WO2010001166A1 - Thiazole derivatives as gpr 119 modulators - Google Patents

Abstract

Compounds of formula (I) or salts, hydrates, solvates or N-oxides thereof formula (I): wherein A, B, R₁, R₂ and R₈ are as defined herein, are useful for treating or preventing diseases or conditions which are associated with GPR119 receptor signaling, such as diabetes, obesity and metabolic syndrome.

Description

THIAZOLE DERIVATIVES AS GPR 119 MODULATORS

FIELD OF THE INVENTION

The present invention relates to novel compounds which are GPRl 19 receptor modulators, especially positive modulators (agonists), and to compositions and methods for treating or preventing diseases or conditions which are associated with GPRl 19 receptor signaling, such as diabetes, obesity and metabolic syndrome including associated conditions, such as, glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, vascular conditions, osteoporosis, pain, demyelination, and nonalcoholic fatty liver disease. The invention also relates to pharmaceutical compositions containing the compounds of the invention, and to the use of the compounds optionally in combination with other treatments, for the treatment or prophylaxis of, for example, diabetes, obesity and for obesity-related diseases.

BACKGROUND

The prevalence of obesity in North America and in most European countries has more than doubled in the last 20 years and obesity is now recognized as a chronic disease and a critical global health issue (Fiegal et al, 1998, Int. J. Obesity 22:39-47, Mokdad et al, 1999, JAMA 282:1519-1522; Halford, 2006, Appetite, 46, 6-10). The "identifiable signs and symptoms" of obesity include an excess accumulation of fat or adipose tissue, an increase in the size or number of fat cells (adipocyte differentiation), insulin resistance, increased glucose levels (hyperglycemia), increased blood pressure, elevated cholesterol and triglyceride levels and decreased levels of high-density lipoprotein. Obesity is associated with a significantly elevated risk for type 2 diabetes, coronary heart disease, stroke, hypertension, various types of cancer and numerous other major illnesses, and overall mortality from all causes (Must et al, 1999, JAMA 282:1523-1529, Calle et al, 1999, N. Engl. J. Med. 341:1097-1105). A cluster of metabolic risk factors for cardiovascular disease and Type 2 diabetes is often referred to as metabolic syndrome, syndrome X or insulin resistance syndrome. The major components of metabolic syndrome include excess abdominal fat (also known as visceral, male-pattern or apple-shaped adiposity), atherogenic dyslipidemia (decreased high-density lipoprotein cholesterol (HDL-C)), elevated triglycerides, hypertension, hyperglycaemia (diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance), a proinflammatory state and a prothrombotic state (cf. AHA/NHLB I/ADA Conference Proceedings, Circulation 2004; 109:551-556). Other abnormalities often associated with the metabolic syndrome include increased apolipoprotein B concentrations, low adiponectin plasma levels, small dense low-density lipoprotein (LDL) particles, hyperuricaemia, non-alcoholic fatty liver disease/hepatic steatosis, elevated liver transaminases, gamma-glutamyl-transferase and microalbuminuria.

Diabetes mellitus is a group of disorders characterized by abnormal glucose homeostasis resulting in high levels of blood glucose. The most common cases of diabetes mellitus are Type 1 and Type 2 diabetes of which the latter accounts for approximately 90% of all diabetic cases. The increasing prevalence of obesity together with an ageing population is predicted to rapidly increase the number of people with diabetes. Thus, there is a medical need for new and novel antidiabetic and antiobesity therapies that are well tolerated with few adverse effects.

Type 1 diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune destruction of the insulin producing pancreatic beta-cells, and requires regular administration of exogenous insulin. Type 1 diabetes usually start in childhood or young adulthood manifesting sudden symptoms of high blood sugar (hyperglycemia).

Type 2 diabetes (T2D) or diabetes mellitus type 2 (formerly called non-insulin-dependent diabetes mellitus (NIDDM), or adult-onset diabetes) is a progressive disease characterized by impaired glucose metabolism resulting in elevated blood glucose levels. T2D may be characterized by a defect in insulin secretion or by insulin resistance, namely those that suffer from T2D have too little insulin or cannot use insulin effectively. Insulin resistance refers to the inability of body tissues to respond properly to endogenous insulin. Insulin resistance develops because of multiple factors, including genetics, obesity, increasing age, and having high blood sugar over long periods of time. T2D is a serious progressive disease that results in the development of microvascular complications (e.g. retinopathy, neuropathy, nephropathy) as well as macrovascular complications (e.g. accelerated atherosclerosis, coronary heart disease, stroke). More than 75% of people with T2D die of cardiovascular diseases. Current oral medications for T2D have a number of side effects, including hypoglycemia, weight gain and edema, prompting continued efforts to develop therapeutics to improve treatments for patients with diabetes. For effective control of diabetes, combination therapy is being commonly used because a single drug is insufficient to target diabetes and its associated complications.

Current treatments of T2D aim to reverse insulin resistance, control intestinal glucose absorption, normalize hepatic glucose production, and improve beta-cell glucose sensing and insulin secretion. The sulfonylurea class of oral antihyperglycemic agents promotes insulin secretion from pancreatic beta-islet cells. However, this enhanced insulin production is not glucose dependent and there is risk for developing hypoglycaemia. Antihyperglycemic agents include: insulin sensitizers that reduce hepatic glucose production by inhibiting gluconeogenesis; alpha-glucosidase inhibitors that inhibit breakdown of complex carbohydrates thus delaying glucose absorption and dampening postprandial glucose and insulin peaks; and activators of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), such as the thiazolidinediones (TZDs), which enhances insulin action. There are, however, deficiencies associated with currently available treatments, including hypoglycemic episodes, weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema. For example, a major side effect of TZDs is weight gain due to fluid retention and increase in total body fat. Thus, new treatments for type 2 diabetes are highly desirable.

