WO2008151184A1 - Dérivés benzamides modulateurs allostériques positifs récepteurs métabotropiques du glutamate 5 (mglur5) et leurs procédés de fabrication et d'utilisation - Google Patents

Dérivés benzamides modulateurs allostériques positifs récepteurs métabotropiques du glutamate 5 (mglur5) et leurs procédés de fabrication et d'utilisation Download PDF

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Publication number
WO2008151184A1
WO2008151184A1 PCT/US2008/065647 US2008065647W WO2008151184A1 WO 2008151184 A1 WO2008151184 A1 WO 2008151184A1 US 2008065647 W US2008065647 W US 2008065647W WO 2008151184 A1 WO2008151184 A1 WO 2008151184A1
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WIPO (PCT)
Prior art keywords
optionally substituted
hydrogen
amino
carbon atoms
compound
Prior art date
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PCT/US2008/065647
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English (en)
Inventor
P. Jeffrey Conn
Craig W. Lindsley
Charles David Weaver
Alice L. Rodriguez
Colleen M. Niswender
Carrie K. Jones
Richard Williams
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Vanderbilt University
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Publication date
Priority to MX2009013169A priority Critical patent/MX2009013169A/es
Priority to EA200971143A priority patent/EA200971143A1/ru
Priority to AU2008259776A priority patent/AU2008259776A1/en
Priority to JP2010511277A priority patent/JP5622568B2/ja
Priority to EP08770045A priority patent/EP2162136A4/fr
Priority to NZ581817A priority patent/NZ581817A/en
Application filed by Vanderbilt University filed Critical Vanderbilt University
Priority to CN200880100770.6A priority patent/CN101795689B/zh
Priority to BRPI0812363-2A2A priority patent/BRPI0812363A2/pt
Priority to CA002689282A priority patent/CA2689282A1/fr
Publication of WO2008151184A1 publication Critical patent/WO2008151184A1/fr
Priority to IL202508A priority patent/IL202508A0/en
Priority to HK11101174.3A priority patent/HK1147068A1/xx

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Definitions

  • L-glutamic acid the most commonly occurring neurotransmitter in the central nervous system, plays a role in a large number of physiological processes.
  • the glutamate-dependent stimulus receptors are divided into two main groups.
  • the first main group forms ligand- controlled ion channels.
  • the second main group is metabotropic glutamate receptors (mGluRs), which belong to the family of G-protein-coupled receptors.
  • Metabotropic glutamate receptors, including mGluR5 have been implicated in a wide range of biological functions, indicating a potential role for the mGluR5 receptor in a variety of disease processes in mammals.
  • Ligands of metabotropic glutamate receptors can be used for the treatment or prevention of acute and/or chronic neurological and/or psychiatric disorders associated with glutamate dysfunction, such as psychosis, schizophrenia, age-related cognitive decline, and the like.
  • Selective positive allosteric modulators are compounds that do not directly activate receptors by themselves, but binding of these compounds increase the affinity of a glutamate - site agonist at its extracellular N-terminal binding site. Positive allosteric modulation (potentiations) is thus an attractive mechanism for enhancing appropriate physiological receptor activation.
  • selective positive allosteric modulators for the mGluR5 receptor Unfortunately, there is a scarcity of selective positive allosteric modulators for the mGluR5 receptor. Further, conventional mGluR5 receptor modulators typically lack satisfactory aqueous solubility and exhibit poor oral bioavailability. Therefore, there remains a need for methods and compositions that overcome these deficiencies and that effectively provide selective positive allosteric modulators for the mGluR5 receptor.
  • the invention in one aspect, relates to compounds useful as positive allosteric modulators (i.e., potentiators) of the metabotropic glutamate receptor subtype 5 (mGluR5), methods of making same, pharmaceutical compositions comprising same, and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using same.
  • positive allosteric modulators i.e., potentiators
  • mGluR5 metabotropic glutamate receptor subtype 5
  • Disclosed are methods for the treatment of a disorder in a mammal comprising the step of administering to the mammal at least one compound having a structure represented by a formula:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • Also disclosed are methods for potentiation of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one compound having a structure represented by a formula:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; and wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • Also disclosed are methods for partial agonism of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one compound having a structure represented by a formula:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • Also disclosed are methods for the treatment of a disorder in a mammal comprising the step of administering to the mammal at least one compound having a structure:
  • R 1 and R 2 are independently optionally substituted organic radicals comprising from
  • each is an optional covalent bond; wherein Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Z 1 , Z 2 , and Z 3 are independently selected from N and C-R 4 , with the proviso that no more than two of Z 1 , Z 2 , and Z 3 are nitrogen; and wherein R 4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkenyl or
  • R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein each is an optional covalent bond; wherein Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Z 1 , Z 2 , and Z 3 are independently selected from N and C-R 4 , with the proviso that no more than two of Z 1 , Z 2 , and Z 3 are nitrogen; wherein R 4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl
  • R 1 and R 2 are independently optionally substituted organic radicals comprising from
  • each is an optional covalent bond; wherein Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Z 1 , Z 2 , and Z 3 are independently selected from N and C-R 4 , with the proviso that no more than two of Z 1 , Z 2 , and Z 3 are nitrogen; and wherein R 4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkenyl or
  • R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein each is an optional covalent bond; wherein Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Z 1 , Z 2 , and Z 3 are independently selected from N and C-R 4 , with the proviso that no more than two of Z 1 , Z 2 , and Z 3 are nitrogen; wherein R 4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl; an isoindoline-l,3-dione derivative having a structure:
  • R 1 is hydrogen or is selected from optionally substituted Cl -C 12 alkyl, optionally substituted Cl -C 12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, with the proviso that R 1 does not comprise silicon; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl, and with the proviso that if R 1 is methyl, then R 5 is an organic radical comprising 4 to 14 carbon atoms; a 3,4-dihydroisoquinolin-l(2H)-one derivative having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; wherein each R 2a and R 2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms; an isoquinoline-l,3(2H,4H)-dione derivative having a structure:
  • R is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that R 5 does not comprise a triphenylamine residue or a benzimidamide residue; or a bicyclic compound having a structure:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • compositions comprising a therapeutically effective amount of at least one disclosed compound and a pharmaceutically acceptable carrier.
  • Also disclosed are methods for the manufacture of a medicament for potentiation of metabotropic glutamate receptor activity in a mammal comprising combining at least one disclosed compound, or a pharmaceutically acceptable salt or N-oxide thereof, with a pharmaceutically acceptable carrier.
  • Figure 1 shows a schematic of the NMDA receptor.
  • Figure 2 shows a schematic illustrating that activation of mGluR5 potentiates NMDA receptor function.
  • Figure 3 illustrates allosteric modulation of mGluR5.
  • Figure 4 shows CDPPB as a potent and selective mGluR5 potentiator having modest efficacy in rodent behavioral models for antipsychoticic activity.
  • Figure 5 shows classification of compounds as agonists, potentiators, and antagonists.
  • Figure 6 shows a schematic illustrating optimization of candidates.
  • Figure 7 tabulates displacement of [3H]methoxyPEPy and shows binding to the MPEP site with varying affinities.
  • Figure 8 shows in vivo efficacy for (4-hydroxypiperidin-l-yl)(4- (phenylethynyl)phenyl)methanone (Compound VUl 3).
  • Figure 9 shows in vivo efficacy for (4-hydroxy-4-propylpiperidin-l-yl)(4- (phenylethynyl)phenyl)methanone (Compound VU60).
  • Figure 10 shows in vivo efficacy for (4-(hydroxymethyl)piperidin-l-yl)(4- (phenylethynyl)phenyl)methanone (Compound VU14/C104B2).
  • Figure 11 shows cognitive improvement in a novel object recognition (NOR) paradigm by ADX47273.
  • Figure 13 shows effects of VU000098 on amphetamine-induced hyperlocomotion
  • Figure 15 shows the chemical structures of mGluR5 PAMs with in vivo activity in preclinical antipsychotic models.
  • Figure 16 shows reversal of amphetamine-induced hyperlocomotion by CDPPB
  • Figure 17 shows reversal of amphetamine-induced hyperlocomotion by VUOOO 13 and VU000067.
  • Figure 18 shows reversal of amphetamine-induced prepulse inhibition (PPI) by CDPPB.
  • Figure 19 shows reversal of amphetamine-induced prepulse inhibition (PPI) by ADX47273.
  • Figure 20 shows the increase in strength of synaptic connections after applying a stimulus to the synapse in the absence and presence of two structurally distinct mGluR5 PAMs, VU29 (top panel) and ADX47273 (bottom panel).
  • Ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another 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 another 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.
  • a residue of a chemical species 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.
  • an ethylene glycol residue in a polyester refers to one or more -OCH 2 CH 2 O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more -CO(CH 2 )SCO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • mGluR5 receptor positive allosteric modulator refers to any exogenously administered compound or agent that directly or indirectly augments the activity of the mGluR5 receptor in the presence or in the absence of the endogenous ligand (such as glutamate) in an animal, in particular a mammal, for example a human.
  • mGluR5 receptor positive allosteric modulator includes a compound that is an "mGluR5 receptor allosteric potentiator” or an “mGluR5 receptor allosteric agonist,” as well as a compound that has mixed activity as both an “mGluR5 receptor allosteric potentiator” and an “mGluR5 receptor allosteric agonist.”
  • mGluR5 receptor allosteric potentiator refers to any exogenously administered compound or agent that directly or indirectly augments the response produced by the endogenous ligand (such as glutamate) when it binds to the orthosteric site of the mGluR5 receptor in an animal, in particular a mammal, for example a human.
  • the mGluR5 receptor allosteric potentiator binds to a site other than the orthosteric site (an allosteric site) and positively augments the response of the receptor to an agonist.
  • activity of a compound as an mGluR5 receptor allosteric potentiator provides advantages over the use of a pure mGluR5 receptor allosteric agonist. Such advantages can include, for example, increased safety margin, higher tolerability, diminished potential for abuse, and reduced toxicity.
  • mGluR5 receptor allosteric agonist refers to any exogenously administered compound or agent that directly augments the activity of the mGluR5 receptor in the absence of the endogenous ligand (such as glutamate) in an animal, in particular a mammal, for example a human.
  • the mGluR5 receptor allosteric agonist binds to the orthosteric glutamate site of the mGluR5 receptor and directly influences the orthosteric site of the mGluR5 receptor.
  • activity of a compound as an mGluR5 receptor allosteric agonist provides advantages over the use of a pure mGluR5 receptor allosteric potentiator, such as more rapid onset of action.
  • treatment is meant 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.
  • 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.
  • prevent or “preventing” is meant to preclude, avert, obviate, forestall, stop, or hinder 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.
  • diagnosisd with a need for potentiation 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 potentiation of metabotropic glutamate receptor activity.
  • diagnostics with a need for partial agonism 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 agonism of metabotropic glutamate receptor activity.
  • diagnosisd with a need for treatment of one or more neurological and/or psychiatric disorder 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 disorder associated with glutamate dysfunction.
  • administering refers 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, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • 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 affects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety 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.
  • 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.
  • a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.
  • a "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.
  • 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 injectable organic esters such as ethyl oleate.
  • Proper fluidity may 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 may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form may 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 may 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.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • 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.
