ES2369944T3 - GPCR PIPERIDINIC AGONISTS. - Google Patents

Abstract

A compound of formula (I), or a pharmaceutically acceptable salt thereof: in which one of X and Y is O and the other is N; one of E and Q is N and the other is CH; R 1 is SO2R 5 or -CONHR 6; R 2 is hydrogen or methyl; R 3 is hydrogen or methyl; R 4 is C2-5 alkyl; R 5 is C 1-3 alkyl; and R 6 is hydrogen, C1-3 alkyl, or C2-3 alkyl substituted with hydroxy.

Description

Piperidine GPCR agonists

BACKGROUND OF THE INVENTION

The present invention relates to G protein coupled receptor agonists (GPCR). In particular, the present invention relates to GPCR agonists that are useful for the treatment of obesity, for example as regulators of satiety, metabolic syndrome and for the treatment of diabetes.

Obesity is characterized by an excessive mass of adipose tissue in relation to body size. Clinically, body fat mass is estimated by body mass index (BMI; weight (kg) / height (m) 2), or waist circumference. Individuals are considered obese when the BMI is greater than 30, and there are medical consequences established by the fact of being overweight. It has long been an accepted medical point of view that an increase in body weight, especially as a result of abdominal body fat, is associated with an increased risk of diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis , stroke, vesicular disease, muscle and respiratory problems, low back pain, and even certain cancers.

Pharmacological approaches to the treatment of obesity have been mainly related to the reduction of fat mass by altering the balance between intake and energy expenditure. Many studies have clearly established the relationship between adiposity and cerebral circuitry involved in the regulation of energy homeostasis. Direct and indirect signs suggest that serotonergic, dopaminergic, adrenergic, cholinergic, endocannabinoid, opioid, and histaminergic routes, in addition to many neuropeptide routes (for example, neuropeptide Y and melanocortins), are involved in the central control of intake and expenditure of expenditure Energy. The hypothalamic centers are also able to perceive peripheral hormones involved in maintaining body weight and adiposity grade, such as insulin and leptin, and fatty tissue derived peptides.

Drugs targeting the pathophysiology associated with insulin-dependent Type I diabetes and non-insulin-dependent Type II diabetes have many potential side effects and do not adequately address dyslipidemia and hyperglycemia in a high proportion of patients. Treatment is often focused on the individual needs of the patient using diet, exercise, hypoglycemic agents and insulin, but there is a continuing need for new antidiabetic agents, particularly those that can be better tolerated with less adverse effects.

Similarly, metabolic syndrome (syndrome X) puts people at high risk for coronary artery disease, and is characterized by a cluster of risk factors, including central obesity (excessive fatty tissue in the abdominal region), glucose intolerance , high triglycerides and low HDL cholesterol, and high blood pressure. Myocardial ischemia and microvascular disease is an established morbidity, associated with untreated or poorly controlled metabolic syndrome.

There is a continuing need for new agents against obesity and antidiabetics, particularly those that are well tolerated with few adverse effects.

GPR119 (previously referred to as GPR116) is a GPCR identified as SNORF25 in WO 00/50562 which describes both human and rat receptors, and US 6,468,756 also describes the mouse receptor (accession numbers: AAN95194 ( human), AAN95195 (rat) and ANN95196 (mouse)).

In humans, GPR119 is expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPR119 receptor indicates its potential utility as a target for the treatment of obesity and diabetes.

International Patent Applications WO 2005/061489, WO 2006/070208, WO 2006/067531 and WO 2006/067532 describe heterocyclic derivatives as agonists of the GPR119 receptor. International Patent Applications WO 2007/003960, WO 2007/003961, WO 2007/003962 and WO 2007/003964 (published after the priority date of this Application) describe additional GPR119 receptor agonists.

The present invention relates to GPR119 agonists that are useful for the treatment of obesity, for example as peripheral regulators of satiety, metabolic syndrome and for the treatment of diabetes.

SUMMARY OF THE INVENTION

The compounds of formula (I): or pharmaceutically acceptable salts thereof, are GPR119 agonists, and are useful for the prophylactic or therapeutic treatment of obesity and diabetes.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof:

in which one of X and Y is O and the other is N; one of E and Q is N and the other is CH;

R1 is SO2R5 or -CONHR6; R 2 is hydrogen or methyl; R3 is hydrogen or methyl;

R4 is C2-5 alkyl;

R5 is C1-3 alkyl; Y

R6 is hydrogen, C1-3 alkyl, or C2-3 alkyl substituted with hydroxy.

In one embodiment of the invention, X is O and in another Y is O. X is preferably O. Y is preferably N. Q is preferably N. E is preferably CH.

When R1 is CONHR6, R2 is preferably methyl.

In one embodiment of the invention, R3 is hydrogen, and in another R3 it is methyl. When R3 is methyl, the stereocenter created preferably has the configuration (R). R4 is preferably C3-4 alkyl, particularly n-propyl, isopropyl, or tert-butyl, even more preferably

C3 alkyl, especially isopropyl. R5 is preferably methyl. When R6 is C2-3 alkyl substituted with hydroxy, it may be substituted with one or more, for example 1 or 2, preferably 1 hydroxy group.

R6 is preferably C1-3 alkyl or C2-3 alkyl substituted with hydroxy, more preferably C2-3 alkyl substituted with hydroxy, for example 2-hydroxyethyl, 2-hydroxy-1-methylethyl, 2,3-dihydroxypropyl or 2 -hydroxy-1-hydroxymethyl ethyl, preferably 2-hydroxyethyl or 2-hydroxy-1-methyl ethyl, even more preferably 2-hydroxy-1-methyl ethyl, especially (R) -2-hydroxy-1-methyl ethyl.

Although the preferred groups for each variable have generally been set forth separately before for each variable, the preferred compounds of this invention include those in which several or each variable in the formula (I) is selected from the preferred, most preferred listed groups or particularly listed for each variable. Therefore, this invention is intended to include all combinations of preferred, most preferred and particularly listed groups.

The specific compounds of the invention that can be mentioned are those included in the Examples and their pharmaceutically acceptable salts.

As used herein, unless otherwise stated, "alkyl" means carbon chains that can be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, and pentyl.

The term "halo" includes fluorine, chlorine, bromine and iodine atoms, in particular fluorine or chlorine, especially fluorine.

The compounds described herein may contain one or more asymmetric centers, and thus may give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. The above formula (I) is shown without a stereochemistry defined in certain positions. The present invention includes all stereoisomers of formula (I) and their pharmaceutically acceptable salts. Additionally, mixtures of stereoisomers as well as specific isolated stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be a mixture of stereoisomers.

When the compound of formula (I) and its pharmaceutically acceptable salts exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited to the extent that the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including organic and inorganic acids. Such acids include, for example, hydrochloric acid, methanesulfonic acid, sulfuric acid, p-toluenesulfonic acid and the like.

Since the compounds of formula (I) are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight to weight basis).

The compounds of formula (I) can be prepared as described below. PG represents a protecting group, G is a substituted oxadiazole as defined above, and R1, R2, R3 and R4 are also as defined above.

The compounds of formula (II), in which PG is a suitable protecting group, can be easily prepared from known compounds (Scheme 1). For example, the ethyl ester of compound (II), in which PG is Boc, has been previously disclosed (US Patent 6,518,423). Hydrogenation under standard conditions will produce the racemic compound of formula (III). The chiral reduction of the alkene under suitable conditions, such as hydrogenation in the presence of a chiral catalyst, produces compounds of formula (III) in a high enantiomeric excess. An example of a suitable catalyst is [Rh (norbornadiene) 2] BF4 and (S) -1 - [(R) -2- (di-tert-butylphosphino) ferrocenyl] -ethylbis (2-methylphenyl) phosphino. The compounds of formula (IV) can then be obtained by reduction of the carboxylic acids of formula (III) under standard conditions, for example borane in a suitable solvent such as THF. Elimination of the protective group is then achieved under conditions well known to those skilled in the art.

