HK1164281B - Benzofuranyl derivatives used as glucokinase activators - Google Patents

Description

Benzofuranyl derivatives as glucokinase activators

Technical Field

The present invention relates to substituted benzofuranyl derivatives, to pharmaceutical compositions thereof and to the use thereof as glucokinase activators.

Background

Diabetes is a major public health problem due to its increased prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates, resulting in the failure to maintain adequate blood glucose levels. Two major types of diabetes are recognized. Type I diabetes, or Insulin Dependent Diabetes Mellitus (IDDM), is the result of an absolute deficiency of insulin. Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), typically occurs with normal or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to respond appropriately to insulin. It is necessary to use drugs to aggressively control NIDDM that otherwise develops into IDDM.

As blood glucose increases, it is transported into pancreatic beta cells via glucose transporters. Glucose increases are sensed by Glucokinase (GK) in mammalian cells and activate cellular glycolysis (i.e., conversion of glucose to glucose-6-phosphate) and subsequent insulin release. Glucokinase is found primarily in pancreatic beta-cells and hepatic parenchymal cells. Since the transfer of glucose from the blood to muscle and adipose tissue is insulin dependent, diabetic patients lack the ability to utilize glucose to its fullest extent, resulting in an undesirable accumulation of blood glucose (hyperglycemia). Chronic hyperglycemia results in decreased insulin secretion and contributes to increased insulin resistance. Glucokinase also acts as a sensor in liver parenchymal cells, which induces glycogen synthesis, thereby preventing the release of glucose into the blood. Therefore, the GK process is important for maintaining glucose homeostasis throughout the body.

It is expected that an agent that activates cellular GK will promote glucose-dependent secretion from pancreatic beta cells, correct postprandial hyperglycemia, increase hepatic glucose utilization, and potentially inhibit hepatic glucose release. Thus, GK activators may provide a therapeutic treatment for NIDDM and related complications, especially hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity.

Several drugs of five major classes, each acting by a different mechanism, can be used to treat hyperglycemia and subsequent NIDDM (Moller, D.E., "New drug targets for Type 2 diabetes and the metabolic syndrome" Nature 414; 821-827, (2001)): (A) insulin secretagogues, including sulfonylureas (e.g., glipizide, glimepiride, glyburide) and meglitinides (e.g., nateglinide and repaglinide), act on pancreatic β cells to increase insulin secretion. While this therapy can reduce blood glucose levels, it has limited efficacy and tolerability, leads to weight gain and often induces hypoglycemia. (B) Biguanides, such as metformin (metformin), are thought to act primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, which further limits their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) reduce intestinal glucose absorption. These agents often cause gastrointestinal disorders. (D) Thiazolidinediones such as pioglitazone (pioglitazone) and rosiglitazone (rosiglitazone) act on specific receptors in the liver, muscle and adipose tissue (receptor- γ is activated via an oxide proliferator). They regulate lipid metabolism and then enhance the response of these tissues to the action of insulin. Frequent use of these drugs results in weight gain and can induce edema and anemia. (E) Insulin is used alone or in combination with the above agents in more severe cases.

Ideally, an effective novel therapy for NIDDM should meet the following criteria: (a) it does not cause significant side effects, including induction of hypoglycemia; (b) it does not cause weight gain; (c) it will at least partially replace insulin by acting in a mechanism independent of the action of insulin; (d) it is desirable to have metabolic stability to reduce frequency of use; and (e) it may be used in combination with a tolerable amount of any of the classes of drugs listed herein.

Substituted heteroaryl groups (especially pyridones) have been used to modulate GK and may play an important role in the treatment of NIDDM. For example, U.S. patent publication No. 2006/0058353 and PCT publications No. WO2007/043638, WO2007/043638, WO2007/117995 describe certain heterocyclic derivatives having utility in the treatment of diabetes. Despite ongoing research, there remains a need for more effective and safe therapeutic treatments for diabetes, particularly NIDDM.

Disclosure of Invention

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as a glucokinase mediator, in particular a glucokinase activator; and thus can be used to treat diseases mediated by such activation, such as those associated with type 2 diabetes, and diabetes-related and obesity-related co-disorders (co-morbidentides),

wherein Y is N and Z is C, or Y is C and Z is N; r¹And R²Each independently is methyl or ethyl; and R is³Is 5-firstPyrazinyl-2-yl, 5-methoxypyrazin-2-yl, or 1-methyl-1H-pyrazol-3-yl.

In a preferred embodiment, Y is N and Z is C.

In another preferred embodiment, Y is C and Z is N.

Preferred compounds of formula (1) are those wherein R is¹And R²Are all methyl, and R³A compound that is 5-methylpyrazin-2-yl; or a pharmaceutically acceptable salt thereof.

One preferred compound is N, N-dimethyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl-benzofuran-4-yloxy) pyrazine-2-carboxamide.

Another preferred compound is N, N-dimethyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) -benzofuran-4-yloxy) pyrimidine-2-carboxamide.

Another aspect of the present invention is a pharmaceutical composition comprising (1) a compound of the present invention; and (2) a pharmaceutically acceptable excipient, diluent, or carrier. The compositions preferably comprise a therapeutically effective amount of a compound of the present invention. The composition may also include at least one other agent (described herein). Preferred agents include antiobesity agents and/or antidiabetics (described below).

Yet another aspect of the present invention is a method of treating a disease, condition, or disorder mediated by glucokinase, particularly the activation of the enzyme, in a mammal, comprising the step of administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof.

Diseases, disorders, or conditions mediated by glucokinase activators include: type II diabetes, hyperglycemia, metabolic syndrome, impaired glucose tolerance, diabetes, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and insulin resistance syndrome. Preferred diseases, disorders or conditions include type II diabetes, hyperglycemia, impaired glucose tolerance, obesity, and insulin resistance syndrome. Type II diabetes, hyperglycemia and obesity are more preferable. Most preferred is type II diabetes.

Yet another aspect of the present invention is a method of lowering blood glucose levels in a mammal, preferably a human, comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof.

The compounds of the present invention may be administered in combination with other agents, in particular, the anti-obesity agents and anti-diabetic agents described below. The combination therapy may be administered in the following manner: (a) a single pharmaceutical composition comprising a compound of the invention, at least one other agent described herein, and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical compositions may be administered simultaneously or sequentially and in any order.

Definition of

As used herein, the term "alkyl" refers to a group of formula C_nH_2n+1A hydrocarbon group of (1). The alkyl group may be straight or branched. For example, the term "(C)₁-C₆) Alkyl "refers to a monovalent straight or branched chain aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3-dimethylpropyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, acyl (alkanoyl), alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. When "optionally substituted" is indicated, theThe alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents independently selected from the substituents listed in the definition of "substituted" below (typically 1 to 3 substituents except in the case of halogen substituents such as perchloro or perfluoroalkyl). "halogen-substituted alkyl" refers to alkyl substituted with one or more halogen atoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1-difluoroethyl, and the like).

The term "cycloalkyl" refers to a non-aromatic ring that is fully hydrogenated and may exist as a single ring, bicyclic ring, or helical ring. Unless otherwise indicated, the carbocycle is typically a 3-to 8-membered ring. For example, cycloalkyl groups include the following groups, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, norbornyl (norbonyl), (bicyclo [2.2.1] heptyl), bicyclo [2.2.2 ] octyl, and the like.

The term "heterocycle" refers to a non-aromatic ring that is fully hydrogenated and may exist as a monocyclic, bicyclic, or helical ring. Unless otherwise indicated, the heterocyclic ring is typically a 3-to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Heterocycles include groups such as: epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholino, thiomorpholino, tetrahydrothienyl 1, 1-dioxide, and the like.

The phrase "therapeutically effective amount" means that the compound of the present invention (i) treats or prevents the particular disease, condition, or disorder; (ii) alleviating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder; or (iii) an amount that prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

The term "animal" refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-derived animals, zoo animals, marine animals, birds and other similar animal species. "edible animal" refers to an animal of food origin, such as: cows, pigs, sheep and poultry.

The phrase "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.

