WO2009006245A2 - Calcilytic compounds - Google Patents

Abstract

Novel calcilytic compounds, pharmaceutical compositions, methods of synthesis and methods of using them are provided.

Description

CALCILYTIC COMPOUNDS FIELD OF INVENTION

The present invention relates to novel calcilytic compounds, pharmaceutical compositions containing these compounds, processes for their preparation and their use as calcium receptor antagonists.

BACKGROUND OF THE INVENTION

In mammals, extracellular calcium (Ca²⁺) is under rigid homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation. Extracellular Ca²⁺ inhibits the secretion of parathyroid hormone ("PTH") from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells. Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca²⁺ concentration.

PTH is the principal endocrine factor regulating Ca²⁺ homeostasis in the blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca²⁺ in the blood. This increase in extracellular Ca²⁺ then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between extracellular Ca²⁺ and PTH secretion forms an important mechanism maintaining bodily Ca²⁺ homeostasis.

Extracellular Ca²⁺ acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in extracellular

2+

Ca has been confirmed. See Brown et al., Nature 366:574, 1993. In parathyroid cells, this protein, the calcium receptor, acts as a receptor for extracellular Ca ⁺, detects changes in the ion concentration of extracellular Ca²⁺, and initiates a functional cellular response, PTH secretion.

Extracellular Ca²⁺ influences various cell functions, reviewed in Nemeth et al.,

Cell Calcium 11 :319, 1990. For example, extracellular Ca²⁺ plays a role in parafollicular (C-cells) and parathyroid cells. See Nemeth, Cell Calcium 11 :323, 1990. The role of extracellular Ca²⁺ on bone osteoclasts has also been studied. See Zaidi, Bioscience

Reports 10:493, 1990.

Various compounds are known to mimic the effects of extra-cellular Ca²⁺ on a calcium receptor molecule. Calcilytics are compounds able to inhibit calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca²⁺. Calcilytics are useful as lead molecules in the discovery, development, design, modification and/or construction of useful calcium modulators, which are active at Ca²⁺ receptors. Such calcilytics are useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at one or more Ca²⁺ receptors. Target diseases or disorders for calcilytic compounds include diseases involving abnormal bone and mineral homeostasis.

Abnormal calcium homeostasis is characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels. Thus, calcium receptor antagonists offer a unique approach towards the pharmacotherapy of diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.

SUMMARY OF THE INVENTION

The present invention relates to calcium receptor antagonists represented by Formula (I), indicated hereinbelow, compositions comprising the present compounds, and their use as calcium receptor antagonists in the treatment of a variety of diseases associated with abnormal bone or mineral homeostasis, including but not limited to, hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis.

The present invention further provides a method for antagonizing calcium receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I), indicated hereinbelow.

The present invention further provides a method for increasing serum parathyroid levels in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I) indicated hereinbelow. The present invention further provides methods for preparing compounds of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel compounds according to formula (I):

(I) wherein:

X is N or N-oxide; Y is N or N-oxide;

R1 is selected from the group consisting of hydrogen, halogen, C_3-7cycloalkyl, phenyl, phenylCi_-4alkyl, phenylC_2-4alkenyl and thienyl, wherein the phenyl or thienyl moiety is optionally substituted by

R2 is phenyl, optionally substituted, independently, once or twice, by halogen or OH; R3 is selected from the group consisting of OH, phenyl,

and thienyl, wherein the thienyl moiety is optionally substituted by

R3 and R4 join together to form a phenyl ring; or a pharmaceutically acceptable salt thereof. As used herein, "C_1-4alkyl" refers to a linear or branched saturated hydrocarbon group containing 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert butyl.

As used herein, "C_3-7cycloalkyl" refers to a saturated monocyclic hydrocarbon ring containing 3 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, "C₂-₄alkenyl" refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds having from 2 to 4 carbon atoms.

Examples of such groups include ethenyl, propenyl and butenyl.

As used herein, "C_1-4alkoxy" refers to an

group wherein Ci_-4alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, or butoxy.

As used herein, "phenylCi_-4alkyl" refers to a

group wherein C_1-4alkyl is as defined herein.

As used herein, "phenylC₂-₄alkenyl" refers to a phenyl-C₂-₄alkenyl group wherein C_2-4alkenyl is as defined herein.

As used herein, "halogen" refers to F, Cl, Br or I.

Suitably, X is N or N-oxide.

Suitably, Y is N or N-oxide. In one embodiment, X and Y are N.

In another embodiment, X is N-oxide and Y is N.

In another embodiment, X is N and Y is N-oxide.

In another embodiment, both X and Y are N-oxide.

Suitably, R1 is selected from the group consisting of hydrogen, halogen, C_3-7cycloalkyl, phenyl,

phenylC₂-₄alkenyl and thienyl, wherein the phenyl or thienyl moiety is optionally substituted by

In one embodiment, R1 is phenylC_1-4alkyl.

In another embodiment, R1 is phenylethyl

In one embodiment, R1 is phenylC₂-₄alkenyl. In another embodiment, R1 is phenylethenyl.

In another embodiment, R1 is hydrogen.

In another embodiment, R1 is halogen.

In another embodiment, R1 is Cl.

In one embodiment, R1 is phenyl, wherein the phenyl moiety is optionally substituted by C_1-4alkyl.

In another embodiment, R1 is 4-(1-methylethyl)phenyl.

In one embodiment, R1 is C_3-7cycloalkyl.

In another embodinment, R1 is cyclopentyl or cyclohexyl.

In one embodiment, R1 is thienyl, wherein the thienyl moiety is optionally substituted by Ci_-4alkyl.

In another embodiment, R1 is thienyl, wherein the thienyl moiety is optionally substituted by methyl or ethyl.

Suitably, R2 is phenyl, wherein the phenyl moiety is optionally substituted, independently, once or twice, by halogen or OH. In one embodiment, R2 is monosubstituted phenyl.

In another embodiment, R2 is hydroxyphenyl.

In another embodiment, R2 is 2-hydroxyphenyl.

In one embodiment, R2 is disubstituted phenyl.

In another embodiment, R2 is 3-fluoro-2-hydroxyphenyl. Suitably, R3 is selected from the group consisting of OH, phenyl, Ci_-4alkoxy and thienyl, wherein the thienyl moiety is optionally substituted by Ci_-4alkyl.

In one embodiment, R3 is OH.

In one embodiment, R3 is phenyl. In one embodiment, R3 is Ci_-4alkoxy.

In another embodiment, R3 is methoxy.

In one embodiment, R3 is thienyl, wherein the thienyl moiety is optionally substituted by C_1-4alkyl.

In another embodiment, R3 is methyl-2-thienyl. In another embodiment, R3 is 5-methyl-2-thienyl.

Suitably, R4 is C_1-4alkyl.

In one embodiment, R4 is methyl.

Suitably, R3 and R4 join together to form a phenyl ring.

Illustrative compounds of the present invention include, but are not limited to: 2-[4-oxido-3-(2-phenylethyl)-2-quinoxalinyl]phenol; 2-[3-(2-phenylethyl)-2-quinoxalinyl]phenol;

2-[6-methyl-1-oxido-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-[6-methyl-4-oxido-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-[6-methyl-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-{6-methyl-5-phenyl-3-[(£)-2-phenylethenyl]-2-pyrazinyl}phenol; 2-(3-chloro-6-methyl-5-phenyl-2-pyrazinyl)phenol; 2-[6-methyl-5-(methyloxy)-2-pyrazinyl]phenol; 2-{3-[4-(1-methylethyl)phenyl]-1 ,4-dioxido-2-quinoxalinyl}phenol; 2-{3-[4-(1-methylethyl)phenyl]-1-oxido-2-quinoxalinyl}phenol; 2-{3-[4-(1-methylethyl)phenyl]-4-oxido-2-quinoxalinyl}phenol; 2-{3-[4-(1-methylethyl)phenyl]-2-quinoxalinyl}phenol; 5-(2-hydroxyphenyl)-3-methyl-6-(2-phenylethyl)-2(1 H)-pyrazinone; 2-Fluoro-6-[6-methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-[6-Methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-[6-Methyl-5-(5-methyl-2-thienyl)-1-oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-Fluoro-6-[6-methyl-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-Fluoro-6-[6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinyl]; 2-Fluoro-6-[6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinyl]phenol; and 2-[6-Methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinyl]phenol; or a pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use. Salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the counterion and/or associated solvent is pharmaceutically acceptable. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compound of the invention are within the scope of the invention. With regard to stereoisomers, the present compounds may have one or more asymmetric carbon atom and may occur as recemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.