Scheme 1

The compound of formula (V), in which R3 = H, is a known compound (Scheme 2, Siegel, M. G. et al. Tetrahedron 1999, 55, 11619-11639). The compounds of formula (VII) can be prepared from compounds of formula (V) under standard conditions. For example, treatment of compounds of formula (V) with cyanogen bromide, followed by condensation of the resulting cyanamide (VI) with a compound of formula (IX) under 5 standard conditions produces compounds of formula (VII) in which X is O. The compounds of formula (IX) are commercially available, or are easily prepared from the corresponding carboxylic acids using well known techniques. Alternatively, the synthesis of the regioisomeric oxadiazole, in which Y is O, can be achieved by heating compounds of formula (VI) with hydroxylamine to give N-hydroxyguanidines of formula (VIII), which can be condensed with a carboxylic acid of formula ( X) under appropriate conditions. The acids of formula (X)

10 are commercially available.

Scheme 2

The compounds of the formula (VII) can also be prepared by condensation of amine (V) with an oxadiazole chloride of the formula (XI), as illustrated in Scheme 3 (Buscemi, S. et al. JCS Perkin 1: Org . and Bioorg. 15 Chem. 1988, 1313 and Adembri, G, et al. JCS Perkin I: Org. and Bioorg. Chem., 1981, 1703).

Scheme 3

The compounds of formula (I), in which R 1 is a sulfone, can be produced as depicted in the Scheme

4. For example, the compound of formula (XII), in which R2 is hydrogen, is commercially available. He

Bromo-metal exchange using butyllithium in a suitable solvent such as toluene, in the presence of a chelating agent such as TMEDA if necessary, at low temperature, followed by the addition of dimethyldisulfide, produces compounds of formula (XIII) in which R5 is methyl. Oxidation to sulfone is produced using a standard oxidizing agent, such as m-CPBA, to give compounds of formula (XIV). The compounds of formula (I) are then formed by displacement of the 2-fluoro group in the compounds of formula (XIV) with the alkoxide of a

Compound of formula (VII) under standard conditions.

Scheme 4

Compounds of formula (I) containing an amide can be produced as depicted in Scheme 5. Compounds of formula (XV), in which E or Q are nitrogen, and X is a leaving group, have been given to know 5 previously in the literature, or they can be easily prepared using known techniques. For example, when E is nitrogen, R2 is methyl, Ak is ethyl, and X is -S-ethyl, it has been disclosed by Yamazi, Y., et al. Chemotherapy 1996, 14, 448. Oxidation of the sulfide group to a sulfone under standard conditions, using for example m-CPBA, produces a compound suitable for coupling with a compound of formula (V). Another example is when Q is nitrogen, R2 is methyl, Ak is ethyl, and X is chlorine, has been disclosed by Ramirez, F., et al. J. Org. Chem., 10 1954, 19, 183. The compounds of formula (I) are then produced by replacing the leaving group in compounds of formula (XV) with the alkoxide of a compound of formula (V) under standard conditions. Hydrolysis of the ester of formula (XVI) under standard conditions, for example using aqueous lithium hydroxide at a temperature of about room temperature, produces acids of formula (XVII). The formation of the amide bond under standard conditions well known to those skilled in the art produces the desired compounds of

15 formula (I).

Scheme 5

Other compounds of formula (I) can be prepared by methods analogous to those described above, or by methods known per se. Additional details are found in the examples for the preparation of

20 compounds of formula (I).

The compounds of formula (I) can be prepared individually or as libraries of compounds comprising at least 2 compounds, for example 5 to 1,000, and more preferably 10 to 100 compounds of formula (I). Compound libraries can be prepared by a combinatorial "splitting and mixing" approach or by multiple parallel synthesis using dissolution or solid phase chemistry, using known procedures

25 by those skilled in the art.

During the synthesis of the compounds of formula (I), labile functional groups in the intermediate compounds can be protected, for example hydroxy, carboxy and amino groups. The protecting groups may be removed at any stage in the synthesis of the compounds of formula (I), or they may be present in the final compound of formula (I). A broad exposition of the ways in which various labile functional groups can be protected, and the methods for cleaving the resulting protected derivatives, is provided, for example, in the Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts (1991), Wiley-Interscience, New York, 2nd edition.

Any new intermediates, such as those defined above, may be of use in the synthesis of compounds of formula (I), and therefore are also included in the scope of the invention, for example compounds of formulas (XVI) and (XVII ), or a salt or derivative protected therefrom.

As indicated above, the compounds of formula (I) are useful as agonists of GPR119, for example for the treatment and / or prophylaxis of obesity and diabetes. For such use, the compounds of formula (I) will generally be administered in the form of a pharmaceutical composition.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a drug.

The invention also provides a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier.

Preferably, the composition comprises a pharmaceutically acceptable carrier and a non-toxic, therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In addition, the invention also provides a pharmaceutical composition for the treatment of a disease by modulating GPR119, resulting in the prophylactic or therapeutic treatment of obesity, for example regulating satiety, or for the treatment of diabetes, which comprises a pharmaceutically acceptable carrier and a non-toxic, therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions may optionally comprise other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical and parenteral administration (including subcutaneous, intramuscular and intravenous), although the most appropriate route in any given case will depend on the particular host and the nature and severity of the conditions for which The active ingredient is being administered. The pharmaceutical compositions may conveniently be presented in a unit dosage form, and may be prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds formula (I), or their pharmaceutically acceptable salts, can be combined as the active ingredient in an intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical combination techniques. The vehicle can take a wide variety of forms, depending on the form of preparation desired for administration, for example oral or parenteral (including intravenous).

Thus, pharmaceutical compositions can be presented as discrete units suitable for oral administration, such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient. Additionally, the compositions may be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the usual dosage forms set forth above, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can also be administered by controlled release means and / or by delivery devices. The compositions can be prepared by any of the pharmacy methods. In general, such methods include a step of associating the active ingredient with the vehicle that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately mixing the active ingredient with liquid vehicles or finely divided solid vehicles or both. The product can then be conveniently shaped into the desired presentation.

The compounds of formula (I), or their pharmaceutically acceptable salts, may be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical vehicle used can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, diatomaceous earth, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Examples of liquid vehicles are sugar syrup, peanut oil, olive oil and water. Examples of gaseous vehicles include carbon dioxide and nitrogen.

When preparing the compositions for the oral dosage form, any convenient pharmaceutical means can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations, such as suspensions, elixirs and solutions; although vehicles such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Due to their ease of administration, tablets and capsules are the preferred oral dosage units, whereby solid pharmaceutical carriers are used. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques.

A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. The tablets may be prepared by compressing, in a suitable machine, the active ingredient in a fluid form with powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each sachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient.

For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active ingredient, combined with an appropriate and convenient amount of carrier material that may vary from about 5 to about of 95 percent of the total composition. Unit dosage forms will generally contain between about 1 mg and about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg

The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant may be included, such as, for example, hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Additionally, a preservative can be included to prevent the harmful growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include solutions.

or sterile aqueous dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile, and must be effectively fluid for easy syringe application. Pharmaceutical compositions must be stable under the conditions of manufacture and storage; Thus, they should preferably be preserved from the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, fine powder, or the like. Additionally, the compositions may be in a form suitable for use in transdermal devices. These formulations can be prepared using a compound of formula (I), or a pharmaceutically acceptable salt thereof, through conventional processing methods. As an example, a cream or ointment is prepared by mixing a hydrophilic material and water together with about 5% by weight to about 10% by weight of the compound, to produce a cream or ointment that has a desired consistency.

The pharmaceutical compositions of this invention may be in a form suitable for rectal administration, in which the vehicle is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable vehicles include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with the softened or molten vehicle (s), followed by cooling and mold forming.

In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. In addition, other adjuvants can be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of formula (I), or its pharmaceutically acceptable salts, can also be prepared in the form of powders or liquid concentrates.