  • 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.
  • 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.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • 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.
  • 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, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dode cyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a "lower alkyl” group is an alkyl group containing from one to six (e.g., from one ot four) carbon atoms.
  • 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.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • alkylamino specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like.
  • 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 “alkylalcohol” and the like.
  • 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, norbornyl, and the like.
  • 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, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • polyalkylene group as used herein is a group having two or more CH 2 groups linked to one another.
  • the polyalkylene group can be represented by the formula — (CH 2 ) a — , where "a" is an integer of from 2 to 500.
  • 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.
  • 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.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, optionally substituted 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.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • 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, optionally substituted 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.
  • alkynyl 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, optionally substituted 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.
  • 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 bound.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • 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, optionally substituted 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.
  • 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.
  • 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.
  • 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 aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, optionally substituted 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.
  • biasing is a specific type 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.
  • amine or “amino” as used herein are represented by the formula NA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • esters as used herein is represented by the formula — OC(O)A 1 or — C(O)OA 1 , where A 1 can be an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • 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 optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a” is an interger from 1 to 500.
  • Polyyester 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.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula — (A 1 O-A 2 O) J1 — , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, 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.
  • halide refers to the halogens fluorine, chlorine, bromine, and iodine.
  • hydroxyl as used herein is represented by the formula — OH.
  • 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 optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • nitro as used herein is represented by the formula — NO 2 .
  • nitrile as used herein is represented by the formula — CN.
  • sil as used herein is represented by the formula — SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo is represented by the formulas — S(O)A 1 , — S(O) 2 A 1 , -OS(O) 2 A 1 , or -OS(O) 2 OA 1 , where A 1 can be hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula — S(O) 2 A 1 , where A 1 can be hydrogen or an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 S(O) 2 A 2 is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • 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 optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • 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 alkyl 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.
  • 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
  • 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.
  • radical refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
  • a 2,4- thiazolidinedione radical in a particular compound has the structure
  • radical for example an alkyl
  • substituted 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.
  • Organic radicals 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.
  • 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.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • 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, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • Inorganic radicals 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.
  • 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.
  • DMF dimethyl formamide.
  • EtOAc ethyl acetate.
  • THF tetrahydrofuran.
  • DIPEA or DIEA diisopropylethylamine.
  • HOBt 1- hydroxybenzotriazole.
  • EDC l-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride.
  • DMSO dimethylsulfoxide.
  • DMAP 4-Dimethylaminopyri dine.
  • RT Room temperature.
  • H Hours. Min: Minutes.
  • DCM Dichloromethane.
  • MeCN Acetonitrile.
  • MeOH methanol.
  • iPrOH 2-Propanol.
  • n-BuOH 1-Butanol.
  • compositions of the invention 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 can not 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.
  • 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.
  • Phencyclidine (PCP) and other NMDA receptor antagonists induce a psychotic state in humans similar to schizophrenia.
  • PCP and ketamine exacerbate/precipitate preexisting positive and negative symptoms in stable patients.
  • Treatment with NMDA receptor co-agonists can improve positive and negative symptoms.
  • a schematic of the NMDA receptor is shown in Figure 1.
  • Activation of mGluR5 potentiates NMDA receptor function. See Figure 2.
  • Orthosteric ligands lack subtype selectivity and may cause unwanted side effects. Allosteric modulators (see Figure 3) targeting transmembrane domain offer alternative: TMD is significantly less conserved.
  • CDPPB 4-Cyano-N-(l,3-diphenyl-lH-pyrazol-5-yl)benzamide
  • the invention relates to compounds useful as positive allosteric modulators (potentiators) of the metabotropic glutamate receptor subtype 5 (mGluR5). More specifically, the present invention relates to compounds that allosterically modulate mGluR5 receptor activity, affecting the sensitivity of mGluR5 receptors to agonists without acting as orthosteric agonists themselves.
  • the compounds of the invention are useful in the treatment neurological and psychiatric disorders associated with glutamate dysfunction and other diseases in which metabotropic glutamate receptors are involved, as further described herein.
  • the invention relates to a compound having a structure represented by a formula:
  • R 1 and R 2 are independently optionally substituted organic radicals comprising from
  • each is an optional covalent bond; wherein Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Z 1 , Z 2 , and Z 3 are independently selected from N and C-R 4 , with the proviso that no more than two of Z 1 , Z 2 , and Z 3 are nitrogen; and wherein R 4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkenyl or
  • R 1 and R 2 are independently alkyl having from 1 to 6 carbons.
  • all of Z 1 , Z 2 , and Z 3 are carbon.
  • R 4 comprises up to five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • both of Y 1 and Y 2 are carbon.
  • the compound has a structure represented by a formula:
  • R 1 and R 2 are independently alkyl having from 1 to 6 carbons or N, R 1 , and R 2 together comprise an optionally substituted heterocyclic ring having from two to seven carbons; R comprises three or four substituents independently selected from hydrogen, halogen, and lower alkyl; and R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • the invention relates to a compound having a structure represented by a formula:
  • R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein each is an optional covalent bond; wherein Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Z 1 , Z 2 , and Z 3 are independently selected from N and C-R 4 , with the proviso that no more than two of Z 1 , Z 2 , and Z 3 are nitrogen; wherein R 4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl
  • R 1 and R 2 are independently hydrogen or alkyl having from
  • N, R 1 , and R 2 together comprise an optionally substituted heterocyclic ring having from two to seven carbons.
  • all of Z 1 , Z 2 , and Z 3 are carbon.
  • R 4 comprises up to five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • both of Y 1 and Y 2 are carbon.
  • both of R 7a and R 7b are hydrogen.
  • the compound has a structure represented by a formula:
  • R 1 and R 2 are independently hydrogen or alkyl having from
  • R 1 , and R 2 together comprise an optionally substituted heterocyclic ring having from two to seven carbons;
  • R comprises three or four substituents independently selected from hydrogen, halogen, and lower alkyl; and
  • R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • the invention relates to a compound having a structure represented by a formula:
  • R 1 and R 2 are independently optionally substituted organic radicals comprising from
  • each is an optional covalent bond; wherein Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Z 1 , Z 2 , and Z 3 are independently selected from N and C-R 4 , with the proviso that no more than two of Z 1 , Z 2 , and Z 3 are nitrogen; and wherein R 4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkenyl or
  • R 1 and R 2 are independently hydrogen or alkyl having from
  • N, R 1 , and R 2 together comprise an optionally substituted heterocyclic ring having from two to seven carbons.
  • all of Z 1 , Z 2 , and Z 3 are carbon.
  • R 4 comprises up to five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • both of Y 1 and Y 2 are carbon.
  • R 1 and R 2 are independently alkyl having from 1 to 6 carbons or N, R 1 , and R 2 together comprise an optionally substituted heterocyclic ring having from two to seven carbons; R comprises three or four substituents independently selected from hydrogen, halogen, and lower alkyl; and R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • the invention relates to a compound having a structure represented by a formula:
  • R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein each is an optional covalent bond; wherein Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Z 1 , Z 2 , and Z 3 are independently selected from N and C-R 4 , with the proviso that no more than two of Z 1 , Z 2 , and Z 3 are nitrogen; wherein R 4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl
  • R 1 and R 2 are independently hydrogen or alkyl having from
  • N, R 1 , and R 2 together comprise an optionally substituted heterocyclic ring having from two to seven carbons.
  • all of Z 1 , Z 2 , and Z 3 are carbon.
  • R 4 comprises up to five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • both of Y 1 and Y 2 are carbon.
  • R 8 is hydrogen.
  • the compound has a structure represented by a formula:
  • R 1 and R 2 are independently hydrogen or alkyl having from
  • R 1 , and R 2 together comprise an optionally substituted heterocyclic rin ⁇ having from two to seven carbons;
  • R comprises three or four substituents independently selected from hydrogen, halogen, and lower alkyl; and
  • R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • the invention relates to a compound or pharmaceutically acceptable salt thereof selected from N-cyclopentyl-4-(phenylethynyl)benzamide; (4-((3- fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin- 1 -yl)methanone; morpholino(4- (phenylethynyl)phenyl)methanone; (4-((3 - fluorophenyl)ethynyl)phenyl)(morpholino)methanone; N-cyclohexyl-4- (phenylethynyl)benzamide; (4-((3-fluorophenyl)ethynyl)phenyl)(4-(hydroxymethyl)piperidin- 1 -yl)methanone; (4-((2-fluorophenyl)ethynyl)phenyl)(morpholino)methanone; (4- hydroxypiperid
  • the compound is selected from (2,6- dimethylmorpholino)(4-(phenylethynyl)phenyl)methanone; (3 -hydroxy-3 -(thiophen-2- yl)azetidin- 1 -yl)(4-(phenylethynyl)phenyl)methanone; (3 -hydroxy-3 -methylazetidin- 1 -yl)(4- (phenylethynyl)phenyl)methanone; (3 -hydroxy-3 -propylazetidin- 1 -yl)(4- (phenylethynyl)phenyl)methanone; (3 -hydroxyazetidin- 1 -yl)(4- (phenylethynyl)phenyl)methanone; (3 -hydroxypiperidin- 1 -yl)(4- (phenylethynyl)phenyl)methanone; (4-((((4-(phenyleth
  • the compound is selected from N-cyclopentyl-4- (phenylethynyl)benzamide; N-cyclohexyl-4-(phenylethynyl)benzamide; 4-(phenylethynyl)-N- propylbenzamide; N-(3,3-dimethylbutyl)-4-(phenylethynyl)benzamide; N-isopentyl-4- (phenylethynyl)benzamide; N-(3 -methoxypropyl)-4-(phenylethynyl)benzamide; N-butyl-4- (phenylethynyl)benzamide; (R)-4-(phenylethynyl)-N-(2-phenylpropyl)benzamide; N- (cyclohexylmethyl)-4-(phenylethynyl)benzamide; N-(2-cyclohexenylethyl)-4- (phenylethyl)-4- (pheny
  • the compound is selected from (4-((3- fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin- 1 -yl)methanone; morpholino(4- (phenylethynyl)phenyl)methanone; (4-((3 - fluorophenyl)ethynyl)phenyl)(morpholino)methanone; (4-((3-fluorophenyl)ethynyl)phenyl)(4- (hydroxymethyl)piperidin-l-yl)methanone; (4-((2- fluorophenyl)ethynyl)phenyl)(morpholino)methanone; (4-hydroxypiperidin- 1 -yl)(4- (phenylethynyl)phenyl)methanone; (4-((4-fluorophenyl)ethynyl)phenyl)(4-hydroxypiperidin- 1 -yl)
  • the compound is selected from 4-(3-(4-fluorophenyl)- 1,2,4- oxadiazol-5-yl)-N-(3-methoxypropyl)benzamide; N-(3,3-dimethylbutyl)-4-(3-phenyl-l,2,4- oxadiazol-5-yl)benzamide; 4-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5-yl)-N-propylbenzamide; 4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)-N-propylbenzamide; (4-(3-(4-fluorophenyl)- 1 ,2,4- oxadiazol-5-yl)phenyl)(4-(pyridin-4-yl)piperazin-l-yl)methanone; N-(3,3-dimethylbutyl)-4- (3-(4-fluorophen
  • the compound is selected from 4-(3-(4-fluorophenyl)- 1,2,4- oxadiazol-5-yl)-N-(3-methoxypropyl)benzamide; N-(3,3-dimethylbutyl)-4-(3-phenyl-l,2,4- oxadiazol-5-yl)benzamide; 4-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5-yl)-N-propylbenzamide; 4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)-N-propylbenzamide; (4-(3-(4-fluorophenyl)- 1 ,2,4- oxadiazol-5-yl)phenyl)(4-(pyridin-4-yl)piperazin-l-yl)methanone; and N-(3,3-dimethylbutyl)- 4-(3-(4-fluorophenyl)- 1,2,4
  • the compound is (E)-(4-hydroxypiperidin-l-yl)(4- styrylphenyl)methanone.