The term "treatment" includes prophylactic (i.e., prevention of disease) and palliative treatment.

The term "modulation" as used herein, unless otherwise indicated, refers to the activation of glucokinase by the compounds of the present invention.

As used herein, unless otherwise indicated, the term "mediate" refers to the inhibition of glucokinase regulatory protein (a key regulator of glucokinase activity in the liver) by activating glucokinase (by enhancing glucose binding), by attenuating the inhibitory effect of glucokinase regulatory protein, and/or by increasing the catalytic rate of glucokinase (e.g., by altering V)_max) To (i) treat or prevent a particular disease, condition, or disorder, (ii) alleviate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

The term "compound of the invention" (unless otherwise specifically indicated) refers to compounds of formula (I) and any pharmaceutically acceptable salts of the compounds, as well as all stereoisomers (including diastereomers and enantiomers), tautomers, conformational isomers, and isotopically labeled compounds. Hydrates and solvates of the compounds of the invention, wherein the compound is associated with water or a solvent, respectively, are contemplated compositions of the invention.

Detailed Description

The compounds of the invention can be synthesized by synthetic routes including methods analogous to those well known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.), or are readily prepared by methods well known to those skilled in the art (such as by the methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967 1999), or Beilsteins Handbuch der organischen Chemie, 4, autofl. ed. Springer-Verlag, Bein, including suppl (also available from Beilstein on-line databases)).

For purposes of illustration, the following reaction schemes provide possible routes to the synthesis of the compounds of the present invention and key intermediates. For a more detailed description of the individual reaction steps, see the examples section below. Those skilled in the art will understand that: other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reactants are described in the schemes below and discussed below, other starting materials and reactants can be readily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds made by the methods described below can be further modified in light of this disclosure using conventional chemistry known to those skilled in the art.

In the preparation of the compounds of the present invention, it may be necessary to protect remote functional groups (e.g., primary or secondary amines) of intermediates. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation process. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-Butyloxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy protecting groups (O-Pg) include, for example, allyl, acetyl, silyl, benzyl, p-methoxybenzyl, trityl, and the like. The need for such protection can be readily determined by one skilled in the art. For a general description of protecting Groups and their use, see t.w. greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.

Scheme 1 outlines the general procedures that can be used to provide the compounds of the invention having formula (I).

Scheme 1

Diethyl succinate may be condensed with 5-methyl-2-furfural to form intermediate (Ia) using conventional aldol condensation reaction conditions. For example, the two starting materials can be treated with a strong base and heat (e.g., a refluxing ethanol solution containing sodium ethoxide) and then acidified. The benzofuran ring in intermediate (1b) may be formed by treating intermediate (1a) with acetic anhydride and sodium acetate at about room temperature, followed by heating to reflux. The acetate group is then removed to provide the hydroxy intermediate (1c), followed by addition of the desired pyrazinylamide or pyrimidinyl amide via the free hydroxy group to form intermediate (1 d). Intermediate (1d) may then be reacted with the desired amine (R) by standard amidation reaction conditions known to those skilled in the art³NH₂) The reaction forms the compound of formula (I). The following examples describe the above reaction conditions in more detail.

The compounds of the invention may be isolated or used directly, or as pharmaceutically acceptable salts thereof where possible. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed. Examples of salts include: hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, benzenesulfonate, palmitate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, hexafluorophosphate, benzenesulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthenate, methanesulfonate, glucoheptonate, lactobionate, and laurylsulfonate, and the like. These may include cations based on alkali and alkaline earth metals (e.g., sodium, lithium, potassium, calcium, magnesium, and the like), as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, Berge et al, J.pharm.Sci., 66, 1-19 (1977).

The compounds of the present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention and mixtures thereof (including racemic mixtures) are intended to form part of the present invention. In addition, the present invention includes all geometric and positional isomers. For example, if the compounds of the present invention incorporate double bonds or fused rings, both cis and trans forms, and mixtures are contemplated within the scope of the present invention.

Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physical-chemical differences by methods well known to those skilled in the art (e.g., chromatography and/or fractional crystallization). Enantiomers can be separated by the following steps: enantiomeric mixtures are converted into diastereomeric mixtures by reaction with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or masher's acid chloride), the diastereomers are separated and the individual diastereomers are converted (e.g., hydrolyzed) into the corresponding pure enantiomers. Certain compounds of the invention may also be atropisomers (e.g., substituted biaryls) and are considered a part of this invention. Enantiomers can also be separated by chiral HPLC columns. Alternatively, a particular stereoisomer may be synthesized by using optically active starting materials, by asymmetric synthesis using optically active reactants, substrates, mediators or solvents, or by converting one stereoisomer into another stereoisomer through asymmetric transformations.

The intermediates and compounds of the invention may also exist in different tautomeric forms, and all such forms are contemplated to be within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversion by proton migration, such as keto-enol and imine-enamine isomerizations. A particular example of a proton tautomer is an imidazole moiety, wherein a proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of certain bonding electrons.

Certain compounds of the invention may exist in different stable conformational forms that may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond (e.g., due to steric hindrance or ring-to-ring tension) can separate different conformers.

The invention also includes isotopically-labelled compounds of the invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example each²H、³H、 ¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、 ¹²⁵I and³⁶Cl。

certain isotopically-labelled compounds of the present invention (e.g. with³H and¹⁴c-labeled ones) can be used in compound and/or substrate tissue distribution assays. For its ease and detectability of preparation, by tritiation (i.e.³H) And carbon-14 (i.e.¹⁴C) The isotope is most preferred. In addition, with heavier isotopes such as deuterium (i.e., deuterium²H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and may therefore be preferred in certain circumstances. Positron emitting isotopes (e.g. of the type¹⁵O、¹³N、¹¹C. And¹⁸F) can be used in Positron Emission Tomography (PET) studies to detect substrate occupancy. AIsotopically labeled compounds of the present invention can generally be prepared by following steps analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reactant for a non-isotopically labeled reactant.

Certain compounds of the present invention may exist in more than one crystalline form (commonly referred to as "polymorphs"). Polymorphs can be prepared by crystallization under various conditions, for example, recrystallization using different solvents or mixtures of different solvents; crystallization at different temperatures; and/or cooling in various ways from very fast to very slow during crystallization. Polymorphs can also be obtained by heating or melting the compounds of the present invention followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, X-ray powder diffraction or such other techniques.

The compounds of the present invention are useful in the treatment of diseases, conditions and/or disorders modulated by the activation of glucokinase; accordingly, another embodiment of the present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier. The compounds of the invention (including the compositions and methods used herein) may also be used in the manufacture of medicaments for the therapeutic applications described herein.

Typical formulations are prepared by mixing a compound of the invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as: carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient employed will depend upon the method and purpose for which the compounds of the present invention are to be employed. The solvent is generally selected based on a solvent (GRAS) that one of skill in the art would consider safe for administration to a mammal. Generally, a safe solvent is a non-toxic aqueous solvent (e.g., water and other non-toxic solvents) that is soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulation may also contain one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents and other known additives that impart a good appearance to the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacture of the drug product (i.e., medicament).

The formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug, i.e., a compound of the invention or a stable form of the compound (e.g., a complex with a cyclodextrin or other known complexing agent), is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the invention are typically formulated into pharmaceutical dosage forms to facilitate control of the dosage of the drug and to provide a good and easy to handle product for the patient.

Pharmaceutical compositions also include solvates and hydrates of the compounds of formula (I). The term "solvate" refers to a molecular complex of a compound represented by formula (I), including pharmaceutically acceptable salts thereof, with one or more solvent molecules. Such solvent molecules are those commonly used in pharmaceutical technology and known to be non-toxic to recipients, such as: water, ethanol, ethylene glycol, and the like. The term "hydrate" refers to a complex in which the solvent molecule is water. Such solvates and/or hydrates are preferably present in crystalline form. In making the more desirable solvates, other solvents may be used as intermediate solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S) -propylene glycol, (R) -propylene glycol, 1, 4-butyne-diol, and the like.

