6,5 WESTERN CORE COMPOUNDS AS MGLU5 NEGATIVE ALLOSTERIC MODULATORS AND METHODS OF MAKING AND USING THE SAME

ACKNOWLEDGMENT

[0001] This invention was made with government support under Grant no.

1UG3NS116218 awarded by the National Institute of Health (NIH). The United States government has certain rights in the invention.

BACKGROUND

[0002] Glutamate (L-glutamic acid) is the major excitatory transmitter in the mammalian central nervous system, exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C (also known as family 3) of the G-protein-coupled receptors (GPCRs). They are characterized by a seven transmembrane (7TM) α-helical domain connected via a cysteine rich-region to a large bi-lobed extracellular amino-terminal domain (FIG. 1). While the orthosteric binding site is contained in the amino-terminal domain, currently known allosteric binding sites reside in the 7TM domain. The mGlu family comprises eight known mGlu receptor types (designated as mGlul through mGlu8). Several of the receptor types are expressed as specific splice variants, e.g. mGlu5a and mGlu5b or mGlu8a, mGlu8b and mGlu8c. The family has been classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology. Group I receptors (mGlul and mGlu5) are coupled to G«q, a process that results in stimulation of phospholipase C and an increase in intracellular calcium and inositol phosphate levels. Group II receptors (mGlu2 and mGlu3) and group III receptors (mGlu4, mGlu6, mGlu7, and mGlu8) are coupled to Gαi, which leads to decreases in cyclic adenosine monophosphate (cAMP) levels. While the Group I receptors are predominately located postsynaptically and typically enhance postsynaptic signaling, the group II and III receptors are located presy naptically and typically have inhibitory effects on neurotransmitter release. Without wishing to be bound by theory ⁷ , increasing evidence indicates mGlus play an important role in lasting changes in synaptic transmission, and studies of synaptic plasticity in the Fmrl knockout mouse have identified a connection between the Fragile X phenotype and mGlu signaling. [0003] The identification of small molecule mGlu antagonists that bind at the orthosteric site has greatly increased the understanding of the roles played by these receptors and their corresponding relation to disease. Because the majority of these antagonists were designed as analogs of glutamate, they typically lack desired characteristics for drugs targeting mGlu such as oral bioavailability and/or distribution to the central nervous system (CNS). Moreover, because of the highly conserved nature of the glutamate binding site, most orthosteric antagonists lack selectivity among the various mGlus.

[0004] A more recent strategy that has been able to successfully deal with the aforementioned issues has been the design of compounds that bind the mGlu at a site that is topographically distinct from the othosteric binding site, or an allosteric binding site. Selective negative allosteric modulators (NAMs) are compounds that do not directly deactivate receptors by themselves, but decrease the affinity of a glutamate-site agonist at its extracellular N-terminal binding site. Negative allosteric modulation is thus an attractive mechanism for inhibiting appropriate physiological receptor activation. Among the most studied and characterized small molecules are the mGlu5 NAMs, 2-methyl-6-(phenylethynyl) pyridine (MPEP) and 3-[(2-methyl-l ,3-thiazol-4-yl)ethynyl]pyridine (MTEP). Both MPEP and MTEP have proven efficacious in numerous rodent models of disease, including those for drug addiction and pain as well as anxiety. The compounds were also able to inhibit transient lower esophageal sphincter relaxation (TLESD), the major cause of gastroesophageal reflux disease (GERD), in dogs and ferrets. In addition, MPEP was efficacious in mouse models of Fragile X syndrome (FXS) and Parkinson's disease (PD) as well as a baboon model of binge- eating disorder.

[0005] Although the utility of MPEP and MTEP as tool compounds has been clearly demonstrated, both molecules have issues that complicate or prevent their further development as therapeutic molecules. MPEP has been shown to directly inhibit the N- methyl-D-aspartate (NMD A) receptor activity' at higher concentrations and is a positive allosteric modulator of mGlu4. While these selectivity issues are mitigated with MTEP, it is a potent inhibitor of cytochrome P450 1 A2 and is efficiently cleared following intravenous administration to rhesus monkeys. [0006] Potential adverse effects of known mGlu5 NAMs, however, could reduce their ultimate therapeutic utility. Further, conventional mGlu5 receptor modulators which target the orthosteric binding site can lack satisfactory aqueous solubility, exhibit poor oral bi oavai I ability, and/or exhibit adverse effects. Therefore, there remains a need for methods and compositions that overcome these deficiencies and that effectively provide selective negative allosteric modulators for the mGlu5 receptor.

SUMMARY

[0007] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds useful as negative allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5), methods of making same, pharmaceutical compositions comprising same, and methods of treating disorders associated with glutamate dysfunction using same.

[0008] Disclosed are compounds, or pharmaceutically acceptable salts thereof, having a structure represented by a formula: wherein Xi is CH, CRi, or N; X ₂ is C, or N; X ₃ is C, or N; X ₄ is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi, S, O, NRi, or N; X ₆ is CH, CRi, S, O, NRi, or N;

wiierein X7 is CH, CRi, or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; X10 is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; Xis is CH, CRi. S, O. NRi, or N; X ₁₁ is CH, CRi, S, O, NRi, orN; X15 is CH. CRi, S. O, NRi, or N;

B is cycloalkyl, wherein XISA is CH,

CRi, or N; Xi6 is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyd, alkoxy, OMe, alkyl-OMe, CONH ₂ , CN, O); X18 is CH, CRi, or N; X19 is CH, CRi, or N, and optionally may join with X18 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); X20 is CH, CRi, S, O, NRi, or N; X21 is CH, CRi, S, O, NRi, or N, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, O); X22 is CH, CRi, S, O, NRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2. CN, OH); X23 is CH. CRi. S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, O);

BA is alkyl, CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O. S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, 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.

[0009] Also disclosed are pharmaceutical compositions comprising an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] Also disclosed are methods for manufacturing a medicament comprising combining at least one disclosed compound with a pharmaceutically acceptable carrier or diluent.

[0011] Also disclosed are methods 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 disclosed compound, or a pharmaceutically acceptable salt thereof.

[0012] Also disclosed are methods 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 disclosed compound, or a pharmaceutically acceptable salt thereof.

[0013] Also disclosed are methods for inhibition of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[0014] Also disclosed are methods 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 disclosed compound, or a pharmaceutically acceptable salt thereof.

[0015] Also disclosed are methods 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 disclosed compound, or a pharmaceutically acceptable salt thereof.

[0016] Also disclosed are methods 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 disclosed compound, or a pharmaceutically acceptable salt thereof.

[0017] Also disclosed are methods for modulating metabotropic glutamate receptor activity in at least one cell, comprising the step of contacting at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[0018] Also disclosed are methods for inhibiting 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 a pharmaceutically acceptable salt thereof.

[0019] Also disclosed are uses of at least one disclosed compound, or pharmaceutically acceptable salt, solvate, or polymorph thereof, in the manufacture of a medicament for the treatment of a disorder associated with glutamate dysfunction in a mammal.

[0020] Also disclosed are kits comprising at least one compound of any of the below listed claims, 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.

[0021] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non- express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

[0022] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

[0023] FIG. 1 shows a schematic representation of an mGlu.

[0024] FIG. 2 shows a representative illustration of allosteric modulation of mGlu5.

[0025] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

[0026] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples and Figures included herein. [0027] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0028] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non- express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0029] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation. A. DEFINITIONS

[0030] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, EIZ specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

[0031] As used in the specification and the appended claims, the singular forms

“a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0032] Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0033] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0034] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0035] As used herein, the terms '‘optional’ ⁷ or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0036] As used herein, the term “mGlu5 receptor negative allosteric modulator” refers to any exogenously administered compound or agent that directly or indirectly inhibits the activity of the mGlu5 receptor in the presence of the endogenous ligand (such as glutamate) in an animal, in particular a mammal, for example a human. The term is synonymous with the terms “mGlu5 receptor allosteric inhibitor,” “mGlu5 receptor noncompetitive inhibitor,” “mGlu5 receptor allosteric antagonist,” and “mGlu5 receptor noncompetitive antagonist.”

[0037] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig. rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects. In some aspects of the disclosed methods, the subject has been diagnosed w ith a need for treatment of one or more neurological and/or psychiatric disorders associated with glutamate dysfunction prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for negative allosteric modulation of metabotropic glutamate receptor activity prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for partial antagonism of metabotropic glutamate receptor activity prior to the administering step.

[0038] As used herein, the term “treatment"’ refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory ⁷ animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0039] As used herein, the term “prevent"’ or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0040] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. For example, "diagnosed with a disorder treatable by modulation of mGlu5" means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can modulate mGlu5. As a further example, "diagnosed with a need for modulation of mGlu5” refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition characterized by mGlu5 activity. Such a diagnosis can be in reference to a disorder, such as a neurodegenerative disease, and the like, as discussed herein. For example, the term "‘diagnosed with a need for negative allosteric modulation of metabotropic glutamate receptor activity” refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by negative allosteric modulation of metabotropic glutamate receptor activity. For example, “diagnosed with a need for partial antagonism of metabotropic glutamate receptor activity” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by partial antagonism of metabotropic glutamate receptor activity. For example, “diagnosed with a need for treatment of one or more neurological and/or psychiatric disorders associated with glutamate dysfunction” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have one or more neurological and/or psychiatric disorders associated with glutamate dysfunction.

[0041] As used herein, the phrase “identified to be in need of treatment for a disorder,” or the like, refers to selection of a subject based upon need for treatment of the disorder. For example, a subject can be identified as having a need for treatment of a disorder (e.g., a disorder related to mGlu5 activity) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the disorder. It is contemplated that the identification can, in one aspect, be performed by a person different from the person making the diagnosis. It is also contemplated, in a further aspect, that the administration can be performed by one who subsequently performed the administration. [0042] As used herein, the terms “administering’' and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0043] The term “contacting” as used herein refers to bringing a disclosed compound and a cell, target metabotropic glutamate receptor, or other biological entity together in such a manner that the compound can affect the activity of the target (e.g., spliceosome, cell, etc.), either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity ⁷ of the target is dependent.

[0044] As used herein, the term “effective amount” refers to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety ⁷ of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0045] As used herein, “EC50,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.

[0046] As used herein, “IC50,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an IC50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein. In a further aspect, IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance.

[0047] The term 'pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0048] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0049] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and inj ectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers. [0050] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH ₂ O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH ₂ ) ₈ CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0051] As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms "substitution" or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e. , a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0052] In defining various terms, “A ¹ ,” “A ² ,” “A ³ ,” and “A ⁴ ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents. [0053] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, s-butyl, t-butyl, «-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyd, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alky l” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.

[0054] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alky l group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “alkyl amino” specifically refers to an alky I group that is substituted with one or more amino groups, as described below, and the like. When “alkyl” is used in one instance and a specific term such as “alkylalcohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkydalcohol” and the like.

[0055] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyd.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cy cloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term. [0056] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,’" where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0057] The term “polyalkylene group” as used herein is a group having two or more CH2 groups linked to one another. The polyalkylene group can be represented by the formula — (CHi) _a — , where “a” is an integer of from 2 to 500.

[0058] The terms “alkoxy” and “alkoxy!” as used herein to refer to an alkyd or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as — OA ¹ where A ¹ is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA ¹ — OA ² or — OA ¹ — (OA ² ) _a — OA ³ , where “a” is an integer of from 1 to 200 and A ¹ , A ² , and A ³ are alkyl and/or cycloalkyl groups.

