[go: up one dir, main page]

WO2013049255A1 - Analogues de 5-(prop-1-yn-1-yl)picolinamide substitué comme modulateurs allostériques des récepteurs de mglur5 - Google Patents

Analogues de 5-(prop-1-yn-1-yl)picolinamide substitué comme modulateurs allostériques des récepteurs de mglur5 Download PDF

Info

Publication number
WO2013049255A1
WO2013049255A1 PCT/US2012/057395 US2012057395W WO2013049255A1 WO 2013049255 A1 WO2013049255 A1 WO 2013049255A1 US 2012057395 W US2012057395 W US 2012057395W WO 2013049255 A1 WO2013049255 A1 WO 2013049255A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
further aspect
haloalkyl
polyhaloalkyl
hydroxyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2012/057395
Other languages
English (en)
Inventor
P. Jeffrey Conn
Craig W. Lindsley
Shaun R. Stauffer
Ya ZHOU
Jose Manuel Bartolome-Nebreda
Gregor James Macdonald
Rocco D. Gogliotti
Mark TURLINGTON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vanderbilt University
Original Assignee
Vanderbilt University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vanderbilt University filed Critical Vanderbilt University
Publication of WO2013049255A1 publication Critical patent/WO2013049255A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • MH062646 and MH089870 awarded by the National Institute of Mental Health (NIMH), and under grant number NS031373 awarded by the National Institute of Neurological Disorders and Stroke.
  • NIMH National Institute of Mental Health
  • NS031373 awarded by the National Institute of Neurological Disorders and Stroke.
  • the United States government has certain rights in the invention.
  • Glutamate L-glutamic acid
  • GPCRs G-protein-coupled receptors
  • the mGluR family comprises eight known mGluRs receptor types (designated as mGluRl through mGluR8). Several of the receptor types are expressed as specific splice variants, e.g. mGluR5a and mGluR5b or mGluR8a, mGluR8b and mGluR8c. The family has been classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology.
  • Group I receptors are coupled to Gaq, a process that results in stimulation of phospholipase C and an increase in intracellular calcium and inositol phosphate levels.
  • Group II receptors mGluR2 and mGluR3
  • group III receptors mGluR4, mGluR6, mGluR7, and mGluR8 are coupled to Goti, which leads to decreases in cyclic adenosine monophosphate (cAMP) levels.
  • cAMP cyclic adenosine monophosphate
  • metabotropic glutamate receptors including mGluR5
  • 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.
  • PAMs Selective positive allosteric modulators
  • 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
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alky -O-Ar 1 , -Cy 1 , -(C1-C6 alky -Cy 1 , -(C1-C6 alky -O-Cy 1 , -C(OH)R 3 R 4 ,
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • Cy 1 is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; or wherein R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 2a and R 2b is independently selected from hydrogen,— Ar 2 , -(C1-C6 alkyl)-Ar 2
  • Disclosed are methods for the treatment of a neurological and/or psychiatric disorder associated with glutamate dysfunction in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • Also disclosed are methods for potentiation of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • Also disclosed are methods for enhancing cognition in a mammal comprising the step of administering to the mammal an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • Also disclosed are methods for potentiation of mGluR5 activity in at least one cell comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • kits comprising at least one disclosed compound, or a
  • compositions comprising: (a) at least one agent known to increase mGluR5 activity; (b) at least one agent known to decrease mGluR5 activity; (c) at least one agent known to treat a neurological and/or psychiatric disorder; (d) at least one agent known to treat a disease of uncontrolled cellular proliferation; or (e) instructions for treating a disorder associated with glutamate dysfunction.
  • Also disclosed are methods for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.
  • Figure 1 shows a schematic illustrating structural features of mGluR5 and allosteric binding.
  • Figure 2 shows a schematic of the NMDA receptor.
  • Figure 3 shows a schematic illustrating that activation of mGluR5 potentiates NMDA receptor function.
  • Figure 4 shows a representative study demonstrating the dose-dependent reversal of amphetamine-induced hyperlocomotion by a representative disclosed compound.
  • Figure 5 shows a representative study demonstrating the dose-dependent reversal of amphetamine-induced hyperlocomotion by a representative disclosed compound.
  • Ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about” that particular value in addition to the value itself. For example, if the value "10” is disclosed, then “about 10" is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • allosteric site refers to a ligand binding site that is topographically distinct from the orthosteric binding site.
  • modulator refers to a molecular entity (e.g., but not limited to, a ligand and a disclosed compound) that modulates the activity of the target receptor protein.
  • ligand refers to a natural or synthetic molecular entity that is capable of associating or binding to a receptor to form a complex and mediate, prevent or modify a biological effect.
  • ligand encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates and analogs of natural substrates.
  • natural ligand and “endogenous ligand” are used interchangeably, and refer to a naturally occurring ligand, found in nature, which binds to a receptor.
  • 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 glutamate in an animal, in particular a mammal, for example a human.
  • a mGluR5 receptor positive allosteric modulator increases the activity of the mGluR5 receptor in a cell in the presence of extracellular glutamate.
  • the cell can be human embryonic kidney cells transfected with human mGluR5.
  • the cell can be human embryonic kidney cells transfected with rat mGluR5.
  • the cell can be human embryonic kidney cells transfected with a mammalian mGluR5
  • mGluR5 receptor positive allosteric modulator includes a compound that is a "mGluR5 receptor allosteric potentiator” or a "mGluR5 receptor allosteric agonist,” as well as a compound that has mixed activity comprising pharmacology of both an "mGluR5 receptor allosteric potentiator” and an "mGluR5 receptor allosteric agonist”.
  • the term “mGluR5 receptor positive allosteric modulator also includes a compound that is a "mGluR5 receptor allosteric enhancer.”
  • 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 the endogenous ligand 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, that is, an allosteric site, and positively augments the response of the receptor to an agonist or the endogenous ligand.
  • an allosteric potentiator does not induce desensitization of the receptor, 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 enhancer refers to any exogenously administered compound or agent that directly or indirectly augments the response produced by the endogenous ligand in an animal, in particular a mammal, for example a human.
  • the allosteric enhancer increases the affinity of the natural ligand or agonist for the orthosteric site.
  • an allosteric enhancer increases the agonist efficacy.
  • the mGluR5 receptor allosteric potentiator binds to a site other than the orthosteric site, that is, an allosteric site, and positively augments the response of the receptor to an agonist or the endogenous ligand.
  • An allosteric enhancer has no effect on the receptor by itself and requires the presence of an agonist or the natural ligand to realize a receptor effect.
  • 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 a site that is distinct from the orthosteric glutamate site of the mGluR5 receptor and influences the binding of an agonist or the natural ligand to 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.
