phenyl}thio)-N-(3-methyl- 1 ,2,4-thiadiazol-5-yl)-6-[(4-methyl- 4H- 1 ,2,4-triazol-3-yl)thio]pyridine-2-carboxamide;

3-({4-[(l -methylazetidin-3 -yl)oxy]phenyl}thio)-N-(3 -methyl- 1 ,2,4-thiadiazol-5 -yl)-6- [(4-methyl- 4H- 1 ,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; N-(3-methyl- 1 ,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H- 1 ,2,4-triazol-3-yl)thio]-3- {[4-(2-pyrrolidin- 1 - ylethoxy)phenyl]thio}pyridine-2-carboxamide; and

3-[(4- {2-[(2R)-2-methylpyrrolidin- 1 -yl]ethoxy}phenyl)thio-N-(3-methyl- 1 ,2,4-thiadiazol-5-yl)-6-[(4- methyl-4H-l,2,4-triazol-3-yl)thio]pyridine-2-carboxamide; and pharmaceutically acceptable salts thereof.

Agonists of the GPR-119 receptor that can be used in combination with the compounds of formula I include, but are not limited to:

rac-cis 5-chloro-2- {4-[2-(2- {[5-(methylsulfonyl)pyridin-2-yl]oxy} ethyl)cyclopropyl] piperidin- 1 - yl}pyrimidine;

5-chloro-2-{4-[(lR,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-l- yl}pyrimidine;

rac cz5-5-chloro-2-[4-(2- {2-[4-(methylsulfonyl)phenoxy]ethyl} cyclopropyl)piperidin- 1 - yljpyrimidine;

5-chloro-2-[4-((lS,2R)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl) piperidin-1- yljpyrimidine;

5-chloro-2-[4-((lR,2S)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl} cyclopropyl) piperidin-1- yljpyrimidine;

rac cz5-5-chloro-2-[4-(2- {2-[3-(methylsulfonyl)phenoxy]ethyl} cyclopropyl)piperidin- 1 - yl]pyrimidine; and

rac cis -5 -chloro-2- [4-(2- {2- [3 -(5 -methyl- 1 ,3 ,4-oxadiazol-2-yl)phenoxy]ethyl} cyclopropyl)

piperidin- 1 -yljpyrimidine; and pharmaceutically acceptable salts thereof.

Selective PPARy modulators (SPPARyM's) that can be used in combination with the compounds of formula I include, but are not limited to:

(2iS)-2-( {6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]- 1 ,2-benzisoxazol-5- yl}oxy)propanoic acid;

(2iS)-2-( {6-chloro-3-[6-(4-fiuorophenoxy)-2-propylpyridin-3-yl]- 1 ,2-benzisoxazol-5- yl}oxy)propanoic acid;

(25)-2-{[6-chloro-3-(6-phenoxy-2-propylpyridin-3-yl)-l,2-benzisoxazol-5-yl]oxy}propanoic acid;

(2R)-2-( {6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]- 1 ,2-benzisoxazol-5- yl}oxy)propanoic acid;

(2R)-2- {3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)- lH-indol- 1 - yl]phenoxy}butanoic acid;

(2S)-2- {3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)- lH-indol- 1 - yl]phenoxy}butanoic acid;

2- {3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)- lH-indol- 1 -yTJphenoxy} -2- methylpropanoic acid; and (2R)-2- {3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)- lH-indol- 1 -yl]phenoxy} propanoic acid; and pharmaceutically acceptable salts thereof.

Inhibitors of 11 β-hydroxysteroid dehydrogenase type 1 that can be used in combination with the compounds of formula I include, but are not limited to:

3-[ 1 -(4-chlorophenyl)-tra/75-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H- 1 ,2,4-triazole;3-[ 1 -(4- chloropfienyl)-tra/?s-3 -fluorocyclobutyl] -4-cyclopropyl-5 -( 1 -methylcyclopropyl)-r-4H- 1,2,4- triazole;

3 - [ 1 -(4-chloropfienyl)-tra/?s-3 -fluorocyclobutyl] -4-methyl-5 - [2-(trifluoromethoxy)phenyl] -r-4H- 1,2,4-triazole;

3-[ 1 -(4-chlorophenyl)cyclobutyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazole;

3- {4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]oct- 1 -yl} -4-methyl-5-[2-(trifluoromethyl)phenyl]-4H -1,2,4-triazole;