[0059] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A ¹ A ² )C=C(A ³ A ⁴ ) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyd, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, ary l, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0060] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bond, z.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, and, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0061] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl. aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0062] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bond. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0063] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” also includes “heteroaryl,” which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term “non-heteroaryl,” which is also included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. The ary l group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific ty pe of aryl group and is included in the definition of “aryl.” Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0064] The term “aldehyde” as used herein is represented by the formula — C(O)H.

Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0065] The terms “amine” or “amino” as used herein are represented by the formula — NA ¹ A ² , where A ¹ and A ² can be. independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0066] The term “alkylamino” as used herein is represented by the formula — NH(- alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like. [0067] The term “dialkylamino” as used herein is represented by the formula — N(- alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert- pentyl)amino group, dihexylamino group, A-ethyl-A-methylamino group, /V-methyl-A- propylamino group, A-ethyl-A-propylamino group and the like.

[0068] The term "carboxyl ic acid" as used herein is represented by the formula —

C(O)OH.

[0069] The term " ester" as used herein is represented by the formula — OC(O)A ¹ or — C(O)OA where A ¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester’’ as used herein is represented by the formula — (A ¹ O(O)C-A ² -C(O)O) _a — or — (A ¹ O(O)C-A ² - OC(O)) _a — , where A ¹ and A ² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0070] The term “ether” as used herein is represented by the formula A’OA ² , where A ¹ and A ² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, ar l, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A ¹ O-A ² O) _a — , where A ¹ and A ² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alky nyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0071] The term “halide” as used herein refers to the halogens fluorine, chlorine, bromine, and iodine. [0072] The term “heterocycle,” as used herein refers to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Heterocycle includes pyridinde, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including. 1,2,3-thiadiazole, 1,2,5- thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3 -triazole, 1,3,4-tnazole. tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, including 1 ,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2, 4, 5 -tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like.

[0073] The term “hydroxyl” as used herein is represented by the formula — OH.

[0074] The term “ketone” as used herein is represented by the formula A ¹ C(O)A ² , where A ¹ and A ² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0075] The term “azide” as used herein is represented by the formula — Ns.

[0076] The term “nitro” as used herein is represented by the formula — NO2.

[0077] The term “nitrile” as used herein is represented by the formula — CN.

[0078] The term “silyl” as used herein is represented by the formula — SiA ³ A ² A ³ , where A ¹ , A ² , and A ³ can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl. cycloalkynyl, aryl, or heteroaryl group as described herein.

[0079] The term “sulfo-oxo” as used herein is represented by the formulas —

S(O)A ³ , — S(O)2A ¹ , — OS ODA ¹ , or — OS(O)2OA ¹ , where A ¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, and, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A\ where A ¹ can be hydrogen or an alkyl, cycloalky 1. alkenyl, cycloalkenyl, alkynyl. cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A ¹ S(O)2A ² , where A ¹ and A ² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl. cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A ¹ S(O)A ² , where A ¹ and A ² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alky nyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0080] The term “thiol” as used herein is represented by the formula — SH.

[0081] “R ¹ ,” “R ² ,” “R ³ ,” “R ⁿ .” where n is an integer, as used herein can. independently, possess one or more of the groups listed above. For example, if R ¹ is a straight chain alkyl group, one of the hydrogen atoms of the alkyd group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0082] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety' are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every’ position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e. further substituted or unsubstituted). The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0083] Suitable monovalent substituents on a substitutable carbon atom of an

“optionally substituted” group are independently halogen; -(CH 2) _0-4 R ⁰ ; -(CH ₂ ) _0-4 OR°; - O(CH ₂ ) _0-4 R°, -O-(CH ₂ ) _0-4 C(O)OR ^° ; -(CH ₂ ) _0-4 CH(OR ^° ) ₂ : -(CH ₂ ) _0-4 SR ^° ; -(CH ₂ ) _0-4 Ph, which may be substituted with R°; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph which may be substituted with R°; - CH=CHPh, which may be substituted with R°; -(CH ₂ )o-40(CH ₂ ) _0-1 -pyridyl which may be substituted with R°; -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) _0-4 N(R°) ₂ ; -(CH ₂ ) _0-4 N(R°)C(O)R°; - N(R°)C(S)R°; -(CH ₂ ) _0-4 N(R°)C(O)NR° ₂ ; -N(R ^O )C(S)NR° ₂ ; -(CH ₂ ) ₀ ^N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R ^o )C(O)NR° ₂ ; -N(R°)N(R°)C(O)OR°; -(CH ₂ ) ₀ ^C(O)R°; - C(S)R°; (CH ₂ ) _0-4 C(O)OR ^O ; (CH ₂ ) _0-4 C(O)SR ^° ; -(CH ₂ ) _0-4 C(O)OSIR° ₃ ; (CH ₂ ) _0-4 OC(O)R ^° ; -OC(O)(CH ₂ )O -iSR-. SC(S)SR°; -(CH ₂ ) _0-4 SC(O)R ^O ; -(CH ₂ ) _0-4 C(O)NR ^° ₂ ; -C(S)NR ^° ₂ ; - C(S)SR°; -SC(S)SR°, -(CH ₂ ) _0-4 OC(O)NR° ₂ ; -C(O)N(OR°)R°; -C(O)C(O)R°; - C(O)CH ₂ C(O)R°; -C(NOR°)R°; -(CH ₂ ) _0-4 SSR ^O ; -(CH ₂ ) _0-4 S2O) ₂ R ^O ; -(CH ₂ ) _0-4 S(O) ₂ 0R ^O : - (CH ₂ ) _0-4 OS(O) ₂ R°; -S(O) ₂ NR ^O ₂ ; -(CH ₂ ) _0-4 S(O)R ^O ; -N(R°)S(0) ₂ NR ^° ₂ ; -N(R°)S(0) ₂ R ^O ; - N(OR°)R°; -C(NH)NR° ₂ ; -P(O) ₂ R ^° ; -P(O)R ^O ₂ ; -OP(O)R ^O ₂ ; -OP(O)(OR ^O ) ₂ ; SiR° ₃ ; -(C _1-4 straight or branched alkylene)O-N(R°) ₂ ; or - (Ci^ straight or branched alkylene)C(O)O- N(R°) ₂ , wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH ₂ Ph, -0(CH ₂ )o iPh, -CH ₂ -(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s). form a 3-12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0084] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their interveni ng atoms), are independently halogen, -(CH ₂ ) _0-2 R’, -(haloR*), -(CH ₂ )o- ₂ OH, -(CH ₂ )o ₂ OR°, -(CH ₂ )o-

₂ CH(OR') ₂ ; -O(haloR*). -CN. -N ₃ , -(CH ₂ ) _0-2 C(O)R‘, -(CH ₂ ) _{0 2} C(O)OH, -(CH ₂ ) ₀ 2C(O)OR°, -(CH ₂ ) _0-2 SR°, -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 nhR‘, -(CH ₂ ) _0-2 NR* ₂ , - NO ₂ , -SiR°3. -OSiR°3, -C(O)SR* - (C _1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by " halo" is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0085] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR* ₂ , =NNHC(O)R*, =NNHC(O)0R*, =NNHS(O) ₂ R*, =NR*, =N0R*, -O(C(R* ₂ )) _2-3 O-, or -S(C(R* ₂ )) _2-3 S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR* ₂ ) ₂ 3O-. wherein each independent occurrence of R* is selected from hydrogen, Ci 6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0086] Suitable substituents on the aliphatic group of R* include halogen, -

R‘. -(haloR*), -OH, -OR‘, -O(haloR’), -CN. -C(O)OH. -C(O)OR°. -NH ₂ , -NHR‘, -NR° ₂ , or -NO ₂ , wherein each R ^° is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH ₂ Ph, -0(CH ₂ ) _0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0087] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R ¹ , -NR^, -C(O)R ^f , -C(O)OR ^I , -C(O)C(O)R ^f , - C(O)CH ₂ C(O)R , -S(O) ₂ R ^t , -S(O) ₂ NRt ₂ , -C(S)NR^ ₂ , -C(NH)NR’ ₂ . or -N^S(O)^; wherein each R ¹ ' is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ¹ ', taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0088] Suitable substituents on the aliphatic group of R' are independently halogen, -R*, -(haloR*). -OH. -OR', -O(haloR'), -CN, -C(O)OH, -C(O)OR', -NH ₂ , - NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci 4 aliphatic, -CH2PI1, - 0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0089] The term “leaving group” (“LG”) refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, brosylate, and halides.

[0090] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see. for example.

“Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0091] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon- containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alky l or substituted alkyls, alkoxy or substituted alkoxy, mono or di- substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0092] A very close synonym of the term "residue" is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure: regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0093] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkydsulfinyl, thioalkyl, thiohaloalky 1, alkoxy, substituted alkoxy, haloalky 1, haloalkoxy, ary l, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethy lamino radicals and the like.

[0094] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

[0095] Compounds described herein can contain one or more double bonds and. thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary', the invention includes all such possible isomers, as well as mixtures of such isomers.

[0096] Unless stated to the contrary', a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary', the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art. the products of such procedures can be a mixture of stereoisomers.

[0097] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or w edge of short parallel lines is (bonds to atoms below' the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0098] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number ty pically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ 0, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability , for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0099] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary' number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[00100] The term "co-ciystal" means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the cry stalline lattice. In certain instances, the guest molecules are incorporated in the cry stalline lattice as anhydrates or solvates, see e.g. "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystal s Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[00101] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form. keto form enol form amide form imidic acid form

Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.

[00102] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[00103] In some aspects, a structure of a compound can be represented by a formula: which is understood to be equivalent to a formula: wherein n is typically an integer. That is, R" is understood to represent five independent substituents, R" ^(a) , R' ^,(b) , R" ^(c) , R" ^(d) , R" ^(e) . By “independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R" ^(a) is halogen, then Rn(b) is not necessarily halogen in that instance.

[00104] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Acros Organics (Morris Plains, N.J ), Fisher Scientific (Pittsburgh, Pa ), or Sigma- Aldrich Corporation (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry. (John Wiley and Sons. 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[00105] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow ; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[00106] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[00107] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

B. MGLU5 NEGATIVE ALLOSTERIC MODULATORS

[00108] In one aspect, the invention relates to compounds useful as negative allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5). Negative allosteric modulators are non-competitive antagonists and can include a range of maximal antagonist activity from partial antagonists to inverse agonists. In one aspect, the present invention relates to compounds that allosterically modulate mGlu5 receptor activity, affecting the sensitivity of mGlu5 receptors to agonists without acting as orthosteric agonists themselves. The compounds can, in one aspect, exhibit subtype selectivity ⁷ . The compounds of the invention can be useful in the treatment of neurological and psychiatric disorders associated with glutamate dysfunction and other diseases in which metabotropic glutamate receptors are involved, as further described herein. Generally, the disclosed 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 human embryonic kidney cells are transfected with mGlu5 of a mammal. In a still further aspect, human embry onic kidney cells are transfected with human mGlu5.

[00109] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.

1. STRUCTURE

[00110] In one aspect, the invention relates to compounds, or pharmaceutically acceptable salts thereof, having a structure represented by a formula: wherein Xi is CH, CRi, or N; X2 is C, or N; X3 is C, or N; X4 is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi. S, O. NRi. or N; X , is CH, CRi. S, O. NRi, or N;

wherein X7 is CH, CRi, or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; X10 is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi. S, O. NRi, or N; X ₁₁ is CH, CRi, S, O, NRi, orN; X15 is CH. CRi, S. O, NRi, or N;

B is cycloalkyl, wherein XISA is CH,

CRi, or N; X ₁₁ is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with X ₁₁ to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH?, CN, OH); Xis is CH, CRi, orN; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); X20 is CH, CRi, S, O, NRi, or N; X21 is CH, CRi, S, O, NRi, or N, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, O); X22 is CH, CRi, S, O, NRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2. CN, OH); X23 is CH. CRi. S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH);

BA is alkyl, CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O. S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl or cycloalkyl; R4 is chosen from H. alkyl or cycloalkyl; Rs is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof.