It will be appreciated by those skilled in the art that the compounds of this invention may exist in different tautomeric forms. All tautomeric forms of the compounds described herein are intended to be encompassed within the scope of the present invention.

Furthermore, some of the crystalline forms of the present compounds may exist as polymorphs, which are included in the present invention. Because of their potential use in medicine, the salts of the compounds of Formula

(I) are pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid or base addition salts.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of Formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of Formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2- naphthalenesulfonate) or hexanoate salt. A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of Formula (I) with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.

Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline- earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the the compound of Formula (I).

The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of Formula (I).

Throughout the specification the term "calcilytic" means a compound that blocks the Ca²⁺ receptor, acting as an antagonist at this receptor.

Synthetic Schemes:

The present compounds may be synthesized according to a process comprising the steps of: a) cross-coupling an aryl halide according to Formula (II):

(H) to form a disubstituted pyrazine according to Formula (III):

(HI)

b) oxidizing the disubstituted pyrazine to form a pyrazine-1 -oxide according to Formula (IV):

(IV) c) cross coupling the pyrazine-1 -oxide to form a trisubstituted pyrazine according to Formula (V):

(V) d) chlorinating the trisubstituted pyrazine to form a chloropyrazine according to Formula (Vl):

(Vl) e) coupling the chloropyrazine to form a tetrasubstituted pyrazine, wherein R2 through R4 are as defined herein, to yield a compound according to Formula (I). Novel intermediates are represented by Formulas (IV), (V) and (Vl):

(IV)

(V)

(Vl).

General synthetic methods are detailed below in Schemes 1. The present schemes are intended to be illustrative of the present invention and not limiting in any way. While particular substituents are disclosed, other variables can be made with the present schemes.

Scheme 1

EtOH, H,0

0C

toluene, 11 O ⁰C

microwave

Cross-coupling reaction of 1 (R4 = Me) with arylboronic acid, wherein aryl represents phenyl or optionally substituted thienyl, and Pd(P-f-Bu₃)₄ yields the di- substituted pyrazine 2. Oxidation of 2 using mCPBA provides the c//-substituted pyrazine 1 -oxide 3 which undergoes palladium catalyzed cross-coupling with an aryl halide to provide the fr/^'-substituted pyrazine 1 -oxide 4. Chlorination of 4 with POCI₃ gives the chloropyrazine 5. Cross-coupling of 5 with alkylzinc bromide in presence of PEPPSI-IPr gives the tefra-substituted pyrazine 6.

Scheme 2 mCPBA

6 7

Oxidation of the tefra-substituted pyrazine 6 with mCPBA provides the tetra- substituted pyrazine 1 -oxide 7.

Scheme 3

R2

Oxidation of 1 with mCPBA gives the chloropyrazine 1 -oxide 8 which undergoes palladium catalyzed cross-coupling with aryl bromide to provide the c//-substituted chloropyrazine 1 -oxide 9. Reduction of 9 using ammonium acetate and Pd/C followed by protection of phenol (R2 = o-HO-Ph to R2 = o-PMBO-Ph) using p-methoxybenzyl chloride provides the c//-substituted pyrazine 10. Oxidation of 10 using mCPBA provides the di- substituted pyrazine 4-oxide 11 which undergoes palladium catalyzed cross-coupling reaction to give the f/7-substituted pyrazine 4-oxide 12. Alkylation of 12 with an alkyl Grignard reagent provides the tefra-substituted pyrazine 4-oxide 13.

For the preparation of Formula (I) compounds wherein R3 and R4 join together to form a phenyl ring, dichloroquinoxaline is cross-coupled with an appropriately substituted phenyl boronic acid, phenylCi_-4alkyl boronic acid or phenylC₂-₄alkenyl boronic acid, in the presence of a palladium catalyst. Subsequent steps may be necessary to form Formula (I) compounds. For example, when the R1 group is phenyl substituted by OH, boron tribromide is used to de-methylate the methyl from the corresponding methoxy intermediate.

In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. The calcilytic compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. Alternatively, injection (parenteral administration) may be used, e.g., for intramuscular, intravenous, intraperitoneal, and subcutaneous administration. For injection, the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.

For topical administration, the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art. The amounts of various calcilytic compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC50, EC50, the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.

Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.

In one embodiment, the composition is in unit dosage form. For oral application, for example, a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose. Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula(l). A topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I). The active ingredient may be administered, for example, from 1 to 6 times per day, such as, once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.

As used herein, "treatment" of a disease includes, but is not limited to, prevention, slowing the progression of and prophylaxis of the disease.

Diseases and disorders which might be treated or prevented, based upon the affected cells, include bone and mineral-related diseases or disorders, hypoparathyroidism, central nervous system disorders, seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage (such as occurs in cardiac arrest or neonatal distress), epilepsy, neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease and Parkinson's disease), dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, and Tourette's syndrome. Diseases and disorders that might be treated also include diseases involving excess water reabsorption by the kidney, such as syndrome of inappropriate ADH secretion (SIADH), cirrhosis, congestive heart failure, nephrosis, hypertension, and renal toxicity from cationic antibiotics (e.g., aminoglycoside antibiotics). Gut motility disorders (such as diarrhea and spastic colon), Gl ulcer diseases, Gl diseases with excessive calcium absorption (such as sarcoidosis), might also be treated with the present compounds. Autoimmune diseases, organ transplant rejection, squamous cell carcinoma and pancreatitis might also be treated by the present compounds. In one embodiment of the present invention, the present compounds are used to increase serum parathyroid hormone ("PTH") levels. Increasing serum PTH levels can be helpful in treating diseases such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia malignancy and osteoporosis. Another aspect of the present invention describes a method of treating a patient comprising administering to the patient an amount of a present compound sufficient to increase the serum PTH level. In another embodiment, the method is carried out by administering an amount of the compound effective to cause an increase in duration and/or quantity of serum PTH level sufficient to have a therapeutic effect. In various embodiments, the compound administered to a patient causes an increase in serum PTH having a duration of up to one hour, about one to about twenty- four hours, about one to about twelve hours, about one to about six hours, about one to about five hours, about one to about four hours, about two to about five hours, about two to about four hours, or about three to about six hours. In an alternative embodiment of the present invention, the compound administered to a patient causes an increase in serum PTH having a duration of more than about twenty-four hours provided that it is co-administered with an anti resorptive agent.

In additional different embodiments, the compound administered to a patient causes an increase in serum PTH of up to two fold, two to five fold, five to ten fold, and at least 10 fold, greater than peak serum PTH in the patient. The peak serum level is measured with respect to a patient not undergoing treatment.

In one embodiment of the present invention, the present compound is coadministered with an anti-resorptive agent. Suitable anti-resorptive agents for co- administration include, but are not limited to estrogen, 1 α, 25-(OH)₂D₃, Ia-(OH)D₃, calcitonin, selective estrogen receptor modulators, vitronectin receptor antagonists, V-H+- ATPase inhibitors, src SH2 antagonists, bisphosphonates and cathepsin K inhibitors.

Composition of Formula (I), and their pharmaceutically acceptable salts, which are active when given orally, can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.

Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane. In one embodiment, the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.

The biological activity of the compounds of Formula (I) are demonstrated by the following tests:

(I) Calcium Receptor Inhibitor Assay

Calcilytic activity was measured by determining the IC50 of the test compound for blocking increases of intracellular Ca²⁺ elicited by extracellular Ca²⁺ in HEK 293 4.0-7 cells stably expressing the human calcium receptor. HEK 293 4.0-7 cells were constructed as described by Rogers et al., J. Bone Miner. Res. 10 Suppl. 1 :S483, 1995 (hereby incorporated by reference to the extent required to conduct the present assay). Intracellular Ca²⁺ increases were elicited by increasing extracellular Ca²⁺ from 1 to 1.75 mM. Intracellular Ca²⁺ was measured using fluo-3, a fluorescent calcium indicator.

Cells were maintained in T-150 flasks in selection media (DMEM supplemented with 10% fetal bovine serum and 200 ug/mL hygromycin B), under 5% CO2:95% air at 37⁰C and were grown up to 90% confluency. The medium was decanted and the cell monolayer was washed twice with phosphate-buffered saline (PBS) kept at 37 ⁰C. After the second wash, 6 ml. of 0.02% EDTA in PBS was added and incubated for 4 minutes at 37 ⁰C. Following the incubation, cells were dispersed by gentle agitation. Cells from 2 or 3 flasks were pooled and pelleted (100 x g). The cellular pellet was resuspended in 10-15 ml. of SPF-PCB+ and pelleted again by centrifugation. This washing was done twice.