The incretins, GIP and GLP-I, appear to serve as endogenous antidiabetic hormones, stimulating glucose-dependent insulin secretion. GIP and GLP-I are secreted from enteroendocrine K and L cells, respectively, in response to ingestion of nutrients. In addition, GLP-I inhibits glucagon release, gastric emptying, and appetite. Continuous infusion of GLP-I into patients with T2D improves glucose control. Both GIP and GLP-I are rapidly degraded by dipeptidylpeptidase-4 (DPP-4) that has prompted the development of DPP-4-resistant GLP-I receptor agonists, e.g. liraglutide that improves glycemic control and reduces hemoglobin AIc levels in patients with T2D. Alternatively, incretin activity can be increased by inhibition of the degrading enzyme DPP-4 (e.g. with sitagliptin or vildagliptin) leading to prolonged antidiabetic effects of GLP-I and GIP (L. Lauffer, R. Iakoubov, and P. L. Brubaker, 2008, Endocrinology, 149(5):2035-2037). Treatments to increase GLP-I, therefore, may be used for a variety of conditions and disorders including metabolic disorders such as diabetes mellitus (Type 1 and Type 2), metabolic syndrome, obesity, appetite control, weight loss and satiety

GPRl 19 (GenBank No. NM 178471) is a constitutively active G-protein coupled receptor. GPRl 19 is largely confined to pancreas and intestinal tissues in humans, with extremely low or undetectable expression in all other human tissues examined. The GRPl 19 receptor stimulates insulin production in response to increases in blood glucose and GPRl 19 agonists are not expected to lower normal fasting blood glucose levels or cause hypoglycemia. Moreover, GPRl 19 stimulation has been found to increase the levels and activity of intracellular factors thought to be involved in the preservation of beta cells (Soga et al, 2005, Biochem. Biophys. Res. Commun. 326, 744-751; Chu et al., 2007, Endocrinology 148(6):2601-09; Chu et al., 2008, Endocrinology 149(5):2038-47; Lauffer et al., 2008, Endocrinology, 149(5):2035-37). GPRl 19 also stimulates incretin hormone release and has been shown to regulate glucose homeostasis by this additional mechanism. GPRl 19 mRNA has been found to be expressed at significant levels in intestinal sub-regions (e.g. entero-endocrine L-cells) that produce GIP and GLP-I. Furthermore, in situ hybridization studies indicated that most GLP-I -producing cells co- express GPRl 19 mRNA. Stimulation with the pharmacological GPRl 19 agonist, AR231453, induces GLP-I secretion from entero-endocrine cell lines (GLUTag and STC-I) and enhances the release of both GLP-I and GIP in vivo in mice. Co-administration with the DPP-4 inhibitor, sitagliptin, to amplify the observed incretin effect, results in a further improvement in glycemic control in glucose-challenged animals. Furthermore, the insulin secretion induced by AR231453 was diminished by approximately 50% when the GLP-I receptor antagonist, exendin-49-39, was co-administered with the GPRl 19 agonist (Chu et al., 2008, Endocrinology 149(5):2038-47). Taken together, GPRl 19 -specific agonists appear to provide a useful approach to incretin therapy in patients with diabetes mellitus type 2, increasing glucose-dependent insulin secretion through two complementary mechanisms: directly, through actions on the β-cell, and indirectly, through enhancement of GLP-I and GIP release. In addition, GPRl 19 small molecules and the endogenous GPRl 19 ligand oleoylethanolamide improve various metabolic parameters, including weight loss, glucose tolerance and insulin sensitivity and a selective small-molecule agonist of GPRl 19, PSN632408 has been shown to reduce food intake, body weight gain and white adipose tissue deposition in high-fat fed rats (Overton et al., 2006, Cell Metabol 3:167-75). Thus, GPR119 agonists have the potential to normalize blood glucose levels in a T2D patient in response to postprandial blood glucose elevation and are potentially useful for treating diabetes and/or obesity.

WO 2008/008887, WO 2008/008895, WO 2008/025798, WO 2008/025799, WO 2008/025800, WO 2008/033460, WO 2008/033456, WO 2008/033465, WO 2007/116230, WO 2007/116229, WO 2007/003964, WO 2007/003962, WO 2007/003960, WO 2007/003961, WO 2006/067531, WO 2006/067532, WO 2006/070208, WO 2005/061489, WO 2005/007647, WO 2005/007658, WO 2005/121121, WO 2004/065380 and WO 2004/076413 disclose compounds that are modulators of GPRl 19, also referred to as RUP 3, 19 AJ, AXOR 20, and PSl and SNORF25 (Fredriksson et al., 2003, FEBS Lett, 554, 381- 388), and which inter alia may be used for the treatment of metabolic disorders and complications thereof, such as, diabetes and obesity. WO 2006/076231 discloses a synergistic effect of a GPRl 19 agonist in combination with a DPP- 4 inhibitor, in lowering elevated glucose levels in mice and in increasing blood GLP-I levels after glucose challenge in mice.

Positive modulators or agonists to the GPRl 19 receptor may be used in the treatment or prophylaxis of disorders relating to GPRl 19, e.g. Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, metabolic syndrome, obesity, hypertension, vascular conditions, chronic systemic inflammation, pain, retinopathy, neuropathy, nephropathy, osteoporosis, reduced fibrinolysis, demyelination, nonalcoholic fatty liver disease and endothelial dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, there is provided a compound of formula (I) or a salt, hydrate, solvate or N-oxide thereof:

(I) wherein: ring A is phenyl or pyridyl;

R₁ is hydrogen, -CN, -F, -Cl, -Br, -NO₂, -OR₃, -NR₇COR₆, -NR₇S(O)₂R₆, -COR₆, -SR₃, -S(O)R₃, -CH₂S(O)₂R₃, CH₂SO₂NR₄R₅, -S(O)₂R₃, -SO₂NR₄R₅, C₁-C₄ alkyl, fully or partially fluorinated C₁-C₄ alkyl, C₃-C₅ cycloalkyl, or 5-membered heteroaryl;

R₂ is hydrogen, -CN, -F, -Cl, or -OR₃;

R₈ is hydrogen or -F; provided that R₁, R₂ and R₈ are not simultaneously hydrogen;

R₃ is C₁-C₄ alkyl, C₃-C₅ cycloalkyl, or fully or partially fluorinated C₁-C₄ alkyl;

R₆ is C₁-C₄ alkyl, C₃-C₅ cycloalkyl, or -NR₄R₅;

R₄ and R₅ are independently hydrogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, or taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring;

R₇ is hydrogen, C₁-C₄ alkyl, or C₃-C₅ cycloalkyl;

B is -CO₂R₃, -COR₆, -S(O)₂R₃, or -V-R₇; and

V is a divalent 5-membered heteroarylene radical. Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients.

As used herein, the term "(C_a-C_b)alkyl" wherein a and b are integers, refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 4, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, and t- butyl.

As used herein the term "fully or partially fluorinated (C_a-C_b)alkyl" wherein a and b are integers, refers to a straight or branched chain alkyl radical having from a to b carbon atoms in which one or more hydrogens are replaced by fluorine. Thus when a is 1 and b is 4, for example, the term includes mono-, di- and tri-fluoromethyl, 2-fluoroethyl, 2,2-difluoromethyl, and 2,2,2- trifluoromethyl.