  • the compound is (4-hydroxypiperidin- 1- yl)(4-(pyridin-2-ylethynyl)phenyl)methanone.
  • the compound is (4- (cyclohexylethynyl)phenyl)(4-hydroxypiperidin-l-yl)methanone.
  • the compound is N-(4-fluorophenyl)-4-(2-methylpiperidine- 1 -carbonyl)benzamide.
  • the compound is selected from N-cyclopentyl-4-
  • the compound is selected from N-cyclopentyl-4-
  • the compound is selected from N-cyclopentyl-4-
  • the compound can be a phenylethynylbenzamide derivative, a cycloalkylethynylbenzamide derivative, a styrylbenzamide derivative, a 4-(3- phenyl-l,2,4-oxadiazol-5-yl)benzamide derivative, a 4-(pyridinylethynyl)benzamide derivative, or a N'-phenylterephthalamide derivative.
  • the invention relates to phenylethynylbenzamide derivatives.
  • the compound is a compound or pharmaceutically acceptable salt thereof comprising the structure:
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or wherein N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons; wherein R 3 comprises four substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or
  • the compound exhibits potentiation with an EC50 of less than about 1.0x10 6 .
  • the compound can exhibit potentiation with an EC 50 of less than about 1.0x10 7 .
  • the compound can exhibit potentiation with an EC 50 of less than about 1.0x10 8 .
  • R 1 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • R 2 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • one or more substitutents of R 3 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • one or more substitutents OfR 4 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • each of R 1 , R 2 , R 3 , and/or R 4 comprises an optionally substituted alkyl or an optionally substituted cycloalkyl.
  • the optionally substituted alkyl of R 1 , R 2 , R 3 , and/or R 4 comprises a Cl to C6 substituent; that is, a substituent having from one to six carbons.
  • the optionally substituted alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, or hexyl.
  • all of R 3 are hydrogen.
  • At least one of R 4 is halogen selected from F and Cl.
  • R 4 comprises four hydrogens and one or two substituents selected from hydrogen, F, and Cl.
  • the compound can have have a structure represented by a formula:
  • At least one of R 4 is optionally substituted alkyl selected from methyl and trifluoromethyl.
  • the compound can have a structure represented by a formula:
  • R 4 comprises five hydrogens and one optionally substituted alkyl. In a further aspect, all of R 4 are hydrogen.
  • the compound has a structure represented by a formula:
  • R 1 and R 2 are independently selected from hydrogen, (1- ethylpyrrolidin-2-yl)methyl; 2-(l-methylpyrrolidin-2-yl)ethyl; 2-(dimethylamino)ethyl; 2- (piperidin-l-yl)ethyl; 2,3-dihydro-lH-inden-l-yl; 2-chlorophenethyl; 2-morpholinoethyl; 2- phenylpropyl; 3,3-dimethylbutyl; 3-chlorophenethyl; 3-hydroxypropyl; 3-methoxypropyl; 3- morpholinopropyl; 4-bromophenethyl; 4-chlorophenethyl; butyl; cyclohexenylethyl; cyclohexylcyclohexylmethylcyclopentyl; isopentyl; methylcyclohexyl; and propyl.
  • N, R 1 , and R 2 together comprise a cyclic optionally substituted alkyl residue.
  • the cyclic optionally substituted alkyl residue is selected from (E)-4-hydroxypiperidin-l-yl; (S)-(4-(l-cyclohexylethylamino)piperidin-l-yl; 1- (piperidin-4-yl)-lH-benzo[d]imidazol-2(3H)-one; 1 -(piperidin-4-yl)ethanone; 2-(piperazin-l- yl)benzonitrile; 2,6-dimethylmorpholino; 2-morpholinoethyl; 3-hydroxy-3-(thiophen-2- yl)azetidin-l-yl; 3-hydroxy-3-methylazetidin-l-yl; 3-hydroxy-3-propylazetidin-l-yl; 3- hydroxyazetidin-1-y
  • the compound hasa structure represented by a formula:
  • the compound can be provided by the disclosed methods of making, can be employed in the disclosed compositions, and can be used in the disclosed methods of using.
  • the invention relates to cycloalkylethynylbenzamide derivatives.
  • the compound is a compound or pharmaceutically acceptable salt thereof comprising the structure:
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or wherein N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons;
  • R 3 comprises four substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl;
  • R 4 comprises nine to thirteen substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylamine-carbonyl
  • the compound exhibits potentiation of glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.
  • the compound exhibits potentiation with an EC 50 of less than about 1.Ox 10 6 .
  • the compound can exhibit potentiation with an EC50 of less than about 1.0x10 7 .
  • the compound can exhibit potentiation with an EC50 of less than about 1.0x10 8 .
  • R 1 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • R 2 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • one or more substitutents of R 3 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • one or more substitutents Of R 4 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • the optionally substituted alkyl of R 1 , R 2 , R 3 , and/or R 4 comprises an optionally substituted alkyl or an optionally substituted cycloalkyl. In a further aspect, all of R 3 are hydrogen.
  • N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons. In a further aspect, N, R 1 , and R 2 together comprise 4-hydroxypiperidin-l-yl.
  • Z is one and R 4 comprises eleven substituents.
  • R 4 is halogen selected from F and Cl. In a further aspect, all of R 4 are hydrogen.
  • the compound has a structure represented by a formula:
  • the compound can be provided by the disclosed methods of making, can be employed in the disclosed compositions, and can be used in the disclosed methods of using.
  • the invention relates to styrylbenzamide derivatives.
  • the compound is a compound or pharmaceutically acceptable salt thereof comprising the structure:
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or wherein N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons; wherein R 3 comprises four substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or
  • the compound exhibits potentiation with an EC50 of less than about 1.Ox 10 6 .
  • the compound can exhibit potentiation with an EC 50 of less than about 1.0x10 7 .
  • the compound can exhibit potentiation with an EC 50 of less than about 1.0x10 ⁇ 8 .
  • R 1 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • R 2 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • one or more substitutents of R 3 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • one or more substitutents Of R 4 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons. In a further aspect, N, R 1 , and R 2 together comprise 4-hydroxypiperidin-l-yl.
  • the optionally substituted alkyl of R 1 , R 2 , R 3 , and/or R 4 comprises an optionally substituted alkyl or an optionally substituted cycloalkyl.
  • all of R are hydrogen.
  • R 4 is halogen selected from F and Cl. In a further aspect, all of R 4 are hydrogen. In a further aspect, the compound has a structure represented by a formula:
  • the compound can be provided by the disclosed methods of making, can be employed in the disclosed compositions, and can be used in the disclosed methods of using.
  • the invention relates to 4-(3-phenyl-l,2,4-oxadiazol-5- yl)benzamide derivatives.
  • the compound is a compound or pharmaceutically acceptable salt thereof comprising the structure:
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or wherein N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons; wherein R 3 comprises four substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or
  • the compound exhibits potentiation with an EC50 of less than about 1.0x10 • ⁇ - " 6.
  • the compound can exhibit potentiation with an EC 50 of less than about 1.0x10 7 .
  • the compound can exhibit potentiation with an EC 50 of less than about 1.0x10 ⁇ 8 .
  • R 1 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • R 2 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • one or more substitutents of R 3 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • one or more substitutents Of R 4 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons.
  • N, R 1 , and R 2 together comprise 4-(pyridin-4-yl)piperazin- 1 -yl.
  • the optionally substituted alkyl of R 1 , R 2 , R 3 , and/or R 4 comprises an optionally substituted alkyl or an optionally substituted cycloalkyl.
  • R 1 and R 2 are independently selected from H; 3-methoxypropyl; 3,3-dimethylbutyl; and N-propyl.
  • the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula:
  • all of R are hydrogen. In a further aspect, at least one of
  • R 4 is halogen selected from F and Cl. In a further aspect, four of R 4 are hydrogen and one of R 4 is F. [00186] It is understood that the compound can be provided by the disclosed methods of making, can be employed in the disclosed compositions, and can be used in the disclosed methods of using.
  • the invention relates to 4-(pyridinylethynyl)benzamide derivatives.
  • the compound is a compound or pharmaceutically acceptable salt thereof comprising a structure selected from:
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or wherein N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons; wherein R 3 comprises four substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or
  • the compound exhibits potentiation with an EC50 of less than about 1.0x10 6 .
  • the compound can exhibit potentiation with an EC 50 of less than about 1.0x10 7 .
  • the compound can exhibit potentiation with an EC 50 of less than about 1.0x10 8 .
  • R 1 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • R 2 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • one or more substitutents of R 3 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • one or more substitutents OfR 4 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • the optionally substituted alkyl of R 1 , R 2 , R 3 , and/or R 4 comprises an optionally substituted alkyl or an optionally substituted cycloalkyl.
  • N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons. In a further aspect, N, R 1 , and R 2 together comprise 2-methylpiperidinyl.
  • the compound has a structure represented by a formula:
  • N, R 1 , and R 2 together comprise a cyclic optionally substituted alkyl residue.
  • the cyclic optionally substituted alkyl residue is 2-methylpiperidinyl.
  • all of R are hydrogen.
  • at least one of R 4 is halogen selected from F and Cl.
  • all of R 4 are hydrogen.
  • the compound has a structure represented by a formula:
  • the compound can be provided by the disclosed methods of making, can be employed in the disclosed compositions, and can be used in the disclosed methods of using.
  • the invention relates to N'-phenylterephthalamide derivatives.
  • the compound is a compound or pharmaceutically acceptable salt thereof comprising the structure:
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or wherein N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons; wherein R 3 comprises four substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or
  • the compound exhibits potentiation with an EC 50 of less than about 1.Ox 10 6 .
  • the compound can exhibit potentiation with an EC50 of less than about 1.0x10 7 .
  • the compound can exhibit potentiation with an EC50 of less than about 1.0x10 8 .
  • R 1 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • R 2 is selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and has from two to seven carbons.
  • one or more substitutents of R 3 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • one or more substitutents Of R 4 are selected from optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl and have from two to seven carbons.
  • N, R 1 , and R 2 together comprise an optionally substituted hetrocyclic ring having from two to seven carbons. In a further aspect, N, R 1 , and R 2 together comprise 2-methylpiperidinyl.
  • the optionally substituted alkyl of R 1 , R 2 , R 3 , and/or R 4 comprises an optionally substituted alkyl or an optionally substituted cycloalkyl. In a further aspect, all of R 3 are hydrogen.