Sulfate- and phosphate-free parathyroid cell buffer (SPF-PCB) contained 20 mM Na-Hepes, pH 7.4, 126 mM NaCI, 5 mM KCI, and 1 mM MgC^. SPF-PCB was made up and stored at 4 ⁰C. On the day of use, SPF-PCB was supplemented with 1 mg/mL of D-glucose and 1 mM CaCl2 and then split into two fractions. To one fraction, bovine serum albumin (BSA; fraction V, ICN) was added at 5 mg/mL (SPF-PCB+). This buffer was used for washing, loading and maintaining the cells. The BSA-free fraction was used for diluting the cells in the cuvette for measurements of fluorescence.

The pellet was resuspended in 10 ml. of SPF-PCB+ containing 2.2 uM fluo-3 (Molecular Probes) and incubated at room temperature for 35 minutes. Following the incubation period, the cells were pelleted by centrifugation. The resulting pellet was washed with SPF-PCB+. After this washing, cells were resuspended in SPF-PCB+ at a density of 1-2 x 106 cells/mL.

For recording fluorescent signals, 300 uL of cell suspension were diluted in 1.2 ml_ of SPF buffer containing 1 mM CaCl2 and 1 mg/mL of D-glucose. Measurements of fluorescence were performed at 37 ⁰C with constant stirring using a spectrofluorimeter. Excitation and emission wavelengths were measured at 485 and 535 nm, respectively. To calibrate fluorescence signals, digitonin (5 mg/mL in ethanol) was added to obtain Fmax, and the apparent Fmin was determined by adding Tris-EGTA (2.5 M Tris-Base, 0.3 M EGTA). The concentration of intracellular calcium was calculated using the following equation:

Intracellular calcium = (F-F_mjn/F_max) x K^; where K₀₎ = 400 nM. To determine the potential calcilytic activity of test compounds, cells were incubated with test compound (or vehicle as a control) for 90 seconds before increasing the concentration of extracellular Ca²⁺ from 1 to 2mM. Calcilytic compounds were detected by their ability to block, in a concentration-dependent manner, increases in the concentration of intracellular Ca²⁺ elicited by extracellular Ca²⁺.

The present compounds tested active at IC50 values of lower than 30 uM. The present examples were all testedin the assay described above, except for Example 5. The compounds tested had an IC₅₀ in a range from about 30 nM to about 21 uM. (II) Calcium Receptor Binding Assay

HEK 293 4.0-7 cells stably transfected with the Human Parathyroid Calcium Receptor ("HuPCaR") were scaled up in T180 tissue culture flasks. Plasma membrane was obtained by polytron homogenization or glass douncing in buffer (50 mM Tris-HCI pH 7.4, 1 mM EDTA, 3 mM MgCl2) in the presence of a protease inhibitor cocktail containing 1 uM Leupeptin, 0.04 uM Pepstatin, and 1 mM PMSF. Aliquoted membrane was snap frozen and stored at -8O⁰C. ^H labeled compound was radiolabeled to a radiospecific activity of 44Ci/mmole and was aliquoted and stored in liquid nitrogen for radiochemical stability. A typical reaction mixture contained 2 nM ^H compound ((R,R)-N-4'-Methoxy-t-3-

3'-methyl-1'-ethylphenyl-1-(1-naphthyl)ethylamine), or ^H compound (R)-N-[2-Hydroxy-3- (3-chloro-2-cyanophenoxy)propyl]-1 ,1-dimethyl-2-(4-methoxyphenyl)ethylamine 4-10 ug membrane in homogenization buffer containing 0.1 % gelatin and 10% EtOH in a reaction volume of 0.5 ml_. Incubation was performed in 12 x 75 polyethylene tubes in an ice water bath. To each tube 25 uL of test sample in 100% EtOH was added, followed by 400 uL of cold incubation buffer, and 25 uL of 40 nM ^H-compound in 100% EtOH for a final concentration of 2 nM. The binding reaction was initiated by the addition of 50 uL of 80-200 ug/mL HEK 293 4.0-7 membrane diluted in incubation buffer, and allowed to incubate at 4⁰C for 30 min. Wash buffer was 50 mM Tris-HCI containing 0.1 % PEI. Nonspecific binding was determined by the addition of 100-fold excess of unlabeled homologous ligand, and was generally 20% of total binding. The binding reaction was terminated by rapid filtration onto 1 % PEI pretreated GF/C filters using a Brandel Harvestor. Filters were placed in scintillation fluid and radioactivity assessed by liquid scintillation counting. The present compounds tested active at IC50 values of 10 uM or lower. The present examples were all tested in the Calcium Receptor Binding Assay above, except for Example 5. The tested compounds had an IC₅₀ in a range from about 2 nM to about 10 uM. Examples

Nuclear magnetic resonance spectra were recorded at either 300 or 400 MHz using, respectively, a Bruker ARX 300 or Bruker AVANCE 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-dβ is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (Δ) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad. J indicates the NMR coupling constant measured in Hertz. Fourier transform infrared (FTIR) spectra were recorded on a Nicolet 510 infrared spectrometer. FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm^"''). Mass spectra were taken on either a SCI EX5 or Micromass instruments, using electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin-Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical and preparative HPLC were carried out on Rainin or Beckman chromatographs. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5μ Apex-ODS indicates an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 μ, made by Jones Chromatography, Littleton, Colorado. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada) Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.

The following examples are intended to be illustrative only and not limiting in any way: Example 1 2-r6-Methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinvnphenol

a. 2-Methyl-3-(5-methyl-2-thienyl)pyrazine

To a solution of 2-chloro-3-methylpyrazine (3.86 g, 30.0 mmol) in toluene (100 ml.) was added Na₂CO₃ (10.6 g, 60.0 mmol), followed by EtOH-H₂O (1 mL - 1 mL) then (5-methyl-2-thienyl)boronic acid (8.52 g, 60.0 mmol). Pd(P-f-Bu₃)₂ (1.53 g, 3.0 mmol) was added after bubbling with N₂ for 10 min. The reaction mixture was heated up to reflux and stirred for 5 hr. The solution was cooled to room temperature. After filtering and evaporating solvent, the crude product was purified by flash column chromatograph to provide 5.O g of the title product (53%); LCMS: [MH]⁺ = 191.0.

b. 2-Methyl-3-(5-methyl-2-thienyl)pyrazine 1 -oxide To a solution of 2-methyl-3-(5-methyl-2-thienyl)pyrazine (1.50 g, 7.89 mmol) in 40 mL of CH₂CI₂ was added mCPBA (77% purity, 2.64 g, 1 1.8 mmol). The reaction mixture was stirred at room temperature for 2 hr. The solution was washed with 1 Λ/ NaOH, sat'd Na₂S₂O₃, and dried over Na₂SO₄. After filtering and evaporating solvent, the crude product was purified by flash column chromatograph to provide 5.0 g of the title product (53%); LCMS: [MH]⁺ = 191.0.

c. 2-Methyl-6-[2-(methyloxy)phenyl]-3-(5-methyl-2-thienyl)pyrazine 1 -oxide

K₂CO₃ (0.87 g, 6.30 mmol), P-f-Bu₂Me-HBF₄ (0.16 g, 0.63 mmol), Pd(OAc)₂ (0.14 g, 0.63 mmol), and 2-methyl-3-(5-methyl-2-thienyl)pyrazine 1 -oxide (0.65 g, 3.15 mmol) were weighed to air and placed in a 10 mL round-bottom flask. 1-Bromo-2-

(methyloxy)benzene (0.59 g, 3.15 mmol) was added under N₂ followed by the addition of toluene (2 mL). The reaction mixture was then heated to 110 ⁰C overnight. The solution was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatograph to provide 0.63 g of the title product (64%); LCMS: [MH]⁺ = 313.2. d. 2-Chloro-5-methyl-3-[2-(methyloxy)phenyl]-6-(5-methyl-2-thienyl)pyrazine

