CONN P JEFFREY (US)
FELTS ANDREW S (US)
TEMPLE KAYLA J (US)
RINGUETTE ANNA E (US)
HENDERSON SCOTT H (US)
CLAIMS What is claimed is: 1. A compound having a structure represented by the following formula: A B ; wherein: X1 is CH, CR1, or N; X2 is CH, CR1, or N; X3 is CH, CR1, or N; X4 is CH, CR1, or N; X5 is CH, CR1, or N; X6 is CH, CR1, or N; X7 * , wherein X7 is CH, CR1, or N; X8 is CH, CR1, or N; X9 is CH, CR1, or N; X10 is CH, CR1, or N; X11 is CH, CR1, or N; X12 * X13 X17 X18 * ; X13 is CH, CR1, or N; X14 is CH, CR1, or N; X15 is CH, CR1, or N; X16 is CH, CR1, or N; X17 is CH, CR1, S, O, NR1, or N; X18 is CH, CR1, S, O, NR1, or N; X19 is CH, CR1, S, O, NR1, or N; X20 is CH, CR1, S, O, NR1, or N; wherein at least one of X1-X5 is N, and wherein at least one of X7-X11 is N, and wherein at least one of X12-X16 is N and wherein at least one of X17-X20 is NR1 or N; each R1, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, Me, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl, or cycloalkyl; R4 is chosen from H, alkyl, or cycloalkyl; R5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1, wherein: X1 is CH, CR1, or N; X2 is CH, or CR1; X3 is CH, CR1, or N; X4 is CH, CR1, or N; X5 is CH, CR1, or N; X6 is CH, or CR1; wherein at least one or two of X1-X5 is N; each R1, when present, is independent and chosen from H or D; or a pharmaceutically acceptable salt thereof. 3. A compound of claim 1, wherein: X7 * , wherein X7 is CH, CR1, or N; X8 is CH, or CR1; X9 is CH, CR1, or N; X10 is CH, CR1, or N; X11 is CH, or CR1; wherein at least one of X7-X11 is N; each R1, when present, is independent and chosen from H, D, CH3, or alkyl; or a pharmaceutically acceptable salt thereof. 4. A compound of claim 1, wherein: X12 * X13 X17 * ; X13 is CH, or CR1; X14 is CH, or CR1; X15 is CH, or CR1; X16 is CH, or CR1; X17 is S, N; X18 is CH, or CR1; X19 is CH, or CR1; X20 is S, or N; wherein at least one of X17-X20 is NR1 or N; each R1, when present, is independent and chosen from H, D, halogen, F, Cl, CH3, alkyl; or a pharmaceutically acceptable salt thereof. 5. A compound of claim 1, wherein: (i) X1 is CH, CR1, or N; X2 is CH, or CR1; X3 is CH, CR1, or N; X4 is CH, CR1, or N; X5 is CH, CR1, or N; X6 is CH, or CR1; wherein at one or two of X1-X5 is N; each R1, when present, is independent and chosen from H or D; X7 * X8 , wherein X7 is CH, CR1, or N; X8 is CH, or CR1; X9 is CH, CR1, or or N; X11 is CH, or CR1; wherein at one or two of X7-X11 is N; each R1, when present, is independent and chosen from H, D, CH3, or alkyl; and X12 * X17 * , wherein X12 is CH, CR1, or N; X13 is CH, or CR1; X16 is CH, or CR1; X17 is S, N; X18 is CH, or CR1; X19 is CH, or CR1; X20 is S, or N; wherein at least one of X17-X20 is NR1 or N; each R1, when present, is independent and chosen from H, D, halogen, F, Cl, CH3, alkyl; or a pharmaceutically acceptable salt thereof. 6. A compound of claim 1, of the following formula: A A , 7. A compound of claim 1, of the following formula: A A B , A or N; each R1, when present, is independent and chosen from H, D, CH3, or alkyl; and X12 * X13 X17 * , wherein X12 is CH, CR1, or N; X13 is CH, or CR1; X16 is CH, or CR1; X17 is S, N; X18 is CH, or CR1; X19 is CH, or CR1; X20 is S, or N; wherein at least one of X17-X20 is NR1 or N; each R1, when present, is independent and chosen from H, D, halogen, F, Cl, CH3, alkyl; or a pharmaceutically acceptable salt thereof. 8. A compound of claim 1, wherein: * a pharmaceutically acceptable salt thereof. 9. A compound of claim 1, wherein: N * N * N * S a 10. A compound of claim 1, of the following formula: A A a 11. A compound of claim 1, of the following formula: , , , , or ; or a; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof. 12. A pharmaceutical composition comprising a compound of one of claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. A pharmaceutical composition comprising a compound of claim 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. A method for the treatment of a disorder associated with metabotropic glutamate receptor activity in a subject, the method comprising the step of administering to the subject an effective amount of at least one compound of one of claims 1-11, or a pharmaceutically acceptable salt thereof, thereby treating the disorder associated with metabotropic glutamate receptor activity in the subject. 15. The method of claim 14, wherein the metabotropic glutamate receptor is mGlu5. 16. The method of claim 14, wherein the subject is a human. 17. The method of claim 14, wherein the subject has been diagnosed with a need for treatment of the disorder prior to the administering step. 18. The method of claim 14, further comprising the step of identifying a subject in need of treatment of the disorder. 19. The method of claim 14, wherein the disorder is a neurological and/or psychiatric disorder. 20. The method of claim 19, wherein the neurological and/or psychiatric disorder is selected from affective disorder, age-related cognitive decline, Alzheimer’s disease, amnestic disorders, amyotrophic lateral sclerosis, anxiety disorders, Angelman syndrome, Asperger syndrome, attention deficit hyperactivity disorder, bipolar disorder, brain edema, chronic pain, delirium, dementia, depression, diabetes, Down Syndrome, dystonia, eating disorders, epilepsy, fibromyalgia, Huntington’s-related chorea, levadopa-induced dyskinesia, manic- depressive illness, migraine, movement disorders, multiple sclerosis, narcolepsy, neurofibromatosis type 1, neuropathic pain, obesity, pain, paranoia, Parkinson’s disease, post- herpatic neuropathic pain, psychotic disorders, PTEN harmartoma syndrome, senile dementia, sleep disorder, substance-related disorder, or unipolar depression. 21. The method of claim 19, wherein the neurological and/or psychiatric wherein the disorder is an autism spectrum disorder. 22. The method of claim 21, wherein the autism spectrum disorder is selected from autism, classical autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), sometimes called atypical autism, Fragile X syndrome, Rett syndrome, and Childhood Disintegrative Disorder. 23. A compound of one of claims 1-11 for use in the treatment of a disorder associated with metabotropic glutamate receptor, such as mGlu5, activity in a subject. 24. A compound for use of claim 23, wherein the disorder is a neurological and/or psychiatric disorder, such as affective disorder, age-related cognitive decline, Alzheimer’s disease, amnestic disorders, amyotrophic lateral sclerosis, anxiety disorders, Angelman syndrome, Asperger syndrome, attention deficit hyperactivity disorder, bipolar disorder, brain edema, chronic pain, delirium, dementia, depression, diabetes, Down Syndrome, dystonia, eating disorders, epilepsy, fibromyalgia, Huntington’s-related chorea, levadopa-induced dyskinesia, manic-depressive illness, migraine, movement disorders, multiple sclerosis, narcolepsy, neurofibromatosis type 1, neuropathic pain, obesity, pain, paranoia, Parkinson’s disease, post-herpatic neuropathic pain, psychotic disorders, PTEN harmartoma syndrome, senile dementia, sleep disorder, substance-related disorder, or unipolar depression. 25. A compound for us of claim 24, wherein the neurological and/or psychiatric wherein the disorder is an autism spectrum disorder, such as autism, classical autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), sometimes called atypical autism, Fragile X syndrome, Rett syndrome, and Childhood Disintegrative Disorder. |
, , , , , or ; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof. [00127] In yet a further aspect, the compound exhibits negative allosteric modulation of mGlu5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGlu5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In a further aspect, human embryonic kidney cells are transfected with human mGlu5. In yet a further aspect, human embryonic kidney cells are transfected with mammalian mGlu5. In a further aspect, the compound exhibits partial or total inhibition of mGlu5 in response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with human, rat or mammalian mGlu5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In yet a further aspect, the compound exhibits negative allosteric modulation of mGlu5 after contacting a cell expressing mGlu5. In a further aspect, the compound produced exhibits partial or total inhibition of mGlu5 after contacting a cell expressing mGlu5. [00128] It is contemplated that one or more example structures can be optionally omitted from the disclosed invention. 3. NEGATIVE ALLOSTERIC MODULATION OF MGLU5 RESPONSE [00129] In one aspect, the compounds exhibit negative allosteric modulation of mGlu5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGlu5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In a further aspect, the compound exhibits partial inhibition of mGlu5 response. In a further aspect, the compound exhibits total inhibition of mGlu5 response. In a still further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 1 x 10 -7 M. In yet a further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 5 x 10 -8 M. In an even further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 1 x 10 -7 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 5 x 10 -8 M. In yet a further aspect, the human embryonic kidney cells are transfected with human mGlu5. In an even further aspect, human embryonic kidney cells are transfected with mGlu5 of a mammal. C. METABOTROPIC GLUTAMATE RECEPTOR ACTIVITY [00130] The utility of the compounds in accordance with the present invention as negative allosteric modulators of metabotropic glutamate receptor activity, in particular mGlu5 activity, can be demonstrated by methodology known in the art. HEK 293A cells stably expressing either rat or human mGlu5 were plated in black-walled, clear-bottomed, poly-D- lysine coated 384-well plates in 20 μL of assay medium (DMEM containing 10% dialyzed FBS, 20 mM HEPES, 100 units/mL penicillin/streptomycin plus 250 ng/mL Fungizone, and 1 mM sodium pyruvate) at a density of 20K cells/well. The cells were grown overnight at 37 ºC in the presence of 5% CO 2 . The next day, medium was removed and the cells incubated with 20 μL of 2.3 μM Fluo-4, AM prepared as a 2.3 mM stock in DMSO and mixed in a 1:1 ratio with 10% (w/v) pluronic acid F-127 and diluted in assay buffer (Hank’s balanced salt solution, 20 mM HEPES, and 2.5 mM probenecid) for 45 minutes at 37 °C. Dye was removed, 20 μL of assay buffer was added, and the plate was incubated for 5 minutes at room temperature. [00131] Ca 2+ flux was measured using the Functional Drug Screening System (FDSS7000, Hamamatsu, Japan). After establishment of a fluorescence baseline for about 3 seconds, the compounds of the present invention were added to the cells, and the response in cells was measured. 