Generally, dosage levels of the order of 0.01 mg / kg to about 150 mg / kg body weight per day are useful in the treatment of the conditions indicated above, or, alternatively, about 0.5 mg a around 7 g per patient per day. For example, obesity can be treated effectively by administering about 0.01 to 50 mg of the compound per kilogram of body weight per day, or, alternatively, about 0.5 mg to about 3.5 g. per patient per day.

However, it is understood that the specific dose level for any particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, administration time, route of administration, excretion rate, combination of drugs and the severity of the particular disease the therapy is experiencing.

The compounds of formula (I) can be used in the treatment of diseases or conditions in which GPR119 plays a role.

A method for the treatment of a disease or condition in which GPR119 plays a role comprises a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Diseases or conditions in which GPR119 plays a role include obesity and diabetes. In the context of the present application, the treatment of obesity is intended to encompass the treatment of diseases or conditions such as obesity and other eating disorders associated with excessive food intake, for example by reducing appetite and body weight, maintaining weight reduction and rebound prevention, and diabetes (including Type 1 and Type 2 diabetes, impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidemia). And the treatment of patients who have an abnormal sensitivity to ingested fats, which leads to functional dyspepsia. The compounds of the invention can also be used to treat metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low levels of HDL, and hypertension.

The compounds of the invention can offer advantages over the compounds that act via different mechanisms for the treatment of the aforementioned disorders, in that they can offer protection of beta cells, increased secretion of cAMP and insulin, and also an emptying slow gastric

The compounds of the invention can also be used to treat conditions characterized by low bone mass, such as osteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease, loss of alveolar bone, bone loss due to osteotomy, idiopathic bone loss of childhood , Paget's disease, bone loss due to metastatic cancer, osteolytic lesions, spinal cord curvature, and weight loss.

A method for satiety regulation comprises a step of administering to an individual in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

A method for the treatment of obesity comprises a step of administering to an individual in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

A method for the treatment of diabetes, including Type 1 and Type 2 diabetes, particularly type 2 diabetes, comprises a step of administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt of the same.

A method for the treatment of metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low levels of HDL or hypertension comprises a step of administering to a patient in need of an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above.

The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition as defined above.

In the methods of the invention, the term "treatment" includes both therapeutic and prophylactic treatment.

The compounds of formula (I) may show advantageous properties in comparison with known GPR119 agonists, for example the compounds may show improved potency or stability, or improved solubility, thereby improving the absorption and bioavailability properties, or other advantageous properties for compounds to use as drugs.

The compounds of formula (I), or their pharmaceutically acceptable salts, can be administered alone or in combination with one or more therapeutically active compounds. The other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of formula (I), or a different disease or condition. The therapeutically active compounds can be administered simultaneously, sequentially or separately.

The compounds of formula (I) can be administered with other active compounds for the treatment of obesity and / or diabetes, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonylureas and the like, biguanides, α2 agonists , glitazones, PPAR-γ agonists, mixed PPAR-α / γ agonists, RXR agonists, fatty acid oxidation inhibitors, α-glucosidase inhibitors, dipeptidyl peptidase IV inhibitors, GLP-1 agonists, for example GLP-1 analogs and mimetics, β-agonists, phosphodiesterase inhibitors, lipid reducing agents, glycogen phosphorylase inhibitors, anti-obesity agents, for example pancreatic lipase inhibitors, MCH-1 antagonists and CB-1 antagonists ( or inverse agonists), amylin antagonists, lipoxygenase inhibitors, hemostatin analogues, glucokinase activators, glucagon antagonists, ins signaling agonists ulina, PTP1B inhibitors, gluconeogenesis inhibitors, antilipolytic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic / dopaminergic drugs against obesity, reuptake inhibitors, for example sibutramine, CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors,

or sorbitol dehydrogenase inhibitors.

Combination therapy, which comprises the administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least some other anti-obesity agent, represents a further aspect of the invention.

A method for treating obesity in a mammal, such as a human being, comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another anti-obesity agent, to a mammal that I needed it.

The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another anti-obesity agent, for the treatment of obesity.

The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with another agent against obesity, for the treatment of obesity.

The compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other or other anti-obesity agents can be co-administered or administered sequentially or separately.

Co-administration includes the administration of a formulation that includes both the compound of formula (I), or a pharmaceutically acceptable salt thereof, as the other or other anti-obesity agents, or the simultaneous or separate administration of different formulations of each agent. When permitted by the pharmacological profiles of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other or other anti-obesity agents, co-administration of the two agents may be preferred.

The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another anti-obesity agent in the manufacture of a medicament for the treatment of obesity.

The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another anti-obesity agent, and a pharmaceutically acceptable carrier. The invention also encompasses the use of such compositions in the methods described above.

GPR119 agonists are of particular use in combination with centrally acting anti-obesity agents.

The other anti-obesity agent for use in combination therapies according to this aspect of the invention is preferably a CB-1 modulator, for example a CB-1 inverse antagonist or agonist. Examples of CB-1 modulators include SR141716 (rimonabant) and SLV-319 ((4S) - (-) - 3- (4-chlorophenyl) -N-methyl-N - [(4-chlorophenyl) sulfonyl] -4-phenyl -4,5-dihydro-1H-pyrazol-1-carboxamide); as well as the compounds described in EP576357, EP656354, WO 03/018060, WO 03/020217, WO 03/020314, WO 03/026647, WO 03/026648, WO 03/027076, WO 03/040105, WO 03 / 051850, WO 03/051851, WO 03/053431, WO 03/063781, WO 03/075660, WO 03/077847, WO 03/078413, WO 03/082190, WO 03/082191, WO 03/082833, WO 03 / 084930, WO 03/084943, WO 03/086288, WO 03/087037, WO 03/088968, WO 04/012671, WO 04/013120, WO 04/026301, WO 04/029204, WO 04/034968, WO 04 / 035566, WO 04/037823 WO 04/052864, WO 04/058145, WO 04/058255, WO 04/060870, WO 04/060888, WO 04/069837, WO 04/069837, WO 04/072076, WO 04/072077 , WO 04/078261 and WO 04/108728 and the references described there.

Other diseases or conditions in which GPR119 has been suggested to play a role include those described in WO 00/50562 and US 6,468,756, for example cardiovascular disorders, hypertension, respiratory disorders, gestational abnormalities, gastrointestinal disorders, immune disorders, musculoskeletal disorders, depression, phobias, anxiety, mood disorders and Alzheimer's disease.

The invention will now be described with reference to the following examples for illustrative purposes.

EXAMPLES

Materials and methods

Column chromatography was carried out on SiO2 (40-63 mesh) unless otherwise specified. LCMS data were obtained according to the following: C18 Atlantis column of 3µ (3.0 x 20.0 mm, flow rate = 0.85 ml / min), eluting for 6 minutes with a solution of H2O-CH3CN containing 0, 1% HCO2H, with UV detection at 220 nm. Gradient information: 0.0-0.3 min: 100% H2O; 0.3-4.25 min: ascent up to 10% H2O-90% CH3CN; 4.25-4.4 min: up to 100% CH3CN; 4.4-4.9 min: 100% maintenance of CH3CN; 4.9-6.0 min: return to 100% H2O. Mass spectra were obtained using an electrospray ionization source in the positive ion (ES +) or negative ion (ES-) mode.

Abbreviations and acronyms: Ac: acetyl; nBU: n-butyl; t-Bu: tert-butyl; DIPEA: N, N-diisopropylethylamine; DMF: N, Ndimethylformamide; EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; Et: ethyl; h: hour (s); HOBt: 1 hydroxybenzotriazole; HPLC: high performance liquid chromatography; IH: isohexane; iPr: isopropyl; Me: methyl, RP: reverse phase; RT: retention time; THF: tetrahydrofuran; TMEDA: N ’, N’, N, N-tetramethylethylenediamine.

The synthesis of the following compounds has been previously disclosed: tert-butyl 4 - ((E) -2-ethoxycarbonyl-1-methylvinyl) piperidine-1-carboxylate: US 6,518,423; Ethyl 6-hydroxy-2-methylnicotinate: Tetrahedron 1974, 30, 623-632; N-Hydroxyisobutyramidine: J. Org. Chem. 2003, 68, 7316-7321; 3-Piperidin-4-ilpropan-1-ol: Tetrahedron 1999, 55, 11619-11639. All other compounds were available from commercial sources.