As used herein the term "C₃-C₅cycloalkyl" refers to cyclopropyl, cyclobutyl, and cyclopentyl radicals. As used herein the unqualified term "5-membered heteroaryl" refers to a monocyclic aromatic radical containing one or more, e.g. 1, 2 or 3, heteroatoms selected from S, N and O. Illustrative of such radicals are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, and oxadiazolyl.

As used herein, the term "divalent 5-membered heteroarylene radical" means a 5- membered heteroaryl radical having two unsatisfied valencies.

As used herein the unqualified term "5- or 6-membered heterocyclic" means a monocyclic non-aromatic radical having 5 or 6 ring atoms, one or more of which, e.g. 1 or 2 of which, are heteroatoms selected from S, N and O. Illustrative of such radicals are piperidinyl, morpholinyl piperazinyl, and N-(Ci-C₄alkyl)piperazinyl As used herein the term "salt" includes base addition, acid addition and quaternary salts.

Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L- arginine, L-lysine, N-ethylpiperidine, dibenzylamine and the like. Those compounds of formula (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulfuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulfonic, p-toluenesulfonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002).

The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is employed when said solvent is water. Compounds of the invention which may exist in one or more stereoisomeric form, because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomeres with R or S stereochemistry at each chiral axis. The invention includes all such enantiomers and diastereoisomers and mixtures thereof.

The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of formula (I). So-called "pro-drugs" of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and VJ. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association; CS. Larsen and J. østergaard, Design and application of prodrugs, In Textbook of Drug Design and Discovery, 3^rd Edition, 2002, Taylor and Francis ).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). Such examples could be a prodrug of a carboxyl group (such as - CO-O-CH₂-O-CO-tBu as used in the pivampicillin prodrug of ampicillin), an amide (-CO-NH- CH₂-NAIk₂) or an amidine ( -C(=N-O-CH₃)-NH₂). Also included within the scope of the invention are metabolites of compounds of formula

(I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites include:

(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH₃ -> -CH₂OH); (ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);

(iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR¹R² -> -NHR¹ or -NHR²);

(iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂);

(v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and

(vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH₂ -> COOH). For use in accordance with the invention, the following structural characteristics are currently contemplated, in any compatible combination, in the compounds of formula (I): Ring A is phenyl or pyridyl (i.e. 2-, 3- or 4-pyridyl). Phenyl is preferred. The substituents R₁, R₂, and R₈ in ring A have been defined above in relation to formula (I). At least one such substituent other than hydrogen must be present in ring A. For example, R₁ may be SeIeCtCd IrOm -S(O)₂R₃₁ -SO₂NR₄R₅, -CH₂S(O)₂R₃, -CH₂SO₂NR₄R₅, -COR₆, -NR₇COR₆, or 5-membered heteroaryl, R₃, R₄, R₅, R₆ and R₇ being as defined in relation to formula (I). Thus, when R₁ is -S(O)₂R₃ or -CH₂S(O)₂R_3, R₃ may be, for example, hydrogen, methyl ethyl, n- or iso- propyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, or cyclopentyl; when R₁ is -SO₂NR₄R₅ or -CH₂SO₂NR₄R₅, R₄ and R₅ may independently be, for example, hydrogen, methyl or ethyl, or one of R₄ and R₅ may be hydrogen or methyl, and the other may be n- or iso-propyl, cyclopropyl, cyclobutyl or cyclopentyl, or R₄ and R₅ taken with the nitrogen to which they are attached may form a piperidine, morpholine, thiomorpholine, piperazine, or N-substituted piperazine ring, such as an N-(Ci-C₄alkyl)piperazine ring; when R₁ is -COR_6, -NR₇COR_6, R₆ may be, for example methyl, ethyl, n- or iso-propul, n-sec- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or -NR₄R₅ wherein R₄ and R₅ may independently be, for example, hydrogen, methyl, ethyl, n- or iso-propyl, cyclopropyl, cyclobutyl or cyclopentyl, or R₄ and R₅ taken with the nitrogen to which they are attached may form a piperidine, morpholine, thiomorpholine, piperazine, or N-(CrC₄alkyl)piperazine ring, and R₇ may be, for example, hydrogen, methyl or cyclopropyl; when R₁ is a 5-membered heteroaryl group, examples include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, and oxadiazolyl groups. Often the group R₁ will be in the para position of ring A relative to the carboxamide bond shown in formula (I).

Subject to the proviso that at least one of R₁, R₂ and R₈ in ring A is other than hydrogen, R₂ may be, for example, hydrogen, -F, -CN, or -OR₃ wherein R₃ is as defined in relation to formula (I), such as, for example, hydrogen, methyl, ethyl, or cyclopropyl. Subject to the proviso that at least one of R₁, R₂ and R₈ in ring A is other than hydrogen,

R₈ may be, for example, hydrogen or -F. Often, when R₈ is -F, it will be in an ortho position of ring A relative to the carboxamide bond shown in formula (I).

The N-substituent B in the piperidine ring shown in formula (I) has been defined in relation to formula (I) as a radical -CO₂R₃, -COR₆, -S(O)₂R₃, or -V-R₇; wherein V is a divalent 5- membered heteroarylene radical. Thus in radical B: R₃ may be, for example, methyl, ethyl, n- or iso-propyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, or cyclopentyl; R₆ may be, for example, methyl, ethyl, n- or iso-propyl, n-sec- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or -NR₄R₅ wherein R₄ and R₅ may independently be, for example, hydrogen, methyl, or ethyl, or one of R₄ and R₅ may be hydrogen or methyl, and the other may be n- or iso-propyl, cyclopropyl, cyclobutyl or cyclopentyl, or R₄ and R₅ taken with the nitrogen to which they are attached may form a piperidine, morpholine, thiomorpholine, piperazine, or N-(C₁- C₄alkyl)piperazine ring; R₇ may be, for example, hydrogen, methyl or cyclopropyl; and V may be, for example, a thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxaxadiazolyl ring with two unsatisfied valencies. Specific compounds of the invention include those of the Examples herein and pharmaceutically acceptable salts thereof. As mentioned above, the compounds of the present invention are agonists at the GPRl 19 receptor. Also as mentioned above, agonism at that receptor is known to be an indicator of utility in the treatment or prophylaxis of, diseases or conditions which are associated with GPRl 19 receptor signaling, such as diabetes, obesity and metabolic syndrome including associated conditions, such as, glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, vascular conditions, osteoporosis, pain, demyelination, and nonalcoholic fatty liver disease.