  • mGluR5 receptor neutral allosteric ligand refers to any exogenously administered compound or agent that binds to an allosteric site without affecting the binding or function of agonists or the natural ligand at the orthosteric site in an animal, in particular a mammal, for example a human.
  • a neutral allosteric ligand can block the action of other allosteric modulators that act via the same site.
  • the term "subject" can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • the subject has been diagnosed with a need for treatment of one or more
  • the subject has been diagnosed with a need for positive allosteric modulation of metabotropic glutamate receptor activity prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for partial agonism of metabotropic glutamate receptor activity prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a psychotic disorder, e.g. schizophrenia, a cognitive disorder, or neuropathic pain prior to the administering step.
  • a psychotic disorder e.g. schizophrenia, a cognitive disorder, or neuropathic pain
  • the subject has been identified with a disorder treatable by activation of the mGluR5 receptor and/or or a need for activation/agonism of mGluR5 activity prior to the administering step.
  • the subject has been identified with anxiety or a related disorder prior to the administering step.
  • a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • 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.
  • the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
  • subject also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
  • domesticated animals e.g., cats, dogs, etc.
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.
  • prevent refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • diagnosisd means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
  • diagnosis with a disorder treatable by modulation of mGluR5 means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can modulate mGluR5.
  • diagnosis refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition characterized by mGluR5 activity.
  • a diagnosis can be in reference to a disorder, such as a neurodegenerative disease, and the like, as discussed herein.
  • diagnosis can be in reference to a disorder, such as a neurodegenerative disease, and the like, as discussed herein.
  • the term "diagnosed with a need for positive allosteric modulation of metabotropic glutamate receptor activity” refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by positive allosteric modulation of metabotropic glutamate receptor activity.
  • diagnosisd 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 acetycholine dysfunction.
  • the phrase "identified to be in need of treatment for a disorder," or the like, refers to selection of a subject based upon need for treatment of the disorder.
  • a subject can be identified as having a need for treatment of a disorder (e.g., a disorder related to mGluR5 activity) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the disorder.
  • the identification can, in one aspect, be performed by a person different from the person making the diagnosis.
  • the administration can be performed by one who subsequently performed the administration.
  • administering and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered
  • prophylactically that is, administered for prevention of a disease or condition.
  • contacting refers to bringing a disclosed compound and a cell, a target receptor (e.g. a metabotropic glutamate receptor), or other biological entity together in such a manner that the compound can affect the activity of the target, either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the target is dependent.
  • a target receptor e.g. a metabotropic glutamate receptor
  • the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired 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 effects.
  • 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
  • a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.
  • kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.
  • instruction(s) means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.
  • therapeutic agent include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic,
  • immunogenic, and/or physiologic effect by local and/or systemic action encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64 th edition), and The Pharmacological Basis of Therapeutics (12th edition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term "therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • EC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • EC 50 can refer to the concentration of agonist that provokes a response halfway between the baseline and maximum response in an in vitro assay.
  • in vitro assay systems frequently utilize a cell line that either expresses endogenously a target of interest, or has been transfected with a suitable expression vector that directs expression of a recombinant form of the target.
  • the EC 50 for mGluR5 can be determined using human embryonic kidney cells transfected with human mGluR5.
  • the EC 50 for mGluR5 can be determined using human embryonic kidney cells transfected with rat mGluR5.
  • the EC 50 for mGluR5 can be determined using human embryonic kidney cells transfected with a mammalian GluR5.
  • IC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • IC 50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.
  • an IC 50 for mGluR5 receptor can be determined in an in vitro assay system.
  • receptor assays, including suitable assays for mGluR5 make use of a suitable cell-line, e.g. a cell line that either expresses
  • the IC 50 for mGluR5 can be determined using human embryonic kidney cells transfected with human mGluR5.
  • the IC 50 for mGluR5 can be determined using human embryonic kidney cells transfected with rat mGluR5.
  • the IC 50 for mGluR5 can be determined using human embryonic kidney cells transfected with a mammalian GluR5.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • the term "derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • the term "pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • 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 can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • 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 0- 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 ) 8 CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • 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. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • 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.
  • aliphatic or "aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms.
  • Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • 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, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group is acyclic.
  • the alkyl group can be branched or unbranched.
  • 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, 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 to four) carbon atoms.
  • alkyl is generally used to refer to both
  • substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl or “haloalkyl” 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, 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, 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.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described here
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term
  • cycloalkenyl where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, 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, 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, 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.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry , (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference.
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • 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.
  • aldehyde as used herein is represented by the formula— C(0)H.
  • NA 1 A2 where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is -NH 2 .
  • alkylamino as used herein is represented by the formula— NH(-alkyl) where alkyl is a described herein.
  • Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.
  • dialkylamino as used herein is represented by the formula— N(- alkyl) 2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group,
  • diisopropylamino group dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert- pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N- propylamino group, N-ethyl-N-propylamino group and the like.
  • esters as used herein is represented by the formula— OC(0)A 1 or — C(0)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polyyester as used herein is represented by the formula -(A 1 0(0)C-A 2 -C(0)0) a - or -(A 1 0(0)C-A 2 -OC(0)) a - where
  • a 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a” is an integer from 1 to 500.
  • 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 OA , where A and A can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein
  • a and A can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a" is an integer of from 1 to 500.
  • polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halo refers F, CI, Br, or I.
  • pseudohalide refers to functional groups that behave substantially similar to halides.
  • Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl,
  • heteroalkyl refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted.
  • the heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, 1,2- oxazol-4-yl
  • heterocycle refers to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
  • heterocycle includes pyridinde, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1, 3, 4-oxadiazole, thiadiazole, including, 1,2,3- thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4- triazole, tetra
  • bicyclic heterocycle or "bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
  • Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
  • Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
  • Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[l,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, lH-pyrazolo[4,3-c]pyridin-3-yl; lH-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo [3 ,2-b]pyridin-3 -yl.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
  • the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • hydroxyl as used herein is represented by the formula— OH.
  • ketone as used herein is represented by the formula A C(0)A , where
  • a 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • nitrile as used herein is represented by the formula— CN.
  • sil as used herein is represented by the formula— SiA A A , where
  • a 1 , A2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo as used herein is represented by the formulas— S(0)A 1 ,— SCO ⁇ A 1 , —OSCODA 1 , or— OS ⁇ OA 1 , where A 1 can be hydrogen or an 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(0) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfone as used herein is represented by the formula A 1 S(0) 2 A2 , where A 1 and A2 can be, independently, an 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(0)A2 where A 1 and A2 can be, independently, an alkyl, cycloalkyl, alkenyl,
  • cycloalkenyl alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or,
  • the first group can be pendant (i.e., attached) to the second group.