4- methyl-3- {4-[4-(methylsulfonyl)phenyl]bicyclo[2.2.2]oct- 1 -yl} -5-[2-(trifluoromethyl)phenyl]- 4H- 1,2,4-triazole;

3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct- 1 -yl)-5- (3 ,3 ,3-trifluoropropyl)- 1 ,2,4-oxadiazole;

3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3-yl}bicyclo[2.2.2]oct- 1 -yl)-5- (3 ,3 ,3-trifluoroethyl)- 1 ,2,4-oxadiazole;

5 -(3 ,3 -difluorocyclobutyl)-3 -(4- {4-methyl-5 - [2-(trifluoromethyl)phenyl] -4Η- 1 ,2,4-triazol-3 - yl}bicyclo [2.2.2]oct- 1 -yl)- 1 ,2,4-oxadiazole;

5- (l -fluoro- 1 -methylethyl)-3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3- yl}bicyclo [2.2.2]oct- 1 -yl)- 1 ,2,4-oxadiazole;

2-(l , 1 -difluoroethyl)-5-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3- yl}bicyclo [2.2.2]oct- 1 -yl)- 1 ,3 ,4-oxadiazole;

2-(3 ,3 -difluorocyclobutyl)-5 -(4- {4-methyl-5 - [2-(trifluoromethyl)phenyl] -4H- 1 ,2,4-triazol-3 - yl}bicyclo [2.2.2]oct- 1 -yl)- 1 ,3 ,4-oxadiazole; and

5-(l , 1 -difluoroethyl)-3-(4- {4-methyl-5-[2-(trifluoromethyl)phenyl]-4H- 1 ,2,4-triazol-3- yl}bicyclo[2.2.2]oct-l-yl)-l,2,4-oxadiazole; and pharmaceutically acceptable salts thereof.

Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used in combination with the compounds of formula I include, but are not limited to:

and pharmaceutically acceptable salts thereof.

AMP-activated Protein Kinase (AMPK) activators that can be used in combination with the compounds of formula I include, but are not limited to:

and pharmaceutically acceptable salts thereof.

Inhibitors of acetyl-CoA carboxylase- 1 and 2 (ACC-1 and ACC-2) that can be used in combination with the compounds of formula I include, but are not limited to:

3- { 1 '-[( 1 -cyclopropyl-4-methoxy- 1 H-indol-6-yl)carbonyl]-4-oxospiro[chroman- 2,4'-piperidin]-6- yl}benzoic acid; 5 - { Γ- [( 1 -cyclopropyl-4-methoxy- 1 H-indol-6-yl)carbonyl] -4-oxospiro [chroman-2,4'-piperidin] -6- yl}nicotinic acid;

Γ- [( 1 -cyclopropyl-4-methoxy- 1 H-indol-6-yl)carbonyl] -6-( 1 H-tetrazol-5 -yl)spiro [chroman-2,4'- piperidin]-4-one;

1 '- [( 1 -cyclopropyl-4-ethoxy-3 -methyl- 1 H-indol-6-yl)carbonyl] -6-( 1 H-tetrazol-5 - yl)spiro[chroman-2,4'-piperidin]-4-one; and

5 - { Γ- [( 1 -cyclopropyl-4-methoxy-3 -methyl- 1 H-indol-6-yl)carbonyl] -4-oxo-spiro [chroman-2,4'- piperidin]-6-yl}nicotinic acid; and

pharmaceutically acceptable salts thereof.

In another aspect of the invention, a pharmaceutical composition is disclosed which comprises one or more of the following agents:

(a) a compound of structural formula I;

(b) one or more compounds selected from the group consisting of:

(1) dipeptidyl peptidase-IV (DPP-4) inhibitors;

(2) insulin sensitizers, including (i) PPARy agonists, such as the glitazones (e.g.

pioglitazone, rosiglitazone, netoglitazone, rivoglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARa/γ Ddual agonists, such as muraglitazar, aleglitazar, sodelglitazar, and naveglitazar, (2) PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3) selective PPARy modulators (SPPARyM's), and (4) PPARy partial agonists; (ii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza®, Fortamet®, and

GlucophageXR®; (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;

(3) sulfonylurea and non-sulfonylurea insulin secretagogues, such as tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, and meglitinides, such as nateglinide and repaglinide;

(4) a-glucosidase inhibitors (such as acarbose, voglibose and miglitol);

(5) glucagon receptor antagonists;

(6) LDL cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors

(lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid sequestering agents (such as cholestyramine, colestimide, colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran, (iii) inhibitors of cholesterol absorption, such as ezetimibe, and (iv) acyl CoA: cholesterol acyltransferase inhibitors, such as avasimibe;