Therefore, further aspects of the invention are:

(i) The use of a compound of the invention in the preparation of a composition for treatment or prophylaxis of diseases or conditions which are mediated by, e.g. responsive to stimulation of, GPRl 19 receptor signaling activity. Examples of such diseases and conditions have been listed above; (ii) A compound of the invention for use in the treatment or prophylaxis of diseases or conditions which are mediated by, e.g. responsive to stimulation of, GPRl 19 receptor signaling activity. Examples of such diseases and conditions have been listed above; and (iii) A method for the treatment or prophylaxis of diseases or conditions which are mediated by, e.g. responsive to stimulation of, GPRl 19 receptor signaling activity, which method comprises administering to a subject suffering such disease or condition an effective amount of a compound of the invention. Examples of such diseases and conditions have been listed above.

Compounds of the invention may be used in combination with agents used for treatment or prophylaxis of diabetes or obesity or in combination with agents used for treatment of diseases related to diabetes or obesity. Examples of other agents useful in the present methods for treating type 2 diabetes include i) insulin sensitizers (such as PPAR agonists (include PPAR-gamma agonists such as troglitazone, rosiglitazone, pioglitazone and englitazone), DPP-4 inhibitors (such as sitagliptin, saxagliptin, alogliptin, denagliptin and vildagliptin), protein tyrosine phosphatase (PTP)-IB inhibitors and glucokinase activators (e.g. RO 28-1675); ii) glucose absorption inhibitors (such as alpha-glucosidase inhibitors (e.g. miglitol, acarbose and voglibose) and sodium-glucose transport protein SGLTl inhibitors); iii) insulin secretagogues (such as sulfonylureas (e.g. glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide, acetohexamide, gliamilide, gliclazide, glibenclamide and tolazamide) and non-sulfonylurea drugs such as GLP-I, GLP-I peptide analogues, exendin, GIP, secretin, glipizide, chlorpropamide, nateglinide, meglitinide, glibenclamide, repaglinide and glimepiride); iv) glucagon suppressor (such as amylin agonist analog (pramlintide), glucagon receptor antagonists (e.g. NNC-92-1687 and BAY-27-9955); v) hepatic glucose output lowering compounds (such as metformin); vi) renal sodium-glucose transport protein SGLT2 inhibitors (such as dapagliflozin,

GW869682 and GSK189075); and vii) insulin (including all formulations of insulin, including long acting and short acting forms of insulin and insulin analogues). Compounds of the invention may be administered in combination with anti-obesity agents for the treatment of diabetes. Several such useful potential anti-obesity agents are currently investigated (for a review, see Bays, 2004, Obesity Research, 12, 1197-1211): i) central nervous system agents that affect neurotransmitters or neural ion channels

(e.g. antidepressants (bupropion), noradrenaline reuptake inhibitors (GW320659), selective 5HT 2c receptor agonists, antiseizure agents (topiramate, zonisamide), some dopamine antagonists, cannabinoid CB-I receptor antagonists (rimonabant); ii) leptin/insulin/central nervous system pathway agents (e.g. leptin analogues, leptin transport and/or receptor promoters, CNTF (Axokine), NPY antagonists, AgRP antagonists, POMC promoters, CART promoters, MSH analogues, MC4 receptor agonists, agents that affect insulin metabolism/activity [PTP-IB inhibitors, PPAR receptor antagonists, short-acting D2 agonist (ergoset), somatostatin agonists (octreotide), and adiponectin/Acrp30 (Famoxin or Fatty Acid Metabolic OXidation INducer)]); iii) gastrointestinal-neural pathway agents (e.g. agents that increase CCK and PYY activity, agents that increase GLP-I activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitor), agents that decrease ghrelin activity, amylin (pramlinitide), neuropeptide Y agonists); iv) agents that may increase resting metabolic rate (beta-3 agonists, UCP homologues, thyroid receptor agonists); v) other more diverse agents, such as for example including (MCH) melanin concentrating hormone antagonists, phytostanol analogues, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogues of DHEAS (fluasterone), antagonists of adipocyte 1 lbeta-hydroxysteroid dehydrogenase type 1 activity, CRH agonists, carboxypeptidase inhibitors, inhibitors of fatty acid synthesis (cerulenin and C75), indanones/indanols, aminosterols (trodusquemine), and other gastrointestinal lipase inhibitors (ATL962); and vi) Diet, exercise, gastric bypass surgery or laparoscopic adjustable gastric banding.

Drugs effective in obesity treatment may act by various mechanisms such as by: a reduction of food intake (e.g. by inducing satiety or satiety signals), altering metabolism (e.g. by modifying the absorption of nutrients e.g. by inhibition of fat absorption), increasing energy expenditure (e.g. increase thermogenesis), inhibition of lipogenesis or stimulation of adipocyte apoptosis. However, only few drugs are available for obesity treatment (for reviews, see Gadde and Allison, 2006, Circulation, 114, 974-984; Weigle, 2003, J Clin Endocrinol Metab., 88, 2462- 2469; Schioth, 2006, CNS Neurol. Disorders Drug Targets, 5, 241-249), i.e. sibutramine, a centrally acting mixed inhibitor of serotonin and norepinephrine presynaptic re-uptake; orlistat an inhibitor of gastrointestinal lipases which reduces fat absorption in the gut; and rimonabant a centrally and peripherally acting cannabinoid CB 1 modulator (for a review see Pagotto et al, 2006, Endocrine Reviews, 27, 73-100).

Since obesity leads to, or significantly increases the risk of, co-morbidities involving various body systems (see Bays, 2004, Obesity Research, 12, 1197-1211) including: i) cardiovascular (hypertension, congestive cardiomyopathy, varicosities, pulmonary embolism, coronary heart disease [CHD], neurological (stroke, idiopathic intracranial hypertension, meralgia parethetica); ii) respiratory (dyspnea, obstructive sleep apnea, hypoventilation syndrome,

Pickwickian syndrome, asthma); iii) musculoskeletal (immobility, degenerative osteoarthritis, low back pain); iv) skin (striae distensae or "stretch marks," venous stasis of the lower extremities, lymphedema, cellulitis, intertrigo, carbuncles, acanthosis nigricans, skin tags); v) gastrointestinal (gastro-esophageal reflux disorder, non-alcoholic fatty liver/steatohepatitis, cholelithiasis, hernias, colon cancer); vi) genitourinary (stress incontinence, obesity-related glomerulopathy, breast and uterine cancer); vii) psychological (depression and low self-esteem, impaired quality of life); and viii) endocrine (metabolic syndrome, type 2 diabetes, dyslipidemia, hyperandrogenemia in women, polycystic ovarian syndrome, dysmenorrhea, infertility, pregnancy complications, male hypogonadism). it is also useful to combine a GPRl 19 agonist of the invention with medications used for treatment of such diseases. For example, for treating diabetes, compounds of the invention may also be administered in combination with antihypertensive agents, for example beta-blockers and calcium channel blockers, ACE inhibitors, AT-I receptor antagonists, renin inhibitors and endothelin receptor antagonists. Analogously, other agents used for treatment of above mentioned diseases may be combined with GPRl 19 agonists of the invention.