To 2-methyl-6-[2-(methyloxy)phenyl]-3-(5-methyl-2-thienyl)pyrazine 1 -oxide (0.63 g, 4.0 mmol) was added 1 ml. of POCI3. The solution was then heated to 1 10 ⁰C for 40 min. The reaction mixture was cooled to room temperature and poured into ice water. K₂C0₃was added to adjust pH~7. The aqueous layer was extracted with CH₂CI₂. The organic layer was dried over Na₂SO₄. The solvent was evaporated and the residue was purified by flash column chromatograph to provide 0.45 g of the title product (72%); LCMS: [MH]⁺ = 331.2.

e. 2-Methyl-6-[2-(methyloxy)phenyl]-3-(5-methyl-2-thienyl)-5-(2-phenylethyl)pyrazine

LiBr (38 mg, 0.45 mmol) and PEPPSI-IPR (10 mg, 0.015 mmol) was added to a solution of 0.5 mL of DMI (1 ,3-dimethyl-2-imidazolidinone) and 0.5 mL of THF. The solution was allowed to stir under N₂ until the solid was dissolved. 0.48 mL of phenethylzinc bromide (0.5 M in THF) and 2-chloro-5-methyl-3-[2-(methyloxy)phenyl]-6- (5-methyl-2-thienyl)pyrazine (50 mg, 0.15 mmol) were then added. The reaction mixture was heated under microwave at 100 ⁰C for 10 min. The solution was diluted with CH₂CI₂, washed with water and brine, and dried over Na₂SO₄. The solvent was evaporated and the residue was purified by flash column chromatograph to provide 41 mg of the title product (68%); LCMS: [MH]⁺ = 401.2.

f. 2-[6-Methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinyl]phenol

To a solution of 2-methyl-6-[2-(methyloxy)phenyl]-3-(5-methyl-2-thienyl)-5-(2- phenylethyl)pyrazine (41 mg, 0.10 mmol) in 1 of mL CH₂CI₂ was added 0.60 mL of BBr₃ (1.0 M in CH₂CI₂) at -60 ⁰C. The reaction mixture was stirred at 0 ⁰C for 5 hr. The reaction was quenched by sat'd aqueous NaHCO₃. The aqueous layer was extracted by CH₂CI₂ and the combined organic layer was dried over Na₂SO₄. The solvent was evaporated and the residue was purified by flash column chromatograph to provide 23 mg of the title product (58%); LCMS: [MH]⁺ = 387.2.

Example 2 2-Fluoro-6-r6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinvnphenol

The title compound was prepared following the procedure of Example 1 except for the use of 1-bromo-3-fluoro-2-(methyloxy)benzene in place of 1-bromo-2- (methyloxy)benzene; LCMS: [MH]⁺ = 405.2.

Example 3 2-Fluoro-6-r6-methyl-5-phenyl-3-(2-phenylethyl)-2-pyrazinvnphenol

The title compound was prepared following the procedure of Example 1 except for the use of 1-bromo-3-fluoro-2-(methyloxy)benzene in place of 1-bromo-2- (methyloxy)benzene and phenylboronic acid in place of (5-methyl-2-thienyl)boronic acid; LCMS: [MH]⁺ = 385.2.

Example 4 2-r6-Methyl-5-(5-methyl-2-thienyl)-1 -oxido-3-(2-phenylethyl)-2-pyrazinvnphenol

a. 2-Methyl-6-[2-(methyloxy)phenyl]-3-(5-methyl-2-thienyl)-5-(2-phenylethyl)pyrazine 1 - oxide

To a solution of 2-methyl-6-[2-(methyloxy)phenyl]-3-(5-methyl-2-thienyl)-5-(2- phenylethyl)pyrazine 6 (0.12 g, 0.30 mmol) in 2.0 ml. of CH₂CI₂ was added mCPBA (77% purity, 0.12 g, 0.52 mmol). The reaction mixture was stirred at room temperature for 2 hr. The solution was washed with 1 Λ/ NaOH and sat'd Na₂S₂Os and dried over Na₂SO₄. After filtering and evaporating solvent, the crude product was purified by flash column chromatograph to provide 0.058 g of the title product (46%); LCMS: [MH]⁺ = 417.0.

b. 2-[6-Methyl-5-(5-methyl-2-thienyl)-1 -oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol

To a solution of 2-methyl-6-[2-(methyloxy)phenyl]-3-(5-methyl-2-thienyl)-5-(2- phenylethyl)pyrazine 1-oxide (50 mg, 0.12 mmol) in 1 ml. of CH₂CI₂ was added 0.60 ml_

BBr₃ (1.0 M in CH₂CI_2, 0.60 mmol) at -60 ⁰C. The reaction mixture stirred at 0 ⁰C for 5 hr.

The reaction was quenched with aq NaHCO₃. The aqueous layer was extracted by CH₂CI₂ and the combined organic layer was dried over Na₂SO₄. The solvent was evaporated and the residue was purified by flash column chromatograph to provide 21 mg of the title product (40%); LCMS: [MH]⁺ = 401.2.

Example 5 2-Fluoro-6-r6-methyl-5-(5-methyl-2-thienyl)-1 -oxido-3-(2-phenylethyl)-2- pyrazinyllphenol

The title compound was prepared following the procedure of Example 4 except for the use of 1-bromo-3-fluoro-2-(methyloxy)benzene in place of 1-bromo-2- (methyloxy)benzene; LCMS: [MH]⁺ = 419.2. Example 6a 2-r6-Methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2-pyrazinvnphenol

a. 3-Chloro-2-methylpyrazine 1 -oxide

To a solution of 2-chloro-3-methylpyrazine (7.7 g, 60.0 mmol) in 200 ml. of CH₂Cb was added mCPBA (77% purity, 21.0 g, 90.0 mmol). The reaction mixture was stirred at room temperature for 2 hr. The solution was washed with 1 Λ/ NaOH and sat'd Na₂S₂Os and dried over Na₂SO₄. After filtering and evaporating solvent, the crude product was purified by flash column chromatograph to provide 6.5 g of the title product (75%); LCMS: [MH]⁺ = 145.0.

b. 3-Chloro-2-methyl-6-{2-[(phenylmethyl)oxy]phenyl}pyrazine 1 -oxide K₂CO₃ (4.14 g, 30.0 mmol), p-f-Bu₂Me-HBF₄ (0.74 g, 3.0 mmol), Pd(OAc)₂ (0.67 g,

3.0 mmol), and 3-chloro-2-methylpyrazine 1 -oxide (1.92 g, 15.0 mmol) were weighed to air and placed in a 100 ml. round-bottom flask. 1-Bromo-2-(methyloxy)benzene (3.95 g, 15.0 mmol) was added under N₂ followed by addition of toluene (40 ml_). The reaction mixture was then heated to 120 ⁰C overnight. The solution was cooled to room temperature and filtered the solid off. The filtrate was evaporated and the residue was purified by flash column chromatograph to provide 2.15 g of the title product (59%); LCMS: [MH]⁺ = 327.2.

c. 2-(6-Methyl-2-pyrazinyl)phenol To a solution of 3-chloro-2-methyl-6-{2-[(phenylmethyl)oxy]phenyl}pyrazine 1- oxide (1.52 g, 4.66 mmol) in 20 mL of MeOH were added HCOONH₄ (1.46 g, 23.3 mmol) and 10% Pd/C (0.50 g, 0.47 mmol). The reaction mixture was stirred at 50 ⁰C overnight. The solution was allowed to cool to room temperature and filtered. Solvent was removed and the residue was dissolved in EtOAc. The organic solution was washed with water and brine, and dried over Na₂SO₄. Solvent was removed and moved to next step without purification. 0.70 g of the crude product was obtained; LCMS: [MH]⁺ = 327.2. d. 2-Methyl-6-[2-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]pyrazine

To a solution of 2-(6-methyl-2-pyrazinyl)phenol (0.12 g, 0.65 mmol) in 5 ml. of DMF were added [4-(methyloxy)phenyl]methyl hypochlorite (0.15 g, 0.97 mmol), K₂CO₃ (0.27 g, 1.95 mmol), and Bu₄NI (0.98 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with EtOAc, washed with water and brine, and dried over Na₂SO₄. The solvent was evaporated and the residue was purified by flash column chromatograph to provide 0.16 g of the title product (81%); LCMS: [MH]⁺ = 307.2.

e. 3-Methyl-5-[2-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]pyrazine 1 -oxide

To a solution of 3-methyl-5-[2-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]pyrazine 1-oxide (0.16 g, 0.52 mmol) in 3 ml. of CH₂CI₂ was added mCPBA (70% purity, 0.16 g, 0.63 mmol). The reaction mixture was stirred at room temperature for 2 hr. The solution was washed with 1 Λ/ NaOH and sat'd Na₂S₂O₃ and dried over Na₂SO₄. After filtering and evaporating solvent, the crude product was purified by flash column chromatograph to provide 0.12 g of the title product (71%); LCMS: [MH]⁺ = 323.2.