Preparation 1: 4- (3-Hydroxypropyl) piperidin-1-carbonitrile

A suspension of NaHCO3 (35.2 g, 0.42 mol) in H2O (70 ml) was added to a stirred solution of 3-piperidin4-ylpropan-1-ol (20.0 g, 0.14 mol) in CH2Cl2 at 0 ° C. A solution of BrCN (17.8 g, 0.17 mol) in CH2Cl2 (19 ml) was added to the reaction for 1 min., And then stirring was continued at 0 ° C for 0.5 h. The reaction was then stirred at 20 ° C for 2 h, before washing with saturated aqueous NaHCO3 and brine. The CH2Cl2 solution is

Dried (mugSO4), filtered and concentrated in vacuo to provide an oil that dissolved in a small amount of CH2Cl2, before filtering through a pad of SiO2, eluting with EtOAc. The filtrate was concentrated under reduced pressure to yield the title compound: m / z (ES +) = 169.1 [M + H] +.

Preparation 2: N-Hydroxy-4- (3-hydroxypropyl) piperidin-1-carboxamidine

A mixture of 4- (3-hydroxypropyl) piperidin-1-carbonitrile (Preparation 1, 3.00 g, 17.8 mmol), K2CO3 (2.46 g, 17.8 mmol), and H2NOH-HCl (2 , 48 g, 35.7 mmol) in EtOH (20 ml) and H2O (30 ml) was heated at reflux for 16 h. The EtOH was removed in vacuo, and then the aqueous phase was extracted with EtOAc (5x). The aqueous phase was saturated with NaCl, before being extracted again with EtOAc (5x). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to yield the title compound: m / z (ES +) = 202.1 [M + H] +.

Preparation 3: 3- [1- (S-Isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-4-yl] propan-1-ol

DIPEA (3.25 g, 25.2 mmol), N-hydroxy-4- (3-hydroxypropyl) piperidine-1-carboxamidine (Preparation 2, 1.54 g, 7.6 mmol), and HOBt (1 , 29 g, 8.4 mmol) to a stirred solution of isobutyric acid (0.67 g, 7.6 mmol) in anhydrous DMF (10 ml). After 10 min., EDCI (1.76 g, 9.2 mmol) was added, and then stirring was continued

30 for 16 h. The reaction was diluted with H2O, and then the mixture was extracted with EtOAc (2x). The combined organic extracts were washed with saturated aqueous NaHCO3, with H2O, and with brine, before drying (MgSO4). Filtration and evaporation of the solvent produced a yellow oil that was treated with PhMe. The mixture was heated at reflux for 0.5 h. Upon cooling, the reaction was purified by column chromatography (IH-EtOAc, 2: 3) to yield the title compound: m / z (ES +) = 254.1 [M + H] +.

Preparation 4: 3- [1- (3-Isopropyl [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propan-1-ol ZnCl2 (1M in Et2O, 145 ml, 145 mmol) was added ) for 20 min. to a stirred solution of 4- (3-hydroxypropyl) piperidin-1-carbonitrile (Preparation 1, 20.3 g, 121 mmol) and N-hydroxyisobutyrammidine (14.8 g, 145 mmol) in EtOAc (290 ml) and THF (270 ml) After 2 h, the white precipitate that had formed was collected and washed with THF-EtOAc (1: 1, 50 ml). This precipitate was dissolved in EtOH (550 ml) and 12M HCl (70 ml), and then the solution was stirred with heating to 70 ° C for 16 h. The EtOH was removed in vacuo, the rest was diluted with H2O, and then the pH was adjusted to 7 with solid NaHCO3. The mixture was extracted with EtOAc (3x), and then the combined extracts were washed with brine, before drying (MgSO4). Filtration and solvent removal produced the title compound: m / z (ES +) = 254.1 [M + H] +.

Preparation 5: 2-Fluoro-5-methylsulfanylpyridine

To a solution of 5-bromo-2-fluoropyridine (3.00 g, 17.05 mmol) and TMEDA (3.35 ml, 22.17 mmol) in toluene (200 ml) at -75 ° C in argon was added n- 1.6M butyl lithium in hexane (12.8 ml, 20.46 mmol) for 10 min., and the mixture was stirred for 50 min. before adding dimethyl disulfide (1.84 ml, 20.46 mmol). The reaction was stirred for 1 h at -75 ° C, then heated to 2 ° C, and paralyzed with saturated NH4Cl solution (40 ml). The phase

Organic was collected, washed with brine, dried (MgSO4), and the solvent was removed in vacuo to give a residue that was purified by flash chromatography (SiO2), eluting with 2.5% EtOAc and 97.5% of 1H to produce the title compound. RT = 2.64 min .; m / z (ES +) = 143.95 [M + H] +.

Preparation 6: 2-Fluoro-5-methanesulfonylpyridine

To a solution of 2-fluoro-5-methylsulfanylpyridine (Preparation 5.30 g, 2.10 mmol) in CH2Cl2 (7 ml) at 0 ° C was added 77% 3-chloroperbenzoic acid (0.97 g, 4 , 30 mmol) for 15 min. Another aliquot of CH2Cl2 (5 ml) was added, and the mixture was stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (25 ml), washed with Na2CO3 (15 ml), and the organic phase was collected through a hydrophobic frit. The solvent was removed in vacuo to yield the title compound. RT = 1.64 min .; m / z (ES +) = 175.90 [M + H] +.

Preparation 7: 6-Fluoro-3-methanesulfonyl-2-methylpyridine

3-Bromo-6-fluoro-2-methylpyridine was converted to 6-fluoro-2-methyl-3-methylsulfanylpyridine using a procedure similar to that outlined in Preparation 5: m / z (ES +) = 157.87 [M + H] +. Oxidation, using a protocol similar to that given in Preparation 6, provided the title compound: RT = 2.13 min .; m / z (ES +) =

30 189.89 [M + H] +.

Preparation 8: 4 - ((E) -2-Carboxy-1-methylvinyl) piperidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4 - ((E) -2-ethoxycarbonyl-1-methylvinyl) piperidin-1-carboxylate (18.7 g, 62.9 mmol) in MeOH (90 ml) and H2O (25 ml) It was treated with 2M NaOH (94.5 ml, 189.0 mmol). The reaction was stirred for 16 h, the

MeOH was removed under reduced pressure, and then the rest was partitioned between EtOAc and H2O. The aqueous layer was separated and acidified to pH 2 with 12M HCl, before extracting it with EtOAc (2x). The organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated, and then the rest was recrystallized from EtOAc-1H to give the title compound: m / z (ES-) = 268.3 [ M -H] -.

Preparation 9: 4 - ((R) -2-Carboxy-1-methylethyl) piperidine-1-carboxylic acid tert-butyl ester

Tert-Butyl 4 - ((E) -2-carboxy-1-methylvinyl) piperidine-1-carboxylate (Preparation 8, 130.0 g, 0.483 moles) was placed in a hydrogenation flask in an atmosphere of Ar, and then degassed MeOH (400 ml) was added. [Rh (norbornadiene) 2] BF4 (1.80 g, 4.81 mmol) and (S) -1 - [(R) -2- (di-tert-butylphosphino) ferrocenyl] ethylbis (2-methylphenyl) phosphine were placed (2.90 g, 5.08 mmol) in a separate Schlenk flask, in Ar, before treating them with degassed MeOH (200 ml). This catalytic mixture was stirred for 15 min. at room temperature, before transferring it via a cannula to the hydrogenation flask. The Schlenk flask was rinsed with more degassed MeOH (100 ml). These washes were transferred to the hydrogenation flask, and then more degassed MeOH (300 ml) was added. 10 The hydrogenation flask was tightly closed, the Ar was replaced by H2, and the pressure was adjusted to 1.05 bar. The reaction mixture was heated to 35 ° C, and stirring / shaking was started. After 48 h, the reaction was stopped, and a representative sample of the reaction mixture was analyzed by HPLC and 1 H NMR. The conversion was 100%, and the enantiomeric purity of the crude (R) acid was 98.2% as determined by the following HPLC method: column: CHIRALPAK AD-H (previously used with solvents containing CF3CO2H) 4.6 x 250 15 mm; solvent: C6H14-iPrOH (97: 3 isocratic); temperature: 20 ° C; flow rate: 1 ml / min .; UV detection (210, 230 nm); Sample: 100 ml of reaction solution dissolved with 1 ml of MeOH. Retention times: acid (S): 19.3 min., Acid (R): 20.6 min., Starting enoic acid: 22.1 min. Isolation procedure: MeOH was evaporated, then the crude hydrogenation product was dissolved in t-BuOMe, and extracted with aqueous NaOH. The aqueous phase was added to a mixture of 1M HCl and EtOAc. The aqueous phase was further extracted with EtOAc, and then the combined organic extracts were washed with brine and dried (MgSO4). The title compound was isolated after

filtration and complete solvent removal.