The pharmaceutical composition (or formulation) to be applied may be packaged in various ways, depending on the method used for administering the drug. Generally, articles of manufacture for dispensing (articles) include a container in which a pharmaceutical formulation in a suitable form is deposited. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include tamper-proof fittings to prevent inadvertent access to the contents of the package. In addition, the container has been coated with a label describing the contents of the container. The label may also include appropriate warnings.

The present invention further provides a method of treating a disease, condition, and/or disorder modulated by the activation of glucokinase in an animal comprising administering to an animal in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier. The methods are particularly useful for treating diseases, conditions and/or disorders that benefit from activation of glucokinase, including: eating disorders (such as binge eating, anorexia, bulimia, weight loss or control, and obesity), prevention of obesity and insulin resistance by glucokinase expression in skeletal muscle of transgenic mice (Otaegui, P.J., et al, The FASEB Journal, 17; 2097-; and type II diabetes, insulin resistance syndrome, insulin resistance, and hyperglycemia (Poitout, V et al, "An integrated view of beta-cell dysfunction in type-II diabetes," Annu. Rev. medicine, 47; 69-83, (1996)).

One aspect of the present invention relates to the treatment of obesity and obesity-related disorders, such as overweight, weight gain, or weight maintenance.

Obesity and overweight are generally defined by Body Mass Index (BMI), which is associated with overall fat and assesses the relative risk of disease. BMI is calculated as weight (in kilograms) divided by height (in square meters) (kg/m)²). Overweight is generally defined as 25 to 29.9kg/m²And obesity is generally defined as 30kg/m²The BMI of (1). See, for example, National Heart, Lung, and Blood Institute, Clinical Guidelines on The Identification, Evaluation, and Treatment of upside and inside additives, The Evaluation Report, Washington, DC: U.S. department of Health and Human Service, NIH publication No.98-4083 (1998).

Another aspect of the invention relates to the treatment or delay of progression or onset of diabetes or diabetes-related disorders, including type 1 (insulin-dependent diabetes, also known as "IDDM") and type 2 (non-insulin-dependent diabetes, also known as "NIDDM") diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, and diabetic complications (such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy).

Yet another aspect of the invention relates to the treatment of diabetes or obesity-related co-disorders, such as metabolic syndrome. Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin resistance, diabetes (e.g., type 2 diabetes), weight gain, coronary artery disease, and heart failure. For more detailed information on Metabolic Syndrome, see, for example, Zimmet, p.z. et al, "The Metabolic Syndrome: perhaps an Iologic Mystery but Far From a Myth-Where tools the International Diabetes Federation station? "Diabetes & Endocrinology, 7(2), (2005); and Alberti, K.G. et al, "The Metabolic Syndrome-A New Worldwide Definition," Lancet, 366, 1059-62 (2005). Preferably, administration of a compound of the invention reduces at least one risk factor for cardiovascular disease, such as lowering plasma leptin, C-reactive protein (CRP), and/or cholesterol, statistically significantly (p < 0.05) compared to vehicle control without drug. Administration of the compounds of the invention also reduced glucose serum levels statistically significantly (p < 0.05).

In yet another aspect of the invention, the condition being treated is impaired glucose tolerance, hyperglycemia, diabetic complications (such as diabetic cataract, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy), anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, non-alcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, pulmonary cancer, diabetes mellitus, diabetic complications of diabetes (such as diabetic cataract, diabetic neuropathy, diabetic retinopathy and diabetic cardiomyopathy), hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive, Colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer, and ovarian cancer.

The present invention also relates to a therapeutic method for the treatment of the above-mentioned conditions in mammals, including humans, wherein a compound of formula (I) of the present invention is administered as part of a suitable dosage regimen designed to achieve a therapeutic benefit. The appropriate dosage regimen, the dosage of each administration and the interval between administrations of the compound will depend upon the compound of formula (I) of the invention used, the type of pharmaceutical composition used, the nature of the subject being treated and the severity of the condition.

In general, an effective dose of a compound of the invention is between 0.01 mg/kg/day and 30 mg/kg/day, preferably between 0.01 mg/kg/day and 5 mg/kg/day of the active compound (in single or divided doses). However, some variability in the general dosage range may be required depending on: the age and weight of the subject being treated, the intended route of administration, the particular compound being administered, and the like. Determination of dosage ranges and optimal dosages for a particular patient will be apparent to those skilled in the art having the benefit of this disclosure. The practitioner will understand that "kg" refers to the weight of the patient measured in kilograms.

The compounds or compositions of the present invention may be administered in single (e.g., once daily) or multiple doses or via constant infusion. The compounds of the present invention may also be administered in single or multiple doses, either alone or in combination with a pharmaceutically acceptable carrier, vehicle or diluent. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

The compounds or compositions of the present invention can be administered to a patient in need of treatment by a variety of conventional routes of administration, including orally and parenterally (e.g., intravenously, subcutaneously, or intramedullary). In addition, the pharmaceutical compositions of the present invention may be administered as suppositories intranasally or using "quick-acting" formulations (i.e., allowing the agent to dissolve in the mouth without the use of water).

It should also be noted that the compounds of the present invention may be used in the form of sustained release, controlled release, and delayed release formulations, which are also well known to those skilled in the art.

The compounds of the present invention may also be used in combination with other agents in the treatment of the diseases, conditions and/or disorders described herein. Accordingly, methods of treatment comprising administering the compounds of the invention in combination with other agents are also provided. Suitable agents that may be used in combination with the compounds of the present invention include antiobesity agents (including anorectic agents), antidiabetic agents, antihyperglycemic agents, lipid lowering agents, and antihypertensive agents.

Suitable antidiabetic agents include acetyl-CoA carboxylase-2 (ACC-2) inhibitors, diacylglycerol O-acyltransferase 1(DGAT-1) inhibitors, Phosphodiesterase (PDE) -10 inhibitors, sulfonylureas (e.g., acetohexamide, chlorpropamide, trycrine (diabnese), glibenclamide (gliclamide), glipizide (glibenclamide), glibenclamide (glyburide), glimepiride (glimepiride), gliclazide (gliclazide), glimepiride (gliclazide), gliquidone (gliquidone), glisoxymide (glisolamide), tolazamide (tolazamide), and tolbutamide (tolbutamide), meglitinide (meglitinide), alpha-amylase inhibitors (e.g., amylastatin), palmatin (palmatin), and AL-3688), alpha-glucosidase inhibitors (e.g., alpha-glucosidase inhibitors (liposidase), such as liposidase (liposidase), Caplastose (capigibose), emiglitate (emiglitate), miglitol (miglitol), voglibose (voglibose), pradimicin-Q (pradimicin-Q), and sapelostatin (salstatin)), PPAR_γAgonists (e.g. balaglitazone (balaglitazone), ciglitazone (ciglitazone), darglitazone (darglitazone), englitazone (englitazone), islandinone (isaglitazone), pioglitazoneGlitazone (pioglitazone), rosiglitazone (rosiglitazone) and troglitazone (troglitazone)), PPAR_α/γAgonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), biguanides (e.g., metformin), glucagon-like peptide-1 (GLP-1) agonists (e.g., exendin-3 and exendin-4 (exendin-4)), protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., quinuclidine (rodussamine), cetueraldehyde (hyrbiosal) extract, and compounds disclosed by Zhang, S. et al, Drug Discovery Today, 12(9/10), 373 381 (2007)), SIRT-1 inhibitors (e.g., resveratrol), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin), Vildagliptin (vildagliptin), alogliptin (alogliptin) and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, a2 antagonists, c-jun amino terminal kinase (JNK) inhibitors, insulin mimetics, glycogen phosphorylase inhibitors, and VPAC2 receptor agonists. Preferred antidiabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin).