2.3 minutes later an EC20 concentration of the mGlu5 receptor agonist glutamate was added to the cells, and the response of the cells was measured for 1.9 minutes; an EC80 concentration of agonist was added and readings taken for an additional 1.7 minutes. All test compounds were dissolved and diluted to a concentration of 10 mM in 100% DMSO. Compounds were then serially diluted 1:3 in DMSO into 10 point concentration response curves, transferred to daughter plates, and further diluted into assay buffer to a 2x stock. Calcium fluorescence measures were recorded as fold over basal fluorescence; raw data was then normalized to the maximal response to glutamate. Antagonism of the agonist response of the mGlu5 receptor in the present invention was observed as a decrease in response to nearly maximal concentrations of glutamate in the presence of compound compared to the response to glutamate in the absence of compound. [00132] The raw data file containing all time points was used as the data source in the analysis template. This was saved by the FDSS as a tab-delimited text file. Data were normalized using a static ratio function (F/F 0 ) for each measurement of the total 360 values per well divided by each well’s initial value. Data were then reduced to peak amplitudes (Max – Initial Min) using a time range that starts approximately 3 seconds prior to the glutamate EC 20 /EC 80 addition and continues for approximately 90-120 seconds. This is sufficient time to capture the peak amplitude of the cellular calcium response. Individual amplitudes were expressed as % E Max by multiplying each amplitude by 100 and then dividing the product by the mean of the amplitudes derived from the glutamate EC Max -treated wells. IC 50 values for test compounds were generated by fitting the normalized values versus the log of the test compound concentration (in mol/L) using a 4 parameter logistic equation where none of the parameters were fixed. Each of the three values collected at each concentration of test compound were weighted evenly. [00133] A compound was designated as a negative allosteric modulator (NAM) if the compound showed a concentration-dependent decrease in the glutamate EC80 addition. For NAMs with a CRC that plateaus at a Glu Max (i.e., the amplitude of response in the presence of compound as a percentage of the maximal response to glutamate) below 10%, IC50 values are reported. For NAMs with a CRC that plateaus above 10% Glu Max, the IC50 values are reported, the compound is designated a “partial NAM” and the % Glu Max is reported. For NAMs that show a decrease in the EC80 response, but do not hit a plateau, the average of the Glu Max at a single concentration (30 µM) was determined (% Glu Max), reported, and IC50 values are reported as “>10,000 nM”. Compounds without measurable activity are designated as “>30,000 nM” since the top concentration of compound tested in the assay is 30 µM. Exemplary data are provided in Tables 1 and 2 below. [00134] In particular, the disclosed compounds had activity in modulating the mGlu5 receptor in the aforementioned assays, generally with an IC 50 for modulation of less than about 30 μM. Preferred compounds within the present invention had activity in modulating the mGlu5 receptor with an IC 50 for negative allosteric modulation of less than about 500 nM. Preferred compounds reduced the response to an EC 80 concentration of glutamate to less than 50% of the maximal response and also induced a rightward and downward shift of the glutamate concentration response curve. These compounds are negative allosteric modulators of human and rat mGlu5 and were selective for mGlu5 compared to the other six subtypes of metabotropic glutamate receptors. D. M ETHODS OF M AKING THE C OMPOUNDS [00135] In one aspect, the invention relates to methods of making compounds useful as negative allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5), which can be useful in the treatment neurological and/or psychiatric disorders associated with glutamate dysfunction and other diseases in which metabotropic glutamate receptors are involved. [00136] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein. [00137] The disclosed compounds can be prepared by various routes. In certain specific examples, the disclosed compounds can be prepared by one of ordinary skill in the art, and as exemplified below. [00138] In a further aspect, a compound comprises the product of the disclosed methods. In a still further aspect, the invention comprises a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed methods and a pharmaceutically acceptable carrier. In a still further aspect, the invention comprises a method for manufacturing a medicament comprising combining at least one compound of any of disclosed compounds or at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent. [00139] In a further aspect, the compound produced can further undergo functional group transformation of the remaining substituents to yield additional analogs. [00140] In a further aspect, the compound produced exhibits partial or total inhibition of mGlu5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGlu5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In a still further aspect, human embryonic kidney cells are transfected with human mGlu5. In yet a further aspect, human embryonic kidney cells are transfected with mammalian mGlu5. [00141] In a further aspect, the compound produced exhibits partial or total inhibition of mGlu5 in response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with human, rat or mammalian mGlu5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In a still further aspect, the compound produced exhibits negative allosteric modulation of mGlu5 after contacting a cell expressing mGlu5. In yet a further aspect, the compound produced exhibits partial or total inhibition of mGlu5 after contacting a cell expressing mGlu5. [00142] It is contemplated that each disclosed methods can further comprise additional steps, manipulations, and/or components. It is also contemplated that any one or more step, manipulation, and/or component can be optionally omitted from the invention. It is understood that the disclosed methods can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed methods of using. E. PHARMACEUTICAL COMPOSITIONS [00143] In one aspect, the invention relates to pharmaceutical compositions comprising the disclosed compounds. That is, a pharmaceutical composition can be provided comprising an effective amount of a disclosed compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount. [00144] In certain aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00145] As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N ’ - dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. [00146] As used herein, the term “pharmaceutically acceptable non-toxic acids”, includes inorganic acids, organic acids, and salts prepared therefrom, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. [00147] In practice, the compounds of the invention, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the invention, and/or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and/or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation. [00148] Thus, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. [00149] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. [00150] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques [00151] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. [00152] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00153] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [00154] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. [00155] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency. [00156] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds. [00157] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form. [00158] In the treatment conditions which require negative allosteric modulation of metabotropic glutamate receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day and can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably 0.5 to 100 mg/kg per day. A suitable dosage level can be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response. [00159] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors. Such factors include the age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the type and severity of the particular disease undergoing therapy. [00160] The present invention is further directed to a method for the manufacture of a medicament for modulating glutamate receptor activity (e.g., treatment of one or more neurological and/or psychiatric disorders associated with glutamate dysfunction) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the invention relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent. [00161] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological conditions. [00162] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. [00163] In a further aspect, the compound exhibits partial or total inhibition of mGlu5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with mGlu5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In a still further aspect, the human embryonic kidney cells are transfected with rat mGlu5. In yet a further aspect, the human embryonic kidney cells are transfected with human mGlu5. F. M ETHODS OF U SING THE C OMPOUNDS AND C OMPOSITIONS [00164] The amino acid L-glutamate (referred to herein simply as glutamate) is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS). Within the CNS, glutamate plays a key role in synaptic plasticity (e.g., long term potentiation (the basis of learning and memory)), motor control and sensory perception. It is now well understood that a variety of neurological and psychiatric disorders are associated with dysfunctions in the glutamatergic system. Thus, modulation of the glutamatergic system is an important therapeutic goal. Glutamate acts through two distinct receptors: ionotropic and metabotropic glutamate receptors. The first class, the ionotropic glutamate receptors, is comprised of multi-subunit ligand-gated ion channels that mediate excitatory post-synaptic currents. Three subtypes of ionotropic glutamate receptors have been identified, and despite glutamate serving as agonist for all three receptor subtypes, selective ligands have been discovered that activate each subtype. The ionotropic glutamate receptors are named after their respective selective ligands: kainite receptors, AMPA receptors and NMDA receptors. [00165] The second class of glutamate receptor, termed metabotropic glutamate receptors, (mGlus), are G-protein coupled receptors (GPCRs) that modulate neurotransmitter release or the strength of synaptic transmission, based on their location (pre-or post-synaptic). The mGlus are family C GPCR, characterized by a large (~560 amino acid) “venus fly trap” agonist binding domain in the amino-terminal domain of the receptor. This unique agonist binding domain distinguishes family C GPCRs from family A and B GPCRs