Patent Description:
Formyl peptide receptor <NUM> (FPR2) belongs to a small group of seven-transmembrane domain, G protein-coupled receptors that are expressed in multiple human tissues including immune cells and are known to be important in host defense and inflammation. FPR2 shares significant sequence homology with FPR1 and FPR3 (<NPL>). Collectively, these receptors bind a number of structurally diverse agonists, including N-formyl and non-formyl peptides which act as chemo attractants and activate phagocytes. The endogenous peptide Annexin A1 and its N-terminal fragments are examples of ligands that bind human FPR1 and FPR2. Fatty acids such as the eicosanoid lipoxin A4, which belongs to a class of small pro-resolution mediators (SPMs), has also been reported as an agonist for FPR2 (<NPL>).

Endogenous FPR2 pro-resolution ligands, such as lipoxin A<NUM> and Annexin A1, have been reported to trigger a wide array of cytoplasmatic cascades such as Gi coupling, Ca<NUM>+ mobilization and β-arrestin recruitment. FPR2 regulates both innate and adaptive immune systems including neutrophils, macrophages, T-, and B-cells. In neutrophils, FPR2 ligands modulate movement, cytotoxicity and life span. In macrophages, agonism of FPR2 prevents apoptosis and enhances efferocytosis. The initiation of resolution of inflammation by FPR2 agonism is responsible for enhancing anti-fibrotic wound healing and returning of the injured tissue to homeostasis (<NPL>).

Chronic inflammation is part of the pathway of pathogenesis of many human diseases and stimulation of resolution pathways with FPR2 agonists may have both protective and reparative effects. Ischemia-reperfusion (I/R) injury is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. Non-productive wound healing associated with cardiomyocyte death and pathological remodeling resulting from ischemia-reperfusion injury leads to scar formation, fibrosis, and progressive loss of heart function. FPR2 modulation is proposed to enhance myocardial wound healing post injury and diminish adverse myocardial remodeling (<NPL>). In addition, FPR2 pro-resolution agonists, in the central nervous system, may be useful therapeutics for the treatment of a variety of clinical I/R conditions, including stroke in brain (<NPL>) and I/R induced spinal cord injury (<NPL>).

In addition to beneficial effects of targeting the FPR2 receptor with novel pro-resolution agonists for treatment of I/R induced injury, utility of these ligands can also be applied to other diseases. In the cardiovascular system both the FPR2 receptor and its pro-resolution agonists were found to be responsible for atherogenic-plaque stabilization and healing (<NPL>; and <NPL>). FPR2 agonists also have been shown to be beneficial in preclinical models of chronic inflammatory human diseases, including: infectious diseases, psoriasis, dermatitis, inflammatory bowel syndrome, Crohn's disease, ocular inflammation, sepsis, pain, metabolic/diabetes diseases, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, kidney fibrosis, and organ transplantation (<NPL>, <NPL>).

<NPL>, discloses the discovery of BMS-<NUM>/LAR-<NUM>, a potent FPR2 selective agonist for the prevention of heart failure. <CIT> discloses the use of a formyl peptide receptor <NUM>/lipoxin A4 receptor (FPR2/ALX) agonist for the treatment of heart failure. <CIT> discloses compounds which are FPR2 receptor agonists and/or formyl peptide I (FPRI) receptor agonists, as well as compositions and methods of using the compounds, for example, for the treatment of atherosclerosis, heart failure, and related diseases.

The invention encompasses compounds of Formula (I), which are formyl peptide <NUM> (FPR2) receptor agonists, compositions containing them, and the compounds or compositions for use in the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases, for example.

One aspect of the invention is a compound of Formula (I):
<CHM>
wherein.

Another aspect of the invention is a compound of Formula (I) wherein.

Another aspect of the invention is a compound of Formula (II):
<CHM>
<CHM>
wherein.

Another aspect of the invention is a compound of Formula (II), wherein.

For a compound of Formula (I) or (II), the scope of any instance of a variable substituent, including R<NUM>, R<NUM>, R<NUM>, R<NUM>, and Ar<NUM>, can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects.

Unless specified otherwise, these terms have the following meanings.

Combinations of substituents and bonding patterns are only those that result in stable compounds as understood by practitioners in the art. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

Some examples of compounds where R3a is substituted in the para-position with respect to the imidazole are illustrated below.

Some examples of compounds where R4a is substituted in the para-position with respect to the amide moiety are illustrated below.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, <NUM>-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms including the structure below with the indicated carbon. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereomers. Methods of making and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotational isomers.