As further examples, GPRl 19 agonist of the invention may also be combined with drugs used for treatment of Type 2 diabetes, e.g. by lowering blood glucose levels by stimulating the release of insulin from the pancreas, or with antidiabetic agents that sensitize the body to the insulin that is already present (e.g. certain biguanides, glitazones or thiazolidinediones), or with peptides increasing insulin production (e.g. amlintide, pramlintide, exendin, and liraglutide), or with DPP-4 inhibitors increasing levels of GLP-I and GIP (e.g. sitagliptin, saxagliptin, alogliptin, denagliptin and vildagliptin); or combined with compounds potentially useful with novel mechanisms such as modulators of G-protein coupled receptors TGR5 (G protein-coupled bile acid receptor 1 (GPBARl)), Y2, Y4, GPR39, GPR40, GPR43, and GPR120, ghrelin receptor antagonists, glucagon receptor antagonists, insulin receptor kinase stimulants (e.g. L-783281), tripeptidyl peptidase Il inhibitors (e.g. UCL-1397), glycogen phosphorylase inhibitors (e.g. NN- 4201and CP-368296), fructose-bisphosphatase inhibitors (e.g. R-132917), pyruvate dehydrogenase inhibitors (e.g. AZD-7545), hepatic gluconeogenesis inhibitors (e.g. FR-225659), aldose reductase inhibitors (e.g. epalrestat, fidarestat, imirestat, lindolrestat, minalrestat, ponalrestat, risarestat, tolrestat, zenarestat, zopolrestat), advanced glycation endproducts formation inhibitors (e.g. pyridoxamine, ALT-946, ALT-711, pimagedine), protein kinase C inhibitors (e.g. LY-333531 and midostaurin), glucagon-like peptide-1 analogues (e.g. exendin-4 and CJC-1131), glucagon-like peptide 1 agonists (e.g. AZM-134 and LY-315902), amylin agonists, and amylin analogues. Another object of the present invention is a method for the treatment or prophylaxis of disorders related to GPRl 19, such as but not limited to, Type 1 and Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, metabolic syndrome, obesity, hypertension, vascular conditions, chronic systemic inflammation, pain, retinopathy, neuropathy, nephropathy, osteoporosis, reduced fibrinolysis, demyelination, nonalcoholic fatty liver disease and endothelial dysfunction. It will be understood that the specific dose level of a compound of the invention for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, as is required in the pharmaceutical art. However, for administration to human patients, the total daily dose of the compounds of the invention may typically be in the range 1 mg to 1000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 10 mg to 1000 mg, while an intravenous dose may only require from 1 mg to 500 mg. The total daily dose may be administered in single or divided doses and may, at the physician' s discretion, fall outside of the typical range given herein.

These dosages are based on an average human subject having a weight of about 60 kg to 100 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly, and especially obese patients.

The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.

There are multiple synthetic strategies for the synthesis of the compounds of formula (I) with which the present invention is concerned, but all rely on known chemistry, known to the synthetic organic chemist. Thus, compounds according to formula (I) can be synthesised according to procedures described in the standard literature and are well-known to the one skilled in the art. Typical literature sources are "Advanced organic chemistry", 4^th Edition (Wiley), J March, "Comprehensive Organic Transformation" , 2^nd Edition (Wiley), R.C. Larock , "Handbook of Heterocyclic Chemistry", 2^nd Edition (Pergamon), A.R. Katritzky), P.G.M. Wuts and T. W. Greene "Greene's Protective Groups in Organic Chemistry" 4^th Edition (Wiley) review articles such as found in "Synthesis", "Ace. Chem. Res." , "Chem. Rev", or primary literature sources identified by standard literature searches online or from secondary sources such as "Chemical Abstracts" or "Beilstein".

General synthetic routes: the routes outlined below do not constitute an exhaustive list. Experimental conditions given are generic and can be found in standard literature sources such as those cited above. Specific references are cited for information and conditions may apply to a given substrate with or without modification/optimization.

The compounds of formula (I) may be obtained by introduction of the -C(=O)A moiety to a corresponding 2-aminothiazole derivative as outlined in Scheme A:

Scheme A

wherein the precursor of the -C(=O)A moiety is generally a carboxylic acid (Y = OH). The carboxylic acids can be in activated forms (e.g. acid chlorides (Y = Cl) or active esters) or alternatively the conversion can be made directly from the acid (Y = OH) using suitable coupling reagents such as dicyclohexylcarbodiimide (DCC), and promoters such as 1- hydroxybenzotriazole (HOBT).

The carboxylic acid can be synthesized according to procedures described in the standard literature e.g. upon hydrolysis of a nitrile, ester or amide moiety in either basic or acidic conditions, or upon conversion of an aromatic halide in presence of carbon monoxide and a suitable metal catalyst (e.g. palladium acetate) and ligand (e.g. 1,3- bis(diphenylphosphino)propane) or upon treatment of an aromatic halide for instance with a strong base (e.g. butyllithium), at low temperature in presence of carbon dioxide.

The 2-aminothiazole derivative can be synthesized according to the procedure outlined in Bioorganic & Medicinal Chemistry Letters (2005), 15(8), 2129-2134 as outlined in Scheme B:

Scheme B

Thus, commercially available 4-(2-oxoethyl)piperidine-l-carboxylic acid tert-butyl ester (B = tert-butoxycarbonyl (BOC) protecting group) can be brominated upon reaction with phenyltrimethylammoniumtribromide. The 2-aminothiazole derivative wherein B = BOC can be synthesized upon treatment of the brominated intermediate with thiourea.

Alternatively, the 2-aminothiazole derivative can be obtained according to the procedure outlined in Scheme C:

Scheme C

Thus, commercially available 2-amino-5-bromothiazole and [l-(tert-butoxycarbonyl)- 1,2,3, 6-tetrahydropyridine-4-yl]boronic acid (B = BOC) can be reacted in presence of suitable metal catalyst and ligand to give the unsaturated intermediate which, upon hydrogenation can lead to the formation of the 2-aminothiazole derivative wherein B = BOC.