  • the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an "optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0 2 R*, -(haloR*), -(CH 2 ) 0 2 OH, -(CH 2 ) 0 2 OR*, -(CH 2 ) 0
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR 2 ) 2 3 0-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R include halogen,
  • each R* is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently Ci_ 4 aliphatic, -CH 2 Ph, - 0(CH 2 )o_iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ ,
  • each R ⁇ is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*,
  • each R* is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently Ci_ 4 aliphatic, -CH 2 Ph, - 0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • leaving group refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, brosylate, and halides.
  • hydrolysable group and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
  • hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, "Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).
  • 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,
  • Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
  • the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
  • Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
  • the invention includes all such possible isomers, as well as mixtures of such isomers.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g. , each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F and 36 C1, respectively.
  • Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the compounds described in the invention can be present as a solvate.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the invention includes all such possible solvates.
  • co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction.
  • One or more components of this molecular complex provide a stable framework in the crystalline lattice.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004.
  • Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.
  • ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.
  • amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.
  • polymorphic forms or modifications It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.
  • a structure of a compound can be represented by a formula:
  • n is typically an integer. That is, R" is understood to represent five independent substituents, R" (a) , R" (b) , R" (c) , R" (d) , R" (e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R" ⁇ is halogen, then R" ⁇ is not necessarily halogen in that instance.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • 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 cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary.
  • 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.
  • the invention relates to compounds useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). More specifically, in one aspect, 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 can, in one aspect, exhibit subtype selectivity.
  • 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.
  • each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.
  • the invention relates to a compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alky -O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • Cy 1 is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; or wherein R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 2a and R 2b is independently selected from hydrogen,— Ar 2 , -(C1-C6 alkyl)-Ar 2
  • the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • R 7 is selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • n is an integer from 1-3; wherein each of R a and R is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, Cl- C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • n is an integer from 1-3; wherein each of R a and R is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, Cl- C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • n is an integer from 1-3; wherein each of R a and R is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, Cl- C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • n is an integer from 1-3; wherein each of R a and R is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, Cl- C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • n is an integer from 1-3; wherein each of R a and R is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, Cl- C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • n is an integer from 1-3; wherein each of R a and R is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, Cl- C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • n is an integer from 1-3; wherein each of R 3a and R 3D is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, Cl- C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • n is an integer from 1-3; wherein each of R 3a and R 3D is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, Cl- C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • the compound has a structure represented by a formula:
  • n and m are integers independently selected from 1-3; wherein each of R a and R is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; and wherein each of R 6a and R* 1 is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C
  • the compound has a structure represented by a formula:
  • R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • q is an integer from 1-3; wherein each of R a and R is independently selected from hydrogen, methyl, and ethyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • each of R a , R , and R c is independently selected from hydrogen, hydroxyl, methyl, and ethyl, provided that only one of R 9a , R 9b , and R 9c is hydroxyl.
  • the compound has a structure represented by a formula:
  • each of R a and R is independently selected from hydrogen, methyl, and ethyl.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • q is an integer from 0 to 3.
  • the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3- C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is iinnddeeppeennddeently selected from hydrogen, halo, hydroxyl, cyano,
  • R 7 is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyan
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3
  • R 7 is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3
  • R 7 is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R a and R is independently selected from hydrogen, methyl, and ethyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3
  • R 7 is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalky
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3
  • R is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl, provided that only one of R 9a and R 9b is hydroxyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein R is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein R is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3
  • R is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 haloalkyl, C1-C6 polyhaloalkyl, C 1-C6 alkylamino, C 1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1 -C6 alkyl, C 1-C6 alkoxy, C 1-C6 haloalkyl, C 1-C6 polyhaloalkyl, C 1-C6 alkylamino, and
  • the compound has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C 1-C3 haloalkyl, C 1-C3 polyhaloalkyl, C 1-C3
  • each of R 6a and R 6 * 5 is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1 -C3 alkyl, C 1-C3 alkoxy, C 1-C3 haloalkyl, C 1-C3 polyhaloalkyl, C 1-C3 alkylamino, Cl- C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl;
  • each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl; and wherein R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C 1-C6 alkoxy, C1-C6 haloalkyl, C1 -C6 polyhalo
  • Q is N or N— O-. In a further aspect, Q is N. In a still further aspect, Q is N + — O-.
  • R 1 is selected from -Ar 1 , -(C1-C6 alkyfj-Ar 1 , -(C 1-C6 alkyl)-0- Ar 1 , -Cy 1 , -(C1-C6 alky ⁇ -Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 , -CCOH ⁇ Ar 1 , and -CCOH ⁇ Cy 1 .
  • R 1 is selected from C 1 -C6 alkyl, C 1 -C6 haloalkyl, and C 1 -C6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • R 1 is selected from C 1 -C6 alkyl, C 1 -C6 haloalkyl, and C 1 -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3- dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF
  • R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, methyl, ethyl, propyl, -CF , - CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from F, CI, cyano, and -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH , - NHCH 2 CH 3 , and— N(CH 3 ) 2 .
  • R 1 is selected from C1-C6 alkyl, Cl- C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected F, CI, cyano, methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , - NHCH , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected halo, cyano, -CH 3 , -CF 3 , CH 2 CH 3 , n-propyl, and i-propyl.
  • R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected halo, -CH , and -CF .
  • R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected F, CI, cyano, -CH 3 ,— CF 3 , CH 2 CH 3 , n-propyl, and i-propyl.
  • R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected F, CI, -CH , and -CF .
  • R 1 is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3- dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3-dimethylpentan-2- yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , - CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3
  • R 1 is selected from methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , - NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • R 1 is selected from -Ar 1 , -(C 1-C6 alky -Ar 1 , -(C1-C6 alky -O-Ar 1 , -Cy 1 , -(C 1-C6 alkyfj-Cy 1 , and -(C1-C6 alkyFj-O-Cy 1 .
  • R 1 is Ar 1 .
  • R 1 is Cy 1 .
  • R 1 is selected from -CH 2 OAr 1 , -(CH 2 ) 2 OAr 1 , and -(CH 2 ) 3 OAr 1 .
  • R 1 is -CH 2 OAr 1 .
  • R 1 is selected from— CH 2 Ar 1 ,— (CH 2 ) 2 Ar 1 , and— (CH 2 ) Ar 1 .
  • R 1 is— CH 2 Ar 1 .
  • R 1 is selected from— CH 2 OCy 1 , -(CH 2 ) 2 OCy 1 , and -(CH 2 ) 3 OCy .
  • R 1 is -CH 2 OCy 1 .
  • R 1 is selected from— CH 2 Cy 1 ,— (CH 2 ) 2 Cy 1 , and— (CH 2 ) Cy 1 .