Preparation 10: 4 - ((R) -3-hydroxy-1-methylpropyl) tert-butyl piperidine-1-carboxylate

It was added dropwise over 5 min. BH3-THF (1M, 15.7 ml, 15.7 mmol) at a stirred solution of 4 - ((R) -2

Tert-butyl carboxy-1-methylethyl) piperidine-1-carboxylate (Preparation 9, 1.70 g, 6.3 mmol) in anhydrous THF at 0 ° C. After 1 h, the reaction was treated with Et2O, and then with 2M HCl. The organic layer was washed with brine, before drying (Na2SO4). Filtration, evaporation of the solvent, and column chromatography (EtOAc-CH2Cl2, 1: 3) gave the title compound: RT = 3.17 min .; m / z (ES +) = 258. [M + H] +.

A mixture of tert-butyl 4- ((R) -3-hydroxy-1-methylpropyl) piperidin-1-carboxylate (Preparation 10, 6.2 g, 14.9 mmol) and 4M HCl in dioxane (10 ml) stirred at room temperature. After 3 h, the solvents were removed under reduced pressure to produce the hydrochloride salt of (R) -3-piperidin-4-yl-butan-1-ol: δH ({CD3} 2SO) 0.83 (d, 3H), 1.19-1.28 (m, 1H), 1.38-1.59 (m, 5H), 1.64-1.76 (m, 2H), 2.75-2.87 ( m, 2H), 3.20-3.30 (m, 2H), 3.35

35 3.60 (m, 4H). A stirred mixture of this compound (0.93 g, 4.8 mmol) and NaHCO3 (1.61 g, 19.2 mmol) in CH2Cl2-H2O (4: 1, 15 mL) at 0 ° C was treated with a solution of BrCN (0.61 g, 5.8 mmol) in CH2Cl2 (2 ml). The reaction was stirred at 20 ° C for 2 h, before partitioning between H2O and CH2Cl2. The organic phase was separated and dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (EtOAc) gave the title compound: RT = 2.45 min .; m / z (ES +) = 183.1 [M + H] +.

Preparation 12: (R) -3- [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] butan-1-ol

The condensation of 4 - ((R) -3-hydroxy-1-methylpropyl) piperidin-1-carbonitrile (Preparation 11, 0.53 g, 2.9 mmol) with N-hydroxyisobutyrammidine (0.36 g, 3.5 mmoles), using procedures similar to those outlined in Preparation 4, produced the title compound: RT = 2.92 min .; m / z (ES +) = 268.1 [M + H] +.

Preparation 13: 6- {3- [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} nicotinic acid

Reacted at 65 ° C 3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propan-1-ol (Preparation 4, 1.83 g, 7, 2 mmol) with 6-chloronicotinonitrile (1.00 g, 7.2 mmol), using a procedure similar to that described in the

Example 1, to produce 6-1 {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} nicotinonitrile: m / z (ES +) = 356.0 [M + H] +. A stirred mixture of this compound (1.84 g, 5.2 mmol) and 2M NaOH (15.5 ml, 31.0 mmol) in EtOH (30 ml) was heated for 16 h at 70 ° C. The EtOH was removed in vacuo, then the solution was acidified to pH 5 with 2M HCl. The precipitate produced was collected and dried in vacuo to yield the title compound: RT = 3.59 min .; m / z (ES-) = 373.4 [M-H] -.

Preparation 14: 6- {3- [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} -2-methylnicotinic acid

A stirred solution of ethyl 6-hydroxy-2-methylnicotinate (3.58 g, 19.8 mmol), 3- [1- (3-isopropyl [1,2,4] oxadiazol5-yl) piperidin-4-yl ] propan-1-ol (Preparation 4.00 g, 19.8 mmol), and triphenylphosphine (6.74 g, 25.7 mmol) in CH2Cl2, at 0 ° C, was treated dropwise with diisopropyl azodicarboxylate ( 5.04 ml, 25.7 mmol). After 4 h, reaction 20 was concentrated, before partitioning between EtOAc (300 ml) and 1M NaOH (100 ml). The organic phase was washed with 1M NaOH and brine, before drying (MgSO4). The solution was filtered and concentrated, and then the rest was washed with Et2O-IH, before filtering. The filtrate was concentrated, and then the residue was purified by column chromatography (EtOAc-IH, 1: 4) to provide 6- (3- [1- (3-isopropyl- [1,2,4] oxadiazol-5- il) ethyl piperidin-4-yl] propoxy) -2-methylnicotinate: m / z (ES +) = 417.0 [M + H] +. A mixture of this ester (5.51 g, 13.2 mmol), LiOH • H2O (5.55 g, 132.3

25 mmol), MeOH (200 ml), and H2O (20 ml) was stirred at 50 ° C for 16 h. The reaction was concentrated, before partitioning between H2O and EtOAc. The aqueous phase was isolated and acidified to pH 5 with 2M HCl, before extracting it with EtOAc (2x). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound: RT = 3.77 min .; m / z (ES +) = 389.0 [M + H] +.

Preparation 15: 6- (3- [1- (5-Isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-4-yl] propoxy) -2-methyl-nicotinic acid

Using procedures similar to those outlined in Preparation 14, 3- [1- (5-isopropyl [1,2,4] oxadiazol-3-yl) piperidin-4-yl] propan-1-ol (Preparation 3) is became the title compound: RT = 3.99 min .; m / z (ES +) = 389.30 [M + H] +.

Preparation 16: 6 - {(R) -3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] butoxy} -2-methylnicotinic acid

Prepared from ethyl 6-hydroxy-2-methylnicotinate (3.58 g, 19.8 mmol) and (R) -3- [1- (3-isopropyl [1,2,4] oxadiazol-5-yl ) pipetidin-4-yl] butan-1-ol (Preparation 12), using procedures similar to those outlined in Preparation 14: RT = 3.94 min .; m / z (ES-) = 401.4 [M-H] -.

Preparation 17: 6- {3- [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} -4-methylnicotinic acid

Reacted at 65 ° C 3- [1- (3-isopropyl [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propan-1-ol (Preparation 4, 3.06 g, 12.1 mmol) with 5-bromo-2-chloro-4-methylpyridine (2.50 g, 12.1 mmol), using a procedure similar to that described in Example 1, to produce 5-bromo-2- (3 - [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy) -4-methylpyridine: m / z (ES +) = 422.9 [M + H] +. A solution of this bromide (500 mg, 1.2 mmol) in anhydrous THF (1.5 ml) was added to a stirred solution of nBuLi (1.6 M in hexanes, 1.5 ml, 2.4 mmol) in Anhydrous THF (1.5 ml) at 78 ° C. After 1 h, CO2 (g) was bubbled through the mixture, while the mixture was allowed to warm to room temperature. The solvents were removed under reduced pressure, and then the rest was partitioned between H2O and

15 EtOAc. The aqueous phase was acidified to pH 2 with 2M HCl, before being extracted several times with EtOAc. The combined organic extracts were dried, filtered, and concentrated, and then the residue was purified by column chromatography on CH2Cl2-MeOH-AcOH (97.7: 2.0: 0.3) to yield the title compound: m / z (ES +) = 389.0 [M + H] +.