wherein the agonist binding domains are located within the 7-strand transmembrane spanning (7TM) region or within the extracellular loops that connect the strands to this region. To date, eight distinct mGlus have been identified, cloned and sequenced. Based on structural similarity, primary coupling to intracellular signaling pathways and pharmacology, the mGlus have been assigned to three groups: Group I (mGlu1 and mGlu5), Group II (mGlu2 and mGlu3) and Group III (mGlu4, mGlu6, mGlu7 and mGlu8). Group I mGlus are coupled through Gαq/11 to increase inositol phosphate and metabolism and resultant increases in intracellular calcium. Group I mGlus are primarily located post-synaptically and have a modulatory effect on ion channel activity and neuronal excitability. Group II (mGlu2 and mGlu3) and Group III (mGlu4, mGlu6, mGlu7 and mGlu8) mGlus are primarily located pre-synaptically where they regulate the release of neurotransmitters, such as glutamate. Group II and Group III mGlus are coupled to G ^i and its associated effectors such as adenylate cyclase. [00166] Post-synaptic mGlus are known to functionally interact with post-synaptic ionotropic glutamate receptors, such as the NMDA receptor. For example, activation of mGlu5 by a selective agonist has been shown to increase post-synaptic NMDA currents (Mannaioni et al. (2001) J. Neurosci.21, 5925-5934). Therefore, modulation of mGlus is an approach to modulating glutamatergic transmission. Numerous reports indicate that mGlu5 plays a role in a number of disease states including anxiety (Spooren et al. (2000) J. Pharmacol. Exp. Therapeut.295, 1267-1275 ; Tatarczynska et al. (2001) Br. J. Pharmaol. 132, 1423-1430), addiction to cocaine (Chiamulera et al. (2001) Nature Neurosci.4, 873- 874), Parkinson’s disease (Awad et al. (2000) J. Neurosci.20, 7871-7879 ; Ossowska et al. (2001) Neuropharmacol.41, 413-420), pain (Salt and Binns (2001) Neurosci.100, 375-380), and Fragile X syndrome (FXS) (see, i.e., de Vrij, F. M. S., et al. (2008) Neurobiol. Disease 31, 127-132; Yan, Q. J., et al. (2005) Neuropharmacol 49, 1053-1066). [00167] The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which compounds of formula I or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound will be more efficacious than either as a single agent. [00168] In one aspect, the subject compounds can be coadministered with anti-Alzheimer’s agents, beta-secretase inhibitors, gamma-secretase inhibitors, muscarinic agonists, muscarinic potentiators, HMG-CoA reductase inhibitors, NSAIDs and anti-amyloid antibodies. [00169] In a further aspect, the subject compounds can be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, anti-epileptics, selective serotonin reuptake inhibitors (“SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), tricyclic antidepressant drugs, monoamine oxidase inhibitors (MAOIs), 5-HT2 agonists or antagonists, GlyT1 inhibitors and the like such as, but not limited to: risperidone, clozapine, olanzapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and combinations thereof. [00170] In a further aspect, the subject compound can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor), anti-cholinergics such as biperiden, COMT inhibitors such as entacapone, A2a adenosine antagonists, cholinergic agonists, NMDA receptor agonists or antagonists and dopamine agonists. [00171] In a further aspect, the subject compound can be administered in combination with opiate agonists or antagonists, calcium channel antagonists, sodium channel antagonists, COX-2 selective inhibitors, NK1 antagonists, non-steroidal anti-inflammatory drugs (“NSAID”), GABA-A receptor modulators, dopamine agonists or antagonists, norepinephrine modulators, nicotinic agonists or antagonists including nicotine, and muscarinic agonists or antagonists. In a yet further aspect, the subject compound can be administered in combination with heroin substituting drugs such as methadone, levo-alpha-acetylmethadol, buprenorphine and naltrexone, and disulfiram and acamprosate. In a further aspect, the subject compound can be administered in combination with L-DOPA, buspirone, valproate, and gabapentin. [00172] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. 1. T REATMENT M ETHODS [00173] The compounds disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with glutamate dysfunction. Thus, provided is a method of treating or preventing a disorder in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject. [00174] Also provided is a method for the treatment of one or more neurological and/or psychiatric disorders associated with glutamate dysfunction in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject. [00175] Examples of disorders associated with glutamate dysfunction include: acute and chronic neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS- induced dementia), Alzheimer’s disease, Huntington’s Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson’s disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, addictive behavior, including addiction to substances (including opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal from such addictive substances (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), obesity, psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder. [00176] Anxiety disorders that can be treated or prevented by the compositions disclosed herein include generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder. Addictive behaviors include addiction to substances (including opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal from such addictive substances (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.) and substance tolerance. [00177] Also provided is a method for treating or preventing anxiety, comprising: administering to a subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including anxiety and related disorders. These include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post- traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, and anxiety disorder not otherwise specified. [00178] Further disorders that can be treated or prevented by the compositions disclosed herein include Autism spectrum disorders, which are neuropsychiatric conditions characterized by widespread abnormalities of social interactions and communication, as well as severely restricted interests and highly repetitive behavior. Autism spectrum disorders include Autism, Asperger syndrome, Childhood Disintegrative Disorders, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), sometimes called atypical autism, and Rett Syndrome. Fragile X syndrome (FXS) is a single gene disorder almost universally associated with symptoms of autism spectrum disorder, the most common form of inherited mental retardation, and the most common known cause of autism, affecting 1 in 6,000 births. Therapeutic agents for treatment of patients with FXS are among the most critical of unmet medical needs, and there are very few proven effective treatment strategies for this patient population. Again, without wishing to be bound by theory, increasing evidence has identified a connection between the Fragile X phenotype and mGlu signaling [00179] Compounds of the invention can be used, for example, for the treatment of Fragile X syndrome and autism spectrum disorder in a manner that can improve symptoms (e.g., reduce anxiety and irritability; increase cognitive function, communication and/or social interaction). Thus, the methods of the invention can provide an effective manner to treat a subject having Fragile X syndrome or autism spectrum disorder. a. TREATING A DISORDER [00180] In one aspect, the invention relates to a method for the treatment of a disorder associated with metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one disclosed compound or at least one disclosed product in a dosage and amount effective to treat the disorder in the mammal. In a further aspect, the mammal is a human. In a further aspect, the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. In a further aspect, the method further comprises the step of identifying a mammal in need of treatment of the disorder. [00181] In one aspect, the invention relates to a method for the treatment of a disorder associated with metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula: A or or X 12 * X 13 X 17 or O, NR1, or N; X18 is CH, CR1, S, O, NR1, or N; X19 is CH, CR1, S, O, NR1, or N; X20 is CH, CR- 1, S, O, NR1, or N; wherein at least one of X1-X5 is N, and wherein at least one of X7-X11 is N, and wherein at least one of X12-X16 is N and wherein at least one of X17-X20 is NR1 or N; each R 1 , when present, is independent and chosen from H, D, OH, NH 2 , NR 3 R 4 , OR 5 ,, CHF 2 , CF 3 , halogen, F, Cl, CH 3 , alkyl, alkyl-halogen, Me, CD 3 , cycloalkyl, CN, methoxy, or alkoxy; R 3 is chosen from H, alkyl, or cycloakyl; R 4 is chosen from H, alkyl, or cycloalkyl; R 5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00182] In a further aspect, the compound administered is any disclosed compound or a product of a disclosed method. [00183] In a further aspect, the metabotropic glutamate receptor is mGlu5. [00184] In a further aspect, the mammal is a human. In a still further aspect, the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. In yet a further aspect, the treatment of the disorder further comprises the step of identifying a mammal in need of treatment of the disorder. In an even further aspect, the disorder is a neurological and/or psychiatric disorder associated with metabotropic glutamate receptor dysfunction. In a further aspect, the neurological and/or psychiatric disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, and depression. [00185] In a further aspect, the neurological and/or psychiatric disorder is an autism spectrum disorder. In a still further aspect, the autism spectrum disorder is selected from autism, classical autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), sometimes called atypical autism, Fragile X syndrome, Rett syndrome, and Childhood Disintegrative Disorder. [00186] In a further aspect, the disorder is a disease of uncontrolled cellular proliferation. In a still further aspect, the uncontrolled cellular proliferation is cancer. In yet a further aspect, the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer. In an even further aspect, the disease of uncontrolled cellular proliferation is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma. [00187] In one aspect, the disorder is a neurological and/or psychiatric disorder associated with glutamate dysfunction. In a further aspect, the disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, depression, affective disorder, age-related cognitive decline, Alzheimer’s disease, amnestic disorders, amyotrophic lateral sclerosis, anxiety disorders, Angelman syndrome, Asperger syndrome, attention deficit hyperactivity disorder, bipolar disorder, brain edema, chronic