The invention is intended to include all isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include <NUM>C, <NUM>C and <NUM>C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

N-formyl peptide receptors (FPRs) are a family of chemo attractant receptors that facilitate leukocyte response during inflammation. FPRs belong to the seven-transmembrane G protein-coupled receptor superfamily and are linked to inhibitory G-proteins (Gi). Three family members (FPR1, FPR2 and FPR3) have been identified in humans and are predominantly found in myeloid cells with varied distribution and have also been reported in multiple organs and tissues. After agonist binding, the FPRs activate a multitude of physiological pathways, such as intra cellular signaling transduction, Ca<NUM>+ mobilization and transcription. The family interacts with a diverse set of ligands that includes proteins, polypeptides and fatty acid metabolites which activate both pro-inflammatory and pro-resolution downstream responses. FPR2 and FPR1 Cyclic Adenosine Monophosphate (cAMP) Assays were used to measure the activity of the compounds in this patent.

FPR2 and FPR1 Cyclic Adenosine Monophosphate (cAMP) Assays. A mixture of forskolin (<NUM> final for FPR2 or <NUM> final for FPR1) and IBMX (<NUM> final) were added to <NUM>-well Proxiplates (Perkin-Elmer) pre-dotted with test compounds in DMSO (<NUM>% final) at final concentrations in the range of <NUM> to <NUM>. Chinese Hamster Ovary cells (CHO) overexpressing human FPR1 or human FPR2 receptors were cultured in F-<NUM> (Ham's) medium supplemented with <NUM>% qualified FBS, <NUM>µg/ml zeocin and <NUM>µg/ml hygromycin (Life Technologies). Reactions were initiated by adding <NUM>,<NUM> human FPR2 cells per well or <NUM>,<NUM> human FPR1 cells per well in Dulbecco's PBS (with calcium and magnesium) (Life Technologies) supplemented with <NUM>% BSA (Perkin-Elmer). The reaction mixtures were incubated for <NUM> at room temperature. The level of intracellular cAMP was determined using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to manufacturer's instruction. Solutions of cryptate conjugated anti-cAMP and d2 flurorophore-labelled cAMP were made in a supplied lysis buffer separately. Upon completion of the reaction, the cells were lysed with equal volume of the d2-cAMP solution and anti-cAMP solution. After a <NUM>-h room temperature incubation, time-resolved fluorescence intensity was measured using the Envision (Perkin-Elmer) at <NUM> excitation and dual emission at <NUM> and <NUM>. A calibration curve was constructed with an external cAMP standard at concentrations ranging from <NUM> to <NUM> pM by plotting the fluorescent intensity ratio from <NUM> emission to the intensity from the <NUM> emission against cAMP concentrations. The potency and activity of a compound to inhibit cAMP production was then determined by fitting to a <NUM>-parametric logistic equation from a plot of cAMP level versus compound concentrations.

The examples disclosed below were tested in the FPR2 and FPR1 cAMP assay described above and found having FPR2 and/or FPR1 agonist activity. Table <NUM> below lists EC<NUM> values in the FPR2 and FPR1 cAMP assays measured for the following examples.

The compounds of the present invention may be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders associated with the FPR2 receptor such as Behcet's disease, Sweet disease, systemic lupus erythematosus (SLE), Wegener's granulomatosis, virus infection, diabetes, amputations, cancers, bacterial infection, physical external injuries, physical disorders including exposure to radiation, vasoconstriction, anaphylactic reactions, allergic reactions, rhinitis, shocks (endotoxic, hemorrhagic, traumatic, splanchnic ischemia, and circulatory shocks), rheumatoid arthritis, gout, psoriasis, benign prostatic hyperplasia, myocardial ischemia, myocardial infarction, heart failure, brain injuries, pulmonary diseases, COPD, COAD, COLD, acute lung injury, acute respiratory distress syndrome, chronic bronchitis, pulmonary emphysema, asthma (allergic asthma and non-allergic asthma), cystic fibrosis, kidney fibrosis, nephropathy, renal glomerular diseases, ulcerative colitis, IBD, Crohn's disease, periodontitis, pains, Alzheimer's disease, AIDS, uveitic glaucoma, conjunctivitis, Sjoegren's syndrome, rhinitis, atherosclerosis, neuroinflammatory diseases including multiple sclerosis, stroke, sepsis, and the like.