Prepared using a procedure similar to that outlined in Preparation 4: m / z (ES +) = 240.15 [M + H] +. Example 1: 2- {3- [1 - (, 3-Isopropyl [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} -5-methanesulfonylpyridine

To a solution of 3- [1- (3-isopropyl [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propan-1-ol (Preparation 4, 159 mg, 0.628

25 mmol) in anhydrous THF (5 ml) in argon sodium hydride (60% dispersion in mineral oil, 34.3 mg, 0.857 mmol) was added, and the mixture was stirred for 15 min. before adding 2-fluoro-5-methanesulfonylpyridine (Preparation 6, 100 mg, 0.571 mmol). The reaction mixture was stirred for 20 h, before removing the solvent in vacuo, and the residue was partitioned between CH2Cl2 (30 ml) and water (30 ml), and the aqueous phase was reextracted with CH2Cl2 (30 ml). . The organic extracts were collected through a hydrophobic frit, and the solvent was removed at

30 vacuum to give a residue that was purified by flash chromatography (SiO2) eluting with 40% EtOAc and 60% 1H to yield the title compound. RT = 3.74 min .; m / z (ES +) = 408.93 [M + H] +.

Example 2: 2 - {(R) -3- [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] butoxy} -5-methanesulfonylpyridine Reacted (R ) -3- [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] butan-1-ol (Preparation 12) with 2-fluoro-5methanesulfonylpyridine (Preparation 6) to produce the title compound: δH (CDCl3) 0.99 (d, 3H), 1.31 (d, 6H), 1.33-1.80 (m, 7H), 1.92-2.01 ( m, 1H), 2.92 (sept, 1H), 2.99-3.10 (m, 2H), 3.11 (s, 3H), 4.19-4.25 (m, 2H), 4 , 40-4.56 (m, 2H), 6.85 (d, 1H), 8.04 (dd, 1H), 8.76 (dd, 1H); RT = 3.77 min .; m / z (ES +) = 422.94 [M + H] +.

The procedure outlined in Example 1 was also used to prepare the compounds shown in Table 1 from the appropriate alcohol and 2-fluoropyridine.

Table 1

Ex.

Structure Name Spectrum

3

6- {3- [1- (3-Isopropyl [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] propoxy} -3-methanesulfonyl-2-methylpyridine RT = 3.87 min; m / z (ES +) = 423.22 [M + H] +

4

6 - {(R) -3- [1- (3-Isopropyl [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] butoxy} -3-methanesulfonyl-2-methylpyridine RT = 4.01 min; m / z (ES +) = 437.24 [M + H] +

5

6- {3- [1- (3-Ethyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] propoxy} -3methanesulfonyl-2-methylpyridine RT = 3.68 min; m / z (ES +) = 409.44 [M + H] +

6

5-Methanesulfonyl-2 - {(R) -3- [1- (3propyl- [1,2,4] oxadiazol-5yl) piperidin-4-yl] butoxy} pyridine RT = 3.84 min; m / z (ES +) = 422.96 [M + H] +

Example 7: N - ((R) -2-Hydroxy-1-methylethyl) -6- {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4- il] propoxy} nicotinamide

A solution of 6- {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] -propoxy} nicotinic acid (Preparation 13, 100 mg, 270 µmoles) , EDCI (61 mg, 320 µmoles), HOBt (44 mg, 320 µmoles) and DIPEA (141 µl, 810 µmoles) in anhydrous DMF (3 ml) was stirred for 30 min. (R) -2-Aminopropan-1-ol (21 µl, 270 µmoles) was added, and then stirring was continued for 16 h. The reaction mixture was partitioned between H2O (100 ml) and EtOAc (75 ml). The phase

The aqueous solution was further extracted with EtOAc (75 ml), and then the combined organic extracts were washed with saturated aqueous NaHCO3 (10 ml), before drying (MgSO4). Filtration, solvent evaporation and purification by RP-HPLC yielded the title compound: RT = 3.41 min .; m / z (ES +) = 431.98 [M + H] +.

The amides listed in Table 2 were synthesized by condensation of the appropriate acid with the appropriate amine, using procedures similar to those outlined in Example 7.

Table 2

Ex.

Structure Name Spectrum

8

N - ((R) -2-Hydroxy-1-methylethyl) -6- {3 [1- (3-isopropyl- [1,2,4] oxadiazol-5yl) piperidin-4-yl] propoxy} -2-methylnicotinamide δH (CDCl3) 1.23-1.38 (m, 11H), 1.42-1.62 (m, 3H), 1.80-1.88 (m, 4H), 2.46 (t, 1H ), 2.61 (s, 3H), 2.93 (sept, 1H), 3.02-3.12 (m, 2H), 3.63-3.71 (m, 1H), 3.80- 3.86 (m, 1H), 4.14-4.20 (m, 2H), 4.254.38 (m, 3H), 5.87-5.92 (br m, 1H), 6.58 (d , 1H), 7.64 (d, 1H); RT = 3.24 min; m / z (ES +) = 446.01 [M + H] +

9

6- {3- [1- (3-Isopropyl [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] propoxy} -2-methylnicotinamide RT = 3.27 min; m / z (ES +) = 388.02 [M + H] +

10

N - ((R) -2-Hydroxy-1-methyl-ethyl) -6 {(R) -3- [1- (3-isopropyl [1,2,4] oxadiazol-5-yl) piperidin-4il] butoxy} -2-methylnicotinamide RT = 3.47 min; m / z (ES +) = 460.01 [M + H] +

eleven

N- (2-Hydroxyethyl) -6 - {(R) -3- [1- (3isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] butoxy} -2-methylnicotinamide RT = 3.38 min; m / z (ES +) = 446.00 [M + H] +

12

N - ((R) -2-Hydroxy-1-methyl-ethyl) -6- {3 [1- (3-isopropyl- [1,2,4] oxadiazol-5yl) -piperidin-4-yl] propoxy} -4methylnicotinamide RT = 3.37 min; m / z (ES +) = 445.97 [M + H] +

13

N- (2-Hydroxy-1-hydroxymethyl ethyl) -6 {3- [1- (3-isopropyl [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] propoxy} -2-methylnicotinamide RT = 3.12 min; m / z (ES +) = 462.21 [M + H] +

14

N- (2-Hydroxyethyl) -6- {3- [1- (3isopropyl- [1,2,4] oxadiazol-5il) piperidin-4-yl] propoxy} -2-methylnicotinamide RT = 3.41 min; m / z (ES +) = 432.33 [M + H] +

fifteen

N - ((R) -2-Hydroxypropyl) -6- {3- [1- (3isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} -2-methylnicotinamide RT = 3.27 min; m / z (ES +) = 446.29 [M + H] +

16

N - ((S) -2,3-Dihydroxypropyl) -6- {3 [1- (3-isopropyl- [1,2,4] oxadiazol-5il) -piperidin-4-yl] propoxy} -2-methylnicotinamide RT = 3.09 min, m / z (ES +) = 462.29 [M + H] +

17

N- (2-Hydroxyethyl) -6- {3- [1- (5isopropyl- [1,2,4] oxadiazol-3yl) piperidin-4-yl] propoxy} -2-methylnicotinamide RT = 3.39 min; m / z (ES +) = 432.32 [M + H] +

18

N - ((R) -2-Hydroxy-1-methyl-ethyl) -6- {3 [1- (5-isopropyl- [1,2,4] oxadiazol-3yl) piperidin-4-yl] propoxy} - 2-methylnicotinamide RT = 3.49 min; m / z (ES +) = 446.36 [M + H] +