  • At least one of R 4 is halogen selected from F and Cl. In a further aspect, four of R 4 are hydrogen and one of R 4 is F. In a further aspect, the compound has a structure represented by a formula:
  • the invention relates to compounds useful as positive allosteric modulators (potentiators) of the metabotropic glutamate receptor subtype 5 (mGluR5). More specifically, the present invention relates to compounds that allosterically modulate mGluR5 receptor activity, affecting the sensitivity of mGluR5 receptors to agonists without acting as orthosteric agonists themselves.
  • the compounds of the invention are useful in the treatment neurological and psychiatric disorders associated with glutamate dysfunction and other diseases in which metabotropic glutamate receptors are involved, as further described herein.
  • the disclosed compounds exhibit potentiation of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.
  • the compounds are isoindolin-1-one derivatives, isoindoline-l,3-dione derivatives, 3,4- dihydroisoquinolin-l(2H)-one derivatives, isoquinoline-l,3(2H,4H)-dione derivatives, other related bicyclic compounds, or a pharmaceutically acceptable salts or N-oxides thereof.
  • the invention relates to a compound having a structure represented by a formula:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • a disclosed compound can have
  • a disclosed compound can have a structure represented by a formula:
  • R 1 is hydrogen or alkyl having from 1 to 6 carbons; wherein R 3a and R 3b are independently hydrogen, halogen, or lower alkyl; and wherein R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • a disclosed compound can have a structure represented by a formula:
  • R 1 is hydrogen or alkyl having from 1 to 6 carbons; and wherein R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • a disclosed compound can have a structure represented by a formula:
  • R 1 is hydrogen or alkyl having from 1 to 6 carbons; wherein R 2a , R 2b , R 3a , and R 3b are independently hydrogen, halogen, or lower alkyl; and wherein R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • a disclosed compound can have a structure represented by a formula:
  • R 1 is hydrogen or alkyl having from 1 to 6 carbons; wherein R 3a and R 3b are independently hydrogen, halogen, or lower alkyl; and wherein R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • a disclosed compound can have a structure represented by a formula:
  • R 1 is hydrogen or alkyl having from 1 to 6 carbons; wherein R 2a , R 2b , R 3a , and R 3b are independently hydrogen, halogen, or lower alkyl; and wherein R 4 comprises five substituents independently selected from hydrogen, halogen, and lower alkyl.
  • Y 1 can be selected from N and C-R 4 .
  • Y 2 can be selected from N and C-H.
  • each R 3a and R 3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms.
  • R 4 is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.
  • R 3a and R 3b can together comprise a cycloalkyl having from 2-12 carbon atoms, R 3a and R 3b do not form a bridge with the adjacent aromatic ring.
  • L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsul
  • R 8 is selected from hydrogen, and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroal
  • each 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 also understood that each substitutent can be optionally further substituted. It is also contemplated that any one or more substitutent can be optionally omitted from the invention. a. ISOINDOLIN-1-ONE DERIVATIVES
  • the invention relates to an isoindolin-1-one derivative having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl; or a pharmaceutically acceptable salt or N-oxide thereof.
  • the invention relates to an isoindoline-l,3-dione derivative having a structure:
  • R 1 is hydrogen or is selected from optionally substituted Cl -C 12 alkyl, optionally substituted Cl -C 12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, with the proviso that R 1 does not comprise silicon; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl, and with the proviso that if R 1 is methyl, then R 5 is an organic radical comprising 4 to 14 carbon atoms; or a pharmaceutically acceptable salt or N-oxide thereof.
  • the invention relates to a 3,4-dihydroisoquinolin-l(2H)-one derivative having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; wherein each R 2a and R 2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms; or a pharmaceutically acceptable salt or N-oxide thereof.
  • the invention relates to an isoquinoline-l,3(2H,4H)-dione derivative having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that R 5 does not comprise a triphenylamine residue or a benzimidamide residue; or a pharmaceutically acceptable salt or N-oxide thereof.
  • the invention relates to a bicyclic compound having a structure:
  • R 1 is an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6- C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and -(CH 2 ) m -aryl or -(CH 2 ) m -heterocycle, wherein m is 1, 2, 3 or 4; wherein R 2a and R 2b ,
  • the compound has a structure comprising a formula:
  • the compound has a structure comprising a formula:
  • the compound has a structure comprising a formula:
  • the compound has a structure comprising a formula:
  • the compound has a structure comprising a formula:
  • n is O or 1.
  • the compound has a structure having a formula:
  • a compound wherein R 1 is selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and wherein R 1 is mono- or di- substituted with substituents selected from hydroxy, oxo, halo, C1-C6 alkyl, -CF3, -CHF 2 , - CH 2 F, C1-C4 alky
  • R 1 is a heterocycle selected from optionally substituted C3- C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, and optionally substituted heteroaryl.
  • R 1 is mono- or di- substituted with substituents selected from hydroxy, oxo, halo, C1-C6 alkyl, -CF 3 , -CHF 2 , - CH 2 F, C1-C4 alkyl-CF 3 , Cl-C4alkyl-CHF 2 , Cl-C4alkyl-CH 2 F, C1-C6 alkoxyl, -OCF 3 , - OCHF 2 , -OCH 2 F, C 1 -C4 alkoxyl-CF 3 , C 1 -C4 alkoxyl-CHF 2 , C 1 -C4 alkoxyl-CH 2 F, -hydroxy- C1-C4 alkyl, -S(O) 2 -R 9 , -C(O)-C 1-C6 alkoxyl, -C(O)-NR 9 R 10 , -C(O)-O-C
  • R 1 is selected from residues of pyridine; pyrimidine; furan; thiophene; pyrrole; isoxazole; isothiazole; pyrazole; oxazole; thiazole; imidazole; oxazole; 1,2,3-oxadiazole; 1,2,5-oxadiazole; 1,3,4-oxadiazole; thiadiazole; 1,2,3-thiadiazole; 1,2,5- thiadiazole; 1,3,4-thiadiazole; triazole; 1,2,3-triazole; 1,3,4-triazole; tetrazole; 1,2,3,4- tetrazole; 1,2,4,5-tetrazole; pyridazine; pyrazine; triazine; 1,2,4-triazine; 1,3,5-triazine; tetrazine; 1,2,4,5-tetrazine; pyrrolidine; piper
  • R 1 is mono- or di- substituted with substituents selected from hydroxy, oxo, halo, C1-C6 alkyl, -CF 3 , -CHF 2 , - CH 2 F, C1-C4 alkyl-CF 3 , Cl-C4alkyl-CHF 2 , Cl-C4alkyl-CH 2 F, C1-C6 alkoxyl, -OCF 3 , - OCHF 2 , -OCH 2 F, C 1 -C4 alkoxyl-CF 3 , C 1 -C4 alkoxyl-CHF 2 , C 1 -C4 alkoxyl-CH 2 F, -hydroxy- C1-C4 alkyl, -S(O) 2 -R 9 , -C(O)-C 1-C6 alkoxyl, -C(O)-NR 9 R 10 , -C(O)-O-C
  • R is selected from:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are independently selected from C and N; and wherein R 6 comprises one, two, three, four, five, six, or seven substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted C
  • R 6 is selected from chloro, dimethylamino, fluoro, methoxy, methyl, and trifluoromethyl.
  • R 5 is selected from:
  • R 6 comprises one, two, three, four, or five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 8 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl
  • R 5 is selected from:
  • R 5 comprises a structure having a formula:
  • R 6 comprises one or two substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 8 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl,
  • the compounds can be alkyne derivatives, alkene derivatives, 1,2,4-oxadiazole derivatives, or amide derivatives. That is, in certain aspects, L can be an alkyne residue, and alkene residue, an 1,2,4-oxadiazole residue, or an amide residue. It is understood that the alkyne, alkene, 1,2,4-oxadiazole, and amide residues can be further substuted. It is also contemplated that any one or more alkyne, alkene, 1,2,4- oxadiazole, or amide residue can be optionally omitted from the invention.
  • a compound has a structure having a formula:
  • R 5 is selected from:
  • R 6 comprises one, two, three, four, or five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl
  • a compound is provided as a structure having a formula:
  • n is 0 or 1; wherein R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and -(CH 2 ) m -aryl or -(CH 2 ) m -heterocycle, wherein m is 1, 2, 3 or 4; wherein R 2a and R 2b , when present
  • a compound comprises a structure having a formula:
  • a compound is selected from:
  • a compound is selected from: [00252] In a further aspect, a compound is selected from:
  • a compound comprises a structure having a formula:
  • R is selected from hydrogen and an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and -(CH 2 ) m -aryl or -(CH 2 ) m -heterocycle, wherein m is 1, 2, 3 or 4; wherein n is 0 or 1; wherein if n is 0, then R 3a
  • a compound comprises a structure having a formula
  • a compound wherein R 1 is selected from 2-(4- hydroxypiperidin-l-yl)-2-oxoethyl, 2-(4-hydroxypiperidin-l-yl)ethyl, 2-(azetidin-l-yl), 2- acetamide, 2-morpholino-2-oxoethyl, 2-morpholinoethyl, benzyl, benzyl 2-acetate, cyclobutylmethyl, cyclopropylmethyl, ethyl 2-propanoate, hydrogen, methyl, N-(2- (dimethylamino)ethyl acetamide, N-2-methoxyethyl acetamide, N-cyclopropyl-2-acetamide, and N-cyclopropylmethyl acetamide; wherein R 6 comprises one or two substituents selected from chloro, dimethylamino, fluoro, methoxy, methyl, and trifluoromethyl
  • a compound is selected from:
  • a compound is selected from:
  • a compound is selected from:
  • a compound is selected from:
  • a compound is selected from:
  • a compound is selected from:
  • a compound is present as 6-(pyridin-4-ylethynyl)-3,4- dihydroisoquinolin- 1 (2H)-one.
  • a compound has a structure having a formula:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl,
  • R 5 is selected from:
  • R 6 comprises one, two, three, four, or five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl
  • a compound is comprises a structure having a formula:
  • R 7a and R 7b are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3- C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally
  • R 6 comprises one, two, three, four, or five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl
  • a compound has a structure having a formula:
  • R 5 is selected from:
  • R comprises one, two, three, four, or five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl,
  • a compound has a structure having a formula:
  • R is selected from hydrogen and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R is selected from:
  • R 6 comprises one, two, three, four, or five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl
  • the compound exhibits potentiation of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound, compared to the response to glutamate in the absence of the compound, having an EC50 of less than about 1.0x10 6 , for example, less than about 5.OxIO "7 , less than about 1.0x10 7 , less than about 5.OxIO "8 , or less than about l.OxlO "8 .
  • HEK Human embryonic kidney
  • FDSS Functional Drug Screening System
  • the cells were loaded with a Ca 2+ -sensitive fluorescent dye (e.g., Fluo-4), and the plates were washed and placed in the FDSS instrument. After establishment of a fluorescence baseline for twelve seconds, the compounds of the present invention were added to the cells, and the response in cells was measured.
  • a Ca 2+ -sensitive fluorescent dye e.g., Fluo-4
  • an mGluR5 agonist e.g., glutamate, 3,5-dihydroxyphenylglycine, or quisqualate
  • an mGluR5 agonist e.g., glutamate, 3,5-dihydroxyphenylglycine, or quisqualate
  • the above described assay operated in two modes.