f. 3-Methyl-5-[2-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]-2-(5-methyl-2-thienyl)pyrazine 1 -oxide

K₂CO₃ (0.094 g, 0.68 mmol), p-f-Bu₂Me-HBF₄ (0.033 g, 0.14 mmol), Pd(OAc)₂ (0.015 g, 0.068 mmol) and 3-methyl-5-[2-({[4-

(methyloxy)phenyl]methyl}oxy)phenyl]pyrazine 1-oxide (0.11 g, 0.34 mmol) were weighed to air and placed in a 10 mL round-bottom flask. 2-Bromo-5-methylthiophene (0.060 g, 0.34 mmol) was added under N₂ followed by addition of toluene (2 mL). The reaction mixture was then heated to 12O⁰C overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue was purified by flash column chromatograph to provide 0.085 g of the title product (60%); LCMS: [MH]⁺ = 419.2. g. 3-Methyl-5-[2-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]-2-(5-methyl-2-thienyl)-6-(2- phenylethyl)pyrazine 1 -oxide

To a solution of 3-methyl-5-[2-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]-2-(5- methyl-2-thienyl)pyrazine 1-oxide (42 mg, 0.1 mmol) in 1.5 ml. of THF at -30 ⁰C was slowly added 0.7 ml. of chloro(2-phenylethyl)magnesium (0.7 mmol, 1 M in THF). The reaction mixture was stirred at this temperature for 2 h. The solution was warmed to 0 ⁰C and was stirred with air-bubbling for 1 h. The reaction was quenched by aq NH₄CI at 0 ⁰C. The aqueous layer was extracted with EtOAc and dried over Na₂SO₄. The solvent was evaporated and the residue was purified by flash column chromatograph to provide 36 mg of the title product (62%); LCMS: [MH]⁺ = 523.2.

h. 2-[6-Methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol

To a solution of 3-methyl-5-[2-({[4-(methyloxy)phenyl]methyl}oxy)phenyl]-2-(5- methyl-2-thienyl)-6-(2-phenylethyl)pyrazine 1-oxide (0.18 g, 0.34 mmol) in 1 ml. of acetic acid was added 1 μl of trifluoroacetic acid. The reaction mixture was stirred at 90 ⁰C for 4 hr. The solvent was removed and the residue was purified by flash column chromatograph to provide 0.086 g of the title product (62%); LCMS: [MH]⁺ = 403.2.

Example 6b 2-r6-Methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2-pyrazinvnphenol

a. Methyl 2-{[2-(methyloxy)phenyl]carbonyl}-4-phenylbutanoate

To a suspension of NaH (4.31 g, 179.6 mmol) in DME (100 mL) at ⁰O C was slowly added methyl 4-phenyl butyrate (8.0 g, 44.89 mmol). After stirring for 15 min, methyl 2-(methoxy)benzoate (9.67 mL, 67.32 mmol) was added, followed by addition of 8 drops of methanol using a pipette. The mixture was then refluxed for 3 hr, cooled in an ice-bath, quenched carefully with 1 Λ/ HCI, and extracted with ethyl ether (150 mL x 3). The combined organic layer was dried over MgSO₄ then purified by silica gel chromatography [EtOAc: Hexane, 0% to 4.0%] to provide the title compound (10.5 g, 75%); LCMS (m/z): 313 [M+H]⁺. b. 3-[2-(Methyloxy)phenyl]-4-(2-phenylethyl)-5(4H)-isoxazolone

To a solution of hydroxylamine hydrochloride (2.16 g, 31.08 mmol) and sodium acetate (2.55 g, 31.08 mmol) in water (12 ml.) was added a solution of methyl 2-{[2- (methyloxy)phenyl]carbonyl}-4-phenylbutanoate (1.94 g, 6.22 mmol) in ethanol (44 ml_). The reaction mixture was heated to reflux overnight then it was diluted with chloroform (150 ml.) and washed with water (100 ml_). After second extraction of the aqueous layer, the combined organic layer was dried over MgSO₄, filtered, concentrated in vacuo then purified by flash chromatography (Biotage, EtOAc:Hexane, 15% to 60%) to yield the title compound (1.10 g, 55%); LCMS (m/z): 296 [M+H]⁺.

c. 4-Bromo-3-[2-(methyloxy)phenyl]-4-(2-phenylethyl)-5(4/-/)-isoxazolone

To a solution of 3-[2-(methyloxy)phenyl]-4-(2-phenylethyl)-5(4H)-isoxazolone (0.901 g, 3.05 mmol) in THF (30 ml.) at rt was added PTAB (1.26 g, 3.36 mmol). The reaction mixture was stirred for 10 min then quenched with cold brine (30 ml_). The mixture was extracted with diethyl ether (2 X 50 ml.) and the organic layer was dried over MgSO₄, filtered, concentrated in vacuo, then purified by flash chromatography (Biotage, EtOAc:Hexane, 0% to 20 %) to yield the title compound (0.94 g, 82%); LCMS (m/z): 374, 376 [M+H]⁺.

d. 4-Azido-3-[2-(methyloxy)phenyl]-4-(2-phenylethyl)-5(4H)-isoxazolone

To a solution of 4-bromo-3-[2-(methyloxy)phenyl]-4-(2-phenylethyl)-5(4H)- isoxazolone (0.94 g, 2.51 mmol) in nitromethane (9.5 mL) at rt was added TMG-azide (1.19 g, 7.54 mmol). After stirring for 3 hr at rt, the reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (Biotage, EtOAc- Hexanes: 2.0% to 16 %) to yield the title compound (0.575 g, 68%); LCMS (m/z): 337 [M+H]⁺.

e. 4-Amino-3-[2-(methyloxy)phenyl]-4-(2-phenylethyl)-5(4H)-isoxazolone hydrogen bromide To a solution of 4-azido-3-[2-(methyloxy)phenyl]-4-(2-phenylethyl)-5(4H)- isoxazolone (0.44 g, 1.31 mmol) in acetic acid (4.5 mL) was added a solution of HBr in AcOH (>33% v/v, 4.5 mL). The mixture was heated to 65 ⁰C for 30 min then concentrated in vacuo. The residue was azeotroped with toluene (10 mL X 3) to yield the title compound as solid (0.541 g, quantitative) and carried over without further purification; LCMS (m/z): 311 [M+H]⁺. f. Λ/-[3-[2-(Methyloxy)phenyl]-5-oxo-4-(2-phenylethyl)-4,5-dihydro-4-isoxazolyl]-2- oxopropanamide

To a solution of 4-amino-3-[2-(methyloxy)phenyl]-4-(2-phenylethyl)-5(4/-/)- isoxazolone hydrogen bromide (0.368 g, 0.941 mmol) in dichloromethane (12 ml.) cooled in an ice-bath were added a solution of 2,6-lutidine (0.352 mg, 3.3 mmol) in chloroform (1.0 ml.) and a solution of 2-oxopropanoyl chloride [prepared from chlorination of pyruvic acid with dichloromethylmethyl ether] (0.125g, 1.18 mmol) in chloroform (1.0 ml_). After 10 min, the reaction mixture was quenched with cold dilute hydrochloric acid and extracted with dichloromethane (50 ml. X 2). The organic layer was washed with saturated aq. NaHCO₃, dried over MgSO₄, filtered, concentrated in vacuo then purified by flash column chromatography (Biotage, dichloromethane-hexanes, 70% to 100%) to yield the title compound as solid (0.260 g, 73%); LCMS (m/z): 381 [M+H]⁺.

g. 3-Methyl-5-[2-(methyloxy)phenyl]-6-(2-phenylethyl)-2(1 H)-pyrazinone

To a solution of Λ/-[3-[2-(methyloxy)phenyl]-5-oxo-4-(2-phenylethyl)-4,5-dihydro-4- isoxazolyl]-2-oxopropanamide (0.123 g, 0.324 mmol) in ethanol (3 ml.) was added Lindlar catalyst (45 mg). Hydrogen gas was added to the reaction mixture using a balloon and stirred for 3 hr. After filtration through celite and concentration in vacuo, the residue was purified by flash column chromatography (Biotage, MeOH-CH₂CI₂: 0% to 4.0%) to yield the title compound as white solid (100 mg, 96%); LCMS (m/z): 320.8 [M+H]⁺.