19

N- (2-Hydroxy-1-hydroxymethyl ethyl) -6 {3- [1- (5-isopropyl [1,2,4] oxadiazol-3-yl) piperidin-4yl] propoxy} -2-methylnicotinamide RT = 3.24 min; m / z (ES +) = 462.34 [M + H] +

twenty

N - ((S) -2,3-Dlhydroxypropyl) -6- {3 [1- (5-isopropyl- [1,2,4] oxadiazol-3yl) -piperidin-4-yl] propoxy} -2-methylnicotinamide RT = 3.28 min; m / z (ES +) = 462.36 [M + H] +

twenty-one

6- {3- [1- (5-Isopropyl [1,2,4] oxadiazol-3-yl) -piperidin-4-yl] propoxy-2-methylnicotinamide RT = 3.56 min; m / z (ES +) = 388.29 [M + H] +

22

6 - {(R) -3- [1- (3-Isopropyl δH (CDCl3) 1.20-1.80 (m, 14H),

[1,2,4] oxadiazol-5-yl) piperidin-4

1.87-1.98 (m, 1H), 2.66 (s, 3H),

il] butoxy} -2-methylnicotinamide 2.85-3.08 (m, 3H), 3.51 (q, 2H), 4.18-4.23 (m, 2H), 4.35-4.47 (m, 2H), 5, 75-5.90 (br s, 2H), 6.58 (d, 1H), 7.74 (d, 1H); RT = 3.47 min; m / z (ES +) = 402.21 [M + H] +

The biological activity of the compounds of the invention can be tested in the following test systems:

Yeast Informer Test

Reporting assays based on yeast cells have been previously described in the literature (for example,

5 see Miret J. J. et al, 2002, J. Biol. Chem., 277: 6881-6887; Campbell R.M. et al, 1999, Bioorg. Med. Chem. Lett., 9: 2413-2418; King K. et al, 1990, Science, 250: 121-123); WO 99/14344; WO 00/12704; and US 6,100,042). Briefly, yeast cells have been engineered so that the endogenous yeast G-alpha (GPA1) protein has been suppressed, and replaced by G protein chimeras constructed using multiple techniques. Additionally, GP3 Ste3 from yeast alpha cells has been suppressed

10 endogenous to allow homologous expression of a mammalian GPCR of choice. In yeast, the elements of the pheromone signaling transduction pathway, which are conserved in eukaryotic cells (e.g., the mitogen-activated protein kinase pathway), conducts the expression of Fus1. By placing βgalactosidase (LacZ) under the control of the Fus1 promoter (Fus 1 p), a system has been developed whereby the activation of the receptor leads to an enzymatic reading.

15 Yeast cells were transformed by an adaptation of the lithium acetate method described by Agatep et al. (Agatep, R. et al., 1998, Transformation of Saccharomyces cerevisiae by the lithium acetate / single-stranded carrier DNA / polyethylene glycol (LiAc / ss-DNA / PEG) protocol. Technical Tips Online, Trends Journals, Elsevier). Briefly, yeast cells were grown overnight on yeast tryptone (YT) plates. Carrier single stranded DNA (10 µg), 2 µg of each of two reporter plasmids was pipetted into an Eppendorf tube

20 Fus1p-LacZ (one with a URA selection marker, and one with TRP), 2 µg of GPR119 (human or mouse receptor) in yeast expression vector (2 µg origin of replication) and a lithium acetate buffer / polyethylene glycol / TE. The yeast expression plasmid containing the receptor / no receptor control has a LEU marker. Yeast cells were inoculated in this mixture, and the reaction proceeds at 30 ° C for 60 minutes. The yeast cells were then subjected to a thermal shock at 42 ° C for 15 minutes. The cells were then washed and spread on selection plates. Selection plates are synthetic defined yeast medium except LEU, URA and TRP (SD-LUT). After incubating at 30 ° C for 2-3 days, colonies that grow on the selection plates were then tested in the LacZ test.

In order to perform the fluorometric enzyme assays for β-galactosidase, yeast cells that possess the human or mouse GPR119 receptor were grown overnight in SD-LUT liquid medium to an unsaturated concentration (i.e., the cells were still dividing and had not yet reached the stationary phase). They were diluted in fresh medium to an optimal test concentration, and 90 µl of yeast cells were added to black 96-well polystyrene plates (Costar). The compounds, dissolved in DMSO and diluted in a 10% DMSO solution to a 10X concentration, were added to the plates, and the plates were placed at 30 ° C for 4 h. After 4 h, the substrate for β-galactosidase was added to each well. In these experiments, fluorescein-di- (β-D-galactopyranoside) (FDG), a substrate for the fluorescein-releasing enzyme, which allows a fluorometric reading was used. 20 µl per well of 500 µM FDG / 2.5% Triton X100 was added (the detergent was necessary to make the cells permeable). After incubation of the cells with the substrate for 60 minutes, 20 µl per well of 1M sodium carbonate was added to terminate the reaction and enhance the fluorescent signal. The plates were then read on a fluorometer at 485/535 nm.

The compounds of the invention gave an increase in the fluorescent signal of at least veces1.5 times that of the background signal (ie, the signal obtained in the presence of 1% DMSO without compound). Compounds of the invention that give an increase of at least 5 times may be preferred.

CAMP test

A stable cell line expressing human or recombinant GPR119 was obtained, and this cell line was used to investigate the effect of the compounds of the invention on intracellular levels of cyclic AMP (cAMP). The cell monolayers were washed with phosphate buffered saline, and stimulated at 37 ° C for 30 minutes with various concentrations of compound in stimulation buffer plus 1% DMSO. The cells were then lysed, and the cAMP content was determined using the Perkin Elmer AlphaScreenTM cAMP kit (homogeneous amplified luminescent proximity test). Buffers and test conditions were as described in the manufacturer's protocol.

In vivo feeding study

The effect of the compounds of the invention on body weight and food and water intake can be examined in freely fed Sprague-Dawley male rats maintained in a reverse phase light cycle. Test compounds and reference compounds are dosed by appropriate routes of administration (for example intraperitoneally or orally), and measurements are made during the next 24 h. The rats are caged individually in polypropylene cages with metal grid floors at a temperature of 21 ± 4 ° C and 55 ± 20% humidity. Polypropylene trays with cage pads are placed under each cage to detect any loss of food. The animals are kept in a reverse phase light-dark cycle (the lights are turned off for 8 h from 09: 30-17: 30 h), during which time the room is illuminated by red light. Animals are given free access to a standard powdered diet for rats and tap water during a two-week acclimatization period. The diet is contained in glass feeding jars with aluminum lids. Each lid has a 3-4 cm hole in it to allow access to food. Animals, feeding jars and water bottles are weighed (to the nearest 0.1 g) at the beginning of the dark period. Feed jars and water bottles are subsequently measured 1, 2, 4, 6 and 24 h after the animals are dosed with a compound of the invention, and any significant differences between the treatment groups at the initial value they are compared with vehicle treated controls.

Antidiabetic effects of the compounds of the invention in an in vitro model of pancreatic beta cells (HIT-T15)

Cell culture

HIT-T15 cells (past 60) can be obtained from ATCC, and grown in RPMI1640 medium supplemented with 10% fetal calf serum and 30 nM sodium selenite. All experiments should be carried out with cells with a pass lower than 70, according to the literature, which describes the altered properties of this cell line in pass numbers above 81 (Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships. Diabetes. 1989 Jan; 38 (1): 44-8).

CAMP test

HIT-T15 cells are placed in standard culture medium in 96-well plates at 100,000 cells / 0.1 ml / well, and grown for 24 h and then the medium is discarded. The cells are incubated for 15 minutes at room temperature with 100 µl of stimulation buffer (Hanks buffered saline, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4). This is discarded and replaced by dilutions of compound over the range 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 µM in stimulation buffer in the presence of 0.5% DMSO. The cells are incubated at room temperature for 30 minutes. Then, 75 ul of lysis buffer (5 mM HEPES, 0.3% Tween-20, 0.1% BSA, pH 7.4) is added per well, and the plate is stirred at 900 rpm for 20 minutes The particulate matter is removed by centrifugation at 3000 rpm for 5 minutes, then the samples are transferred in duplicate to 384-well plates, and processed according to the instructions of the Perkin Elmer AlphaScreen cAMP test kit. Briefly, 25 µl reactions containing 8 µl of sample, 5 µl of acceptor bead mixture and 12 µl of detection mixture are established, so that the concentration of the components of the final reaction is the same as established in the kit instructions. The reactions are incubated at room temperature for 150 minutes, and the plate is read using a Packard Fusion instrument. The measurements for cAMP are compared with a standard curve of known quantities of Camp (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000 nM), to convert the readings in absolute amounts of cAMP. Data is analyzed using XLfit 3 software.