  • a range of concentrations of the present compounds were added to cells, followed by a single fixed concentration of agonist. If a compound acted as a potentiator, an EC 50 value for potentiation and a maximum extent of potentiation by the compound at this concentration of agonist was determined by non-linear curve fitting.
  • the second mode several fixed concentrations of the present compounds were added to various wells on a plate, followed by a range of concentrations of agonist for each concentration of present compound; the EC50 values for the agonist at each concentration of compound were determined by non- linear curve fitting.
  • a decrease in the EC50 value of the agonist with increasing concentrations of the present compounds is an indication of the degree of mGluR5 potentiation at a given concentration of the present compound.
  • An increase in the EC 50 value of the agonist with increasing concentrations of the present compounds is an indication of the degree of mGluR5 antagonism at a given concentration of the present compound.
  • the second mode also indicates whether the present compounds also affect the maximum response to mGluR5 to agonists.
  • the disclosed compounds had activity in potentiating the mGluR5 receptor in the aforementioned assays, generally with an EC 50 for potentiation of less than about 10 ⁇ M.
  • certain compounds had activity in potentiating the mGluR5 receptor with an EC 50 for potentiation of less than about 500 nM.
  • Preferred compounds further caused a leftward shift of the agonist EC50 by greater than 3 -fold. These compounds did not cause mGluR5 to respond in the absence of agonist, and they did not elicit a significant increase in the maximal response of mGluR5 to agonists.
  • These compounds are positive allosteric modulators (potentiators) of human and rat mGluR5 and were selective for mGluR5 compared to the other seven subtypes of metabotropic glutamate receptors.
  • compounds of the present invention reverse amphetamine- induced hyperlocomotion in male Sprague-Dawley rats at doses ranging from 1 to 100 mg/kg i.p.
  • EC50 for potentiating the mGluR5 receptor are listed in Table 1 below:
  • Preferred compounds of the present invention also showed in vivo efficacy in a number of preclinical rat behavioral model where known, clinically useful antipsychotics display similar positive responses.
  • compounds of the present invention reverse amphetamine-induced hyperlocomotion in male Sprague-Dawley rats at doses ranging from 1 to 100 mg/kg i.p. Data for three example compounds follow:
  • Figure 8 shows efficacy in reversing amphetamine-induced hyperlocomotion for (4-hydroxypiperidin-l-yl)(4-(phenylethynyl)phenyl)methanone (Compound VU13; In vitro: 13.6nm; 50% GIu Max).
  • Figure 9 shows efficacy in reversing amphetamine-induced hyperlocomotion for (4-hydroxy-4-propylpiperidin- 1 -yl)(4-(phenylethynyl)phenyl)methanone (Compound VU60/C109B2; In vitro: 1250 nm; 90% GIu Max).
  • Figure 10 shows efficacy in reversing amphetamine-induced hyperlocomotion for (4-(hydroxymethyl)piperidin- 1 -yl)(4-(phenylethynyl)phenyl)methanone (Compound VU14/C104B2; In vitro: 29.6 nm; 41%Glu Max).
  • VUOOOl 13 0.001 28.6 ND
  • VUOOOl 14 0.00000047 67.9 ND
  • Schizophrenic patients show decreased measures of sensorimotor gating, such as prepulse inhibition (PPI) of startle, and preclinical models of PPI in rats are routinely used to predict antipsychotic efficacy.
  • PPI can be measured in humans and rats employing identical stimulus parameters yielding similar responses (Braff, D. L.; Geyer, M.A.; Swerdlow, N. R. 'Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies.' Psychopharmacology 2001, 756(2-3), 234-258; Braff, D.L.; Geyer, M.A. 'Sensorimotor gating and schizophrenia.
  • PAMs Positive allosteric modulators
  • mGluR5 from five distinct structural series ( Figure 15) have displayed antipsychotic-like effects in rat behavioral models predictive of antipsychotic efficacy in humans (Lindsley, C. W.; Wisnoski, D.D.; Leister, W.H.;; O'Brien, J.A.; Lemiare, W.; Williams, Jr., D.L.; Burno, M.; Sur, C; Kinney, G.G.; Pettibone, D.J.; Miller, P.R.; Smith, S.; Duggan, M.E .; Hartman, G.D.; Conn, P.J.; Huff, J. R.
  • CDPPB Longdsley, C.W.; Wisnoski, D.D.; Leister, W.H.;; O'Brien, J.A.; Lemiare, W.; Williams, Jr., D. L.; Burno, M.; Sur, C; Kinney, G. G.; Pettibone, D. J.; iller,
  • CDPPB and ADX47273 also demonstrated efficacy in PPI, a preclinical model with direct relevance to clinical efficacy, and a behavior identical in schizophrenic patients.
  • CDPPB reverses PPI in a dose-dependent manner at four different prepulse intensities above background.
  • ADX47273 affords similar results (Figure 19).
  • the invention relates to methods of making compounds useful as positive allosteric modulators (potentiators) of the metabotropic glutamate receptor subtype 5 (mGluR5), which can be useful in the treatment neurological and psychiatric disorders associated with glutamate dysfunction and other diseases in which metabotropic glutamate receptors are involved.
  • positive allosteric modulators potentiators
  • mGluR5 metabotropic glutamate receptor subtype 5
  • 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. Substituent numbering as shown in schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown to attach to the compound where multiple substituents are allowed under the definitions disclosed herein.
  • the invention relates to methods of making phenylethynylbenzamide derivatives, cycloalkylethynylbenzamide derivatives, styrylbenzamide derivatives, 4-(3-phenyl-l,2,4-oxadiazol-5-yl)benzamide derivatives, 4- (pyridinylethynyl)benzamide derivatives, and N'-phenylterephthalamide derivatives.
  • the invention relates to a method for preparing a phenylethynylbenzamide derivative comprising the steps of coupling an arylacetylene with an aryl halide, wherein one of the arylacetylene or the aryl halide bears a carboxyl functionality; and forming an amide derivative of the carboxyl functionality by reaction with an amine.
  • a method involves a coupling reaction (e.g., transition metal catalyzed cross coupling reaction) and a reaction forming an amide moiety.
  • a coupling reaction e.g., transition metal catalyzed cross coupling reaction
  • Such a method can be represented in the following schematic:
  • the method can be represented in the following schematic, which illustrates a synthetic method useful for preparation of larger amounts of the disclosed compounds:
  • the coupling step is performed prior to the forming step.
  • the method further comprises the step of converting the carboxyl functionality to a carboxylic acid.
  • the carboxyl functionality is an ester moiety.
  • the aryl halide bears the carboxyl functionality.
  • the halide can be Br or I. It is understood that a pseudohalide can be substituted for a halide.
  • the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.
  • the coupling step is palladium-catalyzed cross-coupling.
  • the forming step is performed with PS-carbodiimide and 1- hydroxybenzotriazole.
  • the aryl halide has a structure represented by a formula:
  • the arylacetylene has a structure represented by a formula:
  • R 4 comprises five substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the invention relates to a method for preparing a cycloalkylethynylbenzamide derivative comprising the steps of coupling an cycloalkylacetylene with an aryl halide, wherein the aryl halide bears a carboxyl functionality; and forming an amide derivative of the carboxyl functionality by reaction with an amine.
  • a method involves a coupling reaction (e.g., transition metal catalyzed cross coupling reaction) and a reaction forming an amide moiety.
  • a coupling reaction e.g., transition metal catalyzed cross coupling reaction
  • Such a method can be represented in the following schematic:
  • the coupling step is performed prior to the forming step.
  • the method further comprises the step of converting the carboxyl functionality to a carboxylic acid.
  • the carboxyl functionality is an ester moiety.
  • the halide is Br, I, or pseudohalide.
  • the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.
  • the coupling step is palladium-catalyzed cross-coupling.
  • the forming step is performed with PS-carbodiimide and 1- hydroxybenzotriazole.
  • the aryl halide has a structure represented by a formula:
  • R is optionally substituted alkyl; and wherein R 3 comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the cycloalkylacetylene has a structure represented by a formula:
  • Z comprises from zero to two carbons; and wherein R 4 comprises nine to thirteen substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the invention relates to a method for preparing a styrylbenzamide derivative comprising the steps of coupling a styryl bornonic acid or a styryl boronic ester with an aryl halide, wherein one of the styryl bornonic acid or styryl boronic ester or the aryl halide bears a carboxyl functionality; and forming an amide derivative of the carboxyl functionality by reaction with an amine.
  • a method involves a coupling reaction (e.g., transition metal catalyzed cross coupling reaction) and a reaction forming an amide moiety.
  • a coupling reaction e.g., transition metal catalyzed cross coupling reaction
  • Such a method can be represented in the following schematic:
  • the method can be represented in the following schematic, which illustrates a synthetic method useful for preparation of larger amounts of the disclosed compounds:
  • the coupling step is performed prior to the forming step.
  • the method further comprises the step of converting the carboxyl functionality to a carboxylic acid.
  • the carboxyl functionality is an ester moiety.
  • the aryl halide bears the carboxyl functionality.
  • the halide is Br, I, or pseudohalide.
  • the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.
  • the coupling step is palladium-catalyzed cross-coupling.
  • the forming step is performed with PS-carbodiimide and 1- hydroxybenzotriazole.
  • the aryl halide has a structure represented by a formula:
  • R is optionally substituted alkyl; and wherein R 3 comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the styryl bornonic acid or styryl boronic ester has a structure represented by a formula:
  • R is H or optionally substituted alkyl; and wherein R 4 comprises five substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the invention relates to a method for preparing a 4-(3-phenyl- l,2,4-oxadiazol-5-yl)benzamide derivative comprising the steps of condensing an N'- hydroxybenzimidamide with an aryl carboxylic acid, wherein one of the N'- hydroxybenzimidamide or the aryl carboxylic acid bears an ester functionality; and forming an amide derivative of the ester functionality by reaction with an amine.
  • a method involves a condensing reaction (e.g., formation of an oxadiazol) and a reaction forming an amide moiety.
  • a condensing reaction e.g., formation of an oxadiazol
  • Such a method can be represented in the following schematic:
  • the condensing step is performed prior to the forming step.
  • the method further comprises the step of converting the ester functionality to a carboxylic acid.
  • the aryl carboxylic acid bears the ester functionality.
  • the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine. [00321] In one aspect, one or both of the condensing step and the forming step is performed with l-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride and 1- hydroxybenzotriazole.
  • the aryl carboxylic acid has a structure represented by a formula:
  • R is optionally substituted alkyl; and wherein R 3 comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the N'-hydroxybenzimidamide has a structure represented by a formula:
  • R 4 comprises five substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the invention relates to a method for preparing a 4-
  • (pyridinylethynyl)benzamide derivative comprising the steps of coupling an arylacetylene with an aryl halide, wherein one of the arylacetylene or the aryl halide bears a carboxyl functionality; and forming an amide derivative of the carboxyl functionality by reaction with an amine.
  • a method involves a coupling reaction ⁇ e.g., transition metal catalyzed cross coupling reaction) and a reaction forming an amide moiety.