Suitable antiobesity agents include 11 beta-hydroxysteroid dehydrogenase-1 (11 beta-HSD type 1) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetics, beta₃Adrenergic agonists, dopamine agonists (e.g., bromocriptine), melanocyte stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (e.g., tetrahydronepastatin, orlistat), anorectic drugs (e.g., bombesin agonists), neuropeptide-Y antagonists (e.g., NPY 5 antagonists), PYY_3-36(including analogs thereof), thyromimetics, dehydroepiandrosterone or analogs thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (e.g., as available from Regeneron Pharmaceuticals,inc., Tarrytown, NY and Procter&Axokine from Gamble Company, Cincinnati, OH^TM) Human agouti-related protein (AGRP) inhibitors, ghrelin antagonists, histamine 3 antagonists or inverse agonists, neuregulin U agonists, MTP/ApoB inhibitors (such as viscerselective MTP inhibitors, e.g., desloratadine), opioid antagonists, orexin antagonists, and the like.

Preferred anti-obesity agents suitable for use in the combination aspect of the invention include gut-selective MTP inhibitors (e.g. desloratadine, mitratapide and implitapide), R56918(CAS No. 403987 and CAS No. 913541-47-6), CCKa agonists (e.g. N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl-4, 5-dihydro-2, 3, 6, 10 b-tetraaza-benzo [ e ] e as described in PCT publication No. WO2005/116034 or US publication No. 2005-0267100A 1)]Azulen-6-yl]-N-isopropyl-acetamide), 5HT2c agonists (such as lorcaserin), MCR4 agonists (such as the compounds described in US6,818,658), lipase inhibitors (such as cetilistat), PYY_3-36(As used herein, "PYY" is used herein to describe the peptide_3-36"includes analogs, e.g. PEGylated PYY_3-36Such as those described in U.S. publication No. 2006/0178501), opioid antagonists (e.g., naltrexone), oleoyl estrone (CAS number 180003-17-2), obinepitide (TM30338), pramlintide (pramlintide)Tesofensine (NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatideAOD-9604(CAS number 221231-10-3) and sibutramine. The compounds and combination therapies of the present invention are preferably administered in conjunction with exercise and a reasonable diet.

All of the above U.S. patents and publications are incorporated herein by reference.

Embodiments of the present invention are illustrated by the following examples. However, it is to be understood that the invention is not limited to the specific details of these examples, as other variations thereof will be apparent to or are apparent to those skilled in the art in light of the present disclosure.

Detailed Description

Unless otherwise indicated, the starting materials are typically obtained from commercial sources such as: aldrich Chemicals Co. (Milwaukee, Wis.), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, UK), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (UK, London). The following materials are available from the respective sources:

5-methyl-2-furfural-Sigma-Aldrich (Milwaukee, WI);

5-methyl-2-aminopyrazine-Princeton Bimolecular Research, Inc (Monmouth Junction, NJ);

5-methoxypyrazin-2-amine-Anichem (Monmouth Junction, NJ);

5-chloropyrazine-2-carboxylic acid-Ark Pharma, Inc (Libertyville, IL);

1-methyl-1H-pyrazol-3-ylamine-Matrix Scientific (Columbia, SC);

5-bromo-pyrimidine-2-carboxylic acid-Ark Pharma, Inc (Libertyville, IL).

General Experimental procedure

At room temperature and 400MHz, at Varian Unity^TMNMR spectra of protons were recorded on 400 (available from Varian inc., Palo Alto, CA). Chemical shifts are expressed in parts per million (δ) relative to residual solvent as an internal standard. The peak shape is represented as follows: s, singlet; d, double peak; dd, doublet of doublets; t, triplet; q, quartet; m isMultiple peaks; bs, broad singlet; 2s, double singlet. Atmospheric pressure chemical ionization mass spectrometry (APCI) at Fisons^TMObtained on a PlatformII spectrometer (carrier gas: acetonitrile: available from Manchester, Micromass Ltd, UK). Chemical ionization mass spectrometry (CI) in Hewlett-Packard^TM5989 obtained on an instrument (Ammonia ionization, PBMS: available from Hewlett-Packard Company, Palo Alto, Calif.). Electrospray ionization mass spectrometry (ES) at Waters^TMObtained on a ZMD instrument (carrier gas: acetonitrile: purchased from Waters corp., Milford, MA). High Resolution Mass Spectrometry (HRMS) on Agilent Using time of flight method^TMObtained on model 6210. In describing the strength of chlorine-or bromine-containing ions, the expected strength ratio (for chlorine-or bromine-containing compounds) is observed³⁵Cl/³⁷Ion of Cl is about 3: 1, and for⁷⁹Br/⁸¹The ion of Br is about 1: 1) and only the intensity of the lower mass ion is indicated. In some cases, only representative ones are indicated¹H NMR peak. Optical rotation at indicated temperature using sodium D-line (λ 589nm) in PerkinElmer^TM241 polarimeters (available from PerkinElmer inc., wellelsley, MA) and are recorded as follows: [ alpha ] to]_D ^tempConcentration (c ═ g/100ml), and solvent.

Under low nitrogen pressure, in a glass column or Flash 40Biotage^TMColumn (ISC, Inc., Shelton, CT) or Biotage^TMSNAP columella KPsil or Redispe Rf silica (from Teledyne)^TM Isco^TM) In the middle, Baker is utilized^TMSilica gel (40 μm; J.T.Baker, Phillipsburg, NJ) or silica gel 50(EM Sciences)^TMGibbstown, NJ) were subjected to column chromatography.

Preparation of starting materials and key intermediates

Preparation of intermediate (E) -3- (ethoxycarbonyl) -4- (5-methylfuran-2-yl) but-3-enoic acid (I-1 a):

sodium ethoxide (0.93L of a 21 wt% ethanol solution) was added in one portion to a well stirred ethanol solution (1.820L) of 5-methyl-2-furfural (264mL, 2650mmol) and diethyl succinate (840mL, 5050mmol) at room temperature. The reaction mixture was then heated under reflux for 13 hours. After cooling to room temperature, the mixture was concentrated in vacuo (at which point all batches were combined). The resulting residue was partitioned between ethyl acetate (1L) and hydrochloric acid (1L of 2M aqueous solution). After separation, the aqueous layer was extracted with ethyl acetate (2 × 1L). The combined organic extracts were then extracted with sodium bicarbonate (2X 1L of saturated aqueous solution). These aqueous extracts were combined and adjusted to pH 2 using hydrochloric acid (2M aqueous solution), then extracted with ethyl acetate (2 × 1L). These organic extracts were combined and concentrated in vacuo to give the desired (E) -3- (ethoxycarbonyl) -4- (5-methylfuran-2-yl) but-3-enoic acid (I-1 a: 34.34g, 5%). The initial organic extract was extracted with sodium hydroxide (2L of 2M aqueous solution). This aqueous extract was adjusted to pH 2 using hydrochloric acid (2M aqueous solution) and then extracted with ethyl acetate (2 × 1L). These organic extracts were combined and concentrated in vacuo to yield the other desired material as a red liquid (395.2g, 63%).

¹H NMR(CDCl₃，300MHz)δppm 7.48(s，1H)，6.57(d，1H)，6.09(d，1H)，4.24(q，2H)，3.87(s，2H)，2.32(s，3H)，1.31(t，3H)。

Preparation of intermediate ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (I-1 b):

sodium acetate (193g, 2350mmol) was added in one portion to a well stirred solution of acetic anhydride (1.77L, 18.72mol) in (E) -3- (ethoxycarbonyl) -4- (5-methylfuran-2-yl) but-3-enoic acid (1-1 a: 326.6g, 1.371mol) at room temperature. The reaction mixture was then heated at reflux for 2.5 hours. After cooling to room temperature, the mixture was concentrated in vacuo (at which point all batches were combined). The resulting residue was suspended in dichloromethane (1.5L) and filtered, and the solid was washed with dichloromethane (3 × 500 mL). Next, the combined filtrate and washings were washed with sodium bicarbonate (2X 1L of a saturated aqueous solution) and brine (2L), and then concentrated in vacuo to give the desired ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (I-1 b: 549.03g, quantitative).