The compounds of formula (I) may be obtained by introduction of the B moiety as outlined in Scheme D:

Scheme D

Such a procedure may include for instance the synthesis of compounds of general formula (Ia), (Ib), (Ic) and (Id):

Thus, compounds of formula (Ia) may be obtained by treatment of the unsubstituted piperidine intermediate with e.g. an alkylchloroformate or an alkyldicarbonate, in presence of an organic (e.g. triethylamine) or inorganic base (e.g. cesium carbonate), in polar (e.g. tetrahydrofuran, acetonitrile) or apolar (e.g. dichloromethane) aprotic solvents.

Thus, compounds of formula (Ib) may be obtained by treatment of the unsubstituted piperidine intermediate with a carboxylic acid. The carboxylic acids can be in activated forms (e.g. acid chlorides (Y = Cl) or active esters) or alternatively the conversion can be made directly from the acid (Y = OH) using suitable coupling reagents such as dicyclohexylcarbodiimide (DCC), and promoters such as 1-hydroxybenzotriazole (HOBT).

Compounds of formula (Ib) wherein R₆ = -NR₄R₅ may be synthesized in a two-step procedure by treatment of the unsubstituted piperidine intermediate with a carbonylating agent (e.g. phosgene, trisphosgene, carbonyldiimidazole) followed by reaction with an amine of formula HNR₄R₅, in presence of an organic or inorganic base, in polar or apolar aprotic solvents. Compounds of formula (Ib) wherein R₆ = -NHR₄ may be obtained according to the above procedure. Alternatively, these compounds may be obtained by reacting the unsubstituted piperidine intermediate with an alkylisocyanate, according to well known procedures

Thus, compounds of formula (Ic) may be obtained by treatment of the unsubstituted piperidine intermediate with an alkylsulfonyl chloride, in presence of an organic or inorganic base, in polar or apolar aprotic solvents.

Compounds of formula (Ic) wherein R₆ = -NR₄R₅ may be synthesized in a two-step procedure by treatment of the unsubstituted piperidine intermediate with a sulfonylating agent (e.g. sulfonyl chloride) followed by reaction with an amine of formula HNR₄R₅, in presence of an organic or inorganic base, in polar or apolar aprotic solvents.

Thus, compounds of formula (Id) wherein V is a 5-membered heteroarylene may be obtained by treatment of the unsubstituted piperidine intermediate with a suitable activated heteroaryl moiety. For instance such a moiety may be:

Z = O, N, S X = HaI₁ SMe

The coupling reaction usually takes place in presence of a mild or strong base, in aprotic polar solvent, with or without use of metal-coupling catalyst (e.g. CuI), depending upon the nature of the activated heteroaryl moiety. Alternatively, compounds of formula (Id) may be obtained by in situ formation of the heteroaryl moiety. For instance compounds of formula (Id) wherein V is an oxadiazole may be synthesized synthesized as outlined below:

Thus, the unsubstituted piperidine intermediate may first be reacted with cyanogen bromide to give an intermediate which, upon treatment with a suitable alkylamidoxime, may lead to the formation of an oxadiazole of formula (Id), as described in WO 2005/007647.

The following Examples illustrate the preparation and properties of certain compounds of the invention.

Analysis:

¹H NMR resonances were measured on a Bruker Avance AMX 300 MHz spectrometer and chemical shifts are quoted for selected compounds in parts-per-million (ppm) downfield relative to tetramethylsilane as internal standard. LCMS analysis was obtained under standardised conditions as follows:

Column; Gemini C 18, 5μm, 2.0x50mm. Flow: 1.2 ml/min; Gradient: Acetonitrile in 0.1% aqueous trifluoroacetic acid: 10% - 95% acetonitrile over 3.5 minutes then 95% acetonitrile for 1.0 minute. Instrument: Agilent 1100 HPLC/MSD system, 254 nm UV detection. MS-ionisation mode: API-ES (pos. or neg.).

Data is quoted for all compounds as retention time (RT) and molecular ion (M+H)⁺ or (M-H)^". UPLC/MS was performed on a Waters Acquity- under standardised conditions as follows Column: ACQUITY UPLC BEH C18, 1.7μm, 2.1x50mm. Flow: 0.5 ml/min. Gradient: 0.1-1.0 min: 20-98% acetonitrile in water, 1-1.8 min: 98% acetonitrile. Modifier: 0.1% HCOOH. MS- ionisation mode: API-ES (pos. and neg. ionization)

Preparative HPLC:

This was performed with mass-directed fraction collection under standardised conditions as follows: Column: YMC 19x100 mm; Flow: 20 mL/min. Gradient: 0-8 min: 10-70% MeCN in water, 8-9 min: 70-95% MeCN in water, 9-12 min: 95% MeCN. Modifier: 0.1% TFA; MS-ionisation mode: API-ES (pos.)

Synthesis of intermediates: Formula [All

To 4-(2-oxoethyl)piperidine-l-carboxylic acid tert-butyl ester (2g) in THF (5OmL) at ice bath temperature was added phenyltrimethylammoniumtribromide (3.3Ig) and the reaction stirred 50 min. Water (1OmL) was added and the mixture partially concentrated in vacuo, extracted with DCM (3x 5OmL), dried, filtered and concentrated in vacuo. To the residue was added ethanol (100ml) and thiourea (1.34g) and the reaction mixture heated 2h at 80 degrees, cooled, concentrated in vacuo, dissolved in DCM, washed with sodium hydrogen carbonate, dried and concentrated in vacuo to give the title compound (1.6g). LCMS: RT = 1.3 min API-ES, Pos, 284

Example 1 4-r2-(3-Chloro-2-pyridoylamino)thiazol-5-yll-piperidine-l-earboxylie acid tert-butyl ester

To a mixture of 2-chloropyridine-6-carboxylic acid (28mg) and N-methylmorpholine (41mg) in dichloromethane (ImL) was added isobutylchloroformate (24mg) and the reaction stirred for Ih. Compound [Al] (50mg) was then added and the reaction stirred overnight at room temperature. Concentration under reduced pressure and purification by preparative HPLC to give the title compound.