  • a coupling reaction ⁇ e.g., transition metal catalyzed cross coupling reaction
  • the coupling step is performed prior to the forming step.
  • the method further comprises the step of converting the carboxyl functionality to a carboxylic acid.
  • the carboxyl functionality is an ester moiety.
  • the aryl halide bears the carboxyl functionality.
  • the halide is Br, I, or pseudohalide.
  • the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.
  • the coupling step is palladium-catalyzed cross-coupling.
  • the forming step is performed with PS-carbodiimide and 1- hydroxybenzotriazole.
  • the aryl halide has a structure represented by a formula:
  • R is optionally substituted alkyl; and wherein R 3 comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the arylacetylene has a structure represented by a formula:
  • R 4 comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • a method for preparing a N 1 - phenylterephthalamide derivative comprising the steps of reacting an aniline compound with a benzoic acid compound, wherein the benzoic acid compound bears a carboxyl functionality; and forming an amide derivative of the carboxyl functionality by reaction with an amine.
  • a method involves two separate reactions forming amide moieties. Such a method can be represented in the following schematic:
  • the reacting step is performed prior to the forming step.
  • the method further comprises the step of converting the carboxyl functionality to a carboxylic acid.
  • the carboxyl functionality is an ester moiety.
  • the amine is an optionally substituted primary amine or an optionally substituted secondary amine. In a further aspect, the amine is an optionally substituted cyclic amine.
  • the reacting step is performed with l-ethyl-3-[3- dimethylaminopropyl]carbodiimide hydrochloride and 1-hydroxybenzotriazole.
  • the forming step is performed with l-ethyl-3-[3- dimethylaminopropyl]carbodiimide hydrochloride and 1-hydroxybenzotriazole.
  • the benzoic acid compound has a structure represented by a formula:
  • R is optionally substituted alkyl; and wherein R comprises four substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the aniline compound has a structure represented by a formula:
  • R is H or optionally substituted alkyl; and wherein R 4 comprises five substituents independently selected from hydrogen, halogen, and optionally substituted alkyl.
  • the disclosed methods can be useful in providing compounds having a bicyclic benzamide structure, which compounds can be useful as positive allosteric modulators (potentiators) of the metabotropic glutamate receptor subtype 5 (mGluR5).
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in Reaction Schemes I and II, in addition to other standard manipulations known in the literature or to one skilled in the art.
  • the following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.
  • a suitably substituted 6-bromo-3,4- dihydro-2H-isoquinoline 1-1 is subjected to a Sonogashira/Castro-Stephens coupling reaction employing catalytic copper (I) iodide and catalytic palladium (0) and a suitably functionalized acetylene under microwave irradiation to deliver the corresponding product 1-2.
  • the suitably substituted 6-bromo-3,4-dihydro-2H-isoquino lines 1-1 were commercially available, or could be easily prepared according to literature methods.
  • the following examples are provided so that the invention might be ore fully understood. These examples are illustrative only and should not be construed as limiting in any way.
  • a suitably 6-substituted-3,4-dihydro-2H- isoquinoline II- 1 is subjected to an S N 2 reaction with a suitably functionalized electrophile (R3-X) to deliver the corresponding product II-2.
  • R3-X suitably functionalized electrophile
  • the suitably substituted 6- substituted-3,4-dihydro-2H-isoquinoline H-I were prepared according to REACTION SCHEME I and the electrophiles were commercially available, or could be easily prepared according to literature methods.
  • the following examples are provided so that the invention might be ore fully understood. These examples are illustrative only and should not be construed as limiting in any way.
  • (phenylethynyl)isobenzofuran-l,3-dione IV-I is treated with urea in DMF under microwave irradiation to afford 5 -(phenethynyl)isoindo line- 1,3 -dione IV-2.
  • Intermediate IV-2 is alklyated with a suitably functionalized alkly halide (Cl, Br, I) to provide 2-alklyl-5- (phenethynyl)isoindoline-l,3-dione IV-3.
  • the suitably substituted 5- (phenylethynyl)isobenzofuran-l,3-dione IV-I were commercially available, or could be easily prepared according to literature methods.
  • the invention relates to a method for preparing a compound comprising the steps of: providing a first reactant having a structure represented by a formula:
  • n 0, 1, 2, 3 or 4; wherein Y 1 and Y 2 are independently selected from C and N; wherein R 1 is selected from hydrogen and an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and -(CH 2 ) m -aryl or -(CH 2 ) m -heterocycle, wherein
  • R 5 is an organic radical comprising 4 to 14 carbon atoms selected from optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl; and wherein X 2 comprises a halide, a pseudohalide, a carboxylic acid, a carboxylic acid derivative, a terminal acetylene moiety, an activated vinyl moiety, a N'- hydroxybenzimidamide, or a primary or secondary amine;
  • L is an organic divalent radical comprising 1 to 7 carbon atoms selected from optionally substituted C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted amido; wherein, when X 1 is halide or pseudohalide, X 2 is a terminal acetylene moiety, or an activated vinyl moiety; wherein, when X 1 is a carboxylic acid or a carboxylic acid derivative, X 2 is a N'-hydroxybenzimidamide, or a primary or secondary amine; wherein, when X 2 is halide or pseudohalide, X 1 is a terminal acetylene moiety, or an activated vinyl moiety; wherein, when X
  • L is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • a compound when R 1 is H, can be alkylated with an electrophilic alkyl functionality, for example, an alkyl halide or pseudohalide.
  • the reactive vinyl moiety comprises a monosubstituted vinyl moiety, a vinyl boronic acid, a vinyl boronic ester, or a vinyltrialkylstannane.
  • the coupling step comprises a Sonogashira/Castro-Stephens coupling reaction; wherein X 1 comprises a halide or a pseudohalide; wherein X 2 comprises a terminal acetylene moiety; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a Sonogashira/Castro-Stephens coupling reaction; wherein X 1 comprises a terminal acetylene moiety; wherein X 2 comprises a halide or a pseudohalide; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a Suzuki coupling reaction, wherein X 1 comprises a vinyl boronic acid or a vinyl boronic ester; wherein X 2 comprises a halide or a pseudohalide; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a Suzuki coupling reaction, wherein X 1 comprises a halide or a pseudohalide; wherein X 2 comprises a vinyl boronic acid or a vinyl boronic ester; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a Stille coupling reaction; wherein X 1 comprises a vinyltrialkylstannane; wherein X 2 comprises a halide or a pseudohalide; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a Stille coupling reaction; wherein X 1 comprises a halide or a pseudohalide; wherein X 2 comprises a vinyltrialkylstannane; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a Heck reaction, wherein X 1 comprises a monosubstituted vinyl moiety; wherein X 2 comprises a halide or a pseudohalide; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a Heck reaction, wherein X 1 comprises a halide or a pseudohalide; wherein X 2 comprises a monosubstituted vinyl moiety; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a condensation reaction; wherein X 1 comprises a carboxylic acid or a carboxylic acid derivative; wherein X 2 comprises a N'-hydroxybenzimidamide; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises a condensation reaction; wherein X 1 comprises a N'-hydroxybenzimidamide; wherein X 2 comprises a carboxylic acid or a carboxylic acid derivative; and wherein the compound has a structure represented by a formula:
  • the coupling step comprises an amide formation reaction; wherein X 1 comprises a carboxylic acid or a carboxylic acid derivative; wherein X 2 comprises a primary or secondary amine; and wherein the compound has a structure represented by a formula:
  • R 8 is selected from hydrogen and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • the coupling step comprises an amide formation reaction; wherein X 1 comprises a primary or secondary amine; wherein X 2 comprises a carboxylic acid or a carboxylic acid derivative; and wherein the compound has a structure represented by a formula:
  • R is selected from hydrogen and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • the providing a first reactant step comprises the steps of:
  • n 0 or 1; with ammonia or a primary amine to afford a compound having a structure represented by a formula:
  • R 1 is hydrogen, alkylating the imide moiety.
  • the providing a first reactant step comprises the steps of:
  • n 0, 1, 2, 3 or 4; with ammonia or a primary amine to afford an intermediate having a structure represented by a formula:
  • R is hydrogen, alkylating the lactam moiety.
  • the cyclizing step comprises subjecting the intermediate to
  • the first reactant has a structure comprising a formula:
  • the first reactant has a structure comprising a formula:
  • the first reactant has a structure comprising a formula:
  • the first reactant has a structure comprising a formula:
  • the first reactant has a structure comprising a formula:
  • the second reactant has a structure represented by a formula:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are independently selected from C and N; and wherein R 6 comprises one, two, three, four, five, six, or seven substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted C
  • the second reactant has a structure represented by a formula:
  • R comprises one, two, three, four, or five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl,
  • the second reactant has a structure represented by a formula:
  • the second reactant has a structure represented by a formula:
  • R comprises one or two substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulf ⁇ nyl
  • the alkylating step is performed by reaction with a base and an alkyl halide or alkyl pseudohalide.
  • the base is sodium hydride.
  • the alkyl moiety of the alkyl halide or alkyl pseudohalide comprises an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, or -(CH 2 ) m -aryl or -(CH 2 ) m -heterocycle, wherein m is 1, 2, 3
  • the alkylating step is performed before the coupling step.
  • the invention related to a method for preparing a compound comprising the steps of:
  • R is hydrogen
  • R is selected from 2-(4-hydroxypiperidin-l-yl)-2-oxoethyl
  • R 5 is selected from:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are independently selected from C and N; and wherein R 6 comprises one, two, three, four, five, six, or seven substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted C
  • R 5 is selected from:
  • R comprises one, two, three, four, or five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2- C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyl,
  • R 5 is selected from:
  • R 5 is comprises a structure having a formula:
  • R 6 comprises one or two substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 10 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl,
  • L is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl,
  • the alkylating step is performed by reaction with a base and an alkyl halide or alkyl pseudohalide.
  • the base is sodium hydride.
  • the alkyl moiety of the alkyl halide or alkyl pseudohalide comprises an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and -(CH 2 ) m -aryl or -(CH 2 ) m -heterocycle, wherein m is 1, 2, 3
  • the alkylating step is performed before the coupling step.
  • the invention relates to a method for preparing a compound comprising the steps of:
  • R 1 is hydrogen, alkylating the lactam moiety.
  • the cyclizing step comprises subjecting the intermediate to Mitsunobu reaction conditions; or converting the hydroxyl functionality to a pseudohalide.
  • L is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • the alkylating step is performed by reaction with a base and an alkyl halide or alkyl pseudohalide.
  • the base is sodium hydride.
  • the alkyl moiety of the alkyl halide or alkyl pseudohalide comprises an organic radical comprising 1 to 12 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C8 cycloalkyl or C3-C8 cycloalkenyl or C6-C8 cycloalkynyl, optionally substituted C3-C8 heterocycloalkyl or C3-C8 heterocycloalkenyl or C6-C8 heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, and -(CH 2 ) m -aryl or -(CH 2 ) m -heterocycle, wherein m is 1, 2, 3
  • the method provides a disclosed compound, for example, a compound listed in Table 3.
  • a disclosed compound for example, a compound listed in Table 3.
  • Compounds in Table 3 were synthesized as shown in reaction Schemes I and II, but substituing the appropriately substituted acetylene and electrophile as described in Scheme 1 and 2.