pain, delirium, dementia, depression, diabetes, Down Syndrome, dystonia, eating disorders, epilepsy, fibromyalgia, Huntington’s-related chorea, levadopa-induced dyskinesia, manic-depressive illness, migraine, movement disorders, multiple sclerosis, narcolepsy, neurofibromatosis type 1, neuropathic pain, obesity, pain, paranoia, Parkinson’s disease, post- herpatic neuropathic pain, psychotic disorders, PTEN hamartoma syndrome, senile dementia, sleep disorder, substance-related disorder, or unipolar depression. [00188] In a further aspect, the compound exhibits partial inhibition of mGlu5 response. In a still further aspect, the compound exhibits total inhibition of mGlu5 response. In yet a further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 1 x 10 -7 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 5 x 10 -8 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 1 x 10 -7 M. In yet a further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 5 x 10- 8 M. b. DECREASING MGLU5 ACTIVITY [00189] In one aspect, the invention relates to a method for decreasing metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one disclosed compound or at least one disclosed product in a dosage and amount effective to decrease metabotropic glutamate receptor activity in the mammal. In a further aspect, the mammal is a human. In a further aspect, the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. In a further aspect, the method further comprises the step of identifying a mammal in need of treatment of the disorder. [00190] In one aspect, the invention relates to a method for decreasing metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula: A or or X 12 * X 13 X 17 or O, NR1, or N; X18 is CH, CR1, S, O, NR1, or N; X19 is CH, CR1, S, O, NR1, or N; X20 is CH, CR- 1, S, O, NR1, or N; wherein at least one of X1-X5 is N, and wherein at least one of X7-X11 is N, and wherein at least one of X12-X16 is N and wherein at least one of X17-X20 is NR1 or N; each R 1 , when present, is independent and chosen from H, D, OH, NH 2 , NR 3 R 4 , OR 5 , F, CHF 2 , CF 3 , halogen, F, Cl, CH 3 , alkyl, alkyl-halogen, Me, CD 3 , cycloalkyl, CN, methoxy, or alkoxy; R 3 is chosen from H, alkyl, or cycloalkyl; R 4 is chosen from H, alkyl, or cycloalkyl; R 5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00191] In a further aspect, the compound administered is any disclosed compound or a product of a disclosed method. [00192] In a further aspect, the metabotropic glutamate receptor is mGlu5. [00193] In a further aspect, the mammal is a human. In a still further aspect, the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. In yet a further aspect, the treatment of the disorder further comprises the step of identifying a mammal in need of treatment of the disorder. In an even further aspect, the disorder is a neurological and/or psychiatric disorder associated with metabotropic glutamate receptor dysfunction. In a further aspect, the neurological and/or psychiatric disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, and depression. [00194] In a further aspect, the neurological and/or psychiatric disorder is an autism spectrum disorder. In a still further aspect, the autism spectrum disorder is selected from autism, classical autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), sometimes called atypical autism, Fragile X syndrome, Rett syndrome, and Childhood Disintegrative Disorder. [00195] In a further aspect, the disorder is a disease of uncontrolled cellular proliferation. In a still further aspect, the uncontrolled cellular proliferation is cancer. In yet a further aspect, the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer. In an even further aspect, the disease of uncontrolled cellular proliferation is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma. [00196] In one aspect, the disorder is a neurological and/or psychiatric disorder associated with glutamate dysfunction. In a further aspect, the disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, depression, affective disorder, age-related cognitive decline, Alzheimer’s disease, amnestic disorders, amyotrophic lateral sclerosis, anxiety disorders, Angelman syndrome, Asperger syndrome, attention deficit hyperactivity disorder, bipolar disorder, brain edema, chronic pain, delirium, dementia, depression, diabetes, Down Syndrome, dystonia, eating disorders, epilepsy, fibromyalgia, Huntington’s-related chorea, levadopa-induced dyskinesia, manic-depressive illness, migraine, movement disorders, multiple sclerosis, narcolepsy, neurofibromatosis type 1, neuropathic pain, obesity, pain, paranoia, Parkinson’s disease, post- herpatic neuropathic pain, psychotic disorders, PTEN hamartoma syndrome, senile dementia, sleep disorder, substance-related disorder, or unipolar depression. [00197] In a further aspect, the compound exhibits partial inhibition of mGlu5 response. In a still further aspect, the compound exhibits total inhibition of mGlu5 response. In yet a further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 1 x 10 -7 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 5 x 10 -8 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 1 x 10 -7 M. In yet a further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 5 x 10- 8 M. c. INHIBITING MGLU5 ACTIVITY [00198] In one aspect, the invention relates to a method for inhibiting metabotropic glutamate receptor activity in a mammal, comprising the step of contacting the mammal with at least one disclosed compound or at least one disclosed product in an amount effective to inhibit metabotropic glutamate receptor activity in the mammal. [00199] In one aspect, the invention relates to a method for inhibiting metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of least one compound having a structure represented by a formula: A B ; wherein X 1 is CH, CR 1 , or N; X 2 is CH, CR 1 , or N; X 3 is CH, CR 1 , or N; X 4 is CH, CR 1 , or N; X 5 is CH, CR 1 , or N; X 6 is CH, CR 1 , or N; X 7 * X 8 or or O, NR 1 , or N; X 18 is CH, CR 1 , S, O, NR 1 , or N; X 19 is CH, CR 1 , S, O, NR 1 , or N; X 20 is CH, CR- 1 , S, O, NR 1 , or N; wherein at least one of X1-X5 is N, and wherein at least one of X7-X11 is N, and wherein at least one of X 12 -X 16 is N and wherein at least one of X 17 -X 20 is NR 1 or N; each R1, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, Me, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl, or cycloalkyl; R4 is chosen from H, alkyl, or cycloalkyl; R5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00200] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. [00201] In a further aspect, the metabotropic glutamate receptor is mGlu5. [00202] In a further aspect, the mammal is a human. In a still further aspect, the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. In yet a further aspect, the treatment of the disorder further comprises the step of identifying a mammal in need of treatment of the disorder. In an even further aspect, the disorder is a neurological and/or psychiatric disorder associated with metabotropic glutamate receptor dysfunction. In a further aspect, the neurological and/or psychiatric disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, and depression. [00203] In a further aspect, the compound exhibits partial inhibition of mGlu5 response. In a still further aspect, the compound exhibits total inhibition of mGlu5 response. In yet a further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 1 x 10 -7 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 5 x 10 -8 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 1 x 10 -7 M. In yet a further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 5 x 10- 8 M. d. NEGATIVE ALLOSTERIC MODULATION OF MGLU5 ACTIVITY [00204] In one aspect, the invention relates to a method for negative allosteric modulation of metabotropic glutamate receptor activity in a mammal, comprising the step of contacting the mammal with at least one disclosed compound or at least one disclosed product in an amount effective to negatively allosterically modulate metabotropic glutamate receptor activity in the mammal. [00205] In one aspect, the invention relates to a method for negative allosteric modulation of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula: A B ; wherein X 1 is CH, CR 1 , or N; X 2 is CH, CR 1 , or N; X 3 is CH, CR 1 , or N; X 4 is CH, CR 1 , or N; X 5 is CH, CR 1 , or N; X 6 is CH, CR 1 , or N; X 7 * X 8 or or O, NR 1 , or N; X 18 is CH, CR 1 , S, O, NR 1 , or N; X 19 is CH, CR 1 , S, O, NR 1 , or N; X 20 is CH, CR- 1 , S, O, NR 1 , or N; wherein at least one of X1-X5 is N, and wherein at least one of X7-X11 is N, and wherein at least one of X 12 -X 16 is N and wherein at least one of X 17 -X 20 is NR 1 or N; each R1, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, Me, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl, or cycloalkyl; R4 is chosen from H, alkyl, or cycloalkyl; R5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00206] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. [00207] In a further aspect, the metabotropic glutamate receptor is mGlu5. [00208] In a further aspect, the mammal is a human. In a still further aspect, the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. In yet a further aspect, the treatment of the disorder further comprises the step of identifying a mammal in need of treatment of the disorder. In an even further aspect, the disorder is a neurological and/or psychiatric disorder associated with metabotropic glutamate receptor dysfunction. In a further aspect, the neurological and/or psychiatric disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, and depression. e. P ARTIAL A NTAGONISM OF M G LU 5 A CTIVITY [00209] In one aspect, the invention relates to a method for partial antagonism of metabotropic glutamate receptor activity in a mammal, comprising the step of contacting the mammal with at least one disclosed compound or at least one disclosed product in an amount effective to partially antagonize metabotropic glutamate receptor activity in the mammal. [00210] In one aspect, the invention relates to a method for partial antagonism of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula: A or or X12 * X 13 X 17 X 18 ; wherein X12 is CH, CR1, or N; X13 is CH, CR1, or or N; X16 is CH, CR1, or N; X17 is CH, CR1, S, O, or or N; X19 is CH, CR1, S, O, NR1, or N; X20 is CH, CR- 1, S, O, NR1, or N; wherein at least one of X 1 -X 5 is N, and wherein at least one of X 7 -X 11 is N, and wherein at least one of X 12 -X 16 is N and wherein at least one of X 17 -X 20 is NR 1 or N; each R 1 , when present, is independent and chosen from H, D, OH, NH 2 , NR 3 R 4 , OR 5 , CHF 2 , CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, Me, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl, or cycloalkyl; R4 is chosen from H, alkyl, or cycloalkyl; R5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00211] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. [00212] In