¹H NMR(CDCl₃，300MHz)δppm 8.00-7.99(m，1H)，7.64(d，1H)，6.32-6.32(m，1H)，4.38(q，2H)，2.47(d，3H)，2.37(s，3H)，1.39(t，3H)。

Preparation of intermediate ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1 c):

potassium carbonate (266g, 1.92mol) was added in one portion to a stirred ethanol solution (4.00L) of ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (I-1 b: 549.03g, 1.37mol) at room temperature. The reaction mixture was then heated at 60 ℃ for 3 hours. Potassium carbonate (100g, 0.720mol) was then added in one portion and the reaction mixture was heated at 60 ℃ for a further 3 hours. After cooling to room temperature, the mixture was diluted with dichloromethane (2L) and the suspension was filtered and the solid was washed with dichloromethane (2 × 1L) (at which point all batches were combined). The combined filtrate and washings were then washed with citric acid (2.5L of 1M aqueous solution), then concentrated in vacuo and the resulting residue was purified by dry flash chromatography (hexane and 2: 1 hexane: ethyl acetate, respectively). All fractions containing the desired product were combined and concentrated in vacuo. The resulting residue, which solidified on standing, was slurried with cold toluene and filtered. The solid was then stirred with hot toluene and decolorized with charcoal for 1 hour, then the hot mixture was filtered through a pad of celite. The filtrate was cooled and the resulting precipitate was isolated by filtration to obtain the desired ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1 c: 360g, 90%) as an orange powder.

¹H NMR(CDCl₃300MHz) delta ppm 7.73-7.73(m, 1H), 7.45(d, 1H), 6.51-6.50(m, 1H), 5.85(s, 1H), 4.39(q, 2H), 2.48(d, 3H), 1.40(t, 3H). LCMS (liquid chromatography mass spectrometry): m/z 221.06 (purity 96.39%).

Preparation of starting material 5-chloro-N, N-dimethylpyrazine-2-carboxamide (SM-1):

sequentially with catalytic amounts of dimethylformamide and (COCl)₂(0.85ml, 9.46mmol) 5-chloropyrazine-2-carboxylic acid (1.00g, 6.31mmol) in dichloromethane (30ml) was treated. The resulting mixture was stirred overnight. The reaction was concentrated in vacuo and dried in vacuo to afford the desired 5-chloropyrazine-2-carbonyl chloride as a solid (1.05g, 100%).

5-chloropyrazine-2-carbonyl chloride (2.13g, 12.05mmol) and dimethylamine HCl salt (1.06g, 12.7mmol) were suspended in dichloromethane (50ml) with stirring. A solution (25ml) of triethylamine (5.04ml, 36.2mmol) in dichloromethane was added dropwise to the reaction mixture at 0 ℃. The combined solution was allowed to warm to room temperature and stirred for 4 hours. The compound was diluted with dichloromethane, washed with 1N HCl, water, brine and dried (Na)₂SO₄) Filtered and concentrated. The crude product was purified by column chromatography (silica gel, 30 to 80% ethyl acetate in heptane) to afford the desired 5-chloro-N, N-dimethylpyrazine-2-carboxamide (SM-1: 2.24g, 85%).¹H NMR (400MHz, chloroform-d) δ ppm 8.74(d, J ═ 1.37Hz, 1H)8.53(d, J ═ 1.37Hz, 1H)3.15(s, 3H)3.12(s, 3H).

Preparation of intermediate ethyl 4- (5- (dimethylcarbamoyl) pyrazin-2-yloxy) -2-methylbenzofuran-6-carboxylate (I-1 d):

the flask was charged with ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1 c: 6.07g, 27.6mmol), 5-chloro-N, N-dimethylpyrazine-2-carboxamide (SM-1: 5.06g, 27.3mmol), and cesium carbonate (9.78g, 30 mmol). The solid was dissolved in dimethylformamide (60 mL). The reaction was heated to 90 ℃ for 3 hours. After cooling the reaction to room temperature, the dimethylformamide was removed in vacuo. The crude reaction mixture was partitioned between ethyl acetate (100ml) and water (30 ml). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (silica gel, 30 to 80% gradient of ethyl acetate in heptane) to yield the desired light brown solid of ethyl 4- (5- (dimethylcarbamoyl) pyrazin-2-yloxy) -2-methylbenzofuran-6-carboxylate (I-1d) (8.3g, 95%).

¹H NMR (400MHz, chloroform-d) δ ppm 8.48(d, J ═ 1.17Hz, 1H)8.41(d, J ═ 0.98Hz, 1H)8.04(t, J ═ 1.07Hz, 1H)7.71(d, J ═ 1.17Hz, 1H)6.16-6.21(m, 1H)4.38(q, J ═ 7.22Hz, 2H)3.17(s, 3H)3.14(s, 3H)2.45(d, J ═ 1.17Hz, 3H)1.38(t, J ═ 7.12Hz, 3H). MS (M + 1): 370.1.

preparation of SM-25-bromo-N, N-dimethylpyrimidine-2-carboxamide (SM-2):

oxalyl chloride (47.4g, 369mmol) was added to a suspension of 5-bromo-pyrimidine-2-carboxylic acid (50g, 250mmol) in dichloromethane (821ml) at room temperature, followed by 1 to 2 drops of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours and LCMS showed the presence of methyl ester and some acid in the methanol. Dimethylformamide (0.2ml) was added to the reaction mixture. The acid dissolved after 30 minutes. LCMS showed the corresponding methyl ester and no initial material peak was observed. The solvent was removed and dried in vacuo to give crude 5-bromo-pyrimidine-2-carbonyl chloride (55g, 100%).

5-bromo-pyrimidine-2-carbonyl chloride (55g, 250mmol) was dissolved in tetrahydrofuran (828ml) and dimethylamine (2M in tetrahydrofuran) (373ml, 745mmol) was added thereto in portions at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time LCMS indicated completion of the reaction. The mixture was diluted with ethyl acetate (500ml) and washed with H₂O (500ml) wash. By means of CH₂Cl₂The aqueous layer was further extracted (5X 500ml) and all organic layers were combined and dried over magnesium sulphate. The filtrate was concentrated in vacuo and then suspended in methyl-tert-butyl ether (650 ml). The solution was then heated to reflux. The hot solution was allowed to cool overnight to obtain pink crystals. The crystals were filtered and washed with cold methyl-tert-butyl ether (100 ml). The solid was dried in a vacuum oven at 55 ℃ for 12 hours to obtain the title compound 5-bromo-N, N-dimethylpyrimidine-2-carboxamide (SM-2: 44g, 77%) as a pink solid.

¹H NMR (400MHz, chloroform-d) δ ppm 2.94(s, 3H)3.13(s, 3H)8.85(s, 2H) M/z (M +1) ═ 232.

Preparation of intermediate ethyl 4- (2- (dimethylcarbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (I-2 a):

by using N₂Gas cleaning of Cs₂CO₃(62.1g, 191mmol), 5-bromo-N, N-dimethylpyrimidine-2-carboxamide (SM-2: 24g, 104mmol) and a mixture of ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1 c: 20g, 91mmol), 1, 10-phenanthroline (1.64g, 9.07mmol) and copper iodide (864mg, 4.54mmol) in dimethylformamide (200ml), and then heated with a mechanical stirrerTo 90 ℃. The heterogeneous reaction mixture was stirred at this temperature for 18 hours. HPLC showed the reaction was nearly complete. The reaction mixture was cooled to 35 ℃ and diluted with ethyl acetate (300 ml). The mixture was filtered to remove any cesium carbonate. The filtrate was then partitioned between water (500ml) and ethyl acetate (500 ml); however, no separation was observed. Concentrated HCL (20ml) was added to the mixture. When the aqueous phase had a pH of about 1, the phases separated. The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (2X 500 ml). All organic layers were combined and back-extracted with water (200ml) and brine (500 ml). The organic layer was separated and treated with activated carbon (10g) and magnesium sulfate. The mixture was stirred for 10 minutes and then filtered through a pad of celite to obtain a crude yellow solution. The filter cake was washed with ethyl acetate (100 mL). The organics were concentrated in vacuo to give a crude solid, which was dried under high vacuum for 4 days. The dry crude solid was triturated with methanol (80 mL). The solid was dispersed into a fine pale orange crystalline powder using a red liquid. The solid was isolated by filtration and rinsed with methanol (20 mL). The solid was dried in a vacuum oven at 55 ℃ for 12 hours to obtain a yellow solid (18.2g, 54%) of ethyl 4- (2- (dimethylcarbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (1-2 a).