  • the requisite starting materials were commercially available, described in the literature or readily synthesized by one skilled in the art of organic synthesis. TABLE 3
  • the invention relates to pharmaceutical compositions comprising the disclosed compounds.
  • the compositions can comprise one or more phenylethynylbenzamide derivatives, cycloalkylethynylbenzamide derivatives, styrylbenzamide derivatives, 4-(3-phenyl-l,2,4-oxadiazol-5-yl)benzamide derivatives, A- (pyridinylethynyl)benzamide derivatives, and/or N '-phenylterephthalamide derivatives.
  • compositions can comprise one or more of isoindolin-1-one derivatives, isoindoline-l,3-dione derivatives, 3,4-dihydroisoquinolin-l(2H)-one derivatives, isoquinoline-l,3(2H,4H)-dione derivative, and/or bicyclic compounds.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one disclosed compound and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one prduct of a disclosed method and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one phenylethynylbenzamide derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one cycloalkylethynylbenzamide derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one styrylbenzamide derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one 4-(3-phenyl- 1,2,4- oxadiazol-5-yl)benzamide derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one 4-(pyridinylethynyl)benzamide derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one N'-phenylterephthalamide derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one isoindolin-1-one derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one isoindoline-l,3-dione derivativeand a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one 3,4-dihydroisoquinolin-l(2H)-one derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one isoquinoline-l,3(2H,4H)-dione derivative and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one bicyclic compound and a pharmaceutically acceptable carrier.
  • 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.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • 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 nontoxic 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 5 N - dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, triprop
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical media can be employed.
  • 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.
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques
  • 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.
  • 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 .
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • 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.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds. [00413] 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.
  • a potentiated amount of an mGluR agonist to be administered in combination with an effective amount of a compound of formula I is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day and is expected to be less than the amount that is required to provide the same effect when administered without an effective amount of a disclosed compound.
  • Preferred amounts of a co-administered mGluR agonist are able to be determined by one skilled in the art.
  • the present invention is further directed to a method for the manufacture of a medicament for poteniating glutamate receptor activity (e.g., treatment of one or more neurological and/or psychiatric disorder associated with glutamate dysfunction) in mammals (e.g., humans) comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or diluent.
  • a medicament for poteniating glutamate receptor activity e.g., treatment of one or more neurological and/or psychiatric disorder associated with glutamate dysfunction
  • mammals e.g., humans
  • the invention relates to pharmaceutical compositions comprising the disclosed compounds. That is, a pharmaceutical composition can be provided comprising a therapeutically effective amount of at least one disclosed compound or at least one product of a disclosed method and a pharmaceutically acceptable carrier.
  • the disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological conditions.
  • the disclosed compounds and compositions can be coadminstered with one or more antipsychotic agents.
  • an antipsychotic agent can be any compound that has been shown to be useful or is believed to be useful in treating at least a positive symptom of schizophrenia.
  • Antipsychotic agents useful in treating at least a positive symptom of schizophrenia include typical antipsychotic agents, atypical antipsychotic agents, and other antipsychotic agents that may or may not be classified as typical or atypical antipsychotic agents.
  • an antipsychotic agent is a typical antipsychotic agent.
  • an antipsychotic agent is a dopamine D2 receptor antagonist, which may be a selective dopamine D2 receptor antagonist or a partial dopamine D2 receptor antagonist.
  • Typical antipsychotic agents are generally recognized as selective dopamine D2 receptor antagonists.
  • Antipsychotic agents useful in treating positive symptoms of schizophrenia include, but are not limited to, acetophenazine, alseroxylon, amitriptyline, aripiprazole, astemizole, benzquinamide, carphenazine, chlormezanone, chlorpromazine, chlorprothixene, clozapine, desipramine, droperidol, aloperidol, fluphenazine, flupenthixol, glycine, oxapine, mesoridazine, molindone, olanzapine, ondansetron, perphenazine, pimozide, prochlorperazine, procyclidine, promazine, propiomazine, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, terfenadine, thiethylperzaine, thi
  • Examples of typical antipsychotic agents useful for treating positive symptoms of schizophrenia include acetophenazine, chlorpromazine, chlorprothixene, droperidol, fluphenazine, haloperidol, loxapine, mesoridazine, methotrimeprazine, molindone, perphenazine, pimozide, raclopride, remoxipride, thioridazine, thiothixene, and trifluoperazine.
  • Examples of atypical antipsychotic agents useful for treating positive symptoms of schizophrenia include aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone.
  • antipsychotic agents useful for treating positive symptoms of schizophrenia include amisulpride, balaperidone, blonanserin, butaperazine, carphenazine, eplavanserin, iloperidone, lamictal, onsanetant, paliperidone, perospirone, piperacetazine, raclopride, remoxipride, sarizotan, sonepiprazole, sulpiride, ziprasidone, and zotepine; serotonin and dopamine (5HT/D2) agonists such as asenapine and bifeprunox; neurokinin 3 antagonists such as talnetant and osanetant; AMPAkines such as CX-516, galantamine, memantine, modafmil, ocaperidone, and tolcapone; and .alpha.-amino acids such as D-serine, D-alanine, D-cyclos
  • the invention also relates to methods of coadminstering to a mammal at least one disclosed compound and one or more other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological conditions.
  • the disclosed methods can relate to coadministration of therapeutically effective amounts of one or more disclosed compound with one or more antipsychotic agents.
  • kits comprising at least one disclosed compound and one or more other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological conditions.
  • the disclosed kits can comprise therapeutically effective amounts of one or more disclosed compound and one or more antipsychotic agents.
  • the kits can be co-packaged, co- formulated, and/or co-delivered with the antipsychotic agents.
  • a drug manufacturer, a drug reseller, a physician, or a pharmacist can provide a disclosed kit for delivery to a patient.
  • 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.
  • 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.
  • compositions are preferably provided in the from of tablets containing 1.0 to 1000 miligrams 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.
  • the specific dose level for any particular patient will depend upon a variety of factors. Such factors include the age, body weight, general 5 health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the type and severity of the particular disease undergoing therapy.
  • compositions can be employed in the disclosed methods of using.
  • 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
  • Glutamate acts through two distinct receptors: ionotropic and metabotropic glutamate receptors.
  • the first class, the ionotropic glutamate receptors, are multi-subunit
  • ionotropic glutamate receptors 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.
  • the second class of glutamate receptor termed metabotropic glutamate receptors, (mGluRs) are G-protein coupled receptors (GPCRs) that modulate neurotransmitter release or the strength of synaptic transmission, based on their location (pre- or post-synaptic).
  • GPCRs G-protein coupled receptors
  • the mGluRs 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.
  • mGluRs eight distinct mGluRs have been identified, cloned and sequenced. Based on structural similarity, primary coupling to intracellular signaling pathways and pharmacology, the mGluRs have been assigned to three groups: Group I (mGluRl and mGluR5), Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR ⁇ , mGluR7 and mGluR8).
  • Group I mGluRs are coupled through G ⁇ q/11 to increase inositol phosphate and metabolism and resultant increases in intracellular calcium.
  • Group I mGluRs are primarily located post-synaptically and have a modualtory effect on ion channel activity and neuronal excitability.
  • Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR ⁇ , mGluR7 and mGluR8) mGluRs are primarily located pre-synaptically where they regulate the release of neurotransmitters, such as glutamate.
  • Group II and Group III mGluRs are coupled to GDi and its associated effectors such as adenylate cyclase.
  • Post-synaptic mGluRs are known to functionally interact with post-synaptic ionotropic glutamate receptors, such as the NMDA receptor.
  • post-synaptic ionotropic glutamate receptors such as the NMDA receptor.
  • activation of mGluR5 by a selective agonist has been shown to increase post-synaptic NMDA currents (Mannaioni et.al. J. Neurosci. 21 :5925-5934 (2001)). Therefore, modulation of mGluRs is an approach to modulating glutamatergic transmission.
  • Numerous reports indicate that mGluR5 plays a role in a number of disease states including anxiety (Spooren et. al. J. Pharmacol. Exp. Therapeut.
  • the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which compounds of formula I or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone.
  • the other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound.
  • a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred.
  • 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.
  • the subject compounds can be coadministered with ant-
  • Alzheimer's agents beta-secretase inhibitors, gamma-secretase inhibitors, muscarinic agonists, muscarinic potentiatorsHMG-CoA reductase inhibitors, NSAIDs and anti-amyloid antibodies.
  • the subject compounds can be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GIyTl inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and combinations thereof.
  • SSRIs selective serotonin reuptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • 5-HT2 antagonists GIyTl inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and combinations thereof.
  • the subject compound can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor), anitcholinergics such as biperiden, COMT inhibitors such as entacapone, A2a adenosine antagonists, cholinergic agonists, NMDA receptor antagonists and dopamine agonists.
  • anitcholinergics such as biperiden
  • COMT inhibitors such as entacapone
  • A2a adenosine antagonists such as entacapone
  • cholinergic agonists cholinergic agonists
  • NMDA receptor antagonists NMDA receptor antagonists
  • dopamine agonists dopamine agonists.
  • 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.
  • the mGluR of the disclosed methods is a type I mGluR. In some aspects, the mGluR of the disclosed methods is mGluR5. 1. TREATMENT METHODS
  • 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.
  • a method of treating or preventing a disorder in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject .
  • 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.
  • 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
  • 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.
  • the disorder is dementia, delirium, amnestic disorders, age-related cognitive decline, schizophrenia, psychosis including schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-related disorder, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorder, narcolepsy, anxiety, affective disorder, panic attacks, unipolar depression, bipolar disorder, psychotic depression.
  • schizophrenia psychosis including schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-related disorder, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorder, narcolepsy, anxiety, affective disorder, panic attacks, unipolar depression, bipolar disorder, psychotic depression.
  • a method for treating or prevention schizophrenia 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.
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • Also provided is a method for treating or prevention 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 .
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • panic disorder with or without agoraphobia agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic 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.
  • the invention relates to a method for potentiation of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one compound having a structure represented by a formula:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; and wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • Also provided is a method for potentiation of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one compound having a structure:
  • the invention relates to a method for partial agonism of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one compound having a structure represented by a formula:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted
  • Also provided is a method for partial agonism of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal at least one having a structure:
  • Y 1 is selected from N and C-R 4 .
  • Y 2 is selected from N and C-H.
  • each R 3a and R 3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms.
  • R 4 is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.
  • L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • the compound comprises an isoindolin-1-one derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl.
  • the compound comprises an isoindoline-l,3-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or is selected from optionally substituted Cl -C 12 alkyl, optionally substituted Cl -C 12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, with the proviso that R 1 does not comprise silicon; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl, and with the proviso that if R 1 is methyl, then R 5 is an organic radical comprising 4 to 14 carbon atoms.
  • the compound comprises a 3,4-dihydroisoquinolin-l(2H)- one derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; wherein each R 2a and R 2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms.
  • the compound comprises an isoquinoline-l,3(2H,4H)-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that R 5 does not comprise a triphenylamine residue or a benzimidamide residue.