Unless otherwise specified, the following terms have the stated meanings. The term "subject" refers to any human or other mammalian species that could potentially benefit from treatment with a FPR2 and/or FPR1 agonist as understood by practioners in this field. Some subjects include human beings of any age with risk factors for cardiovascular disease. Common risk factors include age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity arrthymia or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" means a person suitable for therapy as determined by practitioners in the field. "Treating" or "treatment" cover the treatment of a patient or subject as understood by practitioners in this field. "Preventing" or "prevention" cover the preventive treatment (i.e., prophylaxis and/or risk reduction) of a subclinical disease-state in a patient or subject aimed at reducing the probability of the occurrence of a clinical disease-state as understood by practitioners in this field. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. "Therapeutically effective amount" means an amount of a compound that is effective as understood by practitioners in this field.

Another aspect of the invention are pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formulae (I)-(II) in combination with a pharmaceutical carrier.

Another aspect of the invention are pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formulae (I)-(II) in combination with at least one other therapeutic agent and a pharmaceutical carrier.

"Pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, <NPL>).

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

Compounds of the present invention may be used in a method for treating heart disease comprising administering a therapeutically effective amount of a compound of Formulae (I)-(II) to a patient.

Compounds of the present invention may be used in a method for treating heart disease wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and cardiac iatrogenic damage.

It will be understood that treatment or prophylaxis of heart failure may involve treatment or prophylaxis of a cardiovascular event as well. Treatment or prophylaxis as referred to herein may refer to treatment or prophylaxis of certain negative symptoms or conditions associated with or arising as a result of a cardiovascular event. By way of example, treatment or prophylaxis may involve reducing or preventing negative changes in fractional shortening, heart weight, lung weight, myocyte cross sectional area, pressure overload induced cardiac fibrosis, stress induced cellular senescence, and/or cardiac hypertrophy properties, or any combination thereof, associated with or arising as a result of a cardiovascular event. Treatment may be administered in preparation for or in response to a cardiovascular event to alleviate negative effects. Prevention may involve a pro-active or prophylactic type of treatment to prevent the cardiovascular event or to reduce the onset of negative effects of a cardiovascular event.

Compounds of Formulae (I)-(II) or a pharmaceutically acceptable salt thereof may be used for the preparation of a pharmaceutical composition for the treatment or prophylaxis of heart failure, for example, heart failure results from hypertension, an ischemic heart disease, a non-ischemic heart disease, exposure to a cardiotoxic compound, myocarditis, Kawasaki's disease, Type I and Type II diabetes, thyroid disease, viral infection, gingivitis, drug abuse, alcohol abuse, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrosis, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, coronary bypass surgery, pacemaker implantation surgery, starvation, an eating disorder, muscular dystrophies, and a genetic defect. The heart failure to be treated may be diastolic heart failure, heart failure with reduced ejection fraction (HFREF), heart failure with preserved ejection fraction (HFPEF), acute heart failure, and chronic heart failure of ischemic and non-ischemic origin.

Compounds of Formulae (I)-(II) may be used in a method to treat systolic and/or diastolic dysfunction, wherein the compound is administered in a therapeutically effective amount to increase the ability of the cardiac muscle cells to contract and relax thereby increasing the filling and emptying of both the right and left ventricles, preferably, the left ventricle.

Compounds of Formulae (I)-(II) may be used in a method to treat heart failure wherein the compound is administered in a therapeutically effective amount to increase ejection fraction in the left ventricle.

Compounds of Formulae (I)-(II) may be used in a method to treat heart failure wherein the compound is administered in a therapeutically effective amount to reduce fibrosis in heart tissue.

Compounds of the present invention may be used in a method for treating heart disease wherein the treatment is post myocardial infarction.

Compounds of the present invention may be used in a method for treating heart disease comprising administering a therapeutically effective amount of a compound of Formulae (I)-(II) to a patient in conjuction with other therapeutic agents.

The compounds of this invention can be administered by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about <NUM> to about <NUM> per day, preferably between about <NUM> to about <NUM> per day, and most preferably between about <NUM> to about <NUM> per day. Intravenously, the most preferred doses will range from about <NUM> to about <NUM>/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about <NUM> milligram to about <NUM> milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about <NUM>-<NUM>% by weight based on the total weight of the composition. A typical capsule for oral administration contains at least one of the compounds of the present invention (<NUM>), lactose (<NUM>), and magnesium stearate (<NUM>). The mixture is passed through a <NUM> mesh sieve and packed into a No. <NUM> gelatin capsule. A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (<NUM>) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with <NUM> of physiological saline, to produce an injectable preparation.

The compounds of the present invention may be employed in combination with other suitable therapeutic agents useful in the treatment of the aforementioned diseases or disorders including: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, memory enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignant tumors, and anti-inflammatory agents.