[00111] 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 embry onic 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, the compound exhibits partial inhibition of mGlu5 response. In yet a further aspect, the compound exhibits total inhibition of mGlu5 response.

[00112] In a further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 1 x 10 ^-7 M. In a still further aspect, the compound exhibits negative allosteric modulation with an IC50 of less than about 5 x 10 ^-8 M.

[00113] In a further aspect, the mGlu5 is rat mGlu5. In a still further aspect, the mGlu5 is human mGlu5.

[00114] In a further aspect, the compound has a structure represented by a formula selected from: wherein Xi is CH, CRi, or N; X ₂ is C. or N; X3 is C, or N; X ₄ is CH, CRi, S, NRi, or N; X ₅ is CH, or CRi; X ₍ , is CH, CRi, NRi, or N; or a pharmaceutically acceptable salt thereof.

[00115] In a further aspect, A is ; wherein: X7 is CH,

CRi, or N; X ₈ is CH, CRi, or N; X ₉ is CH. CRi, or N; X1 0s CH, CRi, or N; X11 is CH, CRi, or N; X12 is CH, CRi, S, NRi, or N; X ₁₃ is CH, CR ₁ , S, NR1, or N; X ₁₄ is CH, CRi. S, NRi, or N; X15 is CH, CRi, S, NRi, or N; or a pharmaceutically acceptable salt thereof. n a further aspect, B is cycloalkyl wherein Xi _5A is CH, CRi, or N; X _i6 is CH, CRi, or N; X _i7 is CH, CRi, or

N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH ₂ , CN, OH); Xi ₈ is CH. CRi, or N; X19 is CH, CRi, or N; X20 is CH, CRi, S. O, or N; X21 is CH, CRi. S, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alky l, alkoxy, OMe, alkyl-OMe, CONH2, CN. OH); X22 is CH, CRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X23 is CH, CRi, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); or a pharmaceutically acceptable salt thereof.

CH, CRi, or N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X18 is CH, CRi, or N; X19 is CH, CRi, orN; X20 is CH, CRi, S, O, or N; X21 is CH, CRi, S, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CDs, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); X22 is CH, CRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me. halogen, F. alkyl, alkoxy, OMe, alkyl-OMe. CONH2, CN, OH); X23 is CH, CRi, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); or a pharmaceutically acceptable salt thereof.

[00118] In a further aspect, the compound is of the following formula:

; or a pharmaceutically acceptable salt thereof.

pharmaceutically acceptable salt thereof.

pharmaceutically acceptable salt thereof.

[00121] In a further aspect, the compound is of the following formula:

acceptable salt thereof. [00122] It is contemplated that the disclosed compounds can be used in connection with the disclosed methods, compositions, products, uses, and kits.

2. EXAMPLE STRUCTURES

[00123] In one aspect, a compound is selected from:

; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof. [00124] 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.

[00125] It is contemplated that one or more example structures can be optionally omitted from the disclosed invention.

3. NEGATIVE ALLOSTERIC MODULATION OF MGLU5 RESPONSE

[00126] 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 1 O’ 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 embry onic 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

[00127] 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 pL 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 °C in the presence of 5% CO2. The next day, medium was removed and the cells incubated with 20 pL of 2.3 pM 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 pL of assay buffer was added, and the plate was incubated for 5 minutes at room temperature.

[00128] 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 EC ₈₀ 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.

[00129] 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/Fo) 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 EC20/EC80 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 my multiplying each amplitude by 100 and then dividing the product by the mean of the amplitudes derived from the glutamate ECMax-treated wells. IC50 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.

[00130] A compound was designated as a negative allosteric modulator (NAM) if the compound showed a concentration-dependent decrease in the glutamate EC so 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 ECso response, but do not hit a plateau, the average of the Glu Max at a single concentration (30 pM) 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 pM. Exemplary data are provided in Table 1 below.

[00131] In particular, the disclosed compounds had activity in modulating the mGlu5 receptor in the aforementioned assays, generally with an IC50 for modulation of less than about 30 pM. Preferred compounds within the present invention had activity in modulating the mGlu5 receptor with an IC50 for negative allosteric modulation of less than about 500 nM. Preferred compounds reduced the response to an ECso concentration of glutamate to less than 50% of the maximal response and also induced a rightward and downw ard shift of the glutamate concentration response curve. These compounds are negative allosteric modulators of human and rat mGlu5 and w ere selective for mGlu5 compared to the other six subtypes of metabotropic glutamate receptors.

D. METHODS OF MAKING THE COMPOUNDS

[00132] 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.

[00133] 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 allow ed under the definitions disclosed herein.

[00134] 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.

[00135] 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 wdth a pharmaceutically acceptable carrier or diluent. [00136] In a further aspect, the compound produced can further undergo functional group transformation of the remaining substituents to yield additional analogs.

[00137] 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.

[00138] 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.

[00139] 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

[00140] 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.

[00141] 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.

[00142] 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, A-ethylmorpholine, A-ethyl piperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. [00143] 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.

[00144] 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.

[00145] 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. [00146] 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.

[00147] 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

[00148] 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.

[00149] 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.

[00150] 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.

[00151] 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.

[00152] 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 w ater, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[00153] 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 earners 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.

[00154] 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.

[00155] 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.

[00156] 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 ri pe and severity of the particular disease undergoing therapy. [00157] 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.

[00158] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological conditions.

[00159] 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.

[00160] 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. METHODS OF USING THE COMPOUNDS AND COMPOSITIONS

[00161] 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.

[00162] 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 (mGlul and mGlu5), Group II (mGlu2 and mGlu3) and Group III (mGlu4, mGlu6, mGlu7 and mGlu8). Group I mGlus are coupled through Gaq/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 Gai and its associated effectors such as adenylate cyclase.

[00163] Post-synaptic mGlus are know n 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 ct 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).

[00164] 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 ⁷ , 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.

[00165] In one aspect, the subject compounds can be coadministered with anti-

Alzheimer's agents, beta-s ecretas e inhibitors, gamma-secretase inhibitors, muscarinic agonists, muscarinic potentiators, HMG-CoA reductase inhibitors, NSAIDs and anti-amyloid antibodies.

[00166] 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, GlyTl 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. [00167] 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.

[00168] 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 C‘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.

[00169] 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. TREATMENT METHODS

[00170] 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 subj ect.

[00171] 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.

[00172] 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.

[00173] 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. [00174] 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 yvith or yvithout 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.

[00175] 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 aty pical 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

[00176] 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. TREATING A DISORDER

[00177] In one aspect, the invention relates to a method for the treatment of a disorder associated with metabotropic glutamate receptor activity ⁷ 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.

[00178] 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: wherein Xi is CH, CRi, or N; X ₂ is C, or N; X ₃ is C, or N; X ₄ is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi, S, O, NRi, or N; X, is CH, CRi, S, O, NRi, or N;

A is or ; wherein X7 is CH, CRi. or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; Xio is CH, CRi, or N; X ₁₁ is CH, CRi, or N; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi, S, O, NRi, or N; X _i4 is CH, CRi, S, O, NRi, orN; X _i5 is CH, CRi, S, O,

NRi, or N; , , , Ri, or N; X17 is CH,

CRi, or N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH ₂ , CN, OH); Xi ₈ is CH, CRi, or N; Xi ₉ is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe. alkyl-OMe, CONH ₂ . CN, OH); X ₂₀ is CH. CRi. S, O, NRi, or N; X ₂₁ is CH, CRi, S, O, NRi, or N, and optionally may join w ith X ₂ o to form a 4, 5, 6, or 7- membered ring (optionally substituted w ith one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH ₂ , CN, OH); X ₂₂ is CH, CRi, S, O, NRi, or N, and optionally may join with X _2i to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH ₂ , CN, OH); X ₂₃ is CH, CRi, S, O, NRi, or N, and optionally may join with X ₂₂ to form a 4, 5, 6. or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH ₂ , CN, OH);

BA is alkyl, CH ₂ , or a bond; wherein at least one of X ₂ -Xg is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O. S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH ₂ , NR3R4, OR5, CHF ₂ , CFs, halogen, F, Cl, CHs, alkyl, alkyl-halogen, CDs, cycloalkyl, CN, methoxy, or alkoxy; Rs is chosen from FI, alkyL or cycloalkyl; R4 is chosen from H, alkyfyor cycloalkyd; R5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof.

[00179] In a further aspect, the compound administered is any disclosed compound or a product of a disclosed method.

[00180] In a further aspect, the metabotropic glutamate receptor is mGlu5.

[00181] 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.

[00182] 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 aty pical autism, Fragile X syndrome, Rett syndrome, and Childhood Disintegrative Disorder.

[00183] 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.

[00184] 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.

[00185] 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

[00186] 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.

[00187] 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: wherein Xi is CH, CRi, or N; X ₂ is C, or N; X ₃ is C, or N; X ₄ is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi. S, O, NRi, or N; X„ is CH. CRi, S, O, NRi, or N;

A is or ; wherein X7 is CH, CRi, or N; Xs is CH, CRi, or N; X ₉ is CH, CRi, or N; X ₁₀ is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi. S, O, NRi, or N; X ₁₄ is CH, CRi, S, O, NRi, orN; X15 is CH, CRi, S. O, NRi, or N;

CRi, or N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH ₂ . CN, OH); X18 is CH, CRi, or N; X ₁₉ is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH ₂ , CN, OH); X ₂₀ is CH, CRi, S, O, NRi, or N; X _2i is CH, CRi, S, O, NRi, or N, and optionally may join with X ₂ o to form a 4, 5, 6, or 7- membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy. OMe, alkyl-OMe, CONH ₂ , CN, OH); X ₂₂ is CH, CRi, S, O, NRi, or N, and optionally may join with X _2i to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen. F, alkyl, alkoxy, OMe. alkyl-OMe, CONH ₂ . CN, OH); X ₂ s is CH, CRi. S, O, NRi, or N, and optionally may join with X ₂₂ to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH ₂ , CN, OH);

BA is alkyl, CH ₂ , or a bond; wherein at least one of X ₂ -X , is O, S, NRi or N. and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O, S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH ₂ , NR3R4, ORs, CHF ₂ . CF3, halogen, F, Cl, CHs, alkyl, alkyl-halogen, CDs, cycloalkyl, CN, methoxy, or alkoxy; Rs is chosen from H, alkyd or cycloalky 1; R4 is chosen from H, alkyl or cycloalkyl; Rs is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof.

[00188] In a further aspect, the compound administered is any disclosed compound or a product of a disclosed method.

[00189] In a further aspect, the metabotropic glutamate receptor is mGlu5.

[00190] 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.

[00191] 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.

[00192] 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.

[00193] 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.

[00194] 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

[00195] 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.