  • R 1 is -CH 2 Cy ⁇
  • R 1 is selected from -C(OH)R 3 R 4 , -C(OH)R 3 Ar', and
  • R 1 is— C(OH)R 3 R 4 .
  • R 1 is selected from a residue having a structure represented by a formula:
  • R 1 is a residue having a structure represented by a formula:
  • R 1 is selected from a residue having a structure represented by a formul
  • R 1 is a residue having a structure represented by a formula:
  • R 1 is— QOH ⁇ Ar 1 .
  • R 1 is selected from a residue having a structure represented by a formula:
  • R 1 is a residue having a structure represented by a formula:
  • R 1 is selected from a residue having a structure represented by a formula:
  • R is a residue having a structure represented by a formula:
  • R 1 is - OH ⁇ Cy 1 .
  • R 1 is selected from a residue having a structure represented by a formula:
  • R 1 is a residue having a structure represented by a formula:
  • R 1 is selected from a residue having a structure
  • R 1 is a residue having a structure represented by a formula:
  • each of R 2a and R 2b is independently selected from hydrogen,— Ar 2 , -(C1-C6 alkyl)-Ar 2 , -Cy 2 , -(C1-C6 alkyl)-Cy 2 , C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and wherein each of R 2a and R 2b is independently substituted with 0-3
  • substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R a and R are the are not the same.
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl, and substituted with 0- 3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • each of R 2a and R 2b is independently selected from hydrogen, -Ar 2 , -(C1-C6 alkyl)-Ar 2 , -Cy 2 , and -(C1-C6 alkyl)-Cy 2 .
  • each of R 2a is hydrogen and R 2b is selected from -Ar 2 , -(C1-C6 alkyl)-Ar 2 , -Cy 2 , and -(C1-C6 alkyl)-Cy 2 .
  • R 2a is hydrogen and R 2b is— Ar 2 .
  • R 2 a is hydrogen and R 2b is— Cy 2.
  • R 2 a is hydrogen and R 2b is selected from— Ar 2 and— (C1-C6 alkyl)- Ar 2 .
  • R 2a is hydrogen and R 2b
  • R 2a is hydrogen and R 2b is selected from cyclopropyl
  • Cy 1 is selected from oxiranyl, (oxiranyl)methyl, (oxiranyl)ethyl, azetidinyl, (azetidinyl)methyl, (azetidinyl)methyl, oxetanyl,
  • R a is hydrogen and R is selected from phenyl, benzyl, phenethyl, pyridinyl, (pyridinyl)methyl, (pyridinyl)ethyl, (pyrimidinyl)methyl, and
  • R 2a is hydrogen and R 2b is selected from benzyl, phenethyl, pyridinyl, (pyridinyl)methyl, and (pyridinyl)ethyl.
  • R 2a is H and R 2b is selected from -Ar 2 , -(C 1 -C6 alkyl)-Ar 2 , -Cy 2 , -(C1-C6 alkyl)-Cy 2 , C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl, and wherein R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 2a is H and R 2b is selected from -Ar 2 , -(C 1 -C6 alkyl)-Ar 2 , — Cy 2 , and— (C1-C6 alkyl)-Cy 2 ; and wherein R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 2a is H and R 2b is selected from -Ar 2 , -(C 1 -C6 alkyl)-Ar 2 , — Cy 2 , and— (C1-C6 alkyl)-Cy 2 ; and wherein R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 2a is H and R 2b is selected from phenyl, benzyl, phenethyl, pyridinyl, (pyridinyl)methyl; and (pyridinyl)ethyl; and R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 2a is H and R 2b is selected from phenyl, benzyl, phenethyl, pyridinyl, (pyridinyl)methyl; and (pyridinyl)ethyl; and R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 2a is H and R 2b is selected from cyclopropyl
  • R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 2a is H and R 2b is selected from cyclopropyl
  • R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 2a is H and R 2b is selected from cyclopropyl
  • R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , and trifluoromethyl.
  • R 2a is H and R 2b is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, and 2,3- dimethylpentan-2-yl; and R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , and trifluoromethyl.
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl, and substituted with 0- 3 substituents selected from halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3- dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3-dimethylpentan-2- yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl, and substituted with 0-3 substituents selected from halo, hydroxyl, cyano, - NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH , and -N(CH ) 2 . .
  • Ar 1 is phenyl substituted with 1-3 substituents selected from F, CI, hydroxyl, cyano, and -NH 2 , methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • substituents selected from F, CI, hydroxyl, cyano, and -NH 2 , methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl, and substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , -CH , -CF , CH 2 CH , n-propyl, and i-propyl.
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl, and substituted with 0-3 substituents selected from F, CI, hydroxyl, cyano, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , n-propyl, and i-propyl.
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl, and substituted with 0-3 substituents selected from halo, hydroxyl, -NH 2 , -CH , and -CF .
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl, and substituted with 0-3 substituents selected from F, CI, hydroxyl, -NH 2 , -CH 3 , and -CF 3 .
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl selected from azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, oxazinanyl, and morpholinyl.
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a morpholinyl group.
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise an azetidinyl group. In an even further aspect, R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a pyrrolidinyl group. In a still further aspect, R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a piperidinyl group.
  • R 2a and R 2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl selected from azetidinyl, pyrrolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, oxazinanyl, and morpholinyl, and substituted with 0-3 substituents selected from halo, hydroxyl, cyano,— NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3- dimethylpentan-2-yl, 2,3
  • each of R 2a and R 2b is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and each of R 2a and R 2b is independently substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3- dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1,
  • each of R 2a and R 2b is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and each of R 2a and R 2b is independently substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • each of R 2a and R 2b is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and each of R 2a and R 2b is independently substituted with 1-3 substituents selected from F, CI, hydroxyl, cyano, and -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • each of R 2a and R 2b is independently selected from C1-C8 alkyl, Cl- C8 haloalkyl, and C1-C8 polyhaloalkyl; and each of R 2a and R 2b is independently substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , -CH 3 , -CF 3 , CH 2 CH 3 , n- propyl, and i-propyl.
  • each of R 2a and R 2b is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and each of R 2a and R 2b is independently substituted with 0-3 substituents selected from F, CI, hydroxyl, cyano,— NH 2 , — CH 3 , -CF 3 , -CH 2 CH 3 , n-propyl, and i-propyl.
  • each of R 2a and R 2b is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and each of R 2a and R 2b is independently substituted with 0-3 substituents selected from halo, hydroxyl, -NH 2 , -CH 3 , and -CF 3 .
  • each of R 2a and R 2b is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and each of R 2a and R 2b is independently substituted with 0-3 substituents selected from F, CI, hydroxyl, -NH 2 , -CH 3 , and -CF 3 .