a further aspect, the metabotropic glutamate receptor is mGlu5. [00213] In a further aspect, the mammal is a human. In a still further aspect, the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. In yet a further aspect, the treatment of the disorder further comprises the step of identifying a mammal in need of treatment of the disorder. In an even further aspect, the disorder is a neurological and/or psychiatric disorder associated with metabotropic glutamate receptor dysfunction. In a further aspect, the neurological and/or psychiatric disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, and depression. f. MODULATING MGLU5 ACTIVITY [00214] In one aspect, the invention relates to a method for modulating metabotropic glutamate receptor activity in a mammal, comprising the step of contacting the mammal with at least one disclosed compound or at least one disclosed product in an amount effective to modulate metabotropic glutamate receptor activity in the mammal. [00215] In one aspect, the invention relates to a method for modulating metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula: A or or X 12 * X 17 ; wherein X 12 is CH, CR 1 , or N; X 13 is CH, CR 1 , or or N; X16 is CH, CR1, or N; X17 is CH, CR1, S, O, NR 1 , or N; X 18 is CH, CR 1 , S, O, NR 1 , or N; X 19 is CH, CR 1 , S, O, NR 1 , or N; X 20 is CH, CR- 1 , S, O, NR 1 , or N; wherein at least one of X1-X5 is N, and wherein at least one of X7-X11 is N, and wherein at least one of X12-X16 is N and wherein at least one of X17-X20 is NR1 or N; each R 1 , when present, is independent and chosen from H, D, OH, NH 2 , NR 3 R 4 , OR 5 , CHF 2 , CF 3 , halogen, F, Cl, CH 3 , alkyl, alkyl-halogen, Me, CD 3 , cycloalkyl, CN, methoxy, or alkoxy; R 3 is chosen from H, alkyl, or cycloalkyl; R 4 is chosen from H, alkyl, or cycloalkyl; R 5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00216] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. [00217] In a further aspect, modulating is inhibition. In a still further aspect, modulating is noncompetitive inhibition. In yet a further aspect, modulating is noncompetitive antagonism. In an even further aspect, modulating is negative allosteric modulation. [00218] In a further aspect, the metabotropic glutamate receptor is mGlu5. [00219] In a further aspect, the mammal is a human. In a still further aspect, the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. In yet a further aspect, the treatment of the disorder further comprises the step of identifying a mammal in need of treatment of the disorder. In an even further aspect, the disorder is a neurological and/or psychiatric disorder associated with metabotropic glutamate receptor dysfunction. In a further aspect, the neurological and/or psychiatric disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, and depression. g. I NHIBITING M G LU 5 A CTIVITY IN C ELLS [00220] In one aspect, the invention relates to a method for inhibiting metabotropic glutamate receptor activity in at least one cell, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one disclosed product in an amount effective to inhibit metabotropic glutamate receptor activity in the at least one cell. [00221] In one aspect, the invention relates to a method for inhibiting metabotropic glutamate receptor activity in at least one cell, comprising the step of contacting at least one cell with at least one compound having a structure represented by a formula: A or or X 12 * X 13 X 17 or O, NR1, or N; X18 is CH, CR1, S, O, NR1, or N; X19 is CH, CR1, S, O, NR1, or N; X20 is CH, CR- 1, S, O, NR1, or N; wherein at least one of X1-X5 is N, and wherein at least one of X7-X11 is N, and wherein at least one of X12-X16 is N and wherein at least one of X17-X20 is NR1 or N; each R 1 , when present, is independent and chosen from H, D, OH, NH 2 , NR 3 R 4 , OR 5 , CHF 2 , CF 3 , halogen, F, Cl, CH 3 , alkyl, alkyl-halogen, Me, CD 3 , cycloalkyl, CN, methoxy, or alkoxy; R 3 is chosen from H, alkyl, or cycloalkyl; R 4 is chosen from H, alkyl, or cycloalkyl; R 5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00222] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. [00223] In a further aspect, the metabotropic glutamate receptor is mGlu5. [00224] In a further aspect, the cell is mammalian. In a still further aspect, the cell is human. In yet a further aspect, the cell has been isolated from a mammal prior to the contacting step. In an even further aspect, contacting the cell is via administration to a mammal. In a still further aspect, inhibiting metabotropic glutamate receptor activity in the at least one cell decreases metabotropic glutamate receptor activity in the mammal. In yet a further aspect, the decrease in metabotropic glutamate receptor activity in the mammal treats a disorder associated with metabotropic glutamate receptor activity in the mammal. [00225] In a further aspect, the neurological and/or psychiatric disorder is an autism spectrum disorder. In a still further aspect, the autism spectrum disorder is selected from autism, classical autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), sometimes called atypical autism, Fragile X syndrome, Rett syndrome, and Childhood Disintegrative Disorder. [00226] In a further aspect, the disorder is a disease of uncontrolled cellular proliferation. In a still further aspect, the uncontrolled cellular proliferation is cancer. In yet a further aspect, the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer. In an even further aspect, the disease of uncontrolled cellular proliferation is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma. [00227] In one aspect, the disorder is a neurological and/or psychiatric disorder associated with glutamate dysfunction. In a further aspect, the disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, depression, affective disorder, age-related cognitive decline, Alzheimer’s disease, amnestic disorders, amyotrophic lateral sclerosis, anxiety disorders, Angelman syndrome, Asperger syndrome, attention deficit hyperactivity disorder, bipolar disorder, brain edema, chronic pain, delirium, dementia, depression, diabetes, Down Syndrome, dystonia, eating disorders, epilepsy, fibromyalgia, Huntington’s-related chorea, levadopa-induced dyskinesia, manic-depressive illness, migraine, movement disorders, multiple sclerosis, narcolepsy, neurofibromatosis type 1, neuropathic pain, obesity, pain, paranoia, Parkinson’s disease, post- herpatic neuropathic pain, psychotic disorders, PTEN hamartoma syndrome, senile dementia, sleep disorder, substance-related disorder, or unipolar depression. [00228] In a further aspect, the compound exhibits partial inhibition of mGlu5 response. In a still further aspect, the compound exhibits total inhibition of mGlu5 response. In yet a further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 1 x 10 -7 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 5 x 10 -8 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 1 x 10 -7 M. In yet a further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 5 x 10- 8 M. h. MODULATING MGLU5 ACTIVITY IN CELLS [00229] In one aspect, the invention relates to a method for modulating metabotropic glutamate receptor activity in at least one cell, comprising the step of contacting at least one cell with at least one disclosed compound or at least one disclosed product in an amount effective to modulate metabotropic glutamate receptor activity in at least one cell. [00230] In one aspect, the invention relates to a method for modulating metabotropic glutamate receptor activity in at least one cell, comprising the step of contacting at least one cell with at least one compound having a structure represented by a formula: A B ; wherein X1 is CH, CR1, or N; X2 is CH, CR1, or N; X3 is CH, CR1, or N; X4 is CH, CR1, or N; X5 is CH, CR1, or N; X6 is CH, CR1, or N; X7 * X 8 X 9 X 11 A is X 10 , wherein X7 is CH, CR1, or N; X8 is CH, CR1, or N; X9 is CH, CR1, or N; X10 is CH, CR1, or N; X11 is CH, CR1, or N; X 12 * X 13 X 17 X 18 ; wherein X12 is CH, CR1, or N; X13 is CH, CR1, or or N; X16 is CH, CR1, or N; X17 is CH, CR1, S, O, NR1, or N; X18 is CH, CR1, S, O, NR1, or N; X19 is CH, CR1, S, O, NR1, or N; X20 is CH, CR- 1, S, O, NR1, or N; wherein at least one of X 1 -X 5 is N, and wherein at least one of X 7 -X 11 is N, and wherein at least one of X 12 -X 16 is N and wherein at least one of X 17 -X 20 is NR 1 or N; each R1, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF 3 , halogen, F, Cl, CH 3 , alkyl, alkyl-halogen, Me, CD 3 , cycloalkyl, CN, methoxy, or alkoxy; R 3 is chosen from H, alkyl, or cycloalkyl; R 4 is chosen from H, alkyl, or cycloalkyl; R 5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00231] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. [00232] In a further aspect, the metabotropic glutamate receptor is mGlu5. [00233] In a further aspect, modulating is inhibition. In a still further aspect, modulating is noncompetitive inhibition. In yet a further aspect, modulating is noncompetitive antagonism. In an even further aspect, modulating is negative allosteric modulation. [00234] In a further aspect, the cell is mammalian. In a still further aspect, the cell is human. In yet a further aspect, the cell has been isolated from a mammal prior to the contacting step. In an even further aspect, contacting the cell is via administration to a mammal. In a still further aspect, inhibiting metabotropic glutamate receptor activity in the at least one cell decreases metabotropic glutamate receptor activity in the mammal. In yet a further aspect, the decrease in metabotropic glutamate receptor activity in the mammal treats a disorder associated with metabotropic glutamate receptor activity in the mammal. 