[00196] 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:

wherein X7 is CH, CRi, or N; X8 is CH, CRi, or N; X9 is CH, CRi, or N; X10 is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi. S, O. NRi, or N; X ₁₁ is CH, CRi, S, O, NRi, orN; X15 is CH. CRi, S. O, NRi, or N;

B is cycloalkyl, wherein XISA is CH,

CRi, or N; X ₁₁ is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with X ₁₁ to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH?, CN, OH); Xis is CH, CRi, orN; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); X20 is CH, CRi, S, O, NRi, or N; X21 is CH, CRi, S, O, NRi, or N, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X22 is CH, CRi, S, O, NRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2. CN, OH); X23 is CH. CRi. S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH);

BA is alkyl, CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O. S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl or cycloalkyl; R4 is chosen from H. alkyl or cycloalkyl; Rs is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof.

[00197] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound.

[00198] In a further aspect, the metabotropic glutamate receptor is mGlu5.

[00199] 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.

[00200] 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

[00201] 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.

[00202] 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 is or ; wherein X7 is CH, CRi, or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; X10 is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi. S, O. NRi. or N; X ₁₁ is CH, CRi, S, O, NRi, orN; X15 is CH. CRi, S. O, NRi, or N;

CRi, or N; Xi6 is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyd, alkoxy. OMe, alkyl-OMe, CONH2, CN, OH); Xis is CH, CRi, or N; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2. CN, OH); X20 is CH. CRi. S, O, NRi, or N; X21 is CH, CRi, S, O. NRi. or N. and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alky l, alkoxy. OMe, alkyl-OMe, CONH2, CN, OH); X22 is CH, CRi, S, O, NRi, or N. and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CDs, Me, halogen, F, alkyd, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X23 is CH, CRi, S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6. or 7-membered ring (optionally substituted with one or more substituents independently' selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH);

BA is alkyl, CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N. and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O, S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, ORs, CHF2, CFs, halogen, F, Cl, CHs, alkyl, alkyl-halogen, CDs, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl or cycloalkyd; R4 is chosen from H, alkyl or cycloalkyl; Rs is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof.

[00203] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. [00204] In a further aspect, the metabotropic glutamate receptor is mGlu5.

[00205] 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. PARTIAL ANTAGONISM OF MGLU5 ACTIVITY

[00206] 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.

[00207] 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: wherein Xi is CH, CRi, or N; X ₂ is C, or N; X ₃ is C, or N; X ₄ is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi. S, O. NRi, or N; X , is CH. CRi. S, O. NRi, or N;

wherein X7 is CH, CRi, or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; X10 is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi. S, O. NRi, or N; X ₁₁ is CH, CRi, S, O, NRi, orN; X15 is CH. CRi, S. O, NRi, or N;

B is cycloalkyl, wherein XISA is CH,

CRi, or N; X ₁₁ is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with X ₁₁ to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH?, CN, OH); Xis is CH, CRi, orN; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); X20 is CH, CRi, S, O, NRi, or N; X21 is CH, CRi, S, O, NRi, or N, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X22 is CH, CRi, S, O, NRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2. CN, OH); X23 is CH. CRi. S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH);

BA is alkyl, CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O. S, NRi or N: each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, 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.

[00208] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound.

[00209] In a further aspect, the metabotropic glutamate receptor is mGlu5.

[00210] 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

[00211] 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.

[00212] 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:

, , , , ₉ is CH, CRi, or N; X ₁₀ is CH, CRi, or N; X11 Xs CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; Xi? is CH, CRi. S, O. NR1, or N; X14 is CH, CRi, S, O, NRi, orN; X15 is CH. CRi, S. O, NRi, or N; wherein is CH,

CRi, or N; Xi6 is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alky l, alkoxy, OMe, alkyl-OMe, CONH?, CN, OH); X ₁₈ is CH, CRi, orN; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD?, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH?, CN, OH); X20 is CH, CRi, S, O, NRi, or N; X21 is CH, CRi, S, O, NRi, or N, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD?, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X22 is CH, CRi, S, O, NRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X23 is CH, CRi, S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH);

BA is alkyl. CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O, S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CFs, halogen, F, Cl, CHs, alkyl, alkyl-halogen, CD3, cycloalkyd, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl, or cycloalkyl; R4 is chosen from H, alkyl, or cycloalky 1; R5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof.

[00213] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound.

[00214] 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.

[00215] In a further aspect, the metabotropic glutamate receptor is mGlu5.

[00216] 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. INHIBITING MGLU5 ACTIVITY IN CELLS

[00217] 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.

[00218] 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: wherein Xi is CH, CRi, or N; X ₂ is C. or N; X ₃ is C, or N; X ₄ is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi, S, O, NRi, or N; X<, is CH, CRi, S, O, NRi, or N;

A is or ; wherein X7 is CH, CRi. or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; X10 is CH. CRi. or N; X ₁₁ is CH, CRi, or N; X12 is CH, CRi. S, O. NRi, or N; X13 is CH, CRi, S, O, NRi, or N; X _i4 is CH, CRi, S, O, NRi, orN; X15 is CH, CRi, S, O, NRi, or N; B is cycloalkyl, wherein XISA is CH,

CRi, or N; Xi6 is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyd, alkoxy. OMe, alkyl-OMe, CONH2, CN, OH); Xis is CH, CRi, or N; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2. CN, OH); X20 is CH. CRi. S, O, NRi, or N; X21 is CH, CRi, S, O. NRi. or N. and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CDs, Me, halogen, F, alky l, alkoxy. OMe, alkyl-OMe, CONH2, CN, OH); X22 is CH, CRi, S, O, NRi, or N. and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CDs, Me, halogen, F, alkyd, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X23 is CH, CRi, S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6. or 7-membered ring (optionally substituted with one or more substituents independently' selected from H, CDs, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH);

BA is alkyl, CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N. and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O, S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, ORs, CHF2, CFs, halogen, F, Cl, CHs, alkyl, alkyl-halogen, CDs, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl, or cycloalkyl; R4 is chosen from H, alkyl, or cycloalk d; R5 is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof.

[00219] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound. [00220] In a further aspect, the metabotropic glutamate receptor is mGlu5.

[00221] 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.

[00222] 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.

[00223] 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.

[00224] 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 ty pe 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.

[00225] 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 IC ₅₀ 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

[00226] 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.

[00227] 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: wherein Xi is CH, CRi, or N; X ₂ is C, or N; X ₃ is C, or N; X ₄ is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi. S, O. NRi, or N; X , is CH. CRi. S, O. NRi, or N;

wherein X7 is CH, CRi, or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; X10 is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi. S, O. NRi, or N; X ₁₁ is CH, CRi, S, O, NRi, orN; X15 is CH. CRi, S. O, NRi, or N;

B is cycloalkyl, wherein XUA is CH,

CRi, or N; X ₁₁ is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with X ₁₁ to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH?, CN, OH); Xis is CH, CRi, orN; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); X20 is CH, CRi, S, O, NRi, or N; X21 is CH, CRi, S, O, NRi, or N, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X22 is CH, CRi, S, O, NRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2. CN, OH); X23 is CH. CRi. S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH);

BA is alkyl, CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O. S, NRi or N: each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, 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.

[00228] In a further aspect, the compound administered is a disclosed compound or a product of a disclosed method of making a compound.

[00229] In a further aspect, the metabotropic glutamate receptor is mGlu5.

[00230] 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.

[00231] 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. MANUFACTURE OF A MEDICAMENT

[00232] 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. [00233] 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.

[00234] 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.

[00235] 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.

[00236] 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 ty pe 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.

[00237] 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

[00238] 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.

[00239] In one aspect, the invention relates to use of at least one compound having a structure represented by a formula: wherein Xi is CH, CRi, or N; X ₂ is C, or N; X ₃ is C, or N; X ₄ is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi, S, O, NRi, or N; X is CH, CRi, S, O, NRi, or N;

wherein X7 is CH, CRi, or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; X10 is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi. S, O. NRi, or N; X ₁₁ is CH, CRi, S, O, NRi, orN; X15 is CH. CRi, S. O, NRi, or N;

B is cycloalkyl, wherein XISA is CH,

CRi, or N; X ₁₁ is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with X ₁₁ to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH?, CN, OH); Xis is CH, CRi, orN; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); X20 is CH, CRi, S, O, NRi, or N; X21 is CH, CRi, S, O, NRi, or N, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X22 is CH, CRi, S, O, NRi, or N, and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted w ith one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2. CN, OH); X23 is CH. CRi. S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH);

BA is alkyl, CH2, or a bond; wherein at least one of X;X , -Xr, is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O, S, NRi or N; each Ri, when present, is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alkyl, or cycloalkyl: R4 is chosen from H, alkyl, or cycloalkyl: Rs is chosen from H, or alkyl; or a pharmaceutically acceptable salt thereof.

[00240] 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.

[00241] 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.

[00242] 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.

[00243] 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.

[00244] 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.

[00245] 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 IC ₅₀ 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

[00246] In one aspect, the invention relates to a kit comprising at least one compound having a structure represented by a formula: wherein Xi is CH, CRi, or N; X ₂ is C, or N; X ₃ is C, or N; X ₄ is CH, CRi, S, O, NRi, or N;

X ₅ is CH, CRi. S, O, NRi, or N; Xe is CH. CRi, S, O, NRi, or N;

A is or ; wherein X7 is CH, CRi, or N; Xs is CH, CRi, or N; X9 is CH, CRi, or N; X _w is CH, CRi, or N; X ₁₁ is CH, CRi, orN; X12 is CH, CRi, S, O, NRi, or N; X13 is CH, CRi. S, O, NRi, or N; X _i4 is CH, CRi, S, O, NRi, orN; X ₁₅ is CH, CRi, S. O, NRi, or N;

B is cycloalkyl, wherein XISA is CH,

CRi, or N; Xi6 is CH, CRi, or N; X17 is CH, CRi, or N, and optionally may join with Xi6 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD?, Me, halogen, F, alky l, alkoxy. OMe, alkyl-OMe, CONH?, CN, OH); Xis is CH, CRi, orN; X19 is CH, CRi, or N, and optionally may join with Xis to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me. halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); X20 is CH, CRi, S, O, NRi, or N; X21 is CH, CRi, S, O, NRi, or N, and optionally may join with X20 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD?, Me, halogen, F, alkyl, alkoxy. OMe, alkyl-OMe, CONH2, CN, OH); X22 is CH, CRi, S, O, NRi, or N. and optionally may join with X21 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alky l, alkoxy, OMe, alkyl-OMe, CONH2, CN, OH); X23 is CH. CRi, S, O, NRi, or N, and optionally may join with X22 to form a 4, 5, 6, or 7-membered ring (optionally substituted with one or more substituents independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl- OMe, CONH2, CN, OH); BA is alkyl, CH2, or a bond; wherein at least one of X2-X6 is O, S, NRi or N, and wherein at least one of X7-X11 is N and wherein at least one of X12-X15 is O, S, NRi or N; each Ri, when present, is independent and chosen from H, D. OH, NH2, NR3R4, OR5, CHF2. CF3, halogen, F, Cl, CH3, alkyl, alkyl-halogen, CD3, cycloalkyl, CN, methoxy, or alkoxy; R3 is chosen from H, alky l, 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.

[00247] 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.

[00248] 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.

[00249] In a further aspect, the kit comprises a disclosed compound or a product of a disclosed method.

[00250] 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.

[00251] 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. NON-MEDICAL USES

[00252] 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

[00253] 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.