The compounds of the invention may be used with at least one of the following heart failure agents selected from loop diuretics, Angiotensin converting enzyme (ACE) inhibitors, Angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNI), beta blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists and cardiotonic agents. These agents include, but are not limited to furosemide, bumetanide, torsemide, sacubitrial-valsartan, thiazide diruetics, captopril, enalapril, lisinopril, carvedilol, metopolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irbestarain, losartan, olmesartan, telmisartan, and valsartan.

The compounds of the present invention may be employed in combination with at least one of the following therapeutic agents in treating atherosclerosis: anti-hyperlipidemic agents, plasma HDL-raising agents, anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors), LXR agonist, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines (e.g., cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B<NUM>, vitamin B<NUM>, anti-oxidant vitamins, β-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

The compounds of the present invention may be employed in combination at least one of the following therapeutic agents in treating cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor. Examples of suitable HMG-CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

The compounds of the invention may be used in combination with at least one of the following anti-diabetic agents depending on the desired target therapy. Studies indicate that diabetes and hyperlipidemia modulation can be further improved by the addition of a second agent to the therapeutic regimen. Examples of anti-diabetic agents include, but are not limited to, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers, such as selective and non-selective activators of PPARα, PPARβ and PPARγ; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA-SO<NUM>); anti-glucocorticoids; TNFα inhibitors; dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin, saxagliptin), GLP-<NUM> agonists or analogs (such as exenatide), α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide), insulin, as well as the therapeutic agents discussed above for treating atherosclerosis.

The compounds of the invention may be used in combination with at least one of the following anti-obesity agents selected from phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine, β<NUM>-adrenoreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins. Other agents used in treating obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H<NUM> receptors, dopamine D<NUM> receptor modulators, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the FPR2. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving FPR2 activity. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness. The compounds of the present invention may also be used in diagnoswtic assays involving FPR2.

The compounds of the present invention may be used in an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture may comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises a first therapeutic agent, comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemias and the sequelae thereof. The package insert may state that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent for the treatment of dyslipidemias and the sequelae thereof. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries. The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product. The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached. The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).

Abbreviations as used herein, are defined as follows: "1x" for once, "2x" for twice, "3x" for thrice, "°C" for degrees Celsius, "aq" for aqueous, "Col" for column, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "µL" for microliter or microliters, "N" for normal, "M" for molar, "nM" for nanomolar, "mol" for mole or moles, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "ON" for overnight, "atm" for atmosphere, "psi" for pounds per square inch, "conc. " for concentrate, "aq" for "aqueous", "sat" or "sat'd " for saturated, "MW" for molecular weight, "mw" or "µwave" for microwave, "mp" for melting point, "Wt" for weight, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "<NUM>H" for proton, "δ " for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.

The compounds of Formula (I), wherein R<NUM>, R<NUM>, R<NUM>, and R<NUM> are defined below, may be prepared by the exemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples. Protection and de-protection in the processes below may be carried out by procedures generally known in the art (see, for example, <NPL>)). General methods of organic synthesis and functional group transformations are found in: <NPL>); <NPL>); <NPL>); <NPL>), and references therein.

Aminoimidazole compounds of this invention in which R<NUM> is a substituted phenyl can be prepared using the general route as described in Scheme <NUM>. <CHM>
<CHM>.

Displacement of a substituted alpha-bromo ketone G1a, with an aniline in the presence of an inorganic base such as sodium bicarbonate in a suitable solvent such as DMF and subsequent condensation with excess cyanamide in a solvent such as MeOH or NMP can result in G1b. Coupling with an aryl carboxylic acid activated by, for example, HATU or BOP in presence of a tertiary amine base (e.g., TEA, DIEA) can provide substituted aminoimidazole G1c.

The following methods were used in the exemplified Examples, except where noted otherwise. Purification of intermediates and final products was carried out via either normal or reverse phase chromatography. Normal phase chromatography was carried out using prepacked SiO<NUM> cartridges eluting with either gradients of hexanes and EtOAc or DCM and MeOH unless otherwise indicated.

Reverse phase preparative HPLC of Examples was carried out using Waters XBridge C18 column (<NUM> x <NUM>, <NUM>-µm particles) with UV and LCMS detection using variable gradients of mobile phase A (<NUM>% water, <NUM>% ACN) and mobile phase B (<NUM>% water, <NUM>% ACN) containing <NUM>% TFA or <NUM> NH<NUM>OAc.

Reverse phase analytical HPLC/MS was performed on a Waters Acquity system coupled with a Waters MICROMASS® ZQ Mass Spectrometer.