2. M ANUFACTURE OF A M EDICAMENT [00235] In one aspect, the invention relates to a method for manufacturing a medicament comprising combining at least one disclosed compound with a pharmaceutically acceptable carrier or diluent. In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. In a further aspect, the metabotropic glutamate receptor is mGlu5. [00236] In a further aspect, the compound exhibits partial or total inhibition of mGlu5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with mGlu5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In a still further aspect, the human embryonic kidney cells are transfected with rat mGlu5. In yet a further aspect, the human embryonic kidney cells are transfected with human mGlu5. [00237] In a further aspect, the neurological and/or psychiatric disorder is an autism spectrum disorder. In a still further aspect, the autism spectrum disorder is selected from autism, classical autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), sometimes called atypical autism, Fragile X syndrome, Rett syndrome, and Childhood Disintegrative Disorder. [00238] In a further aspect, the disorder is a disease of uncontrolled cellular proliferation. In a still further aspect, the uncontrolled cellular proliferation is cancer. In yet a further aspect, the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer. In an even further aspect, the disease of uncontrolled cellular proliferation is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma. [00239] In one aspect, the disorder is a neurological and/or psychiatric disorder associated with glutamate dysfunction. In a further aspect, the disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain,depression, affective disorder, age-related cognitive decline, Alzheimer’s disease, amnestic disorders, amyotrophic lateral sclerosis, anxiety disorders, Angelman syndrome, Asperger syndrome, attention deficit hyperactivity disorder, bipolar disorder, brain edema, chronic pain, delirium, dementia, depression, diabetes, Down Syndrome, dystonia, eating disorders, epilepsy, fibromyalgia, Huntington’s-related chorea, levadopa-induced dyskinesia, manic-depressive illness, migraine, movement disorders, multiple sclerosis, narcolepsy, neurofibromatosis type 1, neuropathic pain, obesity, pain, paranoia, Parkinson’s disease, post- herpatic neuropathic pain, psychotic disorders, PTEN hamartoma syndrome, senile dementia, sleep disorder, substance-related disorder, or unipolar depression. [00240] In a further aspect, the compound exhibits partial inhibition of mGlu5 response. In a still further aspect, the compound exhibits total inhibition of mGlu5 response. In yet a further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 1 x 10 -7 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 5 x 10 -8 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 1 x 10 -7 M. In yet a further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 5 x 10- 8 M. 3. USE OF COMPOUNDS [00241] Also provided are the uses of the disclosed compounds and products. In one aspect, the use relates to a treatment of a disorder in a mammal. In one aspect, the use is characterized in that the mammal is a human. In one aspect, the use is characterized in that the disorder is a neurological and/or psychiatric disorder associated with glutamate dysfunction. In one aspect, the use relates to negative allosteric modulation of metabotropic glutamate receptor activity in a mammal. [00242] In one aspect, the invention relates to use of at least one compound having a structure represented by a formula: A or or X 12 * X 13 X 17 or O, NR1, or N; X18 is CH, CR1, S, O, NR1, or N; X19 is CH, CR1, S, O, NR1, or N; X20 is CH, CR- 1, S, O, NR1, or N; wherein at least one of X1-X5 is N, and wherein at least one of X7-X11 is N, and wherein at least one of X12-X16 is N and wherein at least one of X17-X20 is NR1 or N; each R 1 , when present, is independent and chosen from H, D, OH, NH 2 , NR 3 R 4 , OR 5 , CHF 2 , CF 3 , halogen, F, Cl, CH 3 , alkyl, alkyl-halogen, Me, CD 3 , cycloalkyl, CN, methoxy, or alkoxy; R 3 is chosen from H, alkyl, or cycloalkyl; R 4 is chosen from H, alkyl, or cycloalkyl; R 5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof. [00243] In a further aspect, the compound is any disclosed compound or product of a disclosed method. In a further aspect, the metabotropic glutamate receptor is mGlu5. [00244] In a further aspect, the compound exhibits partial or total inhibition of mGlu5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with mGlu5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In a still further aspect, the human embryonic kidney cells are transfected with rat mGlu5. In yet a further aspect, the human embryonic kidney cells are transfected with human mGlu5. [00245] In a further aspect, the neurological and/or psychiatric disorder is an autism spectrum disorder. In a still further aspect, the autism spectrum disorder is selected from autism, classical autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), sometimes called atypical autism, Fragile X syndrome, Rett syndrome, and Childhood Disintegrative Disorder. [00246] In a further aspect, the disorder is a disease of uncontrolled cellular proliferation. In a still further aspect, the uncontrolled cellular proliferation is cancer. In yet a further aspect, the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer. In an even further aspect, the disease of uncontrolled cellular proliferation is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma. [00247] In one aspect, the disorder is a neurological and/or psychiatric disorder associated with glutamate dysfunction. In a further aspect, the disorder is selected from addiction, anxiety, Fragile X syndrome, gastroesophageal reflux disease (GERD), Parkinson’s disease, pain, depression, affective disorder, age-related cognitive decline, Alzheimer’s disease, amnestic disorders, amyotrophic lateral sclerosis, anxiety disorders, Angelman syndrome, Asperger syndrome, attention deficit hyperactivity disorder, bipolar disorder, brain edema, chronic pain, delirium, dementia, depression, diabetes, Down Syndrome, dystonia, eating disorders, epilepsy, fibromyalgia, Huntington’s-related chorea, levadopa-induced dyskinesia, manic-depressive illness, migraine, movement disorders, multiple sclerosis, narcolepsy, neurofibromatosis type 1, neuropathic pain, obesity, pain, paranoia, Parkinson’s disease, post- herpatic neuropathic pain, psychotic disorders, PTEN hamartoma syndrome, senile dementia, sleep disorder, substance-related disorder, or unipolar depression. [00248] In a further aspect, the compound exhibits partial inhibition of mGlu5 response. In a still further aspect, the compound exhibits total inhibition of mGlu5 response. In yet a further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 1 x 10 -7 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 5 x 10 -8 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 1 x 10 -7 M. In yet a further aspect, the compound exhibits partial or total inhibition with an IC50 of less than about 5 x 10- 8 M. 4. KITS [00249] In one aspect, the invention relates to a kit comprising at least one compound having a structure represented by a formula: A or or X12 * X 13 X 17 X 18 ; wherein X12 is CH, CR1, or N; X13 is CH, CR1, or or N; X16 is CH, CR1, or N; X17 is CH, CR1, S, O, or or N; X19 is CH, CR1, S, O, NR1, or N; X20 is CH, CR- 1, S, O, NR1, or N; wherein at least one of X 1 -X 5 is N, and wherein at least one of X 7 -X 11 is N, and wherein at least one of X 12 -X 16 is N and wherein at least one of X 17 -X 20 is NR 1 or N; each R 1 , when present, is independent and chosen from H, D, OH, NH 2 , NR 3 R 4 , OR 5 , CHF 2 , CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, Me, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl, or cycloalkyl; R4 is chosen from H, alkyl, or cycloalkyl; R5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof; and one or more of: (a) at least one agent known to increase mGlu5 activity; (b) at least one agent known to decrease mGlu5 activity; (c) at least one agent known to treat a neurological and/or psychiatric disorder; or (d) instructions for treating a disorder associated with glutamate dysfunction. [00250] In a further aspect, the at least one compound and the at least one agent are co- formulated. In a further aspect, the at least one compound and the at least one agent are co- packaged. [00251] In a further aspect, the kit, wherein the compound present is any disclosed compound or at least one product of a disclosed method of making. [00252] In a further aspect, the kit comprises a disclosed compound or a product of a disclosed method. [00253] The kits can also comprise compounds and/or products co-packaged, co- formulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient. [00254] It is contemplated that the disclosed kits can be used in connection with the disclosed methods of making, the disclosed methods of using, and/or the disclosed compositions. 5. N ON -M EDICAL U SES [00255] Also provided are the uses of the disclosed compounds and products as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of potentiators of mGlu related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents of mGlu. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of potentiators of mGlu5 related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents of mGlu5. G. EXPERIMENTAL [00256] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ^C or is at ambient temperature, and pressure is at or near atmospheric. [00257] Several methods for preparing the compounds of this invention are illustrated in the following Examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated herein. All 1 H NMR spectra were obtained on instrumentation at a field strength of 300 to 500 MHz. 1. GENERAL SCHEMES General Scheme I a 4, solvent (e.g., DMF) and heat (e.g., microwave irradiation at 140 °C) may provide a mixture of intermediates A2 and A3. Intermediate A2 with boronic acids or boronic esters (B1) under standard Suzuki reaction conditions may provide intermediate A4. Reaction of intermediate A4 under basic hydrolysis conditions (e.g, NaOH) and heat (e.g, 100 °C) may provide intermediate A5. General Scheme II General Scheme II shows a method for preparing intermediates of the invention. Reaction of intermediate A6 with boronic acids or boronic esters (B1) under standard Suzuki reaction condtions may provide intermediate A7. Intermediate A7 in the presence of a palladium catalyst (e.g., (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride), base (e.g, potassium acetate), carbon monoxide and solvent (e.g., DMF/MeOH) may provide intermediate A8. Reaction of intermediate A8 under basic hydrolysis conditons (e.g., NaOH) and heat (e.g., 50 °C) may provide intermediate A9. General Scheme III As shown in be prepared under standard Suzuki reaction conditions with intermediates like A10 (e.g., X is halogen), boronic acids or boronic esters (B1) and heat (e.g, microwave irradiation). General Scheme IV General a Reaction of intermediates A12 (e.g., X is halogen) can be transformed into a boronic ester A13, followed by standard Suzuki reaction conditions to provide analogues A14. Intermediates A14 may be subjected to basic hydrolysis conditions (e.g., NaOH) and heat (e.g.100 °C) to provide intermediates A15. General Scheme V General Intermediates like A16, where R 2 is H (carboxylic acid), Na (sodium carboxylate) or an alternative carboxylate (e.g., Lithium), under standard amide formation conditions (e.g., amine (R 3 -NH 2 ), POCl3 and pyridine; or amine (R 3 -NH2) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) provides analogues A17. 2. E XEMPLARY S CHEMES Exemplary Scheme 1 Exemplary Scheme 2 Exemplary Scheme 4