h. 3-Methyl-5-[2-(methyloxy)phenyl]-6-(2-phenylethyl)-2-pyrazinyl trifluoromethanesulfonate To a solution of 3-methyl-5-[2-(methyloxy)phenyl]-6-(2-phenylethyl)-2(1 H)- pyrazinone (0.044 g, 0.138 mmol) in CH₂CI₂ (3.0 mL) in an ice-bath were added triethylamine (0.032 mL, 0.232 mmol) and trifluoromethanesulfonic anhydride (0.065 g, 0.232 mmol). After 20 min, the reaction mixture was diluted with dichloromethane (20 mL) and washed with dilute HCI, and saturated aq. NaHCO₃. The organic layer was dried over MgSO₄, filtered, concentrated in vacuo and purified through a pad of silica gel using ethyl ether as the eluent to yield the title compound (62 mg, quantitative); LCMS (m/z): 453 [M+H]⁺.

i. 5-Methyl-3-[2-(methyloxy)phenyl]-2-(2-phenylethyl)pyrazine To a solution of 3-methyl-5-[2-(methyloxy)phenyl]-6-(2-phenylethyl)-2-pyrazinyl trifluoromethanesulfonate (0.174 g, 0.385 mmol) in DMF (3.0 ml.) were added triethylamine (0.161 ml_, 1.53 mmol), Pd(OAc)₂ (0.0086 g, 0.038 mmol), and PPh₃ (10.1 mg, 0.038 mmol). The mixture was degassed by bubbling N₂ then formic acid was added (0.029 ml.) and the reaction mixture was heated to 60 ⁰C overnight. After concentration in vacuo, the residue was purified by flash column chromatography (Biotage, EtOAc- Hexanes: 5% to 30%) to yield the title compound as yellowish oil (109 mg, 93 %); LCMS (m/z): 305 [M+H]⁺.

j. 5-Methyl-3-[2-(methyloxy)phenyl]-2-(2-phenylethyl)pyrazine 1 -oxide

To a solution of 5-methyl-3-[2-(methyloxy)phenyl]-2-(2-phenylethyl)pyrazine (0.103 g, 0.339 mmol) in CH₂CI₂ (6 ml.) in an ice-bath was added mCPBA (0.067 g, 0.271 mmol) and the mixture was allowed to stir overnight at rt. The reaction was then quenched with saturated NaHCO3, extracted with CH₂CI₂ (2 X 50 ml_), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was filtered and purified by flash column chromatography (Biotage, EtOAc-Hexanes: 0% to 40 %) to yield the title compound (64 mg, 59%); LCMS (m/z): 321 [M+H]⁺.

k. 3-Methyl-5-[2-(methyloxy)phenyl]-2-(5-methyl-2-thienyl)-6-(2-phenylethyl)pyrazine 1- oxide

To a sealed tube under nitrogen were added 5-methyl-3-[2-(methyloxy)phenyl]-2- (2-phenylethyl)pyrazine 1-oxide (0.064 g, 0.20 mmol), K₂CO₃ (0.087 g, 0.60 mmol), Pd(OAc)₂ (0.007 g, 0.03 mmol), di-terf-butylmethyl phosphonium tetrafluoroborate (0.015g, 0.06 mmol), and 2-bromo-5-methylthiophene (0.106g, 0.60 mmol). Degassed toluene with N₂ was added to the reagents and the mixture was heated to 1 15 ⁰C overnight. After stirring overnight, additional reagents were added as follows: K₂CO₃ (41 mg, 1.5 equiv), Pd(OAc)₂ (34 mg, 0.075 equiv), di-terf-butylmethyl phosphonium tetrafluoroborate (7.5 mg, 0.15 equiv), then 2-bromo-5-methylthiophene (53 mg, 1.5 equiv). After heating the mixture for 2h, it was filtered, concentrated in vacuo and purified by flash column chromatography (Biotage, EtOAc-Hexanes: 10% to 55%) to yield the title compound as yellowish solid (0.060 g, 72%); LCMS (m/z): 417 [M+H]⁺. I. 2-[6-Methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol

To a solution of 3-methyl-5-[2-(methyloxy)phenyl]-2-(5-methyl-2-thienyl)-6-(2- phenylethyl)pyrazine 1-oxide (0.057 g, 0.137 mmol) in dichloromethane (4 ml.) cooled to ^■ 40 ⁰C was added a solution of BBr₃ in dichloromethane (1.22 ml_, 1.0 M solution). The temperature was raised to -25 ⁰C and stirring was continued for 7 hr. The mixture was quenched with cold saturated NaHCOs, extracted with dichloromethane (50 ml_x2), dried over MgSO₄, filtered, concentrated, and purified by reverse phase chromatography (Gilson: ACN:H₂O (0.10 % TFA)) to yield the title compound (8.8 mg, 16%); LCMS (m/z): 403 [M+H]⁺.

Example 7

2-fluoro-6-r6-methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2- pyrazinyllphenol

The title compound was prepared following the procedure of example 6 except for the use of 1-bromo-3-fluoro-2-[(phenylmethyl)oxy]benzene in place of 1-bromo-2- [(phenylmethyl)oxy]benzene; LCMS: [MH]⁺ = 421.2.

Example 8 5-(2-hvdroxyphenyl)-3-methyl-6-(2-phenylethyl)-2(1H)-pyrazinone

The title compound was prepared by demethylation of the intermediate from step 7 of the synthetic scheme for example 6 (scheme 4). The intermediate, 3-methyl-5-[2- (methyloxy)phenyl]-6-(2-phenylethyl)-2(1 H)-pyrazinone (15 mg, 0.047 mmol) was dissolved in CH₂CI₂ (I mL) and cooled in an ice bath. A solution of BBr₃ (0.018 mL, 1 M in CH₂CI₂) was added and the reaction mixture was stirred for 4 hr at rt. The reaction mixture was quenched with ice water, extracted with CH₂CI₂ (30 ml_), and washed with saturated NaHCOs. After drying over MgSO₄, filtering, and concentrating in vacuo, the residue was purified by flash column chromatography (MeOH-CH₂CI₂: 0%-3.5 %) to yield the title compound as solid (7.5 mg, 52%); LCMS (m/z): 306 [M+H]⁺.

Example 9 2-f3-r4-(1 -methylethyl)phenvn-2-quinoxalinyl>phenol

Pd(PPh₃)₄, Dioxane, H₂O

a. 2-[4-(1-methylethyl)phenyl]-3-[2-(methyloxy)phenyl]quinoxaline

To a solution of dichloroquinoxaline (0.50 g, 2.51 mmoles) in deoxygenated dioxane was added 4-isopropylphenylboronic acid (0.41 g, 2.51 mmoles), 2- methoxyphenylboronic acid (0.38 g, 2.51 mmoles) and aqueous Na₂CO₃ (0.53 g, 5.01 mmoles) in a sequential manner. The reaction mixture was vigorously stirred and

Pd(PPh₃)₄ (0.058 g, 0.05 moles) was added and placed in a microwave reactor. The reaction mixture was irradiated at 150 oC for 1200 sec. The reaction mixture was cooled and the solid was filtered off and the filtrate was concentrated. The crude residue was purified by flash column chromatography using 20% EtOAc in hexanes to give 0.30 g of the desired product in 34% yield. MS (m/z): 355.2 [M+H]⁺. b. 2-{3-[4-(1 -Methylethyl)phenyl]-2-quinoxalinyl}phenol

2-[4-(1-Methylethyl)phenyl]-3-[2-(methyloxy)phenyl]quinoxaline (0.30 g, 0.85 mmol) in 16 mL of dichloromethane was cooled to 0 ⁰C. 1 M solution of BBr₃ (16 ml_, 1.70 mmoles) was then added and let the reaction mixture warmed to RT. Stirred for 16 h. The reaction mixture was diluted with dichloromethane and aqueous NaHCO₃ was then added. Organic layer was separated and washed with H₂O, brine and dried over Na₂SO₄. Filtered, concentrated and purified by purified by chromatography on silica gel (Biotage, 0-20% ethyl acetate/hexane) to afford pure compound (0.23 g) in 80% yield. MS (m/z): 341.2 [M+H]⁺.