¹H NMR (400MHz, chloroform-d) δ ppm 1.41(t, J ═ 7.12Hz, 3H)2.50(d, J ═ 0.98Hz, 3H)3.00(s, 3H)3.17(s, 3H)4.41(d, J ═ 7.22Hz, 2H)6.29(s, 1H)7.62(d, J ═ 1.17Hz, 1H)8.06(s, 1H)8.50(s, 2H). M/z (M +1) ═ 370.5.

Preparation of starting material 5-bromo-N-ethyl-N-methylpyrimidine-2-carboxamide (SM-3):

oxalyl chloride (1.45g, 11.1mmol) was added to a suspension of 5-bromo-pyrimidine-2-carboxylic acid (1.5g, 7.4mmol) in dichloromethane (50ml) at room temperature, followed by 1 to 2 drops of dimethylformamide. The reaction mixture was stirred under nitrogen for 2 hours and LCMS showed the presence of methyl ester and some acid in the methanol. Dimethylformamide (0.2ml) was added to the reaction mixture and all the acid was dissolved after 30 minutes. LCMS showed the corresponding methyl ester and no raw material peak was observed. The solvent was removed and dried in vacuo to give crude 5-bromo-pyrimidine-2-carbonyl chloride (1.6 g).

5-bromo-pyrimidine-2-carbonyl chloride (1600mg, 7.225mmol) was dissolved in dichloromethane (25mL), and triethylamine (4.03mL, 28.9mmol) and ethyl-methylamine (0.68mL, 7.92mmol) were added sequentially. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time LCMS indicated completion of the reaction. The mixture was diluted with dichloromethane (50ml) and washed sequentially with water (50ml), 10% citric acid (50ml) and brine (50 ml). The organic layer was separated and washed with MgSO 4₄Dry above, filter the residue and remove the solvent in vacuo to obtain the title compound 5-bromo-N-ethyl-N-methylpyrimidine-2-carboxamide (SM-3) (1.4g, 79.4%) as a brown oil.

¹H NMR (400MHz, chloroform-d) δ ppm 1.08-1.31(m, 3H)2.99(d, J-79.05 Hz, 3H)3.19(q, J-7.22 Hz, 1H)3.59(q, J-7.22 Hz, 1H)8.84(d, J-3.12 Hz, 2H).

Preparation of intermediate ethyl 4- (2- (ethyl (methyl) carbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (I-5 a):

5-bromo-N-ethyl-N-methylpyrimidine-2-carboxamide (SM-3: 615mg, 2.5mmol), 4-hydroxy-2-methylbenzofuran-6-carboxylic acid ethyl ester (I-1 c: 378mg, 1.7mmol), Cs₂CO₃The flask was charged with (1.15g, 3.5mmol), 1, 10-phenanthroline (30.3mg, 0.17mmol), copper iodide (16mg, 0.08mmol), and dimethylformamide (17 mL). By using N₂The reaction mixture was degassed for 5 minutes and then under N₂Heat to 90 ℃ under atmosphere and last 16 hours. By using acetic acid BThe reaction mixture was diluted with ester (250mL), washed with water (3X 100mL), and dried (MgSO)₄) And concentrated. The crude material was purified by biotage on a 50g silica gel column (20% to 100% EtOAc in Hep) to give the title compound ethyl 4- (2- (ethyl (methyl) carbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (I-5 a: 180mg, 28%) as a yellow solid.

¹H NMR (400MHz, chloroform-d) δ ppm 1.07-1.26(m, 3H)1.34(t, J ═ 7.12Hz, 3H)2.42(d, J ═ 0.98Hz, 3H)2.97(d, J ═ 65.77Hz, 3H)3.14-3.66(m, 2H)4.33(q, J ═ 7.22Hz, 2H)6.14-6.32(m, 1H)7.54(dd, J ═ 3.32, 1.17Hz, 1H)7.92-8.04(m, 1H)8.43(d, J ═ 4.10Hz, 2H). MS (M +1) ═ 384.3.

Preparation of starting material 5-chloro-N-ethyl-N-methylpyrazine-2-carboxamide (SM-4):

the title compound (I-7a) was prepared by a method similar to that described for the preparation of SM-1 using 5-chloropyrazine-2-carboxylic acid (2g, 12.62mmol) and ethyl-methylamine (0.846g, 13.9mmol) to obtain the title compound 5-chloro-N-ethyl-N-methylpyrazine-2-carboxamide (SM-4: 2.05g, 81%) as a clear oil.

¹H NMR (400MHz, chloroform-d) δ ppm 8.72(dd, J ═ 7.41, 1.37Hz, 1H), 8.53(d, J ═ 1.56Hz, 1H), 3.60(q, J ═ 7.22Hz, 1H), 3.42(q, J ═ 7.02Hz, 1H), 3.09(d, J ═ 10.73Hz, 3H), 1.17-1.31(m, 3H).

Preparation of intermediate ethyl 4- (5- (ethyl (methyl) carbamoyl) pyrazin-2-yloxy) -2-methylbenzofuran-6-carboxylate (I-7 a):

ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1 c: 2.25g, 10.22mmol), potassium carbonate (2.1g, 15.3mmol) and 5-chloro-N-ethyl-N-methylpyrazine-2-carboxamide (SM-4: 2.04g, 10.2mmol) were mixed in acetonitrile (30 ml). The mixture was heated at 100 ℃ overnight, after which the reaction mixture was diluted with ethyl acetate (50ml) and filtered. The organic layer was concentrated and purified by silica gel column chromatography (eluting with 20% to 100% ethyl acetate in heptane) to obtain ethyl 4- (5- (ethyl (methyl) carbamoyl) pyrazin-2-yloxy) -2-methylbenzofuran-6-carboxylate as a gum (I-7 a: 3.9g, 99.5%).

¹H NMR (400MHz, chloroform-d) δ ppm 8.45(dd, J ═ 7.43, 1.17Hz, 1H), 8.40(s, 1H), 8.04(t, J ═ 1.07Hz, 1H), 7.71(d, J ═ 0.98Hz, 1H), 6.18(d, J ═ 0.98Hz, 1H), 4.38(q, J ═ 7.04Hz, 2H), 3.60(q, J ═ 7.23Hz, 1H), 3.48(q, J ═ 6.91Hz, 1H), 3.11(d, J ═ 10.36Hz, 3H), 1.38(t, J ═ 7.13Hz, 3H), 1.20 to 1.28(m, 3H).

Example 1

Preparation of N, N-dimethyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl-benzofuran-4-yloxy) pyrazine-2-carboxamide (1):

5-methyl-2-aminopyrazine (6.8g, 63mmol) was dissolved in 70mL of dimethyl ether and cooled to 0 ℃. Dimethylaluminum chloride (131mmol, 1M hexane) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. Next, a dimethyl ether solution (70mL) containing ethyl 4- (5- (dimethylcarbamoyl) pyrazin-2-yloxy) -2-methylbenzofuran-6-carboxylate (I-1 d: 10.1g, 27.3mmol) was added to the active amine solution via cannula. The combined solution was heated to reflux overnight. The reaction was cooled on ice and quenched slowly by the dropwise addition of aqueous Rochelle salt (concentrated, 100 mL). The mixture was stirred for 20 minutes. The mixture was separated. The organic layer was washed with aqueous Rochelle salt (30mL), 1N HCl (30mL), brine (30mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, heptane gradient from 50 to 100% ethyl acetate) to obtain the desired N, N-dimethyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) -benzofuran-4-yloxy) pyrazine-2-carboxamide (1: 8.5g, 72%).

¹H NMR (400MHz, chloroform-d) δ ppm 9.57(d, J ═ 1.37Hz, 1H), 8.49(d, J ═ 1.37Hz, 1H), 8.45(d, J ═ 1.37Hz, 1H), 8.42(s, 1H), 8.14(dd, J ═ 1.56, 0.59Hz, 1H), 7.91-7.94(m, 1H), 7.62(d, J ═ 1.37Hz, 1H), 6.22(t, J ═ 0.98Hz, 1H), 3.18(s, 3H), 3.15(s, 3H), 2.55(s, 3H), 2.48(d, J ═ 1.17Hz, 3H).