  • R 2a is hydrogen and R 2b is selected from C 1 -C8 alkyl, C 1 -C8 haloalkyl, and C1-C8 polyhaloalkyl; and R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3- dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2
  • R 2a is hydrogen and R 2b is selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF 3 , -CCI 3 , -CH 2 CF 3 , -CH2CCI3, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, and -N(CH 3 ) 2 .
  • R 2a is hydrogen and R 2b is selected C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and R 2b is substituted with 1-3 substituents selected from F, CI, hydroxyl, cyano, and -NH 2 , methyl, ethyl, propyl, -CF 3 , -CCI3, -CH 2 CF 3 , -CH 2 CC1 3 , -OCH3,
  • R 2a is hydrogen and R 2b is selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , -CH 3 , -CF 3 , CH 2 CH 3 , n-propyl, and i-propyl.
  • R 2a is hydrogen and R 2b is selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and R 2b is substituted with 0-3 substituents selected from F, CI, hydroxyl, cyano, -NH 2 , -CH 3 , -CF 3 , CH 2 CH 3 , n- propyl, and i-propyl.
  • R 2a is hydrogen and R 2b is selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and R 2b is substituted with 0-3 substituents selected from halo, hydroxyl, -NH 2 , -CH 3 , and -CF 3 .
  • R 2a is hydrogen and R 2b is selected from C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and R 2b is substituted with 0-3 substituents selected from F, CI, hydroxyl, -NH 2 , -CH 3 , and -CF 3 .
  • each of R 2a and R 2b is independently selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec-butyl, isobutyl, tert- butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI 3 , -CH 2 CH 2 F,
  • each of R 2a and R 2b is independently selected from methyl, ethyl, propyl, isopropyl, -CF 3 , -CCI 3 , — CH 2 CF 3 , and -CH 2 CCI 3 .
  • each of R 2a and R 2b is independently selected from -CF 3 , -CCI 3 , -CH 2 CF 3 , and -CH 2 CCI 3 .
  • each of R 2a and R 2b is independently selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec- pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2- yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, and 2,3-dimethylpentan-2-yl.
  • R 2a is hydrogen and R 2b is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3- dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CI, -CH 2 CHCI 2 , and -CH 2 CCI 3 .
  • R 2a is hydrogen and R 2b is selected from methyl, ethyl, propyl, isopropyl, -CF 3 , -CCI 3 , -CH 2 CF 3 , and — CH 2 CCI 3 .
  • R 2a is hydrogen and R 2b is selected from -CF 3 , -CCI 3 , — CH 2 CF 3 , and -CH 2 CCI 3 .
  • R a is hydrogen and R is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, and 2,3-dimethylpentan-2-yl.
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and
  • R 3 is hydrogen. In a still further aspect, R 3 is selected from hydrogen, methyl, ethyl, and propyl. In an even further aspect, R is hydrogen or methyl.
  • R is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3- dimethylbutan-2-yl, 2,3-dimethylbutan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , and -CH 2 CC1 3 .
  • R is selected from methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , and -CH 2 CC1 3 .
  • R 3 is selected from methyl, -CF , and -CC1 3 .
  • R 3 is selected from methyl and -CF 3 .
  • R is methyl.
  • R 3 is— CF 3 .
  • R is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3- dimethylbutan-2-yl, and 2,3-dimethylbutan-2-yl.
  • R is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, and isopropyl. In a still further aspect, R is selected from methyl and ethyl.
  • R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl. In a further aspect, R 4 is hydrogen. In a still further aspect, R 4 is selected from hydrogen, methyl, ethyl, and propyl. In an even further aspect, R 4 is hydrogen or methyl.
  • R 4 is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3- dimethylbutan-2-yl, 2,3-dimethylbutan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , and -CH 2 CC1 3 .
  • R 4 is selected from methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , and -CH 2 CC1 3 . In an even further aspect, R 4 is selected from methyl, -CF 3 , and -CC1 3 . In a still further aspect, R 4 is selected from methyl and -CF 3 . In a yet further aspect, R 4 is methyl. In an even further aspect, R 4 is— CF 3 .
  • R 4 is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3- dimethylbutan-2-yl, and 2,3-dimethylbutan-2-yl.
  • R 4 is selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, and isopropyl. In a still further aspect, R 4 is selected from methyl and ethyl.
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 5a is hydrogen and R 5b is selected from halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • each of R 5a and R 5b is hydrogen.
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , and -N(CH
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 ,— NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 5a is hydrogen and R 5b is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , and -N(CH 3 ) 2 , -NHCH 3
  • R 5a is hydrogen and R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CCI 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CI, -CH 2 CHCI 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , — NHCH , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 5a is hydrogen and R 5b is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 ,— NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • each of R 5a and R 5b is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHCI 2 , -CCI 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CI, -CH 2 CHCI 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 ,
  • each of R 5a and R 5b is
  • each of R 5a and R 5b is independently selected from hydrogen, methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 5a is hydrogen and R 5b is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHCI 2 , -CC1 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CI, -CH 2 CHCI 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , and -N(CH )CH 2 CH .
  • R 5a is hydrogen and R 5b is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHCI 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CI, -CH 2 CHCI 2 , -CH 2 CC1 3 , -OCH 3 ,
  • R 5a is hydrogen and R 5b is selected from hydrogen, methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 ,— NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, -CF , and -CC1 3 .
  • R 5a is hydrogen
  • R 5b is selected from halo, hydroxyl, cyano, -NH 2 , methyl, -CF 3 , and -CC1 3 .
  • each of R 5a and R 5b is independently selected from hydrogen, halo, hydroxyl, -NH 2 , and -CF 3 .
  • R 5a is hydrogen, and R 5b is selected from halo, hydroxyl, -NH 2 , and -CF 3 .
  • each of R 5a and R 5b is independently selected from hydrogen, F, hydroxyl, -NH 2 , and -CF 3 .
  • R 5a is hydrogen, and R 5b is selected from F, hydroxyl, -NH 2 , and -CF 3 .
  • each of R 5a and R 5b is independently selected from hydrogen, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl.
  • each of R 5a and R 5b is independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl.
  • each of R 5a and R 5b is independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • each of R 5a and R 5b is independently selected from hydrogen, oxiranyl, azetidinyl, oxetanyl, pyrollidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, morpholinyl, oxazinanyl, and oxazolidinyl.
  • R 5a is hydrogen and R 5b is selected from hydrogen, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl.
  • R 5a is hydrogen and R 5b is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl.