[00254] 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 ^J H NMR spectra were obtained on instrumentation at a field strength of 300 to 500 MHz. 1. GENERAL SCHEMES

General Scheme I shows a method for preparing compounds of the invention. Reaction of intermediate Al (e.g, X is halogen) with mCPBA and solvent (e.g., DCM) may provide intermediates A2. Intermediates A2 with Dimethyl carbamyl chloride (DMCC) and trimethylsilyl cyanide (TMSCN) may provide intermediates A3. Intermediates A3 with boronic acids or boronic esters (Bl) under standard Suzuki reaction conditions may provide intermediates A4, followed by basic hydrolysis conditions (e.g., NaOH) and heat may afford carboxylic acids A5. Intermediates A5 may be subjected to amide formation conditions (e.g., amine (R ³ -NH2). POCh and pyridine) to provide compounds A6.

General Scheme II

As shown in General Scheme II, an alternative method to prepare compounds A6 is provided. Intermediates A3 (e.g, X is a halogen) under basic hydrolysis conditions (e.g., NaOH) and heat may provide intermediates A7, which can be subjected to amide formation conditions (e.g., amine (R ³ -NH2), POCh and pyridine) to provide intermediates AS. Intermediates AS with boronic acids or boronic esters (Bl) under standard Suzuki conditions may afford compounds A6.

General Scheme III shows a method for preparing compounds of the invention. Intermediates

A9 with alkyl halides (e.g., R ⁴ -X ³ ; X ¹ is a halogen) and base (e.g., NaH) may provide intermediates A10. Intermediates A10 may be transformed into boronic acid or boronic ester All, followed by standard Suzuki reaction conditions with aryl or heteroaryl halides (e.g., X^R ¹ ; X ¹ is halogen) to provide intermediates A12. A12 may be subjected to basic hydrolysis conditions to afford carboxylic acids A13, followed by amide formation conditions (e.g., amine (R ³ -NH2), POCk and pyridine) to provide analogues A14.

General Scheme IV

As shown in General Scheme IV, an alternative method for preparing intermediates A4 is provided. Intermediates A3 may be transformed into boronic esters A15. Intermediates A15 with aryl or heteroaryl halides (e.g., R1-X ¹ ; X ¹ is a halogen) under standard Suzuki reaction conditions may provide intermediates A4.

General Scheme V General Scheme V shows a method for preparing compounds of the invention. Intermediates A16 with boronic acids or boronic esters (Bl) under standard Suzuki reactions may provide intermediates A17. In the presence of zinc cyanide, a palladium catalyst (e.g., Pd(PPh3)i) and heat (e.g., pW at 140 °C), intermediates A17 may be transformed to intermediates A18.

Intermediates A18 under basic hydrolysis conditions (e g., NaOH) and heat (e.g.. 100 °C) may provide carboxylic acids A19, followed by amide formation conditions (e.g., amine (R ³ -NH2), POCh and pyridine) to provide compounds A20.

General Scheme VI

A21 A22

As shown in General Scheme VI, intermediates A21 with chloroacetaldehyde, base (e.g., Na2COs) and heat (e.g., 80 °C) may provide intermediates A22.

General Scheme VII

General Scheme VII shows a method for preparing compounds of the invention. Intermediates A23 (e.g., X is halogen) with boronic acids or boronic esters (Bl) under standard Suzuki reaction conditions may provide intermediates A24. Intermediates A24 may be subjected to cabon monoxide, a palladium catalyst (e.g., Pd(dppf)Ch), base (e.g., KOAc) and heat (e.g., 80 °C) to afford intermediates A25, followed by basic hydrolysis (e.g., NaOH) to provide intermediates A26. Intermediates A26 under amide formation conditions (e.g., amine (R ³ -NH2), POCh and pyridine) may provide analogues A27.

General Scheme VIII

W=N, Y=Z=CH;

Y=N, W=Z=CH;

Z=N, W=Y=CH

General Scheme VIII shows an alternative method to prepare carboxylic acid intermediates A26. Intermediates A24 in the presence of zinc cyanide, a palladium catalyst (e.g., Pd(PPhs)4) and heat (e.g., pW at 140 °C), may be transformed to intermediates A28.

Intermediates A28 under basic hydrolysis (e.g., NaOH) and heat (e.g., 100 °C) may provide intermediates A26.

General Scheme IX

General Scheme IX shows a method for preparing analogues of the invention. Intermediates A29 (e.g., X is a halogen) with boronic acids or boronic esters (Bl) under standard Suzuki reaction conditions may provide intermediates A30. Intermediates A30 may be subjected to cabon monoxide, a palladium catalyst (e.g., Pd(dppf)Ch), base (e.g., KOAc) and heat (e.g., 80 °C) to afford intermediates A31, followed by basic hydrolysis (e.g., NaOH) to provide intermediates A32. Intermediates A32 may undergo amide formation with amine (e.g., R ³ - NHi), POCk and base (e.g., pyridine) to provide analogues A33.

Exemplary Scheme III

Exemplary Scheme V Exemplary Scheme VI Exemplary Scheme VIII Exemplary Scheme X

3. CHARACTERIZATION OF EXEMPLARY COMPOUNDS

[00255] Tables 1 and 2 below lists specific compounds, experimentally determined molecular mass, and mGlu5 activity determined in a cell-based assay. The mGlu5 activity was determined using the metabotropic glutamate receptor activity assays in human embryonic kidney cells as described herein, wherein the human embryonic kidney cells were transfected with rat mGlu5. The mGlu5 activity' data for some compounds 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.

[00256] The following abbreviations may be used herein: Ac acetate

ACN acetonitrile aq aqueous atm atmosphere(s) CDCh chloroform-d CD ₃ OD methanol-d4 Celite® diatomaceous earth cone. concentrated Cpd compound DCM dichloromethane d doublet dd doublet of doublets ddd doublet of doublet of doublets DMCC dimethylcarbamyl chloride DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 dimethylsulfoxide-d6 (deuterated dimethylsulfoxide) dppf 1 , 1 '-bis(diphenylphosphino)ferrocene dppp 1.3-bis(diphenylphosphino)propane dt doublet of triplets ES-MS electrospray mass spectrometry EtOAc ethyl acetate EtOH ethanol Et ₃ N triethylamine eq./equiv equivalents h or hr hour(s) Hex/hex hexanes HPLC high performance liquid chromatography HRMS high resolution mass spectrometry Hz hertz IPA isopropyl alcohol KOAc potassium acetate LCMS liquid chromatography-mass spectrometry M molarity (for concentration) m multiplet mCPBA 3-chloroperbenzoic acid Me methyl MeCN acetonitrile MeOH methanol MHz megahertz min minute(s) pW microwave Pd(OAc) ₂ palladium(II)acetate Pd(dppf)Cl ₂ (1 J '-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd(dppf)C1 ₂ DCM (l,r-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride, complex with dichloromethane tetrakis(triphenylphosphine)palladium(0)

Ph phenyl

PPm parts per million

RP reverse phase r.t./rt/RT room temperature s singlet sat. saturated soln. solution

TFA trifluoroacetic acid

THF tetrahydrofuran

TMS trimethyl silyl

TMSCN trimethyl silyl cyanide

Scheme I

7-Chlorothieno [3, 2-b\ pyridine 4-oxide (SI). 7-Chlorothieno[3,2-6]pyridine (2.00 g, 11.8 mmol, 1.00 eq) was dissolved in DCM (57 mL) and fliCPBA (3.20 g. 14.1 mmol, 1.20 eq) was added in portions. The reaction was stirred for 2 hours then cooled to 0 °C where an aqueous 10% sodium thiosulfate solution was added. The mixture was added to a separatory funnel and the layers separated. The organic phase was washed with aqueous 10% K2CO3 and the combined aqueous phases were back extracted with 3: 1 CHCI3/IPA. The combined organic layers were dried (MgSCfi), filtered, and concentrated in vacuo. The crude mixture was purified using normal-phase column chromatography on silica gel (0-8% MeOH/DCM with 1% NH4OH additive) to afford 2.2 g (98%) of the title compound. 'H NMR (400 MHz, CDCh) δ 8.23 (d, J = 6.6 Hz, 1H), 7.85 (d, J= 5.7 Hz, 1H), 7.73 (d, J= 5.7 Hz, 1H), 7.21 (d, J= 6.6 Hz, 1H); ES-MS [M+l] ⁺ : 186.0. 7-Chlorothieno[3,2-Z>]pyridine-5-carbonitrile (S2). Intermediate SI (2.20 g, 11.8 mmol, 1.00 eq) was dissolved in DCM (60 mL) and trimethylsilyl cyanide (2.96 mL, 23.7 mmol, 2.00 eq) was added. After 15 minutes, dimethylcarbamoyl chloride (2. 17 mL, 23.7 mmol, 2.00 eq) was added dropwise and the reaction was stirred at room temperature for 24 hours. Additional portions of trimethylsilyl cyanide (2.96 mL, 11.8 mmol, 2.00 eq) and dimethyl carbamoyl chloride (2.17 mL, 23.7 mmol, 2.00 eq) were added and the reaction was allowed to stir for another 48 hours. The reaction was poured into a separator} ⁷ funnel and washed with an aqueous 10% K2CO3 solution. The aqueous phase was back-extracted with DCM and the combined organic layers were dried (MgSCL), filtered and concentrated in vacuo. The crude mixture was purified using normal-phase column chromatography on silica gel (0-20% EtOAc/hexanes) to afford 1.89 g (80%) of the title compound. ^J H NMR (400 MHz, CDCL) <5 7.99 (d, J = 5.6 Hz, 1H), 7.67 (d, J = 5.6 Hz, 1H), 7.65 (s, 1H); ES-MS [M+l] ⁺ : 195.2.

7-(4-MethyIpyridin-3-yl)thieno[3,2-/>]pyridine-5-carbo nitriIe (S3). Intermediate S2 (1.00 g, 5.14 mmol, 1.00 eq), cesium carbonate (5.02 g, 15.4 mmol, 3.00 eq) and 4-picoline-3- boronic acid (1.41 g, 10.3 mmol, 2.00 eq) were added to a microwave vial equipped with a stir bar. Next 1,4-dioxane (10 mL) was added to the vial and degassed with nitrogen for 10 minutes. Next, Pd(dppf)Ch (377 mg, 0.510 mmol, 0.100 eq) was added and the vial was sealed and irradiated in a microwave at 120 °C for 15 minutes. The reaction was cooled to room temperature, filtered over Celite, and washed with 10% MeOH/DCM. The organic layers were concentrated and the residue diluted with DCM and dried on Celite. Dry loading and purification using normal-phase chromatography on silica gel (0-2% MeOH/DCM) afforded 1.1 g (81%) of the title compound. 'H NMR (400 MHz, CDCL) 5 8.67 (d, J= 5.1 Hz, 1H), 8.57 (s, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.75 (d, J= 5.6 Hz, 1H), 7.55 (s, 1H), 7.37 (d, 5.2 Hz, 1H), 2.25 (s, 3H); ES-MS [M+l]+: 252.4.

7-(4-Methylpyridin-3-yl)thieno[3,2-Z>]pyridine-5-carbo xylic acid (S4). Intermediate S3 (300 mg, 1.20 mmol. 1.00 eq) was dissolved in 1,4-dioxane (10 mL) then M aqueous sodium hydroxide (3.0 mL, 6.0 mmol, 5.0 eq) was added and the reaction was heated at 100 °C for 12 hours. The reaction was neutralized to pH 5 with a 2711 aqueous HO and the reaction was concentrated in vacuo. The residue was suspended in 10% MeOH/DCM and the salts removed by filtration. The organics were concentrated to afford 322 mg (100%) of the title compound that was used without further purification. ES-MS [M+l]+: 271.4.