(7) HDL-raising drugs, such as niacin or a salt thereof and extended-release versions thereof; MK-524A, which is a combination of niacin extended-release and the DP-1 antagonist MK-524; and nicotinic acid receptor agonists;

(8) antiobesity compounds; (9) agents intended for use in inflammatory conditions, such as aspirin, non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;

(10) antihypertensive agents, such as ACE inhibitors (such as enalapril, lisinopril, ramipril, captopril, quinapril, and tandolapril), A-II receptor blockers (such as losartan, candesartan, irbesartan, olmesartan medoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors (such as aliskiren), beta blockers (such as and calcium channel blockers (such as;

(11) glucokinase activators (GKAs), such as LY2599506;

(12) inhibitors of 11 β-hydroxysteroid dehydrogenase type 1;

(13) inhibitors of cholesteryl ester transfer protein (CETP), such as torcetrapib and MK-

0859;

(14) inhibitors of fructose 1,6-bisphosphatase;

(15) inhibitors of acetyl CoA carboxylase- 1 or 2 (ACC1 or ACC2);

(16) AMP-activated Protein Kinase (AMPK) activators;

(17) agonists of the G-protein-coupled receptors: GPR-109, GPR-119, and GPR-40;

(18) SSTR3 antagonists;

(19) neuromedin U receptor agonists, including, but not limited to, neuromedin S (NMS);

(20) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);

(21) GPR-105 antagonists;

(22) inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and SGLT- 3;

(23) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and

DGAT-2);

(24) inhibitors of fatty acid synthase;

(25) inhibitors of acetyl-CoA carboxylase- 1 and 2 (ACC-1 and

ACC-2);

(26) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);

(27) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); and

(28) bromocriptine mesylate and rapid-release formulations thereof; and

(c) a pharmaceutically acceptable carrier.

When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

EXAMPLES

General Methods. Reactions sensitive to moisture or air were performed under nitrogen using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) performed with E. Merck precoated TLC plates, silica gel 60F- 254, layer thickness 0.25 mm or liquid chromatography-mass spectrum (LC-MS). Mass analysis was performed with electrospray ionization in positive ion detection mode. For HPLC/MS data, the two HPLC conditions used were as follows: 1) LC2 (Waters C18 XTerra™, 3.5 μιη, 2.1x20 mm column with gradient 10:90-98:2 v/v CH₃CN/H₂0 + v 0.05 % TFA over 1.25 min then hold at 98:2 v/v CH₃CN/H₂0 + v 0.05 % TFA for 0.75 min; flow rate 1.5 mL/min, UV wavelength

254 nm); and 2) LC4 (Waters C18 Xterra™, 3.5 μιη, 2.1x20 mm column with gradient 10:90- 98 :2 v/v CH₃CN/H₂0 + v 0.05 % TFA over 3.25 min then hold at 98 :2 v/v CH₃CN/H₂0 + v 0.05 % TFA for 0.75 min; flow rate 1.5 mL/min, UV wavelength 254 nm). Preparative reverse phase high performance liquid chromatography (RP-HPLC) used for the purification of samples was performed using a Gilson™ RP-HPLC system with an Akzo-Nobel Kromasil™ 100-5C18 column

(21.2 mm x 10 cm), 25 mL/ min gradient elution 10:90 to 100:0 CH₃CN/H₂0 + 0.05 v % TFA over 12 min unless indicated otherwise. Concentration of solutions was carried out on a rotary evaporator under reduced pressure or by lyophilization. Flash chromatography was performed on silica gel using a commercial MPLC system.

DGAT1 CPM Assay 20uL substrate mixture of 300uM diolein, 40uM oleoyl-CoA, 10% ethanol and luL of the compound with different concentrations were delivered to a 384 well assay plate (Corning 3573) using a Tecan with TeMO module. Later 19uL of enzyme mixture of 1.05ug/ml human DGAT1 in buffer (200mM Tris, pH7, 200mM sucrose, 200mM MgC12 + 20ug/ml NEM-treated BSA) was added via a Multidrop Combi using a microcassette. 20uL of 90uM CPM reagent in 90% ethanol was added after 1 hour incubation at room temperature. After 30 minutes at room temperature in dark, fluorescence measurement on Envision was carried out and IC50s were calculated.