  • R 5a is hydrogen and R 5b is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • each of R 5a and R 5b is independently selected from oxiranyl, azetidinyl, oxetanyl, pyrollidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, morpholinyl, oxazinanyl, and oxazolidinyl.
  • R 5a and R 5b can involve multiple occurrences of the various selected substituents, each such substituent independently selected.
  • the invention relates to a structure represented by a fo
  • R 5a is selected from hydrogen, methyl, and ethyl
  • R 5b is selected from hydrogen, methyl, and ethyl.
  • Such structures are also understood to refer to a moiety having a structure alternatively represented by a formula:
  • each of R 5al , R 5bl , R 5a2 , and R 5b2 is independently selected from hydrogen, methyl, and ethyl (again, irrespective of the other selections).
  • each of R 6a and R 6 * 5 is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 6a is hydrogen and R 6 * 5 is selected from halo, hydroxyl, cyano, -NH 2 , C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkylamino, C1-C3 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • each of R 6a and R* is hydrogen.
  • each of R 6a and R 6b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHCI 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , and -N(CH 3 ) 2 , and -N
  • each of R 6a and R* is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , — NHCH , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • each of R 6a and R 6 * 5 is independently selected from hydrogen, halo, hydroxyl, cyano, — NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 ,— NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 6a is hydrogen and R 6 * 5 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , and -N(CH 3 ) 2 , and -N
  • R ba is hydrogen and R 6b is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , - CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , - NHCH 3 , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 6a is hydrogen and R 6 * 5 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -
  • each of R 6a and R 6b is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 ,
  • each of R 6a and R 6 * 5 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , -NHCH(CH 3 ) 2 , -NHCH(CH 3 ) 2 , -NHCH(CH 3 ) 2 , -NHCH(CH 3
  • each of R 6a and R* is independently selected from hydrogen, methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 6a is hydrogen and R 6 * 5 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, - CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , and -N(CH 3 )CH 2 CH 3 .
  • R 6a is hydrogen and R 6 * 5 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 ,
  • R 6a is hydrogen and R* is selected from hydrogen, methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 ,— NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • each of R 6a and R 6b is independently selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, -CF 3 , and -CC1 3 .
  • R 6a is hydrogen, and R is selected from halo, hydroxyl, cyano, -NH 2 , methyl, -CF 3 , and -CC1 3 .
  • each of R 6a and R 6 * 5 is independently selected from hydrogen, halo, hydroxyl, -NH 2 , and -CF .
  • R 6a is hydrogen, and R 6 * 5 is selected from halo, hydroxyl, -NH 2 , and -CF 3 .
  • each of R 6a and R 6b is independently selected from hydrogen, F, hydroxyl, -NH 2 , and -CF 3 .
  • R 6a is hydrogen, and R 6 * 5 is selected from F, hydroxyl, -NH 2 , and -CF 3 .
  • each of R 6a and R 6b is independently selected from hydrogen, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl.
  • each of R 6a and R* 1 is independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl.
  • each of R 6a and R 6b is independently selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • each of R 6a and R 6b is independently selected from hydrogen, oxiranyl, azetidinyl, oxetanyl, pyrollidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, morpholinyl, oxazinanyl, and oxazolidinyl.
  • R 6a is hydrogen and R 6 * 5 is selected from hydrogen, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl.
  • R 6a is hydrogen and R 6b is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl.
  • R 6a is hydrogen and R 6b is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • each of R 6a and R 6b is independently selected from oxiranyl, azetidinyl, oxetanyl, pyrollidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, morpholinyl, oxazinanyl, and oxazolidinyl.
  • R a is selected from hydrogen, methyl, and ethyl
  • R 6 * 5 is selected from hydrogen, methyl, and ethyl.
  • Such structures are also understood to refer to a moiety having a structure alternatively represented by a formula:
  • each of R a , R , R a , and R is independently selected from hydrogen, methyl, and ethyl (again, irrespective of the other selections),
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl.
  • R 7 is hydrogen.
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 -CH 2
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec-butyl, isobutyl, tert- butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , — NHCH 3 , -NHCH 2 CH 3 ,
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 7 is selected from hydrogen, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3- dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3-dimethylpentan-2- yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 ,
  • R 7 is selected from hydrogen, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec- butyl, isobutyl, tert-butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F,
  • R 7 is selected from hydrogen, methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , (CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 ,— NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 7 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, -CF , and -CC1 3 . In a still further aspect, R 7 is selected from halo, hydroxyl, cyano, — NH 2 , methyl, -CF 3 , and -CC1 3 . In a yet further aspect, R 7 is selected from hydrogen, halo, hydroxyl, -NH 2 , and -CF 3 . In an even further aspect, R 7 is selected from halo, hydroxyl, — NH 2 , and -CF 3 .
  • each of R 7 and R* 1 is independently selected from hydrogen, F, hydroxyl, -NH 2 , and -CF .
  • R 7 is selected from F, hydroxyl, -NH 2 , and -CF 3 .
  • R 7 is selected from hydrogen, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl.
  • R 7 is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl,
  • R 7 is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 7 is selected from hydrogen, oxiranyl, azetidinyl, oxetanyl, pyrollidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, morpholinyl, oxazinanyl, and oxazolidinyl.
  • R is selected halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C 1-C6 alkoxy, C 1-C6 haloalkyl, C1-C6 polyhaloalkyl, C 1-C6 alkylamino, C1-C6 dialkylamino, C3-
  • R is hydrogen
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 -CH 2 CF 3 , -
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec-butyl, isobutyl, tert- butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , — NHCH , -NHCH 2 CH 3 , -
  • R 8 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R is selected from hydrogen, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3- dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3-dimethylpentan-2- yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 ,
  • R 8 is selected from hydrogen, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec- butyl, isobutyl, tert-butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F,
  • R is selected from hydrogen, methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 ,
  • R is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, -CF , and -CC1 3 . In a still further aspect, R is selected from halo, hydroxyl, cyano,
  • R is selected from hydrogen, halo, hydroxyl, -NH 2 , and -CF 3 .
  • R is selected from halo, hydroxyl, — NH 2 , and -CF 3 .
  • each of R and R is independently selected from hydrogen, F, hydroxyl, -NH 2 , and -CF 3 .
  • R is selected from F, hydroxyl, -NH 2 , and -CF 3 .
  • R is selected from hydrogen, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl.
  • R is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl,
  • R is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R is selected from hydrogen, oxiranyl, azetidinyl, oxetanyl, pyrollidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, morpholinyl, oxazinanyl, and oxazolidinyl.
  • each of R 9a and R 9b is independently selected from hydrogen, methyl, and ethyl.
  • each of R 9a , R 9b , and R 9c is independently selected from hydrogen, hydroxyl, methyl, and ethyl, provided that only one of R 9a , R 9b , and R 9c is hydroxyl.