<NUM>H NMR spectra were obtained with Bruker spectrometers operating at frequencies <NUM>, <NUM> or <NUM>. Spectra data are reported in the format: chemical shift (multiplicity, coupling constants, and number of hydrogens). Chemical shifts are specified in ppm downfield of a tetramethylsilane internal standard (δ units, tetramethylsilane = <NUM> ppm) and/or referenced to solvent peaks, which in <NUM>H NMR spectra appear at <NUM> ppm for (CD<NUM>)<NUM>SO, <NUM> ppm for CD<NUM>OD, <NUM> ppm for CD<NUM>CN, and <NUM> ppm for CDCl<NUM>.

To a stirred solution of <NUM>,<NUM>-difluoro-<NUM>-methoxyaniline in DMF (<NUM>) at room temperature was added sodium bicarbonate (<NUM>, <NUM> mmol) followed by <NUM>-bromo-<NUM>-phenylethanone (<NUM>, <NUM> mmol). The resulting solution was stirred at room temperature for <NUM>. To the resulting intermediate was added cyanamide (<NUM>, <NUM> mmol). The resulting solution was heated at <NUM> for <NUM>. The crude material was purified by reverse phase HPLC to afford Intermediae <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a stirred solution of <NUM>-(difluoromethoxy) benzoic acid (<NUM>, <NUM> mmol) in DMF (<NUM>) was added BOP (<NUM>, <NUM> mmol) followed by DIEA (<NUM>, <NUM> mmol). The resulting solution was stirred at room temperature for <NUM>. To the resulting mixture was added a solution of Intermediate <NUM> (<NUM>, <NUM> mmol) in DMF (<NUM>) and the reaction was heated at <NUM> for <NUM>. The crude material was purified by reverse phase HPLC to afford Example <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+.

The following Examples in Table <NUM> were prepared as described for Example <NUM>.

To a stirred solution of compound <NUM> (<NUM>, <NUM> mmol) in THF (<NUM>) and MeOH (<NUM>) was added 1N NaOH solution (<NUM>, <NUM> mmol). The resulting mixture was stirred at room temperature for <NUM>. The reaction was adjusted to pH = <NUM> by using 1N HCl, and the mixture was extracted with EtOAc (3x). The combined extracts were dried (Na<NUM>SO<NUM>), filtered and evaporated under reduced pressure to afford Intermediate <NUM>, which was used without further purification.

To a stirred solution of Intermediate <NUM> (<NUM>, <NUM> mmol) in DMF (<NUM>) was added BOP (<NUM>, <NUM> mmol) followed by DIEA (<NUM>, <NUM> mmol). The resulting solution was stirred at room temperature for <NUM>. To the resulting mixture was added (<NUM>H-pyrazol-<NUM>-yl)methanamine (<NUM>, <NUM> mmol) and the reaction was stirred at room temperature for <NUM>. The crude material was purified by reverse phase HPLC to afford the title compound (<NUM>, <NUM> mmol, <NUM> % yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>)
The following Examples in Table <NUM> were prepared as described for Example <NUM>.

To a solution of Intermediate <NUM> (prepared as described for Example <NUM>) (<NUM>, <NUM> mmol) in DCM (<NUM>) was added TFA (<NUM>). The resulting mixture was stirred at room temperature for <NUM>. The material was purified by reverse phase HPLC to afford Example <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

The material was purified by reverse phase HPLC to afford Example <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>).

To a solution of Compound <NUM> (<NUM>, <NUM> mmol) in DCM (<NUM>) was added ethanesulfonyl chloride (<NUM>, <NUM> mmol) followed by DIEA (<NUM>, <NUM> mmol). The resulting solution was stirred at room temperature over night. The crude material was purified by reverse phase HPLC to afford Example <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

To a solution of Compound <NUM> (<NUM>, <NUM> mmol) in DCM (<NUM>) was added ethyl isocyanate (<NUM>, <NUM> mmol) followed by DIEA (<NUM>, <NUM> mmol). The resulting solution was stirred at room temperature ON. The crude material was purified by reverse phase HPLC to afford Example <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (br t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

To a solution of <NUM>-amino-<NUM>-oxobutanoic acid (<NUM>, <NUM> mmol) in DMF (<NUM>) was added BOP (<NUM>, <NUM> mmol) followed by DIEA (<NUM>, <NUM> mmol). The resulting solution was stirred at room temperature for <NUM>. To this mixture was added a solution of Example <NUM> (<NUM>, <NUM> mmol) in DMF (<NUM>). The reaction was stirred at room temperatureover night. The crude material was purified by reverse phase HPLC to afford Example <NUM> (<NUM>, <NUM> mmol, <NUM> % yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). Examples <NUM> and <NUM> (Table <NUM>) were prepared as described for example <NUM>.