The compounds exemplified herein are believed to have a lower Cmax to trough ratio as compared to the Reference Examples. High Cmax to trough ratio is not a desirable feature of a drug. A higher ratio may lead to low therapeutic index due to potential Cmax related adverse events. It is also believed that the compounds exemplified herein show moderate metabolism in vitro in hepatocyte incubations, which may impart multiple mechanism of excretion in vivo.

Compounds found not to be metabolized by liver microsome or hepatocytes may indicate that they might be eliminated in vivo via excretion as intact drug, which may contribute to undesirably long pharmacodynamic half- life in vivo.

Scheme 1

Intermediate 1

Methyl [tra/? -4-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)cyclohexyl]acetate Step A: methyl [4-(4-hydroxyphenyl)cyclohexylidene]acetate. A 2 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of sodium hydride (60% in mineral oil, 42.5 g, 1.1 mol, 1.0 equiv) in tetrahydrofuran (500 mL). This was followed by the addition of a solution of 4-(4-hydroxyphenyl)cyclohexanone (200 g, 1.05 mol, 1.00 equiv) in tetrahydrofuran (1000 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. The resulting solution was assigned as solution A. Into a 5 L 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (63 g, 1.7 equiv, 60%) in tetrahydrofuran (1000 mL). This mixture was treated with a solution of methyl 2-(dimethoxyphosphoryl)acetate (229.7 g 1.2 equiv) in tetrahydrofuran (1500 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at room temperature. To this reaction mixture was added solution A dropwise with stirring. The resulting solution was stirred for 1 h at room temperature then quenched by the addition of water/ice. The resulting solution was extracted with 3x500 mL of ethyl acetate. The combined organic layers were washed with brine (1 L), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by

recrystallization from ether to afford the title compound as a white solid.

Step B: methyl [trans-4-(4-hydroxyphenyl)cyclohexyl]acetate. The product from step A (200 g, 812 mmol, 1.00 equiv) and Pd/C (20 g) in ethyl acetate (2500 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was re-crystallized from ethyl acetate/hexane in the ratio of 1 : 1 to afford the title compound as a white solid.

Step C: methyl [tra/? -4-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)cyclohexyl]acetate. A 250- mL 4-neck round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of the product from step B (7.16 g, 28.9 mmol, 1.00 equiv) in chloroform (60 mL) and triethylamine (4.37 g, 43.2 mmol, 1.50 equiv). A solution of

trifluoromethanesulfonic anhydride (9.76 g, 34.6 mmol, 1.20 equiv) in chloroform (10 mL) was added dropwise with stirring at 0 C. The resulting solution was stirred for 1 h at 0 C, quenched with 100 mL of water/ice. The resulting mixture was washed with aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on silica gel (1 : 10 ethyl acetate/petroleum ether) to afford the title compound as a white solid. HPLC/MS: 381 (M+H ); R_t 1.31 min (LC2).

Intermediate 2

Methyl (tra/? -4- {4-[(2- {[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]phenyl}cyclohexyl)acetate. Into a 1000-mL sealed tube, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Intermediate 1 (100 g, 263.16 mmol, 1.00 equiv) in toluene (500 mL), 2- (tert-butyldimethylsilyloxy)ethanamine (55.3 g, 316.00 mmol, 1.20 equiv), Cs₂C0₃ (85.7 g, 1.00 equiv), Pd(OAc)₂ (5.9 g, 0.10 equiv) and X-Phos (12.6 g, 0.10 equiv). The resulting solution was stirred overnight at 1 16 C, cooled to rt and concentrated under vacuum. The residue was purified by chromatography on silica gel (1 :30 ethyl acetate/petroleum ether) to afford the title compound as a yellow oil. HPLC/MS: 406 (M+H⁺); R_t 3.81 min (LC4). Intermediate s

Methyl (tra/? -4- (4-[(2- ([tert-butyl(dimethyl silylloxylethyl ([4.6-dichloro-2-(methylsulfanyl - pyrimidin-5-yl]carbonyl}amino]phenyl}cyclohexyl)acetate. A 50-mL 3 -necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (700 mg, 2.93 mmol, 1.50 equiv) and N,N-dimethylformamide (1 drop) in dichloromethane (10 mL). The solution was treated with oxalyl chloride (750 mg, 5.91 mmol, 3.00 equiv) dropwise with stirring, stirred for 2 h at room temperature and then treated with a solution of Intermediate 2 (800 mg, 1.97 mmol, 1.00 equiv) in dichloromethane (10 mL) and DIE A (2 mL) dropwise with stirring at 0 C. The resulting solution was stirred for an additional 1 h at room temperature, concentrated under vacuum and the residue was purified by chromatography on silica gel (1 : 10 ethyl acetate/petroleum ether) to afford the title compound as a colorless oil. HPLC/MS: 626 (M+H⁺); R_t 4.78 min (LC4).