  • R 9a and R 9b can involve multiple occurrences of the various selected substituents, each such substituent independently selected.
  • the invention relates to a structure represented by a fo
  • R 9al and R 9bl each such substituent is independently hydrogen, methyl, or ethyl.
  • Such structures are also understood to refer to a moiety having a structure alternatively represented by a formula:
  • each of R a , R , R a , and R is independently selected from hydrogen, methyl, and ethyl (again, irrespective of the other selections),
  • R 10 is selected hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • R 10 is hydrogen.
  • R 10 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 -CH 2 C1, -CH 2
  • R 10 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec-butyl, isobutyl, tert- butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , — NHCH 3 , -NHCH 2 CH 3 ,
  • R 10 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 10 is selected from hydrogen, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3- dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , - CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -
  • R 10 is selected from hydrogen, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-p tyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, -CH 2 F, -CHF 2 , - CF 3 , -CH 2 CI, -CHCI 2 , -CCI 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , - CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 , - NH(CH 2 ) 2 CH 3 , -NH(CH 2 ) 2
  • R 10 is selected from hydrogen, methyl, ethyl, propyl, -CF 3 , -CCI 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 10 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, -CF 3 , and -CC1 3 . In a still further aspect, R 10 is selected from halo, hydroxyl, cyano, — NH 2 , methyl, -CF 3 , and -CC1 3 . In a yet further aspect, R 10 is selected from hydrogen, halo, hydroxyl, -NH 2 , and -CF . In an even further aspect, R 10 is selected from halo, hydroxyl, — NH 2 , and -CF .
  • R 10 is selected from hydrogen, F, hydroxyl, -NH 2 , and -CF 3 . In a yet further aspect, R 10 is selected from F, hydroxyl, -NH 2 , and -CF 3 .
  • R 11 is selected hydrogen, halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • R 11 is hydrogen.
  • R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 -CH 2
  • R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec-butyl, isobutyl, tert- butyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , — NHCH 3 , -NHCH 2 CH 3 ,
  • R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH , -NHCH 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 11 is selected from hydrogen, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3-dimethylbutan-2-yl, 2,3- dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , - CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OCH 3 , -
  • R 11 is selected from hydrogen, methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, -CH 2 F, -CHF 2 , - CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , - CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , - NH(CH 2 ) 2 CH 3 , -NH(CH 2 ) 2
  • R 11 is selected from hydrogen, methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -0(CH 2 ) 2 CH 3 , -OCH(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH(CH 3 ) 2 , and -N(CH 3 ) 2 .
  • R 11 is selected from hydrogen, halo, hydroxyl, cyano, -NH 2 , methyl, -CF , and -CC1 3 . In a still further aspect, R 11 is selected from halo, hydroxyl, cyano, — NH 2 , methyl, -CF 3 , and -CC1 3 . In a yet further aspect, R 11 is selected from hydrogen, halo, hydroxyl, -NH 2 , and -CF 3 . In an even further aspect, R 11 is selected from halo, hydroxyl, — NH 2 , and -CF . In a still further aspect, R 11 is selected from hydrogen, F, hydroxyl, -NH 2 , and -CF . In a yet further aspect, R 11 is selected from F, hydroxyl, -NH 2 , and -CF . In a yet further aspect, R 11 is selected from F, hydroxyl, -NH 2 , and -CF .
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • Ar 1 is phenyl. In a still further aspect, Ar 1 is phenyl substituted with 1-3 substituents. In yet further aspect, Ar 1 is phenyl substituted with 1-2 substituents. In an even further aspect, Ar 1 is monosubstituted phenyl. In a still further aspect, Ar 1 is unsubstituted phenyl. In a yet further aspect, Ar 1 is phenyl substituted with 1-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , -CH , -CF , CH 2 CH , n-propyl, and i- propyl.
  • Ar 1 is phenyl substituted with 1-3 substituents selected from halo, hydroxyl, -NH 2 , -CH 3 , and -CF 3 . In a still further aspect, Ar 1 is phenyl and monosubstituted with the substituent selected from F, CI, and Br. In a yet further aspect, Ar 1 is phenyl and monosubstituted with F.
  • Ar 1 is phenyl substituted with 1-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar 1 is phenyl substituted with 1-3 substituents selected from halo, hydroxyl, cyano, and -NH 2 .
  • Ar 1 is phenyl substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar 1 is phenyl substituted with 1-3 substituents selected from C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar 1 is phenyl substituted with 1-3 substituents selected from C1-C6 alkyl. In a still further aspect, Ar 1 is phenyl substituted with 1-3 substituents selected from C1-C6 alkoxy. In an even further aspect, Ar 1 is phenyl substituted with 1-3 substituents selected from C1-C6 haloalkyl and C1-C6 polyhaloalkyl. In a yet further aspect, Ar 1 is phenyl substituted with 1-3 substituents selected from C1-C6 alkylamino and C1-C6 dialkylamino.
  • Ar 1 is phenyl substituted with 1-3 substituents selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -CH 2 CH 2 F, -CH 2
  • Ar 1 is phenyl substituted with 1-3 substituents selected from methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , - NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • Ar 1 is phenyl substituted with 1-3 substituents selected from F, CI, hydroxyl, cyano, and -NH 2 , methyl, ethyl, propyl, -CF , - CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • substituents selected from F, CI, hydroxyl, cyano, and -NH 2 , methyl, ethyl, propyl, -CF , - CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • Ar 1 is pyridinyl. In a still further aspect, Ar 1 is pyridinyl substituted with 1-3 substituents. In yet further aspect, Ar 1 is pyridinyl substituted with 1-2 substituents. In an even further aspect, Ar 1 is monosubstituted pyridinyl. In a still further aspect, Ar 1 is unsubstituted pyridinyl.
  • Ar 1 is pyridinyl substituted with 1-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , n-propyl, and i-propyl.
  • Ar 1 is pyridinyl substituted with 1-3 substituents selected from halo, hydroxyl, -NH 2 , -CH 3 , and -CF 3 .
  • Ar 1 is pyridinyl and monosubstituted with the substituent selected from F, CI, and Br.
  • Ar 1 is pyridinyl and monosubstituted with F.
  • Ar 1 is pyridinyl substituted with 1 -3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar 1 is pyridinyl substituted with 1-3 substituents selected from halo, hydroxyl, cyano, and -NH 2 .
  • Ar 1 is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar 1 is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar 1 is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkyl. In a still further aspect, Ar 1 is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkoxy. In an even further aspect, Ar 1 is pyridinyl substituted with 1-3 substituents selected from C1-C6 haloalkyl and C1-C6 polyhaloalkyl. In a yet further aspect, Ar 1 is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkylamino and C1-C6 dialkylamino.