7-(4-Methylpyridin-3-yl)-7V-(4-inethylthiazol-2-yl)thieno [3,2-Z>]pyridine-5-carboxamide (1). Intermediate S4 (300 mg, 1.1 1 mmol, 1.00 eq) and 2-amino-5 -methylthiazole (253 mg, 2.22 mmol, 2.00 eq) were dissolved in pyridine (7.4 mL) and cooled to 0 °C.

Phosphorous(V) oxychloride (207 pL, 2.20 mmol, 2.00 eq) was added and the reaction was allowed to warm to room temperature over 30 minutes. An aqueous 10% K2CO3 solution was added to the reaction mixture followed by EtOAcand the layers were separated. The aqueous layer was extracted with an additional portion of EtOAc and the combined organic layers were dried (MgSCL), filtered, and concentrated in vacuo. The crude mixture was purified using RP-HPLC (25 - 75% ACN/ 0.1% aqueous TFA,) to afford 110 mg (27%) of the title compound as an off-white solid. 'H NMR (400 MHz, DMSO-tL) 3 8.62 (d, J = 5.1 Hz. 1H), 8.58 (s, 1H), 8.39 (d, J = 5.5 Hz, 1H), 8.04 (s, 1H), 7.83 (d, J = 5.5 Hz, 1H), 7.50 (d, J = 5.1 Hz, 1H), 6.91 (s, 1H), 2.32 (s, 3H), 2.18 (s, 3H); ES-MS [M+l] ⁺ : 367.0. Scheme II

7-Chlorothieno [3,2-6] pyridine-5-carboxylic acid (S5). 7-Chlorothieno[3,2-b]pyridine-5- carbonitrile (1.13 g, 5.83 mmol, 1.00 eq) was dissolved in 1,4-dioxane (20 mL) and 2M aqueous sodium hydroxide (14.6 mL, 29.1 mmol, 5.00 eq) was added and the reaction heated at 100 °C overnight. After cooling, the reaction was neutralized to pH 5 with 2M aqueous HC1 solution and concentrated in vacuo. The crude residue was suspended in 10% MeOH/DCM and insoluble salts were removed by filtration. The organics were concentrated to afford 1.24 g (100%) of the title compound that was used without further purification. ES- MS [M+l] ⁺ : 214.3.

7-Chloi o- A-(4-methyl thiazol-2-yl )thieno [3,2-6] pyridine-5-carboxamide carboxamide (S6). To a round bottom flask was added intermediate S5 (1.24 g, 5.80 mmol, 1.00 eq), 2- amino-4-methylthiazole (1.33 g, 1 1.6 mmol, 2.00 eq) and pyridine (20 mL). The reaction was cooled to 0°C and phosphorus(V) oxychloride (1.30 mL, 13.9 mmol, 2.4 eq) was added dropwise to the reaction at which point the reaction was allowed to warm to room temperature over 30 minutes. The reaction was cooled to 0° C where water was slowly added and the resulting mixture was concentrated. The residue was taken up in DCM/MeOH and dried on Celite. Dry loading and purification using normal-phase chromatography on silica gel (0 - 80% EtOAc/hexane) afforded 134 g (75%) of the title compound. 'H NMR (400 MHz, CDCE) 5 11.23 (s, 1H), 8.28 (s, 1H), 7.96 (d, J= 5.4 Hz, 1H), 7.61 (d, J= 5.6 Hz, 1H), 6.65 (s, 1H), 2.43 (s, 3H); ES-MS [M+l]+: 310.2.

7-(l,3-Dimethyl-lH-pyrazol-4-yl)-7V-(4-methylthiazol-2-yl )thieno[3,2-Z>]pyridine-5- carboxamide (17). Intermediate S6 (10 mg, 0.032 mmol, 1.0 eq), l,3-dimethylpyrazole-4- boronic acid pinacol ester (11 mg, 0.048 mmol, 1.5 eq), I AT aqueous sodium carbonate (0.8 mL, 0.0966 mmol, 3.00 eq) and Pd(PPh3)4 (3.7 mg, 0.0032 mmol, 0.10 eq) were added to a micro wave vial followed by 1,4-dioxane (1 mL). The vial was purged with nitrogen, sealed, and the reaction mixture was irradiated in a microwaveat 140 °C for 15 minutes. After cooling, the reaction was diluted with EtOAcand washed with water. The organic layer was separated, dried (MgSCL), filtered and concentrated in vacuo. The crude residue was purified by RP-HPLC (25-75% ACN/0.1% aqueous TFA) to afford 6.7 mg (56%) of the title compound as a white solid. 'H NMR (400 MHz, CDCL) <5 8.23 (s, 1H), 7.90-7.87 (m, 2H), 7.66 (d, J= 5.7 Hz, 1H), 6.63 (s. 1H), 3.98 (s, 3H), 2.48 (s, 3H), 2.45 (s, 3H): ES-MS [M+l] ⁺ : 370.2.

Scheme 3

7-Chloro-2-methyl-thieno[3,2-/>]pyridine (9). A solution of 7-Chloro-4-azabenzothiophene (200 mg, 1.18 mmol, 1.00 eq) in THF (5 mL) was added dropwise to a solution of n- butyllithium (1.05 mL, 2.63 mmol, 2.23 eq) [2.5 M in hexanes] in THF (10 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h. A solution of iodomethane (0.22 ml, 3.5 mmol, 3.0 eq) in THF (1.0 mL) was added dropwise via syringe, and the mixture was stirred at -78 °C for 3 h. After determination of completion by LCMS the reaction w as quenched with w ater and w armed to room temperature. The aqueous phase w as extracted with DCM (3x) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate. filtered, and concentrated. The residue was purified by flash chromatography on silica gel using 0-50% hexanes/ethyl acetate to afford 191 mg (88%) of the title compound as a tan oil: 'H NMR (400 MHz, CDCh) 88.50 (d, J= 5.1 Hz, 1H), 7.24 (q, J= 1.2 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 2.66 (d, J= 1.2 Hz, 3H); ES-MS [M+l] ⁺ : 184.2

7-Chloro-2-methyl-4-oxido-thieno[3,2-Z>]pyridin-4-ium (10). Compound 9 (190 mg, 1.03 mmol, 1.00 eq) was dissolved in DCM (5 mL). 3-Chloroperoxybenzoic acid (280 mg, 1.25 mmol, 1.20 eq) was added and the reaction was stirred overnight at room temperature. After determination of completion by LCMS the reaction was quenched with 10% sodium thiosulfate solution at 0 °C. The mixture was extracted with DCM (3x) and the combined organic components were washed with 10% potassium carbonate solution. The combined organic components were concentrated and purified by flash chromatography on silica gel using 0-10% DCM/methanol to afford 175 mg (85%) of the title compound as a yellow solid: 'H NMR (400 MHz, CDCh) d 8.17 (d, J = 6.7 Hz, 1H), 7.55 (q, J= 1.2 Hz, 1H), 7.13 (d, J = 6.7 Hz. 1H), 2.67 (d. J= 1.2 Hz. 3H); ES-MS [M+l] ⁺ : 200.3

7-Chloro-2-methyl-thieno[3,2-Z>]pyridine-5-carbonitril e (11). Compound 10 (175 mg, 0.880 mmol, 1.00 eq) was dissolved in DCM (5 mL). Dimethylcarbamoyl chloride (0.16 mL, 1.7 mmol, 2.0 eq) was added and the mixture stirred for 15 min at room temperature. Trimethylsilyl cyanide (0.22 mL, 1.8 mmol. 2.0 eq) was added and the mixture was stirred overnight at room temperature. After determination of completion by LCMS a 10% potassium carbonate solution was added and the mixture was stirred for 15 min. The reaction was diluted with DCM, washed with water (2x) and the aqueous phase was back extracted with DCM. The combined organics were dried (MgSCL). filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using 0-25% hexanes/ethyl acetate afforded 178 mg (97%) of the title compound as a white solid: 'l l NMR (400 MHz, CDCL) <5 7.55 (s, 1H), 7.30 (q, J= 1.2 Hz, 1H), 2.71 (d, J= 1.2 Hz, 3H); ES-MS [M+l] ⁺ : 209.4

Scheme III

7-Chloro- 1-ethyl- LH-pyrrolo [3,2-b] pyridine-5-carbonitrile (S7). 7-Chloro- 1H- pyrrolo[3,2-d]pyridine-5-carbonitrile (600 mg, 3.38 mmol, 1.00 eq) was dissolved in DMF (13.5 mL) and cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil) (203 mg, 5.07 mmol, 1.50 eq) was added in portions and the reaction was allowed to stir for 30 minutes at 0 °C. lodoethane (408 pL, 5.07 mmol, 1.50 eq) was added dropwise and the reaction was stirred at 0 °C for 1 hour. The reaction was slowly added to water and the mixture was extracted with EtOAc (3x). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified using normal-phase column chromatography on silica gel (0-50% EtOAc/hexanes) to afford 462 mg (67%) of the title compound. 'H NMR (400 MHz, DMSO-c/ ) 5 8.06 (d, J= 3.4 Hz, 1H), 7.95 (s, 1H), 6.82 (d, J= 3.2 Hz, 1H), 4.55 (q, J= 7.1 Hz, 2H), 1.39 (t, J= TA Hz, 3H); ES-MS [M+l] ⁺ : 206.3.

Scheme IV l-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrr olo[2,3-6]pyridine-6- carbonitrile (S8). 4-Chloro-l-methyl-lF7-pyrrolo[2,3-b]pyridine-6-carbonitrile (678 mg, 3.54 mmol, 1.00 eq), bis(pinacolato)diboron (1.80 g, 7.08 mmol, 2.00 eq), potassium acetate (1.39 g, 14.2 mmol, 4.00 eq), Pd(dppf)Ch (260 mg, 0.350 mmol, 0.100 eq) and 1,4-dioxane (24 mL) were added to a pressure vial. The vial was sealed, evacuated and backfilled with nitrogen (3x). The mixture was stirred for 16 hours at 100 °C. After cooling to room temperature, the reaction mixture was filtered through a plug of Celite and washed with EtOAc and DCM. The residue was purified using normal-phase column chromatography on silica gel (0-30% EtOAc/hexanes) to afford 1.0 g (99%) of the title compound as a pale yellow solid. 'H NMR (400 MHz, CDsOD) 87.74 (s, 1H), 7.71 (d, J= 3.4 Hz, 1H), 6.92 (d, J= 3.4 Hz, 1H), 3.91 (s, 3H), 1.43 284.4 l-Methyl-4-(4-methyl-3-py ridyl)pyrrolo [ 2,3-/; | pyridine-6-carbonitrile (S9). 3 -Bromo-4- picoline (66 mg, 0.39 mmol, 1.1 eq), intermediate S8 (100 mg, 0.350 mmol, 1.00 eq), Pd(dppf)Ch (39 mg, 0.050 mmol, 0.15 eq), cesium carbonate (173 mg, 0.530 mmol, 1.50 eq) and 9: 1 acetonitrile:water (1 mL) were added to a pressure vial. The vial was sealed, evacuated and backfilled with nitrogen (3x). After 4 hours at 80 °C the reaction mixture was cooled to room temperature and filtered through a plug of Celite washing with EtOAc and DCM. The residue was purified using normal-phase column chromatography on silica gel (0-10% MeOH/DCM) to afford 60 mg (68%) of the title compound as an off-white solid. 'H NMR (400 MHz, CDsOD) 8 8.52 (d, J= 5.2 Hz, 1H), 8.45 (s, 1H), 7.74 (d, J= 3.5 Hz, 1H), 7.54 (s, 1H), 7.50 (d, J= 5.2 Hz, 1H), 6.35 (d, J= 3.5 Hz, 1H), 3.98 (s, 3H), 2.27 (s, 3H); ES- MS [M+l] ⁺ : 249.4 l-Methyl-4-(4-methyl-3-py ridyl)pyrrolo 12.3-/? | pyridine-6-carboxylic acid (S 10).