Intermediate 4

Methyl (tra -4- {4-[ {[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]carbonyl}(2- hydroxyethyl)amino]phenyl}cyclohexyl)acetate. A 2-L round-bottom flask was charged with a solution of Intermediate 3 (80 g, 128.00 mmol, 1.00 equiv) in methanol (800 mL) and HC1 (36%, 10 mL). The resulting solution was stirred for 1 h at room temperature, then concentrated under vacuum. The residue was dissolved in 500 mL of EtOAc and washed with 500 mL of aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and

concentrated under vacuum to afford the title compound as a yellow oil. HPLC/MS: 512 (M+H⁺); R_t 3.65 min (LC4).

Intermediate 5

Methyl (tra -4- {4-[4-chloro-2-(methylsulfanyl)-5-oxo-7,8-dihydropyrimido[5^- ][l ,4]oxazepin- 6(5H)-yl]phenyl}cyclohexyl)acetate. A 1-L round-bottom flask was charged with a solution of Intermediate 4 (60 g, 1 17.19 mmol, 1.00 equiv) and triethylamine (80 mL) in acetonitrile (600 mL). The resulting solution was stirred for 5 h at 80 C, cooled to room temperature with a water/ice bath and concentrated under vacuum. The residue was diluted with 500 mL of DCM and washed with 1x500 mL of H₂0. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by recrystallization from methanol to afford the title compound as a white solid. HPLC/MS: 476 (M+H⁺); R_t 3.69 min

(LC4).

Intermediate 6

Methyl (trafts-4- {4-[4-ammo-2-(methylsu^

6(5H -yl]phenyl}cyclohexyl)acetate. A 2 L 3 -neck round-bottom flask was charged with

Intermediate 5 (40 g, 84.2 mmol, 1.00 equiv) and a 1 M solution ofNH₃ in 1 ,4-dioxane (1200 mL, 1200 mmol, 14 equiv). The resulting solution was stirred overnight at room temperature, concentrated under vacuum. The residue was diluted with 500 mL of dichloromethane, washed with 500 mL of water and 500 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification by recrystallization from methanol afforded the title compound as a white solid. HPLC/MS: 457 (M+H⁺); R_t 3.38 min (LC4); Human DGAT1 IC₅₀ 687 nM.

Intermediate 7

(trafts-4- {4-[4-ammo-2-(methylsulfo

yljphenyl} cyclohexyPacetic acid.

Step A: (tra -4- {4-[4-amino-2-(methylsulfanyl)-5-oxo-7,8-dihydropyrimido[5,4- ] [ 1 ,4]oxazepin-6(5H)-yl]phenyl} cyclohexyPacetic acid. A 250 mL single neck round bottom flask was charged with Intermediate 6 (5.45 g, 1 1.9 mmol) and THF (60 ml). The mixture was treated with a 2 M aqueous lithium hydroxide solution (29.8 ml, 59.7 mmol), warmed to 55 °C for

16 h, cooled to rt and partitioned between 2 M aq HC1 (300 mL) and dichloromethane (400 mL).

The aqueous phase was washed with dichloromethane (2 x 150 mL) and the combined organic layers were washed with water (4x150 mL) and then concentrated under reduced pressure to afford the title compound as a crude residue which was used without further purification.

HPLC/MS: 443 (M+H⁺); R_t 1.1 1 min (LC2); Human DGAT1 IC₅₀ 163 nM. Step B: (tra -4- {4-[4-amino-2-(methylsulfonyl)-5-oxo-7,8-dihydropyrimid^

f] [ 1 ,4]oxazepin-6(5H -yl]phenyl} cyclohexyDacetic acid. The product from step A (5.28 g, 1 1.9 mmol) in THF (100 ml) was treated with magnesium bis(monoperoxyphthalate) hexahydrate (8.88 g, 18.0 mmol) was slowly added portionwise to the suspension. The reaction mixture was stirred for 16 h and concentrated under reduced pressure. The residue was dissolved in DMSO (50 mL) and the solution was poured into water (500 mL) with vigorous stirring. The resulting precipitate was collected by vacuum filtration and the filter cake was washed with water (500 ml) and dried under vacuum to afford the title compound as a colorless solid. HPLC/MS: 475 (M+H⁺); R_t 1.05 min (LC2); Human DGAT1 IC₅₀ 475 nM.