It was found that representative compounds of the invention increase cAMP to an EC50 of less than 10 mM. Compounds showing an EC50 of less than 1 mM may be preferred in the cAMP assay.

Insulin Secretion Assay

HIT-T15 cells are placed in standard culture medium in 12-well plates at 106 cells / 1 ml / well, and cultured for 3 days and then the medium is discarded. The cells are washed x 2 with supplemented Krebs-Ringer buffer (KRB) containing 119 mM NaCl, 4.74 mM KCl, 2.54 mM CaCl3, 1.19 mM MgSO4, 1.19 mM KH2PO4 , 25 mM NaHCO3, 10 mM HEPES at pH 7.4 and 0.1% bovine serum albumin. The cells are incubated with 1 ml of KRB at 37 ° C for 30 minutes, which is then discarded. This is followed by a second incubation with KRB for 30 minutes, which is collected and used to measure basal insulin secretion levels for each well. Then dilutions of compound (0, 0.1, 0.3, 1, 3, 10 uM) are added in duplicate to the wells in 1 ml of KRB, supplemented with 5.6 mM glucose. After a 30 minute incubation at 37 ° C, the samples are removed for the determination of insulin levels. Insulin measurement is performed using the Mercodia rat insulin ELISA kit, following the manufacturer's instructions, with a standard curve of known insulin concentrations. For each well, insulin levels are subtracted from the level of basal secretion from preincubation in the absence of glucose. Data is analyzed using XLfit 3 software.

Oral glucose tolerance tests

The effects of the compounds of the invention on oral glucose (Glc) tolerance were evaluated in male Sprague-Dawley rats. The food was removed 16 h before the administration of Glc, and remained unrepleased during the study. The rats had free access to water during the study. A cut was made in the animals' tails, blood (1 drop) was then removed to measure the baseline Glc levels 60 minutes before the administration of the Glc charge. The rats were then weighed and orally tested test compound or vehicle (20% aqueous hydroxypropyl-β-cyclodextrin) 45 minutes before removal of an additional blood sample and treatment with the Glc load (2 g kg-1 po). Blood samples were then taken from the tail cutting tip 5, 15, 30, 60, 120 and 180 minutes after the administration of Glc. Blood glucose levels were measured right after collection using a commercially available blood glucose meter (OneTouch® UltraTM from Lifescan). Representative compounds of the invention statistically reduced Glc excursion at doses of ≤10 mg

kg-1

The effects of the compounds of the invention on oral glucose (Glc) tolerance can also be evaluated in male C57BU6 mice or male ob / ob mice. The food was removed 5 h before the administration of Glc, and remained un replenished throughout the study. Mice had free access to water during the study. The animals were cut in the tails, then blood (20 µl) was removed to measure baseline Glc levels 45 minutes before administration of the Glc load. The mice were then weighed and orally tested test compound or vehicle (20% aqueous hydroxypropyl-β-cyclodextrin or 25% aqueous Gelucire 44/14) 30 minutes before removal of an additional blood sample (20 µl) and treatment with the Glc load (2-5 g kg-1 po). Blood samples (20 µl) were then taken 25, 50, 80, 120 and 180 minutes after the administration of Glc. Blood samples of 20 µl for the measurement of Glc levels are taken from the tail cutting tip in disposable micropipettes (Dade Diagnostics Inc., Puerto Rico), and the sample is added to 480 µl of hemolysis reagent . Duplicate aliquots of 20 µl of the hemolyzed blood diluted to 180 µl of Trinder glucose reagent (enzymatic colorimetric method (Trinder) of Sigma) are then added in a 96-well test plate. After mixing, the samples are left at rt for 30 minutes before being read against Glc standards (Sigma urea glucose / nitrogen combined standard set).

Claims (35)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: in which one of X and Y is O and the other is N; 5 one of E and Q is Ny the other is CH; R1 is SO2R5 or -CONHR6; R2 is hydrogen or methyl; R3 is hydrogen or methyl; R4 is C2-5 alkyl; R5 is C1-3 alkyl; Y R6 is hydrogen, C1-3 alkyl, or C2-3 alkyl substituted with hydroxy.

2.

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O.

3.

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is O.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1 is SO2R5.

5.

A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R1 is SO2CH3.

6.

A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1 is -CONHR6.

A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R6 is C1-3 alkyl or C2-3 alkyl substituted with hydroxy. 8. A compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R6 is C2-3 alkyl substituted with hydroxy. 9. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R6 is 225 hydroxyethyl or 2-hydroxy-1-methyl ethyl.

10.

A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.

eleven.

A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl.

12. A compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl, and the stereocenter produced has the configuration (R). 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R4 is C3-4 alkyl. 14. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R4 is isopropyl.

fifteen.

N - ((R) -2-Hydroxy-1-methylethyl) -6- {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} -2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

16.

6- {3- [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] propoxy} -2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

17.

N - ((R) -2-Hydroxy-1-methyl-ethyl) -6 - {(R) -3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin- 4-yl] butoxy} -2-methylnicotinamide;

or a pharmaceutically acceptable salt thereof.

18.

N- (2-Hydroxyethyl) -6 - {(R) -3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] butoxy} -2- methylnicotinamide; or a pharmaceutically acceptable salt thereof.

19.

N - ((R) -2-Hydroxy-1-methyl-ethyl) -6- {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-yl ] propoxy} -4-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

twenty.

N- (2-Hydroxy-1-hydroxymethyl ethyl) -6- {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] propoxy} -2- methylnicotinamide;

or a pharmaceutically acceptable salt thereof.

twenty-one.

N- (2-Hydroxyethyl) -6- {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} -2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

22

N - ((R) -2-Hydroxypropyl) -6- {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] propoxy} -2- methylnicotinamide; or a pharmaceutically acceptable salt thereof.

2. 3.

N - ((S) -2,3-Dihydroxypropyl) -6- {3- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidin-4-yl] propoxy} - 2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

24.

N- (2-Hydroxyethyl) -6- {3- [1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-4-yl] propoxy} -2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

25.

N - ((R) -2-Hydroxy-1-methylethyl) -6- {3- [1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperidin-4-yl] propoxy } -2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

26.

N- (2-Hydroxy-1-hydroxymethyl ethyl) -6- {3- [1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) piperidin-4-yl] propoxy} -2-methylnicotinamide ;

or a pharmaceutically acceptable salt thereof.

27.

N - ((S) -2,3-Dihydroxypropyl) -6- {3- [1- (5-isopropyl- [1,2,4] oxadiazol-3-yl) -piperidin-4-yl] propoxy} - 2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

28.

6- {3- [1- (5-Isopropyl- [1,2,4] oxadiazol-3-yl) -piperidin-4-yl] propoxy} -2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

29.

 6 - {(R) -3- [1- (3-Isopropyl- [1,2,4] oxadiazol-5-yl) piperidin-4-yl] butoxy} -2-methylnicotinamide; or a pharmaceutically acceptable salt thereof.

30

 2- {3- [1- (3-Isopropyl [1,2,4] oxadiazol-5-yl) piperidin-4-yl] propoxy} -5-methanesulfonylpyridine or 2 - {(R) -3- [1- (3-Isopropyl [1,2,4] oxadiazol-5-yl) piperidin-4-yl] butoxy} -5-methanesulfonylpyridine; or a pharmaceutically acceptable salt thereof.

31.

A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32

A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in satiety regulation.

33.

A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

3. 4.

A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetes.

35

A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, or hypertension

36.

A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use as a medicament.

37.

A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or condition as defined in any one of claims 32 to 35 .