To a solution of N,N'-di-Boc-<NUM>H-pyrazole-<NUM>-carboxamidine (<NUM>, <NUM> mmol) in chloroform (<NUM>) was added <NUM>,<NUM>-difluoro-<NUM>-methoxyaniline (<NUM>, <NUM> mmol) and the mixture was stirred at <NUM> for <NUM>. Additional N,N'-di-Boc-<NUM>H-pyrazole-<NUM>-carboxamidine (<NUM>) was added and heating continued for an additional <NUM>. The mixture was allowed to cool to room temperature and then purified by silica gel chromatography eluting with <NUM> to <NUM>% EtOAc/hexanes to give di-tert-butyl [(<NUM>,<NUM>-difluoro-<NUM>-methoxyphenyl)carbonimidoyl]biscarbamate (<NUM>, <NUM>% yield) as a white solid.

The white solid was then treated with 4N HCl in dioxane (<NUM>, <NUM> mmol) and the mixture aged for <NUM>. The mixture was evaporated, then co-evaporated from ACN followed by diethyl ether to give <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-methoxyphenyl)guanidine, HCl (<NUM>, <NUM> % yield) as a white solid. MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d6) δ <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). Intermediate <NUM>: <NUM>-(<NUM>,<NUM>-Difluoro-<NUM>-methoxyphenyl)-<NUM>-isopropyl-<NUM>H-imidazol-<NUM>-amine: To a mixture of Intermediate <NUM> (<NUM>, <NUM> mmol) and potassium carbonate (<NUM>, <NUM> mmol) in EtOH (<NUM>) was added <NUM>-bromo-<NUM>-methylbutan-<NUM>-one (<NUM>µl, <NUM> mmol) and the mixture heated at reflux for <NUM>. The mixture was allowed to cool to room temperature and solvent removed under vacuum. The residue was purified by silica gel chromatography eluting with <NUM> to <NUM>% MeOH/DCM to give the title compound (<NUM>, <NUM> mmol, <NUM> % yield) as a white solid. MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, CHLOROFORM-d) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (spt, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a solution of Intermediate <NUM> (<NUM>, <NUM> mmol) and <NUM>-(difluoromethoxy)benzoic acid (<NUM>, <NUM> mmol) in DMF (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) followed by HATU (<NUM>, <NUM> mmol) and the mixture stirred for <NUM>. The mixture was diluted with <NUM>% EtOAc/hexanes and washed with saturated NH<NUM>Cl, <NUM> K<NUM>HPO<NUM> then dried (Na<NUM>SO<NUM>) filtered and concentrated. The residue was purified by silica gel chromatography eluting with <NUM> to <NUM>% EtOAc/hexanes followed by reverse phase HPLC to afford the title compound (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Examples <NUM> and <NUM> (Table <NUM>) was prepared as described for example <NUM>.

To a solution of compound <NUM> (prepared as described for Example <NUM>) (<NUM>, <NUM> mmol) in DCM (<NUM>) was added hydrazine (<NUM>, <NUM> mmol) and the mixture stirred for <NUM>. The mixture was evaporated twice from DCM and place under vacuum to give N-(<NUM>-(<NUM>,<NUM>-difluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-hydrazinyl-<NUM>-oxoethyl)-<NUM>-imidazol-<NUM>-yl)-<NUM>-(difluoromethoxy)benzamide (<NUM>, <NUM> mmol, <NUM> % yield) as a white solid. To a solution of the solid (<NUM>, <NUM> mmol) and acetic acid (<NUM>µl, <NUM> mmol) in dioxane (<NUM>) was added <NUM>-propanephosphonic acid cyclic anhydride (<NUM>% in EtOAc) (<NUM>, <NUM> mmol) and the reaction heated at <NUM> for <NUM>. Additional <NUM>-propanephosphonic acid cyclic anhydride (<NUM>% in EtOAc) (<NUM>, <NUM> mmol) was added and the reaction heated at <NUM> for <NUM>. The reaction was allowed to cool to room temperature, evaporated under a stream of nitrogen and then filtered. The crude material was purified by reverse phase HPLC to afford the title compound (<NUM>, <NUM>µmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J=<NUM>, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a solution of <NUM>-(<NUM>-(benzyloxy)cyclobutyl)ethan-<NUM>-one (<NUM>, <NUM> mmol) in EtOH (<NUM>) at <NUM> was added a solution of bromine (<NUM>µl, <NUM> mmol) in EtOH (<NUM>) dropwise. The mixture was stirred at <NUM> for <NUM>, warmed to room temperature and stirred for <NUM>. The mixture was poured into saturated NaHCO<NUM> solution and extracted with DCM. The combined organic extracts were washed with brine, dried over Na<NUM>SO<NUM> and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with <NUM> to <NUM> % EtOAc/hexane to afford intermediate <NUM> (<NUM>, <NUM> mmol, <NUM>% yield) as a mixture of cis and trans isomers which was used directly in the next step.