Example 1

[tra -4-(4- {4-amino-2-[(2-cyclopropylethyl)amino]-5-oxo-7,8-dihydropyrimido[5,4- f][l ,4]oxazepin-6(5H)-yl}phenyl)cyclohexyl]acetic acid trifluoroacetate salt. A mixture of Intermediate 7 (100 mg, 0.21 1 mmol) in DMF (1 ml) treated at rt with 2-cyclopropyl-l- ethylamine (39.5 mg, 0.464 mmol) and DBU (0.070 ml, 0.464 mmol). The resulting homogenous mixture was stirred at rt for 4 h, diluted with 10% aq DMSO (0.5 mL) and glacial AcOH (0.5 mL). Purification by preparative RP-HPLC (5% to 80% ACN/ water+0.05% TFA over 10 min) afforded the title compound. HPLC/MS: 480 (M+H⁺); human DGAT1 IC₅₀ 341 nM.

The following examples were prepared in a similar manner to Example

Example 57

[tra -4-(4-4-amino-2-[(3-methylbutyl)sulfanyl]-5-oxo-7,8-dihydropyrim

6(5H)-ylphenyl)cyclohexyl]acetic acid trifluoroacetate salt.

A mixture of Intermediate 7 (114.4 mg, 0.241 mmol) and 3-methyl-l-butanethiol (0.158 ml, 1.27 mmol) in THF (2 ml) was treated at rt with a 1 M solution of potassium tert-butoxide in THF (1.1 ml, 1.100 mmol) and the mixture was stirred for 16 h at rt. The mixture was diluted with DMSO (2 mL) and directly purified by RP-HPLC (20% to 90% ACN/ water+0.05% TFA over 10 min) to afford the title compound. HPLC/MS: 499 (M+H⁺); human DGAT1 IC₅₀ 5 iiM.

The following examples were prepared in a similar manner to Example 57. Example 79 was prepared in a manner similar to the preparation of Intermediate 7 (Step B) with the use of 1.2 equiv of MMPP and purification of the crude reaction mixture by preparative RP-HPLC (25% to 65% ACN/ water+0.05% TFA over 10 min). Examples 80 and 81 were prepared from Example 59 in a similar manner to Intermediate 7 and Example 79.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I)

or pharmaceutically acceptable salts thereof, wherein X is selected from the group consisting of - NH-, -NR²-, -S-, -SO- and -SO²-;

-R¹ is selected from the group consisting of hydrogen, Ci-Ci₀alkyl, C₃-C₆cycloalkyl, aryl, Ci- C₆alkylaryl, heterocycle, Ci-C₆alkyl-0-aryl and Ci-C₆alkylheterocycle;

wherein any alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, Ci-C₆halogen-substitutedalkyl, C₃-C₆cycloalkyl, Ci-C₆alkoxy, - COOH, NHCOOCi-C₆alkyl, NR²COOCi-C₆alkyl, S0₂N(Ci-C₆alkyl)₂ and -OH,

wherein any aryl and heterocycle are unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, d-C₆alkoxy and Ci-C₆halogen-substitutedalkyl; and

-R² is selected from the group consisting of Ci-Ci₀alkyl.

2. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein X is NH- or -NR²-.

3. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein X is -

S-, -SO- or -SO²-.

4. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein R¹ is Ci-Cio alkyl.

5. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein R¹ is phenyl or Ci-C₆alkylphenyl.

6. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein R is a heterocycle selected from the group consisting of pyridine or pyrimidine.

7. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein R is Ci-C₆alkylheterocycle, wherein the heterocycle is selected from the group consisting of pyridine, pyrrolidinone, pyrrolidine, pyrimidine, pyrazole, pyrazine, oxolane, oxane and indazole.

8. A compound of claim 1 or pharmaceutically acceptable salt thereof wherein R² is methyl.

9. A compound of claim 1 , comprising the stereochemistry of formula la

10. A compound or pharmaceutically acceptable salt thereof selected from the group

11. A pharmaceutical composition comprising a compound of any one of claims 1-10_? or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. Use of a compound of ^anY ^one of claims 1-10_? or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a condition selected from the group consisting of obesity and diabetes.

13. A method for the treatment of a condition selected from the group consisting of obesity and diabetes comprising administering to an individual a pharmaceutical composition comprising the compound of any one of claims 1-10.

14. A compound according to claim 1 for use in therapy.