UPLCMS: RT= 1.36 min M⁺= 423

The Examples shown in Table 1 were prepared using the method described for Example 1. Table 1

Analysis

Compound Name

Compound /-^. Ar UPLC/MS Number

4-[2-(2-Fluoro-4-nitro- benzoylamino)thiazol-5-yl] -

Example 2 RT = 1.29min. [M+H]⁺ =450 piperidine-1-carboxylic acid

tert-butyl ester

4-[2-(4-Cyano- benzoylamino)thiazol-5-yl] - RT = 1.25min. [M+H]⁺

Example 3 piperidine-1-carboxylic acid

=412.1 tert-butyl ester

4-[2-(3-Chloro-4- pyridoylamino)thiazol-5 -yl] - RT = 1.26min. [M+H]⁺

Example 4 piperidine-1-carboxylic acid =423.1 tert-butyl ester

4-[2-(2-Nitro-4-chloro- benzoylamino)thiazol-5-yl] - RT = 1.29min. [M+H]⁺

Example 5 piperidine-1-carboxylic acid =467.0

tert-butyl ester

4-[2-(4-Acetamido- benzoylamino)thiazol-5-yl] - RT = 1.12min. [M+H]⁺

Example 6 piperidine-1-carboxylic acid

=445.1 tert-butyl ester

4-[2-(4-Methanesulfonyl- benzoylamino)thiazol-5-yl] - RT = 1.15min. [M+H]⁺

Example 7 piperidine-1-carboxylic acid

=466.1 tert-butyl ester

Example 19

4-[2-(4-Methanesulfonylbenzoylamino)thiazol-5-vnpiperidine-l-carboxylic acid isopropyl ester

To a solution of 4-[2-(4-methanesulfonylbenzoylamino)thiazol-5-yl]piperidine-l- carboxylic acid tert-butyl ester (180mg) in THF (2mL) was added HCl (6mL of IM in ether) and the mixture stirred overnight at room temp and concentrated in vacuo. To this residue was added DCM (3mL), triethylamine (0.2mL) and isopropylchloroformate (0.2mL of a IM solution in toluene) and the mixture stirred for 50min. Sodium hydroxide (few drops of 4N aqueous solution) was added and the mixture stirred for 2h, neutralized with dil HCl, concentrated in vacuo and purified by flash chromatography (eluant heptane/ethyl acetate) to give the title compound (2.8mg) UPLCMS RT = 1.15min. [M+H]⁺ =442.1

Biological data

Compounds were tested in the functional GPRl 19 assay described below, and their EC₅₀ values for activating the GPRl 19 receptor were assessed. The compounds are grouped in three classes:

A: EC₅₀ value lower than 0.5 μM B: EC₅₀ value between 0.5 μM and 5 μM C: EC₅₀ value higher than 5 μM

Table 2 shows results for compounds of the invention, synthesized as above.

Table 2 - Compounds of general formula (I)

Biological Evaluation Method

Transfection and Cell Culture - The cDNA (GenBank accession number: AY288416) encoding the human GPRl 19 receptor (synonyms: GDIR, RUP3, SNORF25, ATRA receptor, GPR2, GPCR2, 19AJ, SMT3, OSGPRl 16) was cloned from a human pancreas cDNA library (Clontech BD-biosciences, 7410-1) and cloned into the inducible expression vector pcDNA™4/TO (Invitrogen), which is a tetracycline-regulated expression system for mammalian cells. Chinese Hamster Ovary cells (CHO-T-Rex) stably expressing recombinant human

GPRl 19 were generated by transfecting the plasmid containing the coding sequence of the human GPRl 19 receptor N-terminally flagged with Ml (Met-Lys-Thr-Ile-Ile-Ala-Leu-Ser-Tyr-Ile-Phe- Cys-Leu-Val-Phe-Ala-Asp-Tyr-Lys-Asp-Asp- Asp-Asp), using lipofectamin™ 2000 reagent, according to the manufacturer instructions. Resistant clones were selected in the presence of 100 μg/ml Zeocin and 5 μg/ml Blasticidin S HCl (Invitrogen). Stably transfected CHO-T-Rex cells were maintained in Ham's F- 12 culture medium (Invitrogen), supplemented with 10 % fetal calf serum (Invitrogen), 100 U/ml penicillin, 100 μg/ml streptomycin (Life Technology), 100 μg/ml Zeocin, and 5 μg/ml Blasticidin S HCl and incubated at 37°C in a humidified atmosphere 5% (v/v) CO₂ in air. GPR119-CHO-T-Rex cells were incused with 0.01 μg/ml tetracycline for 24 hrs after which the cells were frozen following a standard freezing procedure. Frozen cells were thawed one day prior day of assay and recovered in culture for 24hrs.

GPR119 receptor functional assay; ALPHAscreen cAMP assay The ALPHAscreen technology has thoroughly been described in "PerkinElmer ALPHAscreen cAMP assay Kit manual". Briefly, the production of intracellular cAMP will generate a competition between unlabeled cAMP and exogenously added biotinylated cAMP for anti-cAMP antibodies conjugated to a bead (Acceptor bead). A streptavidin coated Donor bead will recognize the biotinylated cAMP bead complex forming a stable unit where the two beads are brought into close proximity. Upon laser excitation at 680 nm, a photosensitizer in the Donor bead converts ambient triplet oxygen to the more excited singlet state. This step is responsible for very high signal amplification. If the beads are in close proximity, energy will be trans-located to the acceptor bead and a cascade of chemical reactions will finally lead to emission of fluorescent light at 520-620 nm. Assay conditions were slightly changed from the standard PerkinElmer procedure. All buffers were as per manufacture instructions (including 0.5 mM IBMX final concentration). The assay was performed in 384-well microplates (OptiPlate-384, PerkinElmer). 0.5 μl of test compound (DMSO solution, 2% final DMSO concentration) were added to empty wells and stored until day of assay. One the day of assay 25 μl of cells (15.000 cells/well) was added and incubated for 60 min. Before addition of beads, the biotinylated cAMP (1 units/well) was pre-incubated with donor beads (1 units/well) for 30 min. 5 μl of acceptor beads (1 units/well) was added followed by 5 μl of the donor bead/bio tinylated cAMP suspension after 10 min of incubation. The plates were read on a Fusion plate reader after three hours of incubation. In parallel with compound screening on the GPRl 19 receptor all compounds were counter screened on the GLPl receptor using the cAMP ALPHAscreen technology to eliminate pathway selective, promiscuous or signaling quenching compounds. Data analysis

Column 1, 2, 23 and 24 on each 384-well plate were dedicated for controls; 32 wells were added a saturating concentration of a GPRl 19 agonist (maximum response) and 32 wells were added DMSO (background). The average of each set of controls was used to define the top and bottom of a full agonist and was used to calculate the efficacy in % of each agonist concentration response curve tested. Moreover, two control agonist concentration response curves were tested on each assay plate.