To a mixture of Intermediate <NUM> (<NUM>, <NUM> mmol) and potassium carbonate (<NUM>, <NUM> mmol) in EtOH (<NUM>) was added Intermediate <NUM> (<NUM>, <NUM> mmol) and the mixture was stirred at <NUM> for <NUM>. The mixture was cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography eluting with <NUM> to <NUM> %MeOH/DCM to afford Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). LCMS (Method B) Rt = <NUM>, (M+H)+ = <NUM>.

To a solution of Intermediate <NUM> (<NUM>, <NUM> mmol) and <NUM>-(difluoromethoxy)benzoic acid (<NUM>, <NUM> mmol) in DMF (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) followed by HATU (<NUM>, <NUM> mmol) and the mixture stirred at <NUM> for <NUM> days. The mixture was diluted with EtOAc, washed with water, 1N HCl and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with <NUM> to <NUM>% EtOAc/hexane to afford Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> % yield) as a mixture of cis and trans isomers. LCMS (Method B) Rt = <NUM>, (M+H)+ = <NUM>.

To a solution of Intermediate <NUM> (<NUM>, <NUM> mmol) in EtOH (<NUM>) was added <NUM>% Pd-C (<NUM>, <NUM> mmol). The reaction was stirred under hydrogen atomsphere at room temperature overnight. The mixture was filtered through a pad of Celite and concentrated under reduced pressure. The material was purified by reverse phase HPLC to afford the title compound (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d6) δ <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a stirred solution of N,O-Dimethylhydroxylamine hydrochloride (<NUM>, <NUM> mmol) and <NUM>-(tert-butoxycarbonyl)-<NUM>-azaspiro[<NUM>]heptane-<NUM>-carboxylic acid (<NUM>, <NUM> mmol) and TEA (<NUM>, <NUM> mmol) in DCM (<NUM>) at <NUM>° C was added T3P ( <NUM>% in EtOAc, <NUM>, <NUM> mmol) dropwise under argon atmosphere. The reaction mixture was allowed to stir at room temperature for <NUM>. The mixture was diluted with EtOAc, washed with water, 1N HCl solution and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography eluting with <NUM>-<NUM>% EtAOc/hexane which was then treated with Methylmagnesiumbromide (<NUM> in THF) (<NUM>, <NUM> mmol) to afford the title compound (<NUM>, <NUM> mmol, <NUM> % yield).

To a mixture of Intermediate <NUM> (<NUM>, <NUM> mmol) and potassium carbonate (<NUM>, <NUM> mmol) in ACN (<NUM>) was added Intermediate <NUM> (<NUM>, <NUM> mmol) and carbon tetrabromide (<NUM>, <NUM> mmol). The mixture was heated at <NUM> overnight. The mixture was diluted with DCM and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase preparative HPLC to afford Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+.

To a solution of Intermediate <NUM> (<NUM>, <NUM> mmol) and <NUM>-(difluoromethoxy)benzoic acid (<NUM>, <NUM> mmol) in DMF (<NUM>) was added DIPEA (<NUM>, <NUM> mmol) followed by HATU (<NUM>, <NUM> mmol) and the mixture was stirred at <NUM> for <NUM>. The reaction mixture was concentrated under reduced pressure. The crude residue was treated with <NUM>% TFA/DCM (<NUM>) for <NUM>. The mixture was concentrated reduced pressure, and the residue was purified reverse phase HPLC to afford the title compound (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, METHANOL-d<NUM>) δ <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Intermediate <NUM> was prepared as described in Example <NUM> from Intermediate <NUM> and <NUM>-(<NUM>,<NUM>-dioxaspiro[<NUM>]decan-<NUM>-yl)ethan-<NUM>-one to afford Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> % yield). LCMS (Method A, Rt = <NUM>), MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

A mixture of Intermediate <NUM> (<NUM>, <NUM> mmol) and TFA (<NUM>) was stirred at room temperature for <NUM> days. The reaction mixture was concentrated under reduced pressure to give Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> % yield). LCMS (Method A, Rt = <NUM>), MS(ESI) m/z: <NUM> (M+H)+.

To a solution of Intermediate <NUM> (<NUM>, <NUM> mmol) in MeOH (<NUM>) at room temperature was added NaBH<NUM> (<NUM>, <NUM> mmol). The reaction was stirred at room temperature for <NUM>. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford Example <NUM> (<NUM>, <NUM> mmol, <NUM> % yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Intermediate <NUM> was prepared as described for Example <NUM>.