Intermediate S9 (60 mg, 0.24 mmol, 1.0 eq) was added to a pressure vial containing 1,4- dioxane (2 mL) and IM aqueous sodium hydroxide (1.2 mL, 2.4 mmol, 10 eq). The vial w as sealed and the mixture was heated overnight at 100 °C. The reaction mixture was first cooled to room temperature then brought to pH 4-5 with 2M aqueous HC1. The mixture was concentrated and the residue suspended in 10% MeOH/DCM. Insoluble salts were removed by filtration and the organic solvents concentrated in vacuo. Purification by normal-phase column chromatography on silica gel (0-10% MeOH/DCM) afforded 64 mg (99%) of the title compound as a white solid. 'H NMR (400 MHz, CDsOD) <5 8.51 (d, J= 5.2 Hz, 1H), 8.46 (s, 1H), 7.87 (s, 1H), 7.67 (d, J= 3.5 Hz, 1H), 7.50 (d, J= 5.2 Hz, 1H), 6.31 (d, J= 3.5 Hz, 1H), 4.03 (s, 3H), 2.27 (s, 3H); ES-MS [M+l] ⁺ : 268.4

1 - Methyl-4-(4-methyl py ridin-3-y l)-/V-( py ridin-2-yl )- 1/7-pyrrolo [2,3-b] pyridine-6- carboxamide (8) (8). To a stirring solution of intermediate S10 (5.0 mg, 0.019 mmol, 1.0 eq) and 2-aminopyridine (2. 13 mg, 0. 11 mmol, 1.2 eq) in pyridine (1 mL) was added phosphorus(V) oxychloride (5.3 pL, 0.057 mmol, 3.0 eq). The reaction mixture was stirred for 30 min at room temperature after which time water was slowly added and solvents removed in vacuo. Purification via RP-HPLC (11-43% ACN/0. 1% aqueous TFA) afforded 2.2 mg (70%) of the title compound as a white solid. ES-MS |M+ 1 ] ⁺ : 364.2

Scheme V

3-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3a,7a-dihydrothieno|3,2- b]pyridine-5-carbonitrile (S12). 7-Chloro-3-methyl-thieno[3.2-b]pyridine-5-carbonitrile (120 mg, 0.57 mmol, 1.0 eq), bis(pinacolato)diboron (219 mg, 0.86 mmol, 1.50 eq), Pd(dppf)C12'DCM adduct (47 mg, 0.058 mmol, 0.10 eq), potassium acetate (169 mg, 1.73 mmol, 3.0 eq) and 1,4-dioxane (3mL) were added to a pressure vial. The vial was sealed, evacuated and backfilled with nitrogen (3x). After stirring the mixture at 80 °C for 16 hours, the mixture was cooled to room temperature and filtered through a pad of Celite washing w ith EtOAc and DCM. The organic solvents were concentrated in vacuo and the material was carried forward withouth further purification. ES-MS [M+l] ⁺ : 219 (mass of boronic acid).

3-methyl-7-(4-methylpyridin-3-yl)-3a,7a-dihydrothieno[3,2 -b]pyridine-5-carbonitrile (S13). 3-Bromo-4-picoline (109 mg, 0.63mmol, 1.1 eq), intermediate S12 (172 mg, 0.58 mmol, 1.0 eq), Pd(dppf)Ch (63 mg, 0.086 mmol, 0.15 eq), cesium carbonate (280 mg, 0.86 mmol, 3.0 eq) and 9:1 acetonitrile: water (2 mL) were added to a pressure vial. The vial was sealed, evacuated and backfilled with nitrogen (3x). After 4 hours at 80 °C the reaction mixture was cooled to room temperature and filtered through a plug of celite washing with EtOAc and DCM. The residue was purified using normal-phase column chromatography on silica gel (0-5% MeOH/DCM) to afford 152 mg (99%) of the title compound as a yellow oil. ES-MS [M+l] ⁺ : 266.2.

Scheme VI

6-Chloro-8-(4-methylpyridin-3-yl)imidazo[ l,2-/>|py ridazine (S14). 8-Bromo-6- chloroimidazo[1.2-b]pyridazine (200 mg, 0.860 mmol, 1.00 eq), 4-picoline-3-boronic acid (189 mg, 1.38 mmol, 1.60 eq), Pd(dppf)Ch (63.1 mg, 0.860 mmol, 0.086 eq) and cesium carbonate (846 mg, 2.58 mmol, 3.00 eq) were added to a flask followed by a 5: 1 mixture of 1,4-di oxane/ water (4.3 mL) and the reaction was heated at 90 °C for 18 hours. The reaction was cooled and filtered over Celite, washing, with 10% MeOH/DCM and the organics were removed in vacuo. The crude residue was purified using normal-phase column chromatography on silica gel (0-4% MeOH/DCM with 1% NH4OH additive) to afford 1 5 mg (78%) of the title compound. 'H NMR (400 MHz, DMSO-d6) 3 7.74 (d, J = 5.2 Hz, 1H), 7.72 (s, 1H), 7.41 (d. J = 1.3 Hz, 1H), 6.96 (d, J = 1.3 Hz, 1H), 6.69-6.66 (m, 1H), 6.55 (s. 1H), 1.49 (s, 3H); ES-MS [M+l] ⁺ : 245.3

8-(4-Methylpyridin-3-yl)imidazo[l,2-Z>]pyridazine-6-ca rbonitrile (S15). Intermediate S14 (165 mg, 0.674 mmol, 1.00 eq), zinc cyanide (95.0 mg, 0.809 mmol, 1.20 eq) and Pd(PPhs)4 (77.9 mg, 0.0674 mmol, 0.100 eq) were added to a microwave vial followed by DMF (4.1 mL). The mixture was irradiated in a microwave at 140 °C for 15 minutes. After cooling, the reaction mixture was poured into a separatory' funnel containing a saturated aqueous NaHCCL solution and extracted with EtOAc (3x). The combined organic layers were dried (MgSCL), filtered and concentrated in vacuo. The crude mixture was purified using normal-phase column chromatography on silica gel (0-4% MeOH/DCM with 1 % NH4OH additive) to afford 104 mg (46%) of the title compound. ^] H NMR (400 MHz. CDCh) 3 7.75-7.72 (m, 2H), 7.61 (d, J = 1.4 Hz. 1H), 7.17 (d. J = 1.4 Hz, 1H). 6.83 (s. 1H), 6.70-6.66 (m. 1H), 1.49 (s, 3H); ES-MS [M+l] ⁺ : 236.3.

Sodium 8-(4-methylpyridin-3-yl)imidazo[l,2-/;|pyridazine-6-carboxyl ate (S16).

Intermediate S15 (104 mg. 0.309 mmol, 1.00 eq) was dissolved in 1,4-dioxane (0.5 mL) and 2M aqueous sodium hydroxide (774 pL, 1.55 mmol, 5.00 eq) was added. The vial was sealed and heated at 100 °C for 1 hour. After cooling, the reaction was diluted with w ater (3 mL)and extracted with DCM (2x). The aqueous layer was concentrated to dry ness to afford 240 mg (98%) of title compound that was used without further purification. ES-MS [M+l] ⁺ : 255.2 (mass of the carboxylic acid).

7V-(5-Fluoropyridin-2-yl)-8-(4-methyIpyridin-3-yl)imidazo [l,2-/»]pyi'idazine-6- carboxamide (30). Intermedaite S16 (43 mg, 0.059 mmol, 1.0 eq) and 2-amino-5- fluoropyridine (6.7 mg, 0.060 mmol, 1.0 eq) were dissolved in pyridine (0.5 mL) and cooled to 0 °C. Phosphorous(V) oxychloride (14 pL, 0.015 mmol, 2.0 eq) was added and after 1 hour at room temperature, to the reaction was added aqueous 10% K2CO3 with EtOAc. The layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (MgSCfi). fdtered and concentrated in vacuo The crude residue was purified using RP-HPLC (5 - 70% ACN/0.05% aqueous NH4OH) to afford 6.5 mg (32%) of the title compound as a yellow solid. 'H NMR (400 MHz, CDCI3) 5 9.91 (s, 1H), 8.65 (s, 1H), 8.62 (d, J= 5.1 Hz, 1H), 8.43 (dd, J= 9.1, 4.0 Hz, 1H), 8.26 (d, J= 2.9 Hz, 1H), 8.15 (d, J= 1.2 Hz, 1H), 7.95 (d, J= 1.3 Hz, 1H), 7.92 (s, 1H), 7.55 (ddd, J= 9.1, 7.5, 3.0 Hz, 1H), 7.33 (dt, J= 5.1, 0.8 Hz, 1H), 2.34 (s, 3H); ES-MS [M+l] ⁺ : 349.3.

Scheme VII

5-Bromo-7-chloroimidazo[ 1,2- a] pyridine (S17). To a solution of 6-bromo-4-chloro-2- aminopyridine (300 mg, 1.45 mmol, 1.00 eq) in ethanol (3.9 mL) was added sodium bicarbonate (243 mg, 2.89 mmol, 2.00 eq) followed by chloroacetaldehyde solution (~50 wt% in water) (220 pL, 1.74 mmol, 1.20 eq). The mixture was heated to 80 °C for 18 hours then concentrated. The crude product was purified using normal-phase column chromatography on silica gel (0 - 4% MeOH/DCM) to afford 213 mg (64%) of title compound. 'H NMR (400 MHz, CD3OD) 5 8.00 (dd, J = 1.5, 0.8 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.68 (dd, J = 1.9, 0.8 Hz, 1H), 7.38 (d, J= 1.8 Hz, 1H); ES-MS [M+l] ⁺ : 233.0.

Scheme 8 VIII

5-Chloro-7-(4-methylpyridin-3-yl)pyrazolo[l,5-a] pyridine (S18). To a vial was added 5- chloro-7-iodo-pyrazolo[l,5-a]pyridine (220 mg, 0.790 mmol, 1.00 eq), 4-picoline-3-boronic acid (141 mg, 1.03 mmol, 1.30 eq), cesium carbonate (777 mg, 2.37 mmol, 3.00 eq) and Pd(dppf)Ch (58 mg, 0.079 mmol, 0.10 eq) followed by 1.4-dioxane (4.8 mL). The vial was sealed and heated at 100 °C for 2 The vial was recharged with 58mg of Pd(dppf)C12 (0.1 eq) and 30 mg (0.3 eq) of 4-picoline-3-boronic acid followed by heating at 100 °C for 1 hour. After this process was repeated twice more, the reaction was filtered over Celite and washed with 10% MeOH/DCM. The crude residue was purified using normal -phase column chromatography on silica gel (0-3% MeOH/DCM with 1% NH4OH additive) to afford 112 mg (58%) of the title compound. *HNMR (400 MHz, CDCh) <5 7.75 (d, J = 5.2 Hz, 1H), 7.69 (s, 1H). 7. 14 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.66 (d, J = 5.2 Hz, 1H), 6.13 (d, J = 2.2 Hz, 1H), 5.91 (d, J = 2.3 Hz, 1H), 1.33 (s, 3H); ES-MS [M+l] ⁺ : 244.0.

Methyl 7-(4-methylpyridin-3-yl)pyrazolo[l,5-«]pyridine-5-carboxyla te (S19).