Claims

CLAIMS:

1. A compound of formula (I) or a salt, hydrate, solvate or N-oxide thereof:

(I) wherein: ring A is phenyl or pyridyl;

R₁ is hydrogen, -CN, -F, -Cl, -Br, -NO₂, -OR₃, -NR₇COR₆, -NR₇S(O)₂R₆, -COR₆, -SR₃, -S(O)R₃, -CH₂S(O)₂R₃, CH₂SO₂NR₄R₅, -S(O)₂R₃, -SO₂NR₄R₅, C₁-C₄ alkyl, fully or partially fluorinated C₁-C₄ alkyl, C₃-C₅ cycloalkyl, or 5-membered heteroaryl;

R₂ is hydrogen, -CN, -F, -Cl, or -OR₃;

R₈ is hydrogen or -F; provided that R₁, R₂ and R₈ are not simultaneously hydrogen;

R₃ is C₁-C₄ alkyl, C₃-C₅ cycloalkyl, or fully or partially fluorinated C₁-C₄ alkyl;

R₆ is C₁-C₄ alkyl, C₃-C₅ cycloalkyl, or -NR₄R₅;

R₄ and R₅ are independently hydrogen, C₁-C₄ alkyl or C₃-C₅ cycloalkyl, or taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring;

R₇ is hydrogen, C₁-C₄ alkyl, or C₃-C₅ cycloalkyl;

B is -CO₂R₃, -COR₆, -S(O)₂R₃, or -V-R₇; and

V is a divalent 5-membered heteroarylene radical.

2. A compound according to claim 1 wherein ring A is phenyl.

3. A compound according to claim 1 or claim 2 wherein R₁ is not hydrogen and is in para position of ring A relative to the carboxamide bond.

4. A compound according to any of the preceding claims wherein R₁ is selected from -S(O)₂R₃ -SO₂NR₄R_5, -CH₂S(O)₂R_3, CH₂SO₂NR₄R₅, -COR_6, -NR₇COR_6, or 5-membered heteroaryl, R₃, R₄, R₅, R₆ and R₇ being as defined in claim 1.

5. A compound according to any of the preceding claims wherein R₈ is not hydrogen and is in an ortho position of ring A relative to the carboxamide bond.

6. A compound according to any of the preceding claims wherein B is -CO₂R₃ or -V-R₇, R₃,

R₇ and V being as defined in claim 1.

7. A compound according to any of the above claims wherein Ri is selected from -S(O)₂Rs_, or 5-membered heteroaryl, R₃ being as defined in claim 1

8. A compound according to claim 1, selected from: 4-[2-(4-Methanesulfonylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid tert- butyl ester;

4-[2-(2-Fluoro-4-methanesulfonylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid tert-butyl ester;

4-[2-(2,6-Difluoro-4-methanesulfonylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid tert-butyl ester;

4-{2-[(3-Fluoro-5-methanesulfonylpyridine-2-carbonyl)amino]thiazol-5-yl}piperidine-l- carboxylic acid tert-butyl ester;

4-[2-(4-Methanesulfonylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid isopropyl ester; 4-[2-(2-Fluoro-4-methanesulfonylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid isopropyl ester;

4-[2-(2,6-Difluoro-4-methanesulfonylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid isopropyl ester;

4-{2-[(3-Fluoro-5-methanesulfonylpyridine-2-carbonyl)amino]thiazol-5-yl}-piperidine-l- carboxylic acid isopropyl ester;

N-{5-[l-(5-Isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-yl]thiazol-2-yl}-4- methanesulf onyl-benzamide ;

2-Fluoro-N-{5-[l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-yl]thiazol-2-yl}-4- methanesulf onylbenzamide ; 2,6-Difluoro-N-{5-[l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-yl]thiazol-2-yl}-4- methanesulf onylbenzamide ;

3-Fluoro-5-methanesulfonylpyridine-2 -carboxylic acid {5-[l-(5-isopropyl- [l,2,4]oxadiazol-3-yl)piperidin-4-yl]thiazol-2-yl}amide;

N-{5-[l-(5-Isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-yl]thiazol-2-yl}-4-[l,2,4]triazol- 1-ylbenzamide;

2-Fluoro-N-{5-[l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-yl]thiazol-2-yl}-4- [l,2,4]triazol-l-ylbenzamide;

2,6-Difluoro-N-{5-[l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-yl]thiazol-2-yl}-4- [l,2,4]triazol-l-ylbenzamide; N-{5-[l-(5-Isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-yl]thiazol-2-yl}-6-[l,2,4]triazol-

1-ylnicotinamide;

4-[2-(4-[l,2,4]Triazol-l-yl-benzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid isopropyl ester;

4-[2-(2-Fluoro-4-[l,2,4]triazol-l-ylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid isopropyl ester; 4-[2-(2,6-Difluoro-4-[l,2,4]triazol-l-ylbenzoylarrrino)thiazol-5-yl]piperidine-l- carboxylic acid isopropyl ester;

4-{2-[(6-[l,2,4]Triazol-l-ylpyridine-3-carbonyl)amino]thiazol-5-yl}piperidine-l- carboxylic acid isopropyl ester; 4-[2-(4-[l,2,4]Triazol-l-ylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid tert- butyl ester;

4-[2-(2-Fluoro-4-[l,2,4]triazol-l-ylbenzoylamino)thiazol-5-yl]piperidine-l-carboxylic acid tert-butyl ester;

4-[2-(2,6-Difluoro-4-[l,2,4]triazol-l-ylbenzoylamino)thiazol-5-yl]piperidine-l- carboxylic acid tert-butyl ester, and

4-{2-[(6-[l,2,4]Triazol-l-yl-pyridine-3-carbonyl)amino]thiazol-5-yl}piperidine-l- carboxylic acid tert-butyl ester, and pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising a compound according to any of the preceding claims, together with one or more pharmaceutically acceptable carriers or excipients.

10. The use of a compound as claimed in any of claims 1 to 9 for the treatment or prophylaxis of diseases or conditions responsive to stimulation of the GPRl 19 receptor.

11. A method of treatment or prophylaxis of diseases or conditions responsive to stimulation of the GPRl 19 receptor, comprising administering to a subject in need of such treatment or prophylaxis an effective amount of a compound as claimed in any of claims 1 to 9.

12. The use as claimed in claim 10, or a method as claimed in claim 11, wherein the disease or condition is diabetes, obesity, metabolic syndrome, glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, atherosclerosis, a vascular condition, osteoporosis, pain, demyelination, or nonalcoholic fatty liver disease.