To a stirred solution of Intermediate <NUM> (<NUM>, <NUM> mmol) in THF/MeOH (<NUM>:<NUM>, <NUM>) was added 1N NaOH (<NUM>, <NUM> mmol). The mixture was stirred at room temperature for <NUM> d. The mixture was concentrated and used directly in next step.

A mixture of Intermediate <NUM> (<NUM>, <NUM> mmol), <NUM>-fluoropyridine-<NUM>,<NUM>-diamine (<NUM>, <NUM> mmol), HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) in ACN (<NUM>) was stirred at room temperature overnight. The crude material was diluted with DCM, washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with <NUM> to <NUM>% EtOAc to give Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM>% yield).

A mixture of Intermediate <NUM> (<NUM>, <NUM> mmol) and AcOH (<NUM>) was heated at <NUM> for <NUM>. The mixture was cooled to room temperature, diluted with DMF and purified by reverse phase HPLC to afford the title compound (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, CD<NUM>OD) δ <NUM> (br s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Examples <NUM>-<NUM> (Table <NUM>) were prepared as described in Example <NUM>.

To a solution of Example <NUM> (<NUM>, <NUM> mmol) in THF (<NUM>) and TEA (<NUM>µl, <NUM> mmol) was added <NUM>,<NUM>,<NUM>-trifluoroethyl trifluoromethanesulfonate (<NUM>, <NUM> mmol). The resulting solution was stirred at room temperature for <NUM>. The reaction mixture was diluted with DMF and purified by reverse phase HPLC to afford Example <NUM> (<NUM>, <NUM> mmol, <NUM>% yield). MS(ESI) m/z: <NUM> (M+H)+. <NUM>H NMR (<NUM>, CD<NUM>OD) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>).

The following Examples in Table <NUM> were synthesized according to the procedures described above.

Claim 1:
A compound of Formula (I):
<CHM>
wherein
R<NUM> is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxycarbonyl)alkyl, alkoxycarbonyl, (NR<NUM>R<NUM>)carbonyl, Ar<NUM>, or (Ar<NUM>)alkyl;
Ar<NUM> is cycloalkyl, aryl, heteroaryl comprising carbon atoms and <NUM>-<NUM> heteroatoms selected from N, NR5a, O, and S, heterocyclyl comprising carbon atoms and <NUM>-<NUM> heteroatoms selected from N, NR5a, O, and S, or spiroheterocyclyl comprising carbon atoms and <NUM>-<NUM> heteroatoms selected from N, NR5a, O, and S, each substituted with <NUM>-<NUM> R<NUM>;
R<NUM> is hydrogen, alkyl, or haloalkyl;
R<NUM> is phenyl or pyridinyl substituted with <NUM> R3a and <NUM>-<NUM> R3b;
R3a is halo, haloalkyl, alkoxy, or haloalkoxy;
R3b is hydrogen, halo, or haloalkyl;
R<NUM> is phenyl or pyridinyl substituted with <NUM>-<NUM> R4a;
R4a is halo, alkoxy, or haloalkoxy;
R<NUM> is hydrogen, hydroxyl, cyano, halo, alkyl, haloalkyl, amino, haloalkylamino, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, alkylsulfonylamino, or hydroxyalkylcarbonyl;
R5a is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, hydroalkylcarbonyl, carboxamide, alkylaminocarbonyl, aminocarbonylalkylcarbonyl, alkylsulfonyl, or alkoxycarbonyl;
R<NUM> and R<NUM> are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl comprising carbon atoms and <NUM>-<NUM> heteroatoms selected from N, NR8a, O, and S, heterocyclyl comprising carbon atoms and <NUM>-<NUM> heteroatoms selected from N, NR8a, O, and S, arylalkyl, or heteroarylalkyl comprising carbon atoms and <NUM>-<NUM> heteroatoms selected from N, NR8a, O, and S; wherein said cycloalkyl, aryl, heteroaryl, or heterocyclyl is substituted with <NUM>-<NUM> R<NUM>;
or R<NUM> and R<NUM>, together with the nitrogen to which they are attached, form a heterocyclyl or heteroaryl comprising carbon atoms and <NUM>-<NUM> additional heteroatoms selected from N, NR8a, O, S, wherein said heteroaryl or heterocyclyl is substituted with <NUM>-<NUM> R<NUM>;
R<NUM> is hydrogen, halo, hydroxy, hydroxyalkyl, alkyl, alkoxy, or oxo;
R8a is hydrogen, hydroxyalkyl, or alkyl;
or a pharmaceutically acceptable salt thereof.