Exemplary Scheme 5 H 2 N N N N S POCl 3 H O N N N Na Pyridine 0 o C N N N S 3 O 1 O S 3. CHARACTERIZATION OF EXEMPLARY COMPOUNDS [00258] Table 1 below lists specific compounds, experimentally determined molecular mass, and mGlu5 activity determined in a cell-based assay. The mGlu5 activity was determined in a calcium mobilization assay using human embryonic kidney cells expressing human mGlu5. The mGlu5 activity data are shown as the average of at least three experiments with the standard error in these cases. If no error is indicated for the mGlu5 activity, the values given represent the results from a single experiment or the average of two experiments. The compounds in Table 1 were synthesized with methods identical or analogous to those shown herein. The requisite starting materials were commercially available, described in the literature, or readily synthesized by one skilled in the art of organic synthesis. [00259] The following abbreviations may be used herein: Ac acetyl aq aqueous atm atmosphere(s) BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ - biphenyl)]palladium(II) methanesulfonate methanesulfonate CDCl3 chloroform-d CD3OD methanol-d4 Celite® diatomaceous earth conc. concentrated DCM dichloromethane d doublet δ chemical shift in parts per million dd doublet of doublets ddd doublet of doublet of doublets dt doublet of triplets DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 dimethylsulfoxide-d6 (deuterated dimethylsulfoxide) dppf 1,1'-bis(diphenylphosphino)ferrocene ES-MS electrospray mass spectrometry Et ethyl EtOAc ethyl acetate eq./equiv equivalents h or hr hour(s) HPLC high performance liquid chromatography Hz hertz IPA isopropyl alcohol J Coupling constant in Hertz KOAc potassium acetate M molarity (for concentration) m multiplet Me methyl MeCN acetonitrile MeOH methanol MHz megahertz min minute(s) µW microwave NMR nuclear magnetic resonance Pd(dppf)Cl2 (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd(PPh3)4 tetrakis(triphenylphosphine)-palladium(0) ppm parts per million q quartetet RP reverse phase r.t./rt/RT room temperature s singlet sat. saturated soln. solution t triplet TFA trifluoroacetic acid Scheme 1 4-Chloro-1,8-naphthyridine-2-carbonitrile and 2-chloro-1,8-naphthyridine-4-carbonitrile (S1): To a vial was added 2,4-dichloro-1,8-naphthyridine (200 mg, 1 mmol, 1.0 eq), tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.10 mmol, 0.10 eq), and zinc cyanide (71 mg, 0.60 mmol, 0.6 eq) in DMF (10 mL). The vial was sealed and heated to 120 °C for 1.5 hours. Additional zinc cyanide (35 mg, 0.30 mmol, 0.3 eq) was added and the mixture heated for 30 minutes, then tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.10 mmol, 0.10 eq) was added and the mixture heated for 30 minutes. The reaction mixture was diluted with water (120 mL) and extracted with EtOAc (3x). The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated under vacuum. Crude product was purified using Teledyne ISCO Combi-Flash system (solid loading, 40G column, 0 - 4% DCM/MeOH/1% NH 4 OH, 13 min run) to give a mixture of unseperatable title compounds (1.8:1). ES-MS [M+1] + : 190.0. 4-(4-Methylpyridin-3-yl)-1,8- (S2): Equally divided into two 5 mL microwave vials was added a mixture of 4-chloro-1,8-naphthyridine-2-carbonitrile/2-chloro-1,8- naphthyridine-4-carbonitrile (243.9 mg, 1.29 mmol, 1.0 eq), 4-picoline-3-boronic acid (352 mg, 2.57 mmol, 2.0 eq), Pd(dppf)Cl 2 (95 mg, 0.13 mmol, 0.10 eq), and cesium carbonate (1.27 g, 3.86 mmol, 3.0 eq) in 1,4-dioxane (6 mL). The mixture was stirred at 100 °C for 1 hour. The mixture was filtered over celite, washed with DCM/MeOH and concentrated. Crude product was purified using Teledyne ISCO Combi-Flash system (liquid loading with DCM, 40G column, 1% DCM/MeOH for 8 min; then 1 – 2.5% DCM/MeOH for 12 min) to give 95 mg (30% over 2 steps) of title compound. 1 H NMR (400 MHz, CD 3 OD) δ 9.26 (dd, J = 4.2, 1.9 Hz, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.45 (s, 1H), 8.08 (dd, J = 8.5, 1.9 Hz, 1H), 8.05 (s, 1H), 7.77 (dd, J = 8.5, 4.2 Hz, 1H), 7.56 (dt, J = 5.2, 0.8 Hz, 1H), 2.14 (d, J = 0.7 Hz, 3H); ES-MS [M+1] + : 247.2. Sodium 4-(4-methylpyridin-3-yl)-1,8- (S3): To a vial was added 4-(4- methyl-3-pyridyl)-1,8-naphthyridine-2- mmol, 1.0 eq), 2M aqueous sodium hydroxide (771 μL, 3.85 mmol, 10 eq), and 1,4-dioxane (0.5 mL). The reaction was then heated to 100 °C for 2 hours. The aqueous mixture was extracted with DCM (2x). The aqueous layer was concentrated to afford title compoundwhich was used without further purification. 1 H NMR (400 MHz, CD 3 OD) δ 9.15 (dd, J = 4.4, 1.9 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.44 (s, 1H), 8.17 – 8.11 (m, 1H), 8.00 (dd, J = 8.4, 1.8 Hz, 1H), 7.65 (dd, J = 8.3, 4.2 Hz, 1H), 7.54 (dt, J = 5.2, 0.7 Hz, 1H), 2.13 (s, 3H); ES-MS [M+1] + : 266.1. Scheme 2 7-chloro-5-(4-methylpyridin-3-yl) a vial was added a mixture of 5-bromo-7- chloroquinoxaline (200 mg, 0.82 mmol, 1.0 eq), 4-picoline-3-boronic acid (146 mg, 1.1 mmol, 1.3 eq), Pd(dppf)Cl2 (61 mg, 0.08 mmol, 0.10 eq), and cesium carbonate (808 mg, 2.46 mmol, 3.0 eq) in 1,4-dioxane (4.5 mL). The mixture was stirred at 100 °C for 2 hours. The mixture was cooled and additional 4-picoline-3-boronic acid (34 mg, 0.25 mmol, 0.30 eq) was added. The mixture was then heated at 100 °C for an additional 1 hour. The reaction mixture was then cooled and filtered over celite, washed with DCM/MeOH, and concentrated. Crude product was purified using Teledyne ISCO Combi-Flash system (solid loading, 40G column, 0 - 90% EtOAc/DCM for 15 min, then 0 – 3.5% MeOH/DCM with 1% NH4OH additive, 20 min run) to afford 146 mg of title compound (70% yield). 1 H NMR (400 MHz, CD3OD) δ 8.93 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.45 (dt, J = 5.2, 0.7 Hz, 1H), 2.11 (s, 3H); ES-MS [M+1] + : 256.2. Methyl 8-(4-methylpyridin-3-yl)quinoxaline-6-carboxylate (S5): To a solution of 7-chloro-5-(3- methyl-4-pyridyl)quinoxaline (146 mg, 0.57 mmol, 1.0 eq) in methanol (1.5 mL) and DMF (1.4 mL) was added potassium acetate (169 mg, 1.72 mmol, 3.0 eq) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42 mg, 0.06 mmol, 0.10 eq). The mixture was placed under an atmosphere of CO(g). The resulting reaction was stirred overnight at 80 ° C. The reaction was recharged with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42 mg, 0.06 mmol, 0.10 eq), replaced under an atmosphere of CO (g) , and stirred at 80 °C for an additional 18 hours. The mixture was filtered over celite, washed with DCM/MeOH, and concentrated. Crude product was purified using Teledyne ISCO Combi-Flash system (liquid loading with DCM, 12G column, 0 - 4% DCM/MeOH, 12 min run) to afford 114 mg of title compound (68% yield). 1 H NMR (400 MHz, CD 3 OD) δ 9.01 (d, J = 1.8 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.39 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 7.46 (dt, J = 5.2, 0.7 Hz, 1H), 4.04 (s, 3H), 2.10 (s, 3H); ES-MS [M+1] + : 280.2. Sodium 8-(4-methylpyridin-3-yl) (S6): To a vial was added methyl 8-(4- methyl-3-pyridyl)quinoxaline-6- mg, 1.0 eq) and 2M aqueous sodium hydroxide (611 μL, 1.22 mmol, 3.0 eq) in 1,4-dioxane (0.5 mL). The reaction was then heated to 50 °C for 1 hr. The aqueous mixture was extracted with DCM (2x). The aqueous layer was concentrated to afford title compound which was carried forward without further purification. 1 H NMR (400 MHz, CD3OD) δ 8.92 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.40 (s, 1H), 8.30 (d, J = 1.8 Hz, 1H), 7.44 (dt, J = 5.2, 0.8 Hz, 1H), 2.11 (s, 3H); ES-MS [M+1] + : 266.1. Scheme 3 4-(4-Methylpyridin-3-yl)-1,7-naphthyridine-2-carboxylic acid (S7): In a vial was added a mixture of methyl 4-chloro-1,7-naphthyridine-2-carboxylate (70 mg, 0.31 mmol, 1.0 ew), 4-picoline-3-boronic acid (69 mg, 0.5 mmol, 1.6 eq), Pd(dppf)Cl2 (23 mg, 0.03 mmol, 0.10 eq), and cesium carbonate (309 mg, 0.94 mmol, 3.0 eq) in 1,4-dioxane (2.2 mL). The mixture was stirred at 90 °C for 3 hours. The mixture was filtered over celite, washed with DCM/MeOH, and concentrated. Residue was dissolved in water which was made basic with 1M aqueous sodium hydroxide. The aqueous solution was then extracted with DCM (3x). The pH of the aqueous layer was then adjusted to pH = 3 and extracted with chloroform/IPA (4:1) (3x) to give 50 mg title compound (60% yield) which was carried forward without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.62 (d, J = 0.9 Hz, 1H), 8.68 (d, J = 5.8 Hz, 1H), 8.64 (d, J = 5.1 Hz, 1H), 8.48 (s, 1H), 8.20 (s, 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.37 (dd, J = 5.8, 1.0 Hz, 1H), 2.05 (s, 3H); ES-MS [M+1] + : 266.2. Scheme 4 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-c arbonitrile (S8): To a microwave vial was added a mixture of 4-chloroquinoline-2-carbonitrile (50 mg, 0.27 mmol, 1 eq), bis(pinacolato)diboron (101 mg, 0.40 mmol, 1.5 eq), potassium acetate (78 mg, 0.80 mmol, 3 eq), and dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium(ii) dichloromethane adduct (22 mg, 0.027 mmol, 0.10 eq) dissolved in 1,4-dioxanes (2 mL). The reaction mixture was placed under inert atmosphere and irradiated in a microwave to 120 °C for 1 hour. The reaction mixture was filtered through a plug of Celite and washed with EtOAc/DCM. The solvents were concentrated to afford title compound which was carried forward without further purification. ES-MS [M+1]+: 199.2 (boronic acid). N N 4-(4-Methylpyridin-3-yl)quinoline-2- a vial was added 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinoline-2- mmol, 1.4 eq), 3-bromo-4-picoline (40 mg, 0.23 mmol, 1 eq), potassium carbonate (98 mg, 0.70 mmol, 3 eq), and BrettPhos Pd G3 (21 mg, 0.023 mmol, 0.1 eq) in 1,4-dioxane (1.8 mL) and water (0.2 mL). The mixture was heated to 100 °C for 1 hour under inert atmosphere then cooled to ambient temperature. The reaction mixture was filtered over Celite and rinsed with EtOAc/DCM. The organic washes were pooled, concentrated, and the residue was carried forward without further purification. ES-MS [M+1] + : 246.4. 4-(4-methylpyridin-3-yl)quinoline-2- 4-(4-Methylpyridin-3-yl)quinoline-2- carbonitrile (33 mg, 0.13 mmol, 1 eq) was dissolved in 1,4-dioxanes (2.8 mL) and 2M aqueous sodium hydroxide was added (2 mL, 4 mmol, 30 eq). The mixture was heated to 100 °C for 16 hours then cooled to ambient temperature. The pH of the reaction mixture was adjusted to a pH 4-5 with 2M aqueous HCl and concentrated to dryness. The residue was suspending in 10% MeOH/DCM and filtered to remove insoluble salts to afford title compound which was used carried forward without further purification. ES- MS [M+1] + : 265.4. Scheme 5 4-(4-Methylpyridin-3-yl)-N-(4- 2-carboxamide (1): A mixture of sodium 4-(4-methylpyridin-3-yl)-1,8-naphthyridine-2-carboxylate (15 mg, 0.06 mmol, 1.0 eq), 2-amino-4-methylthiazole (13 mg, 0.11 mmol, 2.0 eq) in pyridine (0.25 mL) was cooled to 0 °C where phosphorus(V) oxychloride (13 μL, 0.14 mmol, 2.4 eq) was added dropwise. The reaction was stirred and allowed to slowly warm to room temperature for 1 hour. Upon completion, the reaction was cooled to 0 °C and saturated aqueous NaHCO3 was added to the reaction mixture. The aqueous layer was extracted with CHCl 3 /IPA (3:1) (3x), the organic layers were passed through a phase separator then concentrated. Crude product was dissolved in DMSO (1 mL), syringe filtered, and purified using the RP-HPLC (30 × 50 mm column, 5 - 60% MeCN/ 0.05% aqueous NH4OH, 4 min run). Fractions containing desired product were combined and concentrated to yield title compound as a yellow solid (1.1 mg, 5% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.28 (dd, J = 4.1, 1.9 Hz, 1H), 8.67 (d, J = 5.1 Hz, 1H), 8.47 (s, 1H), 8.40 (s, 1H), 7.95 (dd, J = 8.4, 1.9 Hz, 1H), 7.58 (dd, J = 8.4, 4.1 Hz, 1H), 7.37 (dt, J = 5.2, 0.8 Hz, 1H), 6.64 (q, J = 1.0 Hz, 1H), 2.42 (d, J = 1.1 Hz, 3H), 2.11 (s, 3H); ES- MS [M+1] + : 362.3. N-(5-fluoropyridin-2-yl)-4-(4- 2-carboxamide (2): Synthesized in a similar manner as a colorless solid (1.5 mg, 8% yield). 