Example 10 2-{3-r4-(1 -methylethyl)phenvπ-4-oxido-2-quinoxalinyl}phenol

To a solution of 2-{3-[4-(1-methylethyl)phenyl]-2-quinoxalinyl}phenol (0.2 g, 0.59 mmoles) in dry DCM was added MCPBA (0.31 g, 0.17 mmoles). This mixture was placed under nitrogen atmosphere and stirred for 16 h. The reaction mixture was concentrated and purified by reversed phase HPLC to give the desired product (0.027 g) in 13% yield (MS (m/z): 357.2 [M+H]⁺) along with other mono oxidized product and bis oxidized product.

Example 11 2-f 3-r4-(1 -methylethyl)phenvn-1 -oxido-2-quinoxalinyl}phenol

The title compound purified from the previous reaction mixture (Example 2). (MS (m/z): 357.2 [M+H]⁺).

Example 12 2-f3-r4-(1-methylethyl)phenvn-1.4-dioxido-2-quinoxalinyl>phenol

The title compound purified from the previous reaction mixture (Example 2). (MS

(m/z): 372.2 [M+H]⁺).

Example 13 2-r6-methyl-5-(methyloxy)-2-pyrazinvnphenol

a. 2-Methyl-3-(methyloxy)pyrazine 1 -oxide

To a solution of 2-Methyl-3-(methyloxy)pyrazine (3.0 g, 0.024 moles) in dry DCM was added MCPBA (6.26 g, 0.3 moles). This mixture was placed under nitrogen atmosphere and stirred for 16 h. The reaction mixture was concentrated and purified Biotage purification system to give the desired product (1.58 g) in 47% yield.

b. 2-Methyl-3-(methyloxy)-6-[2-(methyloxy)phenyl]pyrazine 1 -oxide

2-Methyl-3-(methyloxy)pyrazine 1 -oxide (0.2 g, 1.43 mmol) was dissolved in toluene. To this was added K₂CO₃ (0.098 g, 0.714 mmol), P-f-Bu₂Me-HBF₄ (17.6 mgs, 0.29 mmol) and Pd(OAc)₂ (0.14 g, 0.14 mmol) were and placed in a 10 ml. round-bottom flask. The reaction was then deoxygenated by bubbling nitrogen (10 min) and 1-bromo-2- (methyloxy)benzene (0.044 ml_, 1.43 mmol) was added under N₂. The reaction mixture was then heated to 120 ⁰C overnight. The solution was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatograph to provide 0.051 g of the title product (58%). c. 3-Methyl-2-(methyloxy)-5-[2-(methyloxy)phenyl]pyrazine

Lithium chloride (0.79 g, 18.6 mmol) and NaBH₄ (0.71 g, 18.6 mmol) were mixed in dry THF and cooled to O⁰C. To this was added 2-Methyl-3-(methyloxy)-6-[2- (methyloxy)phenyl]pyrazine 1 -oxide (4.6 g, 17.7 mmol) and heated to 65⁰C until all the starting material is consumed. The reaction was cooled to room temperature and quenched with 1 N HCI and basified with NaHCOs. The reaction was extracted with EtOAc (x3) and combined organic layers were washed with brine. The organic layer was concentrated and purified by Biotage to provide the product (1.9 g) in 44% yield.

d. 2-[6-methyl-5-(methyloxy)-2-pyrazinyl]phenol

Demethylation using BBr₃ as previously described provided the title compound. ¹H NMR (400 MHz, DMSO-D₆) δ ppm 2.48 (s, 3 H), 3.97 (s, 3 H), 6.90-6.95 (m, 3H), 7.23 - 7.26 (m, 1 H), 7.89 - 7.91 (m, 1 H), 8.80 (s, 1 H), 10.80 (brs, 1 H).

Example 14 2-(3-chloro-6-methyl-5-phenyl-2-pyrazinyl)phenol

a. 3-Methyl-5-[2-(methyloxy)phenyl]-2(1 H)-pyrazinone

3-Methyl-2-(methyloxy)-5-[2-(methyloxy)phenyl]pyrazine (0.79 g, 3.43 mmols) was dissolved in glacial acetic acid. To this was added aqueous HBr (1.87 ml_, 0.034 moles) and heated to 9O⁰C for 2 h. The reaction mixture was cooled to room temperature and concentrated. The pure product (0.43 g) crashed out as the crude reaction mixture was taken up in DCM in 58% yield.

b. 2-Chloro-3-methyl-5-[2-(methyloxy)phenyl]pyrazine

3-Methyl-5-[2-(methyloxy)phenyl]-2(1 /-/)-pyrazinone (0.076 g, 0.35 mmols) was placed in a round bottom flask equipped with a condenser. To this was added POCI3 (1.0 ml.) and refluxed for 3 h. At this time PCI₅ (0.072 g, 0.035 mmols) was added and continued to reflux overnight. The reaction was cooled and quenched with cold water and extracted with DCM. The organic layer was concentrated and purified by Biotage to provide the product (0.06 g) in 73% yield.

c. 3-Methyl-5-[2-(methyloxy)phenyl]-2-phenylpyrazine

To a solution of 2-chloro-3-methyl-5-[2-(methyloxy)phenyl]pyrazine (0.06 g, 0.26 mmol) in dioxane (3 ml.) was added phenylboronic acid (0.062 g, 0.52 mmol), 0.2 ml_ ethanol, and 0.1 ml. aqueous sodium carbonate (0.054 g, 0.52 mmol) in a microwave reaction vessel. After 10 min. of deoxygenation, tetrakis(triphenylphosphine)palladium (0.06 g, 0.052 mmol) was added. The mixture in sealed vessel was irradiated to 15O⁰C for 40 min. The reaction mixture was filtered through syringe filter (Acrodisc CR25mm with 0.2 μm PTFE membrane). The vessel and filter were washed with dichloromethane. The dichloromethane was concentrated and the residue was purified by flash chromatography (40% ethyl acetate/ hexane) to afford the title compound (0.06 g, 85.2%).

d. 3-Methyl-5-[2-(methyloxy)phenyl]-2-phenylpyrazine 1 -oxide

Oxidation of 3-methyl-5-[2-(methyloxy)phenyl]-2-phenylpyrazine using MCPBA as described previously described provided the product in 46% yield.

e. 2-Chloro-5-methyl-3-[2-(methyloxy)phenyl]-6-phenylpyrazine

Chlorination of 3-methyl-5-[2-(methyloxy)phenyl]-2-phenylpyrazine 1 -oxide using

POCI₃ as previously described provided the product in 93% yield.

f. 2-(3-Chloro-6-methyl-5-phenyl-2-pyrazinyl)phenol

Demethylation using BBr₃ as described previously provided the title compound.

MS (m/z): 297.4 [M+H]⁺. Example 15 2-f6-methyl-5-phenyl-3-f(E)-2-phenylethenvn-2-pyrazinyl}phenol

To a solution of 2-chloro-3-methyl-5-[2-(methyloxy)phenyl]pyrazine (0.2 g, 0.65 mmol) in dioxane (3 ml.) was added [(£)-2-phenylethenyl]boronic acid (0.19 g, 1.3 mmol), 0.2 ml. ethanol, and 0.1 ml. aqueous sodium carbonate (0.136 g, 1.3 mmol) in a microwave reaction vessel. After 10 min. of deoxygenation, tetrakis(triphenylphosphine)palladium (0.06 g, 0.052 mmol) was added. The mixture in sealed vessel was irradiated to 15O⁰C for 1200 seconds. The reaction mixture was filtered through syringe filter (Acrodisc CR25mm with 0.2 μm PTFE membrane). The vessel and filter were washed with dichloromethane. The dichloromethane was concentrated and the residue was purified by flash chromatography (40% ethyl acetate/ hexane) to afford the desired compound with some minor impurities (0.23 g). Subsequent demethylation using BBr₃ produced the title compound. MS (m/z): 367.2 [M+H]⁺

Example 16 2-f6-methyl-5-phenyl-3-(2-phenylethyl)-2-pyrazinvnphenol

2-Methyl-6-[2-(methyloxy)phenyl]-3-phenyl-5-[(E)-2-phenylethenyl]pyrazine (0.7 g, 1.85 mmol) was dissolved in ethanol. To this was added Lindlar's catalyst (0.05 g) and quinoline (1.85 mmol) and placed under hydrogen atmosphere overnight. The reaction was filtered through a bed of celite and concentrated to get pure product (0.67 g) in 96% yield. Subsequent demethylation using BBr₃ produced the title compound. MS (m/z): 365.2 [M+H]⁺

Example 17 2-r6-methyl-4-oxido-5-phenyl-3-(2-phenylethyl)-2-pyrazinvnphenol

Oxidation of 2-[6-methyl-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol using MCPBA produced the title compound. MS (m/z): 383.2 [M+H]⁺ Example 18 2-f6-methyl-1-oxido-5-phenyl-3-(2-phenylethyl)-2-pyrazinvnphenol