MS(M+1)：433.1。

Example 2

Preparation of N, N-dimethyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) -benzofuran-4-yloxy) pyrimidine-2-carboxamide (2):

at 0 ℃ Me₂AlCl (1M in hexane) (715mL) was added to a solution of 5-methyl-2-aminopyrazine (38.9g, 356mmol) in dimethyl ether (315mL) in a three-necked flask equipped with an overhead stirrer and condenser. The mixture was warmed to room temperature and stirred for 1.5 hours. In a separate flask, ethyl 4- (2- (dimethylcarbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (I-2 a: 52.6g, 142.5mmol) was dissolved in dimethyl ether (210 mL). This mixture was then added to the complexing amine. The gum precipitated and dissipated as a solid when the flask was scraped. The resulting reaction was refluxed for 3.5 hours and HPLC showed the reaction to be 93% complete. 5L Roche to be made up in Waterlle salt and 2l of 2-methyltetrahydrofuran were added to the mixture. The reaction mixture was then poured into the two-phase system. The mixture was stirred with an overhead stirrer for 14 hours, after which a yellow solid precipitated. The solid was collected by filtration. The retained solid was washed with 2-methyltetrahydrofuran. The resulting solid was dried in a vacuum oven overnight to give the title compound N, N-dimethyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) -benzofuran-4-yloxy) pyrimidine-2-carboxamide (2): (49.98g, 81%).

¹H NMR (400MHz, chloroform-d) d ppm 2.49(d, J ═ 1.17Hz, 3H), 2.55(s, 3H), 2.98(s, 3H), 3.14(s, 3H), 6.28(t, J ═ 0.98Hz, 1H), 7.52(d, J ═ 1.37Hz, 1H), 7.88-7.92(m, 1H), 8.14(d, J ═ 0.78Hz, 1H), 8.37(s, 1H), 8.50(s, 2H), 9.54(d, J ═ 1.56Hz, 1H).

m/z(M+1)＝433.4，m/z(M-1)＝431.5。

Example 3

Preparation of 5- (6- ((5-methoxypyrazin-2-yl) carbamoyl) -2-methylbenzofuran-4-yloxy) -N, N-dimethylpyrimidine-2-carboxamide (3):

the title compound (3) was prepared by an analogous method to that described in example 1, using 5-methoxypyrazin-2-amine and ethyl 4- (2- (dimethylcarbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (I-2 a).

¹H NMR (400MHz, chloroform-d) delta ppm 2.49(s, 3H), 2.99(s, 3H), 3.15(s, 3H), 3.98(s, 3H), 6.28(s, 1H), 7.51(s, 1H), 7.89(s, 1H), 7.94(s, 1H), 8.30(s, 1H), 8.50(s, 2H), 9.17(s, 1H). m/z 449.1(MH +).

Example 4

Preparation of N, N-dimethyl-5- (2-methyl-6- ((1-methyl-1H-pyrazol-3-yl) carbamoyl) benzofuran-4-yloxy) pyrimidine-2-carboxamide (4):

the title compound (4) was prepared by an analogous method to that described in example 1 using 1-methyl-1H-pyrazol-3-amine and ethyl 4- (2- (dimethylcarbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (I-2 a).

¹H NMR (400MHz, chloroform-d) delta ppm 8.55(b r.s., 2H), 8.08(s, 1H), 7.41-7.42(m, 1H), 7.03-7.05(m, 1H), 6.34(s, 1H), 3.92(s, 3H), 3.19(s, 3H), 3.09(s, 3H), 2.50(s, 3H). m/z 421.1(MH +).

Example 5

Preparation of N-ethyl-N-methyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) benzofuran-4-yloxy) pyrimidine-2-carboxamide (5):

the title compound (5) was prepared by a method similar to that described in example 1 using ethyl 4- (2- (ethyl (methyl) carbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (I-5 a: 99mg, 0.26mmol), 5-methyl-2-aminopyrazine (84mg, 0.77mmol), dimethylaluminum chloride (1.29mmol, 1M hexane) and dimethyl ether (4.5mL), to give N-ethyl-N-methyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) benzofuran-4-yloxy) pyrimidine-2-carboxamide as an off-white solid (5: 70mg, 61%).

¹H NMR (400MHz, chloroform-d) δ ppm 1.15-1.24(m, 3H), 2.44(s, 3H), 2.49(s, 3H), 2.99(d, J ═ 58.94Hz, 3H), 3.20-3.59(m, 2H), 6.23(d, J ═ 1.17Hz, 1H), 7.50(dd, J ═ 2.93, 1.17Hz, 1H), 7.89(d, J ═ 1.17Hz, 1H), 8.01(s, 1H), 8.46(d, J ═ 4.10Hz, 2H), 9.22(d, J ═ 3.71Hz, 1H), 9.48(s, 1H). MS (M + 1): 447.3.

example 6

Preparation of N-ethyl-N-methyl-5- (2-methyl-6- ((1-methyl-1H-pyrazol-3-yl) carbamoyl) benzofuran-4-yloxy) pyrimidine-2-carboxamide (6):

the title compound (6) was prepared by a method similar to that described in example 1 using ethyl 4- (2- (ethyl (methyl) carbamoyl) pyrimidin-5-yloxy) -2-methylbenzofuran-6-carboxylate (I-5 a: 90mg, 0.24mmol), 5-methyl-2-aminopyrazine (84mg, 0.70mmol), dimethylaluminum chloride (1.17mmol, 1M hexane) and dimethyl ether (4.5mL) to obtain the title compound N-ethyl-N-methyl-5- (2-methyl-6- ((1-methyl-1H-pyrazol-3-yl) carbamoyl) benzofuran-4-yloxy) pyrimidine-2-carboxamide (6: 49mg, 48%).

¹H NMR (400MHz, chloroform-d) δ ppm 1.12-1.26(m, 3H), 2.43(s, 3H), 2.99(d, J ═ 63.04Hz, 3H), 3.20-3.60(m, 2H), 3.68(s, 3H), 6.22(s, 1H), 6.78(d, J ═ 1.56Hz, 1H), 7.18-7.30(m, 1H), 7.47(d, J ═ 2.93Hz, 1H), 7.82(s, 1H), 8.43(d, J ═ 4.10Hz, 2H), 9.18(s, 1H). MS (M + 1): 435.3.

example 7

Preparation of N-ethyl-N-methyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) benzofuran-4-yloxy) pyrazine-2-carboxamide (7):

the title compound (7) was prepared by a method analogous to that described in example 1 using ethyl 4- (5- (ethyl (methyl) carbamoyl) pyrazin-2-yloxy) -2-methylbenzofuran-6-carboxylate (I-7 a: 2.5g, 6.52mmol), 5-methyl-2-aminopyrazine (1.42g, 13mmol), dimethylaluminum chloride (26.1mmol, 1M hexane) and dimethyl ether (50mL), to obtain N-ethyl-N-methyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) -benzofuran-4-yloxy) pyrazine-2-carboxamide (7: 2.89g, 99%) as an off-white solid.

¹H NMR (400MHz, chloroform-d) δ ppm 9.56(d, J ═ 1.37Hz, 1H), 8.37 to 8.52(m, 2H), 8.13(d, J ═ 0.78Hz, 1H), 7.93(t, J ═ 1.07Hz, 1H), 7.61(s, 1H), 6.10 to 6.27(m, 1H), 3.60(q, J ═ 7.17Hz, 1H), 3.40 to 3.53(m, 1H), 3.12(d, J ═ 12.70Hz, 3H), 2.55(s, 3H), 2.47(s, 3H), 1.22 to 1.28(m, 3H). MS (M + 1): 447.3(M-1) 445.4.

Pharmacological testing

The practice of the invention for treating diseases modulated by the activation of glucokinase may be evidenced by the activity of at least one of the protocols described below. The following abbreviations are used in the following analyses and have corresponding definitions. The source of supply is shown in parentheses.