1 H NMR (400 MHz, CDCl3) δ 10.84 (s, 1H), 9.28 (dd, J = 4.1, 1.9 Hz, 1H), 8.67 (d, J = 5.1 Hz, 1H), 8.48 (s, 1H), 8.46 (dd, J = 9.0, 4.1 Hz, 1H), 8.43 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 7.96 (dd, J = 8.4, 1.9 Hz, 1H), 7.58 (dd, J = 8.4, 4.1 Hz, 1H), 7.52 (ddd, J = 9.0, 7.6, 3.0 Hz, 1H), 7.37 (dd, J = 5.1, 1.0 Hz, 1H), 2.11 (s, 3H); ES-MS [M+1] + : 360.2. N-(6-methylpyridin-2-yl)-4-(4- 2-carboxamide (3): Synthesized in a similar manner as compound 1 to afford title compound as a yellow solid (1.7 mg, 9% yield). 1 H NMR (400 MHz, CDCl3) δ 10.79 (s, 1H), 9.27 (dd, J = 4.1, 2.0 Hz, 1H), 8.67 (d, J = 5.1 Hz, 1H), 8.48 (s, 1H), 8.43 (s, 1H), 8.24 (dt, J = 8.3, 0.8 Hz, 1H), 7.95 (dd, J = 8.4, 2.0 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.57 (dd, J = 8.4, 4.1 Hz, 1H), 7.36 (dt, J = 5.1, 0.8 Hz, 1H), 6.97 (dt, J = 7.5, 0.7 Hz, 1H), 2.53 (s, 3H), 2.11 (d, J = 0.6 Hz, 3H); ES-MS [M+1] + : 356.4. 4-(4-Methylpyridin-3-yl)-N-(pyridin-2-yl)-1,8-naphthyridine- 2-carboxamide (4): Synthesized in a similar manner as compound 1 to afford title compound as a yellow solid (3.5 mg, 18% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 10.82 (s, 1H), 9.28 (dd, J = 4.1, 2.0 Hz, 1H), 8.67 (d, J = 5.1 Hz, 1H), 8.48 (s, 1H), 8.47 – 8.39 (m, 3H), 7.95 (dd, J = 8.4, 1.9 Hz, 1H), 7.79 (td, J = 7.9, 2.0 Hz, 1H), 7.57 (dd, J = 8.4, 4.1 Hz, 1H), 7.36 (dt, J = 5.2, 0.8 Hz, 1H), 7.11 (ddd, J = 7.4, 4.8, 1.0 Hz, 1H), 2.11 (s, 3H); ES-MS [M+1] + : 342.4. 8-(4-Methylpyridin-3-yl)-N-(4- 6-carboxamide (5): Synthesized in a similar manner as compound 1 to afford title compound as a yellow solid (2.2 mg, 11% yield). 1 H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 1.7 Hz, 1H), 8.90 (d, J = 1.7 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 5.1 Hz, 1H), 8.43 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 5.1 Hz, 1H), 6.62 (q, J = 0.8 Hz, 1H), 2.31 (d, J = 1.0 Hz, 3H), 2.08 (s, 3H); ES-MS [M+1] + : 362.2. N-(6-methylpyridin-2-yl)-8-(4- 6-carboxamide (6): Synthesized in a similar manner as compound 1 to afford title compound as an off-white solid (3.4 mg, 17% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.97 (d, J = 1.7 Hz, 1H), 8.90 (d, J = 1.7 Hz, 1H), 8.79 (s, 1H), 8.75 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 5.1 Hz, 1H), 8.50 (s, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.70 (dd, J = 8.3, 7.5 Hz, 1H), 7.30 (dt, J = 5.1, 0.7 Hz, 1H), 6.99 (dt, J = 7.4, 0.8 Hz, 1H), 2.50 (s, 3H), 2.10 (s, 3H); ES-MS [M+1] + : 356.4. 8-(4-Methylpyridin-3-yl)-N-(pyridin-2-yl)quinoxaline-6-carbo xamide (7): Synthesized in a similar manner as compound 1 to afford title compound as an off-white solid (5.2 mg, 27% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (s, 1H), 8.97 (d, J = 1.8 Hz, 1H), 8.90 (d, J = 1.7 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 5.1 Hz, 1H), 8.50 (s, 1H), 8.42 (dt, J = 8.4, 1.0 Hz, 1H), 8.36 – 8.29 (m, 1H), 8.26 (d, J = 2.1 Hz, 1H), 7.81 (ddd, J = 8.4, 7.4, 1.9 Hz, 1H), 7.30 (dt, J = 5.1, 0.7 Hz, 1H), 7.12 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 2.10 (s, 3H); ES-MS [M+1] + : 342.4. N-(5-fluoropyridin-2-yl)-4-(4- 2-carboxamide (8): Synthesized in a similar manner as compound 1 to afford title compound as an off-white solid (8.1 mg, 40% yield). 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 9.73 (s, 1H), 8.90 – 8.65 (m, 2H), 8.58 – 8.34 (m, 3H), 8.30 (d, J = 3.0 Hz, 1H), 7.56 (ddd, J = 9.1, 7.5, 3.0 Hz, 1H), 7.41 (d, J = 5.0 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 2.14 (s, 3H); ES-MS [M+1] + : 360.3. 4-(4-Methylpyridin-3-yl)-N-(4- 2-carboxamide (9): Synthesized in a similar manner as compound 1 to afford title compound as a yellow solid (2.7 mg, 13% yield). ES-MS [M+1] + : 362.4. 4-(4-Methylpyridin-3-yl)-N-(pyridin-2-yl)quinoline-2-carboxa mide (10): Synthesized in a similar manner as compound 1 to afford title compound (17.2 mg, 66% yield). ES-MS [M+1] + : 341.2. N-(5-Fluoropyridin-2-yl)-4-(4- 2-carboxamide (11): Synthesized in a similar manner as compound 1 to afford title compound (13.8 mg, 50% yield). ES-MS [M+1] + : 359.2. N-(6-Methylpyridin-2-yl)-4-(4- 2-carboxamide (12): Synthesized in a similar manner as compound 1 to afford title compound (14.8 mg, 54% yield). ES-MS [M+1] + : 355.2. 4-(4-Methylpyridin-3-yl)-N-(4-methylthiazol-2-yl)quinoline-2 -carboxamide (13): Synthesized in a similar manner as compound 1 to afford title compound (12.6 mg, 45% yield). ES-MS [M+1] + : 361.2. TABLE 1 ES-MS hmGlu5 NAM Compound Structure Chemical Name [M+1] IC 50 (nM) 4-(4-methylpyridin-3-yl)-N-(4- 1 methylthiazol-2-yl)-1,8- 362.3 1399 naphthyridine-2-carboxamide N-(5-fluoropyridin-2-yl)-4-(4- 2 methylpyridin-3-yl)-1,8- 360.2 1171 naphthyridine-2-carboxamide N-(6-methylpyridin-2-yl)-4-(4- 3 methylpyridin-3-yl)-1,8- 356.4 2957 naphthyridine-2-carboxamide 4-(4-methylpyridin-3-yl)-N- 4 (pyridin-2-yl)-1,8- 342.4 2463 naphthyridine-2-carboxamide 8-(4-methylpyridin-3-yl)-N-(4- 5 methylthiazol-2- 362.2 3968 yl)quinoxaline-6-carboxamide N-(6-methylpyridin-2-yl)-8-(4- 6 methylpyridin-3- 356.4 >10,000 yl)quinoxaline-6-carboxamide 8-(4-methylpyridin-3-yl)-N- (pyridin-2-yl)quinoxaline-6- 342.4 >10,000 carboxamide N-(5-fluoropyridin-2-yl)-4-(4- methylpyridin-3-yl)-1,7- 360.3 396 naphthyridine-2-carboxamide 4-(4-methylpyridin-3-yl)-N-(4- methylthiazol-2-yl)-1,7- 362.4 302 naphthyridine-2-carboxamide 4-(4-methylpyridin-3-yl)-N- (pyridin-2-yl)quinoline-2- 341.2 93 carboxamide N-(5-fluoropyridin-2-yl)-4-(4- methylpyridin-3-yl)quinoline- 359.2 225 2-carboxamide N-(6-methylpyridin-2-yl)-4-(4- methylpyridin-3-yl)quinoline- 355.2 287 2-carboxamide 4-(4-methylpyridin-3-yl)-N-(4- methylthiazol-2-yl)quinoline- 361.2 258 2-carboxamide 4. METABOTROPIC GLUTAMATE RECEPTOR ACTIVITY ASSAY [00260] The utility of the compounds in accordance with the present invention as negative allosteric modulators of metabotropic glutamate receptor activity, in particular mGlu5 activity, can be demonstrated by methodology known in the art. HEK 293A cells stably expressing either rat or human mGlu5 were plated in black-walled, clear-bottomed, poly-D- lysine coated 384-well plates in 20 μL of assay medium (DMEM containing 10% dialyzed FBS, 20 mM HEPES, 100 units/mL penicillin/streptomycin plus 250 ng/mL Fungizone, and 1 mM sodium pyruvate) at a density of 20K cells/well. The cells were grown overnight at 37 ºC in the presence of 5% CO 2 . The next day, medium was removed and the cells incubated with 20 μL of 2.3 μM Fluo-4, AM prepared as a 2.3 mM stock in DMSO and mixed in a 1:1 ratio with 10% (w/v) pluronic acid F-127 and diluted in assay buffer (Hank’s balanced salt solution, 20 mM HEPES, and 2.5 mM probenecid) for 45 minutes at 37 °C. Dye was removed, 20 μL of assay buffer was added, and the plate was incubated for 5 minutes at room temperature. [00261] Ca 2+ flux was measured using the Functional Drug Screening System (FDSS7000, Hamamatsu, Japan). After establishment of a fluorescence baseline for about 3 seconds, the compounds of the present invention were added to the cells, and the response in cells was measured. 2.3 minutes later an EC20 concentration of the mGlu5 receptor agonist glutamate was added to the cells, and the response of the cells was measured for 1.9 minutes; an EC80 concentration of agonist was added and readings taken for an additional 1.7 minutes. All test compounds were dissolved and diluted to a concentration of 10 mM in 100% DMSO. Compounds were then serially diluted 1:3 in DMSO into 10 point concentration response curves, transferred to daughter plates, and further diluted into assay buffer to a 2x stock. Calcium fluorescence measures were recorded as fold over basal fluorescence; raw data was then normalized to the maximal response to glutamate. Antagonism of the agonist response of the mGlu5 receptor in the present invention was observed as a decrease in response to nearly maximal concentrations of glutamate in the presence of compound compared to the response to glutamate in the absence of compound. [00262] The raw data file containing all time points was used as the data source in the analysis template. This was saved by the FDSS as a tab-delimited text file. Data were normalized using a static ratio function (F/F 0 ) for each measurement of the total 360 values per well divided by each well’s initial value. Data were then reduced to peak amplitudes (Max – Initial Min) using a time range that starts approximately 3 seconds prior to the glutamate EC 20 /EC 80 addition and continues for approximately 90-120 seconds. This is sufficient time to capture the peak amplitude of the cellular calcium response. Individual amplitudes were expressed as % EMax by multiplying each amplitude by 100 and then dividing the product by the mean of the amplitudes derived from the glutamate EC Max -treated wells. IC 50 values for test compounds were generated by fitting the normalized values versus the log of the test compound concentration (in mol/L) using a 4 parameter logistic equation where none of the parameters were fixed. Each of the three values collected at each concentration of test compound were weighted evenly. [00263] A compound was designated as a negative allosteric modulator (NAM) if the compound showed a concentration-dependent decrease in the glutamate EC80 addition. For NAMs with a CRC that plateaus at a Glu Max (i.e. the amplitude of response in the presence of compound as a percentage of the maximal response to glutamate) below 10%, IC50 values are reported. For NAMs with a CRC that plateaus above 10% Glu Max, the IC50 values are reported, the compound is designated a “partial NAM” and the % Glu Max is reported. For NAMs that show a decrease in the EC80 response, but do not hit a plateau, the average of the Glu Max at a single concentration (30 µM) was determined (% Glu Max), reported, and IC50 values are reported as “>10,000 nM”. Compounds without measurable activity are designated as “>30,000 nM” since the top concentration of compound tested in the assay is 30 µM. Exemplary data are provided in Table 1. [00264] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
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