  • the compound comprises a bicyclic compound or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • the mammal is a human. In a further aspect, the mammal has been diagnosed with a need for partial agonism of metabotropic glutamate receptor activity prior to the administering step. c. TREATMENT OF A DISORDER IN A MAMMAL
  • the invention relates to a method for the treatment of a disorder in a mammal comprising the step of administering to the mammal at least one compound having a structure represented by a formula:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • the method further comprises identifying a mammal with a need for treatment of the disorder.
  • the mammal has a need for treatment of the disorder prior to administration.
  • the mammal has been diagnosed with a need for treatment of the disorder prior to administration.
  • the disorder is one or more neurological and/or psychiatric disorder associated with glutamate dysfunction in the mammal.
  • the disorder can be one or more of dementia, delirium, amnestic disorders, age-related cognitive decline, schizophrenia, psychosis including schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-related disorder, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorder, narcolepsy, anxiety, affective disorder, panic attacks, unipolar depression, bipolar disorder, and psychotic depression.
  • Also provided is a method for the treatment of a disorder in a mammal comprising the step of administering to the mammal at least one having a structure:
  • Y 1 is selected from N and C-R 4 .
  • Y 2 is selected from N and C-H.
  • each R 3a and R 3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms.
  • R 4 is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.
  • L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyls
  • R 8 is selected from hydrogen, and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound comprises an isoindolin-1-one derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl.
  • the compound comprises an isoindoline-l,3-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or is selected from optionally substituted Cl -C 12 alkyl, optionally substituted Cl -C 12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, with the proviso that R 1 does not comprise silicon; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl, and with the proviso that if R 1 is methyl, then R 5 is an organic radical comprising 4 to 14 carbon atoms.
  • the compound comprises a 3,4-dihydroisoquinolin-l(2H)- one derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; wherein each R 2a and R 2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms.
  • the compound comprises an isoquinoline-l,3(2H,4H)-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • the compound comprises a bicyclic compound or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • the disorder is a neurological and/or psychiatric disorder associated with glutamate dysfunction.
  • the disorder is selected from dementia, delirium, amnestic disorders, age-related cognitive decline, schizophrenia, psychosis including schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-related disorder, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorder, narcolepsy, anxiety, affective disorder, panic attacks, unipolar depression, bipolar disorder, and psychotic depression.
  • 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.
  • Schizophrenia symptoms can be classified as positive, negative, or cognitive.
  • Positive symptoms of schizophrenia include delusion and hallucination, which can be measured using, for example, the Positive and Negative Syndrome Scale (PANSS) (see Kay et al., 1987, Schizophrenia Bulletin 13, 261-276).
  • Negative symptoms of schizophrenia include affect blunting, anergia, alogia, and social withdrawal, which can be measured for example, using the Scales for the Assessment of Negative Symptoms (SANS) (see Andreasen, 1983, Scales for the Assessment of Negative Symptoms, Iowa City, Iowa).
  • Cognitive symptoms of schizophrenia include impairment in obtaining, organizing, and using intellectual knowledge which can be measured using the Positive and Negative Syndrome Scale-cognitive subscale (PANS S -cognitive subscale) (Lindenmayer et al., J Nerv Ment Dis 1994, 182, 631 -638) or by assessing the ability to perform cognitive tasks such as, for example, using the Wisconsin Card Sorting Test (see, e.g., Green et al., Am J Psychiatry 1992, 149, 162-67; and Koren et al., Schizophr Bull 2006, 32(2), 310-26).
  • PANS S -cognitive subscale Positive and Negative Syndrome Scale-cognitive subscale
  • the invention relates to a method for enhancing cognition in a mammal comprising the step of administering to the mammal at least one compound having a structure represented by a formula:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • the cognition enhancement is a statistically significant increase in Novel Object Recognition. In a further aspect, the cognition enhancement is a statistically significant increase in synaptic plasticity. In a further aspect, the cognition enhancement is a statistically significant increase in performance of the Wisconsin Card Sorting Test.
  • Pettibone, D.J.; Williams, Jr., D. W. 'A novel selective allosteric modulator of metabotropic glutamate receptor subtype 5 (mGluR5) has an antipsychotic profile in rat behavioral models' J. Pharmacol. Exp. Therapeut.
  • mGluR5 PAM that enhances hippocampal LTP is also active in preclinical cognition model of Novel Object Recognition (NOR) wherein the mGluR5 PAM, ADX47273, displaying a robust and significant improvement in NOR, equivalent to the known cognitive enhancing H3 antagonist Thioperide ( Figure 11).
  • Also provided is a method for the manufacture of a medicament for treatment of a disorder in a mammal, for partial agonism of metabotropic glutamate receptor activity in a mammal, for enhancing cognition in a mammal, and/or for potentiation of metabotropic glutamate receptor activity in a mammal comprising combining at least one compound having a structure:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • Also provided is a method for the manufacture of a medicament for potentiation of metabotropic glutamate receptor activity in a mammal comprising combining at least one compound having a structure:
  • Y 1 is selected from N and C-R 4 .
  • Y 2 is selected from N and C-H.
  • each R 3a and R 3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms.
  • R 4 is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.
  • L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkyls
  • R 8 is selected from hydrogen, and an organic radical comprising 1 to 6 carbon atoms selected from optionally substituted C1-C6 alkyl or C2-C6 alkenyl or C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl or C2-C6 heteroalkenyl or C2-C6 heteroalkynyl, optionally substituted C3-C6 cycloalkyl or C3-C6 cycloalkenyl or C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkyl or C3-C6 heterocycloalkenyl or C6 heterocycloalkynyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound comprises an isoindolin-1-one derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl.
  • the compound comprises an isoindoline-l,3-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or is selected from optionally substituted Cl -C 12 alkyl, optionally substituted Cl -C 12 heteroalkyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 heterocycloalkyl, with the proviso that R 1 does not comprise silicon; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that if R 1 is hydrogen, then R 5 is optionally substituted phenyl or optionally substituted pyridinyl, and with the proviso that if R 1 is methyl, then R 5 is an organic radical comprising 4 to 14 carbon atoms.
  • the compound comprises a 3,4-dihydroisoquinolin-l(2H)- one derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R is hydrogen or an organic radical comprising 1 to 12 carbon atoms; wherein each R 2a and R 2b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms; and wherein R , 5 is an organic radical comprising 4 to 14 carbon atoms.
  • the compound comprises an isoquinoline-l,3(2H,4H)-dione derivative or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • R 1 is hydrogen or an organic radical comprising 1 to 12 carbon atoms; and wherein R 5 is an organic radical comprising 4 to 14 carbon atoms, with the proviso that R 5 does not comprise a triphenylamine residue or a benzimidamide residue.
  • the compound comprises a bicyclic compound or a pharmaceutically acceptable salt or N-oxide thereof having a structure:
  • each is an optional covalent bond
  • Y 1 and Y 2 are independently selected from N and C-R; wherein each R is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein R 1 and R 2 are independently hydrogen or an optionally substituted organic radical comprising from 1 to 12 carbon atoms; wherein R 0 is an optionally substituted organic radical comprising 4 to 14 carbon atoms; wherein L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:
  • R 7a and R 7b together form an optionally substituted carbocyclic or heterocyclic ring having from two to five carbons or are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, and an organic radical comprising 1 to 5 carbon atoms selected from optionally substituted C1-C5 alkyl or C2-C5 alkenyl or C2-C5 alkynyl, optionally substituted C1-C5 heteroalkyl or C2-C5 heteroalkenyl or C2-C5 heteroalkynyl, optionally substituted C3-C5 cycloalkyl or C3-C5 cycloalkenyl, optionally substituted C3-C5 heterocycloalkyl or C3-C5 heterocycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfmyl, optionally substituted
  • Y 1 is selected from N and C-R 4 .
  • Y 2 is selected from N and C-H.
  • each R 3a and R 3b is independently hydrogen, halogen, hydroxyl, cyano, nitro, thiol, amino, or an organic radical comprising 1 to 6 carbon atoms.
  • R 4 is hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms.
  • L is an organic divalent radical comprising 1 to 7 carbon atoms and is selected from:

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Abstract

Selon un aspect, la présente invention concerne des composés, comprenant des dérivés benzamides et des dérivés benzamides cycliques, qui sont utiles en tant que modulateurs positifs allostériques du récepteur de sous-type 5 du glutamate (mGluR5); des procédés synthétiques pour la fabrication des composés; des compositions pharmaceutiques comportant les composés; et des procédés de traitement de troubles neurologiques et psychiatriques associés au dysfonctionnement glutamatergique mettant en œuvre les composés et les compositions. Cet abrégé est soumis afin de permettre une recherche générale dans ce domaine précis et ne doit pas être utilisé pour limiter la portée de la présente invention.
PCT/US2008/065647 2007-06-03 2008-06-03 Dérivés benzamides modulateurs allostériques positifs récepteurs métabotropiques du glutamate 5 (mglur5) et leurs procédés de fabrication et d'utilisation WO2008151184A1 (fr)

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EA200971143A EA200971143A1 (ru) 2007-06-03 2008-06-03 Бензамидные mglur5 позитивные аллостерические модуляторы и способы их получения и применения
AU2008259776A AU2008259776A1 (en) 2007-06-03 2008-06-03 Benzamide mGluR5 positive allosteric modulators and methods of making and using same
JP2010511277A JP5622568B2 (ja) 2007-06-03 2008-06-03 ベンズアミドｍＧｌｕＲ５の正のアロステリック調節因子ならびにその作製および使用方法
EP08770045A EP2162136A4 (fr) 2007-06-03 2008-06-03 Dérivés benzamides modulateurs allostériques positifs récepteurs métabotropiques du glutamate 5 (mglur5) et leurs procédés de fabrication et d'utilisation
NZ581817A NZ581817A (en) 2007-06-03 2008-06-03 Benzamide mglur5 positive allosteric modulators and methods of making and using same
MX2009013169A MX2009013169A (es) 2007-06-03 2008-06-03 Moduladores alostericos positivos del mglur5 benzamida y metodos de elaboracion y uso de los mismos.
CN200880100770.6A CN101795689B (zh) 2007-06-03 2008-06-03 苯甲酰胺mGluR5正性变构调节剂和制备与使用所述调节剂的方法
BRPI0812363-2A2A BRPI0812363A2 (pt) 2007-06-03 2008-06-03 Moduladores alostéricos positivos de mglurs de benzamida e métodos de preparação e utilização dos mesmos
CA002689282A CA2689282A1 (fr) 2007-06-03 2008-06-03 Derives benzamides modulateurs allosteriques positifs recepteurs metabotropiques du glutamate 5 (mglur5) et leurs procedes de fabrication et d'utilisation
IL202508A IL202508A0 (en) 2007-06-03 2009-12-03 Benzamide mglur5 positive allosteric modulators and methods of making and using the same
HK11101174.3A HK1147068A1 (en) 2007-06-03 2011-02-07 Benzamide mglur5 positive allosteric modulators and methods of making and using same mglur5

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CA (1) CA2689282A1 (fr)
EA (1) EA200971143A1 (fr)
HK (1) HK1147068A1 (fr)
IL (1) IL202508A0 (fr)
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MX2009013169A (es) 2010-04-30
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KR20100033981A (ko) 2010-03-31
SG185285A1 (en) 2012-11-29
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