Intermediate S18 (216 mg, 0.888 mmol, 1.00 eq) was dissolved in methanol (3.3 mL) and DMSO (1.6 mL) in a round bottom flask and l,3-bis(diphenylphosphino)propane (73 mg, 0.18 mmol, 0.20 eq), palladium(II) acetate (40 mg, 0.18 mmol, 0.20 eq) and triethylamine (1.24 mL, 8.88 mmol, 10.0 eq) were added. The reaction was placed under an atmosphere of CO gas (balloon) and heated at 80 °C overnight. After cooling the reaction was filtered over Celite and washed with 10% MeOH/DCM. The organics were concentrated in vacuo and the residue purified using normal-phase column chromatography on silica gel (0-3% MeOH/DCM) to afford 86 mg 37%) of the title compound. 'f l NMR (400 MHz, CDCL) <5 8.63 (d, J= 5.1 Hz, 1H), 8.60 (s. 1H), 8.43 (d. J= 1.8 Hz. 1H), 8.03 (d. J= 2.3 Hz. 1H), 7.35 (d, J= 1.8 Hz, 1H), 7.31 (d, J= 5.1 Hz, 1H), 6.86 (d, J= 2.3 Hz, 1H), 3.98 (s, 3H), 2.15 (s, 3H); ES-MS [M+l] ⁺ : 268.2.

Sodium 7-(4-methylpyridin-3-yl)pyrazolo[l,5-a]pyridine-5-carboxylat e (S20). To a vial was added intermediate S19 (86 mg, 0.24 mmol, 1.0 eq), IM aqueous sodium hydroxide (722 pL, 0.722 mmol, 3.00 eq) and water (0.2 mL). The reaction was heated at 50 °C for 1 hour. The reaction was cooled and washed with DCM (2x). The aqueous layer was concentrated to dryness to afford 106 mg (99%) of the title compound which was used without further purification. 'H NMR (400 MHz, CDjOD) d 8.46 (d, J= 5.3 Hz, 1H), 8.43 (s, 1H), 8.21 (d, J = 1.7 Hz. 1H), 7.85 (d, J = 2.4 Hz. 1H), 7.38 (d, J= 5.3 Hz. 1H), 7.29 (d, J = 1.7 Hz, 1H), 6.75 (d, J= 2.4 Hz, 1H), 2.05 (s, 3H); ES-MS [M+l] ⁺ : 254.2 (mass of the carboxylic acid).

A'-(6-Methylpyridin-2-yl)-7-(4-methylpyridin-3-yl)pyrazol o[l,5-a|pyridine-5- carboxamide (66) . Intermediate S20 (14 mg, 0.057 mmol, 1.0 eq) and 6-amino-2-picoline (12 mg, 0.11 mmol, 2.0 eq) were dissolved in pyridine (0.25 mL) and cooled to 0 °C. Phosphorous(V) oxychloride (13 pL, 0.14 mmol, 2.4 eq) was added and the reaction was allowed to warm to room temperature over 30 minutes. The reaction mixture was then cooled back to 0 °C where a saturated aqueous solution of sodium bicarbonate was slowly added. The resulting mixture was stirred 5 minutes then extracted with 3: 1 CHCfi/IPA (3x). The organic layers were passed through a phase separator and concentrated. The crude residue purified using RP-HPLC (5 - 55% ACN/0.05% aqueous NH4OH) to afford 6.3 mg (33%) of the title compound as a white solid. ' H NMR (400 MHz, CDCI3) 8 8.66 (s, 1H), 8.64 (d, J = 5.1 Hz, 1H), 8.62 (s, 1H), 8.29 (d, 2.0 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.67 (t, .7= 7.8 Hz, 1H), 7.31 (dt, J= 5.1, 0.8 Hz, 1H), 7.27 (d, 2.0 Hz. 1H), 6.97 (d, J= 7.5 Hz, 1H), 6.85 (d, J= 2.4 Hz, 1H), 2.48 (s, 3H). 2.16 (s, 3H); ES-MS [M+l] ⁺ : 344.4.

Scheme IX

5-(4-Methylpyridin-3-yl)imidazo[l,5-a]pyridine-7-carbonit rile (S22). To a micro wave vial was added intermediate S21 (synthesized in a similar manner as intermediate S18) (85.3 mg, 0.30 mmol), Pd(PPhs)4 (34 mg, 0.030 mmol), and zinc cyanide (42 mg, 0.36 mmol) in DMF (2.1 mL). The vial was sealed and irradiated in a microwave at 140 °C for 15 minutes. The mixture was cooled to room temperature then added to a saturated aqueous NaHCOs solution (~75mL) and extracted with EtOAc (3x). The organic layers were pooled, dried (MgSCh). filtered, and concentrated. Crude product was purified using normal-phase column chromatography (0-4% MeOH/DCM with 1% NH4OH additive) to afford 38 mg (54%) of title compound. 'H NMR (400 MHz, CD3OD) 5 8.64 (d, J = 5.2 Hz, 1H), 8.59 (s, 1H), 8.36 - 8.31 (m, 1H), 7.96 (d, J= 0.8 Hz, 1H), 7.87 (d, J= 0.7 Hz, 1H), 7.55 (dd, J= 5.2, 0.9 Hz. 1H), 6.89 (d, J= 1.5 Hz. 1H), 2.21 (s, 3H); ES-MS [M+l] ⁺ : 235.2.

Sodium 5-(4-methylpyridin-3-yl)imidazo[l,5-a]pyridine-7-carboxylate (S23). To a vial was added intermediate S22 (38 mg, 0. 16 mmol) and 2 7 aqueous sodium hydroxide (402 pL. 0.80 mmol), and 1,4-dioxane (0.50 mL). The reaction was then heated to 100 °C for 1 hour then cooled to room temperature. The reaction mixture was then diluted with water (~1.5 mL) and the aqueous layer was extracted twice with DCM. The aqueous layer was then concentrated to afford 44 mg (99%) of title compound which was carried forward without further purification. 'H NMR (400 MHz, CD3OD) 5 8.61 (d, J= 5.2 Hz, 1H), 8.58 (s, 1H), 8.25 (t, J= 1.1 Hz, 1H), 7.75 (d, J= 0.9 Hz, 1H), 7.67 (d, J = 0.8 Hz, 1H), 7.54 (d, J = 5.2 Hz. 1H), 7.21 (d. J= 1.5 Hz. 1H), 2.21 (s, 3H); ES-MS [M+l] ⁺ : 254.2.

Scheme X

5-Bromo-7-(4-methylpyridin-3-yl)-3a,7a-dihydrobenzo[(l]th iazole (S24). In a vial was added a mixture of 5,7-dibromo-l,3-benzothiazole (230 mg, 0.79 mmol, 1.0 eq), 4-picoline-

3-boronic acid (119 mg, 0.86 mmol, 1.1 eq), Pd(dppf)Ch (58 mg, 0.08 mmol, 0.10 eq), and cesium carbonate (772 mg, 2.36 mmol, 3.0 eq) in 1,4-dioxane (5.3 mL). The mixture was stirred at 100 °C for 2 hours then cooled to room temperature. The reaction mixture was filtered through a pad of Celite, washed with 10% MeOH/DCM, and the organic solvents were concentrated. Crude product was purified using normal-phase column chromatography (0-90% EtOAc/DCM) to afford 64 mg (27%) of title compound. 'H NMR (400 MHz.

CD3OD) 5 9.31 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 8.34 (d, J = 1.8 Hz, 1H), 7.62 (d, J= 1.7 Hz, 1H), 7.49 (dt, J = 5.2, 0.8 Hz, 1H), 2.23 (s, 3H); ES-MS [M+l] ⁺ : 307.0.

Methyl 7-(4-methylpyridin-3-yl)-3a,7a-dihydrobenzo[d]thiazole-5-car boxylate (S25). To a pressure vial was added intermediate S24 (64 mg, 0.21 mmol, 1.0 eq), potassium acetate (62 mg, 0.63 mmol, 3.0 eq), and Pd(dppf)C12 (16 mg, 0.02 mmol, 0.10 eq) in methanol (0.54 mL) and DMF (0.51 mL). The vial was sealed, evacuated and backfdled with CO (gas) (3x). The mixture was left under an atm of CO (gas) (balloon) and stirred overnight at 80 °C. After cooling to room temperature, the crude product was purified using normal-phase column chromatography (0-3% MeOH/DCM) to afford 49 mg (83%) of title compound. 'H NMR (400 MHz, CD3OD) 5 9.38 (d, J = 0.5 Hz, 1H). 8.78 (d, J = 1.5 Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.48 (s, 1H), 8.04 (dd, J = 1.5, 0.5 Hz, 1H), 7.50 (dt, J = 5.2, 0.7 Hz, 1H), 4.00 (s, 3H), 2.23 (s, 3H); ES-MS [M+l] ⁺ : 285.1.

Barium 7-(4-methylpyridin-3-yl)benzo[d]thiazole-5-carboxylate hydroxide (S26). To a vial was added intermediate S25 (49 mg, 0.17 mmol, 1.0 eq), barium hydroxide octahydrate (109 mg, 0.35 mmol, 2.0 eq), THF (0.4 mL), and water (0.2 mL). The reaction was heated to 50 °C for 15 minutes. The reaction mixture was then concentrated to afford 70 mg (99%) of title compound that was carried forward without further purification. 'H NMR (400 MHz, DMSO-O 5 9.39 (s, 1H), 8.57 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 8.48 (s, 1H), 7.92 (s, 1H), 7.43 (d, J= 5.1 Hz, 1H), 2.13 (s. 3H); ES-MS [M+l] ⁺ : 271.1 (mass of the carboxylic acid).

7-(4-Methylpyridin-3-yl)-/V-(4-methylthiazol-2-yl)benzo|d |thiazole-5-carboxamide (64).

Intermediate S26 (36 mg, 0.055 mmol, 1.0 eq) and 2-amino-4-methylthiazole (13 mg, 0.11 mmol, 2.0 eq) were dissolved in pyridine (0.25 mL) and cooled to 0 °C. Phosphorous(V) oxychloride (13 pL, 0. 14 mmol, 2.4 eq) was added and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was then cooled back to 0 °C where a saturated aqueous solution of sodium bicarbonate was slowly added. The resulting mixture was stirred 5 minutes then extracted with 3: 1 CHCh/IPA (3x). The organic layaers were passed through a phase separator and concentrated. The crude residue purified using RP- HPLC (5 - 65% ACN/0.05% aqueous NH4OH) to afford 1.4 mg (7%) of the title compound as an off-white solid. ES-MS [M+l] ⁺ : 367.3

TABLE 1

4. METABOTROPIC GLUTAM TE RECEPTOR ACTIVITY ASSAY

[00257] 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 pL 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 °C in the presence of 5% CO2. The next day, medium was removed and the cells incubated with 20 pL of 2.3 pM 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 pL of assay’ buffer was added, and the plate was incubated for 5 minutes at room temperature.

[00258] 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 EC ₈₀ 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.

[00259] The raw data file containing all time points was used as the data source in the analysis template. This w as saved by the FDSS as a tab-delimited text file. Data were normalized using a static ratio function (F/Fo) for each measurement of the total 360 values per ell 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 EC20/EC80 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 % by y multiplying each amplitude by 100 and then dividing the product by the mean of the amplitudes derived from the glutamate EC Max-treated wells. IC50 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.

[00260] 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 ECso response, but do not hit a plateau, the average of the Glu Max at a single concentration (30 pM) 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 pM. Exemplary data are provided in Table 2.

Table 2

*%Glu max at 30 pM

[00261 ] 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.