The title compound was a product of the oxidation step in example 9. MS (m/z): +H]⁺

Example 19 2-r3-(2-phenylethyl)-2-quinoxalinvnphenol

a. 2-[2-(methyloxy)phenyl]-3-[(E)-2-phenylethenyl]quinoxaline

To a solution of dichloroquinoxaline (0.50 g, 2.51 mmoles) in deoxygenated dioxane was added [(£)-2-phenylethenyl]boronic acid (0.5 g, 2.51 mmoles), 2- methoxyphenylboronic acid (0.38 g, 2.51 mmoles) and aqueous Na₂CO₃ (0.71 g, 5.01 mmoles) in a sequential manner. The reaction mixture was vigorously stirred and Pd(PPh₃)₄ (0.39 g, 0.025 mmoles) was added and placed in a microwave reactor. The reaction mixture was irradiated at 15O⁰C for 1200 sec. The reaction mixture was cooled and the solid was filtered off and the filtrate was concentrated. The crude residue was purified by flash column chromatography using 20% EtOAc in hexanes to give 0.47 g of the desired product in 58% yield.

b. 2-[3-(2-phenylethyl)-2-quinoxalinyl]phenol

2-[2-(Methyloxy)phenyl]-3-[(£)-2-phenylethenyl]quinoxaline (0.250 g, 1.03 mmol) was dissolved in ethanol. To this was added Lindlar's catalyst (0.05 g) and quinoline (1.03 mmol) and placed under hydrogen atmosphere overnight. The reaction was filtered through a bed of celite and concentrated to get pure product (0.174 g) in 69% yield. Subsequent demethylation using BBr₃ produced the title compound. MS (m/z): 327.2 [M+H]⁺

Example 20 2-r4-oxido-3-(2-phenylethyl)-2-quinoxalinyllphenol

MCPBA, DCM

Oxidation of 2-[3-(2-phenylethyl)-2-quinoxalinyl]phenol using MCPBA as described previously produced the title compound. MS (m/z): 343.2 [M+H]⁺

The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Claims

What is claimed is:

1. A compound according to Formula (I):

(I)

wherein:

X is N or N-oxide;

Y is N or N-oxide; R1 is selected from the group consisting of hydrogen, halogen, C_3-7cycloalkyl, phenyl, phenylC_1-4alkyl, phenylC_2-4alkenyl and thienyl, wherein the phenyl or thienyl moiety is optionally substituted by

R2 is phenyl, wherein the phenyl moiety is optionally substituted, independently, once or twice, by halogen or OH; R3 is selected from the group consisting of OH, phenyl, C_1-4alkoxy and thienyl, wherein the thienyl moiety is optionally substituted by

R3 and R4 join together to form a phenyl ring; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein X and Y are N.

3. A compound according to claim 1 wherein X is N and Y is N-oxide.

4. A compound according to claim 1 wherein X is N-oxide and Y is N.

5. A compound according to claim 1 wherein X and Y are N-oxide.

6. A compound according to claim 1 wherein R1 is

7. A compound according to claim 6 wherein R1 is phenylethyl.

8. A compound according to claim 1 wherein R1 is phenylethenyl.

9. A compound according to claim 1 wherein R1 is hydrogen.

10. A compound according to claim 1 wherein R1 is halogen.

11. A compound according to claim 10 wherein R1 is Cl.

12. A compound according to claim 1 wherein R1 is phenyl, wherein the phenyl moiety is optionally substituted by Ci_-4alkyl.

13. A compound according to claim 12 wherein R1 is 4-(1-methylethyl)phenyl.

14. A compound according to claim 1 wherein R1 is C_3-7cycloalkyl.

15. A compound according to claim 1 wherein R1 is thienyl, wherein the thienyl moiety is optionally substituted by C_1-4methyl.

16. A compound according to claim 1 wherein R2 is phenyl, wherein the phenyl moiety is optionally substituted, independently, once or twice, by halogen or OH.

17. A compound according to claim 16 wherein R2 is hydroxyphenyl.

18. A compound according to claim 17 wherein R2 is 2-hydroxyphenyl.

19. A compound according to claim 16 wherein R2 is 3-fluoro-2-hydroxyphenyl.

20. A compound according to claim 1 wherein R3 is selected from the group consisting of OH, phenyl, C_1-4alkoxy, and thienyl, wherein the thienyl moiety is optionally substituted by Ci_-4alkyl.

21. A compound according to claim 20 wherein R3 is OH.

22. A compound according to claim 20 wherein R3 is thienyl, wherein the thienyl moiety is optionally substituted by Ci_-4alkyl.

23. A compound according to claim 22 wherein R3 is 5-methyl-2-thienyl.

24. A compound according to claim 1 wherein R4 is

25. A compound according to claim 24 wherein R4 is methyl.

26. A compound according to claim 1 wherein R3 and R4 join together to form a phenyl ring.

27. A compound according to claim 1 selected from the group consisting of

2-[4-oxido-3-(2-phenylethyl)-2-quinoxalinyl]phenol;

2-[3-(2-phenylethyl)-2-quinoxalinyl]phenol;

2-[6-methyl-1-oxido-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol;

2-[6-methyl-4-oxido-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-[6-methyl-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol;

2-{6-methyl-5-phenyl-3-[(E)-2-phenylethenyl]-2-pyrazinyl}phenol;

2-(3-chloro-6-methyl-5-phenyl-2-pyrazinyl)phenol;

2-[6-methyl-5-(methyloxy)-2-pyrazinyl]phenol;

2-{3-[4-(1-methylethyl)phenyl]-1 ,4-dioxido-2-quinoxalinyl}phenol; 2-{3-[4-(1-methylethyl)phenyl]-1-oxido-2-quinoxalinyl}phenol;

2-{3-[4-(1-methylethyl)phenyl]-4-oxido-2-quinoxalinyl}phenol;

2-{3-[4-(1-methylethyl)phenyl]-2-quinoxalinyl}phenol;

5-(2-hydroxyphenyl)-3-methyl-6-(2-phenylethyl)-2(1 H)-pyrazinone;

2-Fluoro-6-[6-methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol; 2-[6-Methyl-5-(5-methyl-2-thienyl)-4-oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol;

2-[6-Methyl-5-(5-methyl-2-thienyl)-1-oxido-3-(2-phenylethyl)-2-pyrazinyl]phenol;

2-Fluoro-6-[6-methyl-5-phenyl-3-(2-phenylethyl)-2-pyrazinyl]phenol;

2-Fluoro-6-[6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinyl];

2-Fluoro-6-[6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinyl]phenol; and 2-[6-Methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-pyrazinyl]phenol; or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, and a pharmaceutically acceptable carrier or diluent.

29. A method of antagonizing a calcium receptor, which comprises administering to a subject in need thereof, an effective amount of a compound according to any one of claims 1 to 27.

30. A method of treating a disease or disorder characterized by an abnormal bone or mineral homeostasis, which comprises administering to a subject in need of treatment thereof an effective amount of a compound according to any one of of claims 1 to 27.

31. A method according to claim 30 wherein the abnormal bone or mineral homeostasis disease or disorder is selected from the group consisting of osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, hypoparathyroidism, humoral hypercalcemia, malignancy and osteoporosis.

32. A method according to claim 31 wherein the bone or mineral disease or disorder is osteoporosis.

33. A method of increasing serum parathyroid levels which comprises administering to a subject in need of treatment an effective amount of a compound according to any one of claims 1 to 27.

34. A method according to claim 33 wherein the compound according to Formula (I) is co-administered with an anti-resorptive agent.

35. A method of synthesizing a compound according to claim 1 comprising the steps of: a) cross-coupling an aryl halide according to Formula (II):

(N) to form a disubstituted pyrazine according to Formula (III):

(III) b) oxidizing the disubstituted pyrazine to form a pyrazine-1 -oxide according to Formula (IV):

CIV) c) cross coupling the pyrazine-1 -oxide to form a trisubstituted pyrazine according to Formula (V):

(V) d) chlorinating the trisubstituted pyrazine to form a chloropyrazine according to Formula (Vl):

(Vl) e) coupling the chloropyrazine to form a tetrasubstituted pyrazine.

36: An intermediate selected from the group consisting of Formula (IV), (V) and (Vl):

(IV) _;

(V) ;

(Vl)