HEPES-N- [ 2-hydroxyethyl ] piperazine-N' - [ 2-ethanesulfonic acid ] (Sigma)

NADH-beta-Nicotinamide adenine dinucleotide, reduced form (Sigma)

PEP-phosphoenolpyruvate (Sigma)

ATP-adenosine triphosphate (Sigma)

DTT-dithiothreitol (Sigma)

PK/LDH pyruvate kinase/lactate dehydrogenase synthase (Sigma)

Glucose- (Calbiochem)

BSA-bovine serum Albumin Cohn fragment (Calbiochem)

Beta cell glucokinase (Molecular Biology)

In vitro assay

His-tag was performed at the N-terminus of full-length glucokinase (. beta. -cell isoform) and purified by Ni column and size exclusion chromatography, in this order. A320 mL column was packed with a grade resin prepared using Superdex75(Amersham Pharmacia, Carlsbad, Calif.). Glucose was obtained from Calbiochem (San Diego, CA) and other reagents were purchased from Sigma-Aldrich (st. louis, MO).

All assays were performed in Corning 384-well plates using a Spectramax PLUS spectrophotometer (Molecular Devices, Sunnyvale, CA) at room temperature. The final assay volume was 40. mu.L. The buffer conditions used in this assay were: 50mM HEPES, 5mM glucose, 2.5mM ATP, 3.5mM MgCl₂0.7mM NADH, 2mM dithiothreitol, 1 unit/mL pyruvate kinase/lactate dehydrogenase (PK/LDH), 0.2mM phosphoenolpyruvate, and 25mM KCl. The buffer pH was 7.1. The test compound-containing dimethylsulfoxide solution was added to the buffer and mixed by a plate shaker for 7.5 minutes. The final concentration of dimethyl sulfoxide introduced into the assay was 0.25%.

Glucokinase is added to the buffer mixture to initiate the reaction, with or without a compound. Since no NADH was contained, the reaction was monitored by absorbance at 340 nm. The initial reaction rate was measured by the slope during the linear time of 0 to 300 seconds. The percentage of highest activation was calculated by the following equation:

% highest activation ═ (Va/Vo-1) × 100;

where Va and Vo are defined as the initial reaction rates in the presence and absence of test compound, respectively.

To determine EC₅₀(half of the highest effective concentration) and% highest activation, compounds were serially diluted 3-fold in dimethyl sulfoxide. Glucokinase activity was measured as a function of compound concentration. Substituting the data into the following equation to obtain EC₅₀And% maximum activation value:

Va/Vo ═ 1+ (% maximum activation/100)/(1 + EC)₅₀Compound concentration)

Beta cell glucokinase His-tag purification

Growth and induction conditions:

BL21(DE3) cells (Invitrogen Corporation, Carlsbad, Calif.) containing the pBCGK (C or N His) vector were grown at 37 deg.C (in 2 XYT) until OD600 was between 0.6 and 1.0. Expression was induced by adding isopropyl thiogalactoside (final concentration 0.1 to 0.2mM) to the cells, followed by incubation of the cells at 23 ℃ overnight. The following day, cells were harvested by centrifugation at 5000rpm for 15 minutes at 4 ℃. The cell pellet was stored at-80 ℃ for later purification.

And (3) purification:

the separation was carried out using a Ni-NTA (Quigan, Germantown, MD) column (15 to 50 mL). Two buffers were prepared: 1) lysis/nickel equilibration and washing buffers and 2) nickel elution buffers. Lysis/equilibration/wash buffers were prepared as follows: 25mM HEPES buffer at pH 7.5, 250mM NaCl, 20mM imidazole, and 14mM β -mercaptoethanol (final concentration). The elution buffer was prepared as follows: 25mM HEPES, 250mM NaCl, 400mM imidazole, and 14mM β -mercaptoethanol at pH 7.5 (final concentration). Each buffer was filtered using a 0.22 μm filter before use. The cell pellet (1L culture) was resuspended in 300mL lysis/equilibration buffer. The cells were then lysed (3 times) using a Microfluidics model 110Y Microfluidics homogenizer (Microfluidics Corporation, Newton, Mass.). The slurry was centrifuged at 40,000rpm for 45 minutes at 4 ℃ using a Beckman Coulter model LE-80K ultracentrifuge (Beckman Coulter, Fullerton, Calif.). The supernatant was transferred to an ice-cold flask. A volume of 20 μ L was retained for gel analysis. Isolation was performed using a Pharmacia AKTA (GMI, inc., Ramsey, MN) purification system. The main circuit was washed with lysis/equilibration buffer. The Ni-NTA column was equilibrated with 200mL lysis/equilibration buffer at a flow rate of 5 mL/min. The supernatant was loaded onto the column at 4 mL/min and the flow was collected in the flask. Unbound protein was washed with lysis/equilibration buffer at a flow rate of 5 mL/min until the uv reached baseline. The protein was then eluted from the column by 320mL of imidazole elution buffer with an imidazole gradient of 20mM to 400mM above. All other proteins in the column were then removed using 80mL of elution buffer. Elution fractions were 8mL each, giving a total of 50 samples. The fractions were analyzed by sodium dodecyl sulfate polyacrylamide (SDS-PAGE), fractions containing the protein of interest were collected and concentrated to 10mL under nitrogen (60psi) using an ultrafiltration grid (cell) with Millipore membrane (Sigma-Aldrich, st.louis, MO) with a molecular weight cut-off (MWCO) of 10,000. The protein was further purified by Size Exclusion Chromatography (SEC) using a Sedex 75 evaporative light scattering detector (320mL) (Amersham Pharmacia, Uppsala, Sweden). SEC was equilibrated with 450mL of sieving buffer containing 25mM HEPES (pH 7.0), 50mM NaCl, and 5mM dithiothreitol. The concentrated protein was then loaded onto SEC and eluted overnight at 0.5 mL/min using 400mL of sieving buffer. The elution fractions were 5mL each. The fractions were analyzed by SDS-PAGE and fractions containing the proteins were collected. Concentrations were determined using Bradford assay/BSA standards. The purified protein was stored in smaller aliquots at-80 ℃.

EC₅₀The (. mu.M) and maximum activation (%) data are summarized in Table 1 below.

TABLE 1

Claims (9)

1. N, N-dimethyl-5- (2-methyl-6- ((5-methylpyrazin-2-yl) carbamoyl) benzofuran-4-yloxy) pyrimidine-2-carboxamide or a pharmaceutically acceptable salt thereof.
2. 2. A compound having the structure:
3. 3. a pharmaceutical composition comprising (i) a compound of claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient, diluent or carrier.
4. 4. The composition of claim 3, wherein the compound or pharmaceutically acceptable salt thereof is present in a therapeutically effective amount.
5. 5. The composition of claim 4, further comprising at least one additional agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent.
6. 6. The composition of claim 5, wherein the anti-obesity agent is selected from the group consisting of: desloratadine, mitratapide, inputadepa, CAS number 913541-47-6, lorcaserin, cetistane, PYY_3-36Naltrexone, oleoyl estrone, ornipitin, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat, exenatide and sibutramine.
7. 7. The composition of claim 5, wherein the antidiabetic agent is selected from the group consisting of: metformin, acetohexamide, chlorpropamide, tryglucamine, glipizide, glibenclamide, glimepiride, gliclazide, glibornuride, gliquidone, glisozide, tolazamide, tolbutamide, amylin, petasitin, acarbose, lipolyticn, canaglibose, emiglitate, miglitol, voglibose, pramipexole-Q, salstatins, balaglitazone, ciglitazone, darglitazone, englitazone, ixolaglitazone, pioglitazone, rosiglitazone, troglitazone, exendin-3, exendin-4, curvatamine, resveratrol, cetearaldehyde extract, sitagliptin, vildagliptin, alogliptin and saxagliptin.
8. 8. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating obesity and obesity-related disorders in an animal.
9. 9. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or delaying the progression or onset of type 2 diabetes and diabetes-related disorders in an animal.