  • Ar 1 is pyridinyl substituted with 1 -3 substituents selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -CH 2 CH 2 F,
  • Ar 1 is pyridinyl substituted with 1 -3 substituents selected from methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , and — N(CH ) 2 .
  • Ar 1 is pyridinyl substituted with 1-3 substituents selected from F, CI, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • substituents selected from F, CI, hydroxyl, cyano, -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • Ar is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or monocyclic hetero
  • Ar 2 is phenyl. In a still further aspect, Ar 2 is phenyl substituted with 1-3 substituents. In yet further aspect, Ar is phenyl substituted with 1-2 substituents. In an even further aspect, Ar is monosubstituted phenyl. In a still further aspect, Ar 2 is unsubstituted phenyl. In a yet further aspect, Ar 2 is phenyl substituted with 1-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , -CH 3 , -CF , CH 2 CH , n-propyl, and i- propyl. In an even further aspect, Ar is phenyl substituted with 1-3 substituents selected from halo, hydroxyl, -NH 2 , -CH 3 , and -CF 3 . In a still further aspect, Ar is phenyl and
  • Ar is phenyl and monosubstituted with F.
  • Ar is phenyl substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar is phenyl substituted with 1-3 substituents selected from C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar is phenyl substituted with 1-3 substituents selected from C1-C6 alkyl. In a still further aspect, Ar is phenyl substituted with 1-3 substituents selected from C1-C6 alkoxy. In an even further aspect, Ar is phenyl substituted with 1-3 substituents selected from C1-C6 haloalkyl and C1-C6 polyhaloalkyl. In a yet further aspect, Ar is phenyl substituted with 1-3 substituents selected from C1-C6 alkylamino and C1-C6 dialkylamino.
  • Ar is phenyl substituted with 1-3 substituents selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 , -OC
  • Ar is phenyl substituted with 1-3 substituents selected from methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , and 2
  • Ar is phenyl substituted with 1-3 substituents selected from F, CI, hydroxyl, cyano, and -NH 2 , methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • Ar 2 is pyridinyl. In a still further aspect, Ar 2 is pyridinyl substituted with 1-3 substituents. In yet further aspect, Ar is pyridinyl substituted with 1-2 substituents. In an even further aspect, Ar is monosubstituted pyridinyl. In a still further aspect, Ar 2 is unsubstituted pyridinyl. In a yet further aspect, Ar 2 is pyridinyl substituted with 1-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , -CH , -CF , CH 2 CH , n-propyl, and i-propyl.
  • Ar is pyridinyl substituted with 1-3 substituents selected from halo, hydroxyl, -NH 2 , -CH 3 , and -CF 3 .
  • Ar is pyridinyl and monosubstituted with the substituent selected from F, CI, and Br.
  • Ar is pyridinyl and monosubstituted with F.
  • Ar is pyridinyl substituted with 1 -3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar is pyridinyl substituted with 1-3 substituents selected from halo, hydroxyl, cyano, and -NH 2 .
  • Ar is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Ar is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkyl. In a still further aspect, Ar is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkoxy. In an even further aspect, Ar is pyridinyl substituted with 1-3 substituents selected from C1-C6 haloalkyl and C1-C6 polyhaloalkyl. In a yet further aspect, Ar is pyridinyl substituted with 1-3 substituents selected from C1-C6 alkylamino and C1-C6 dialkylamino.
  • Ar is pyridinyl substituted with 1 -3 substituents selected from methyl, ethyl, propyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, tert-butyl, sec -butyl, isobutyl, tert-butyl, isopropyl, 3,3-dimethylbutan-2-yl, 3,3-dimethylpentan-2-yl, 2,3- dimethylbutan-2-yl, 2,3-dimethylpentan-2-yl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 C1, -CH 2 CHC1 2 , -CH 2 CC1 3 ,
  • Ar is pyridinyl substituted with 1 -3 substituents selected from methyl, ethyl, propyl, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , and — N(CH 3 ) 2 .
  • Ar is pyridinyl substituted with 1-3 substituents selected from F, CI, hydroxyl, cyano, and -NH 2 , methyl, ethyl, propyl, -CF , -CC1 3 , -CH 2 CF , -CH 2 CC1 3 , -OCH 3 , -OCH 2 CH 3 , -NHCH , -NHCH 2 CH 3 , and -N(CH 3 ) 2 .
  • Cy 1 is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino.
  • Cy 1 is selected from cyclopropyl, cyclobutyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrollidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, morpholinyl, oxazinanyl, and oxazolidinyl.
  • Cy 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a still further aspect, Cy 1 is cyclopropyl. In a yet further aspect, Cy 1 is cyclobutyl. In an even further aspect, Cy 1 is cyclopentyl. In a still further aspect, Cy 1 is cyclohexyl.
  • Cy 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy 1 is substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and Cl- C6 dialkylamino.
  • Cy 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy 1 is substituted with 1-3 substituents selected from halogen, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and Cl- C6 dialkylamino.
  • Cy 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy 1 is substituted with 1-2 substituents selected from halogen, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and Cl- C6 dialkylamino.
  • Cy 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy 1 is substituted with 0-3 substituents independently selected from halogen, cyano, OH, -NH 2 , -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1, -CHC1 2 , -CC1 3 , -CH 2 CH 2 F, -CH 2 C HF 2 , -CH 2 CF 3 , -CH 2 CH 2 CI
  • Cy 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy 1 is substituted with 0-3 substituents independently selected from F, hydroxyl, cyano, - NH 2 , -CH 3 , -CF 3 , -OCH 3 , and -NHCH .
  • Cy 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy 1 is unsubstituted.
  • Cy is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl
  • Cy is selected from cyclopropyl, cyclobutyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrollidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, morpholinyl, oxazinanyl, and oxazolidinyl.
  • Cy 2 is tetrahydrofuranyl.
  • Cy 2 is tetrahydropyranyl.
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cy 2 is cyclopropyl.
  • Cy 2 is cyclobutyl.
  • Cy 2 is cyclopentyl.
  • Cy 2 is cyclohexyl.
  • Cy is selected from cyclopropyl, (cyclopropyl)methyl, (cyclopropyl)ethyl, cyclobutyl, (cyclobutyl)methyl, (cyclobutyl)ethyl, cyclopentyl,
  • Cy is selected from aziridinyl, (aziridinyl)methyl, (aziridinyl)ethyl, oxiranyl, (oxiranyl)methyl, (oxiranyl)ethyl, azetidinyl, (azetidinyl)methyl, (azetidinyl)methyl, oxetanyl, (oxetanyl)methyl, (oxetanyl)ethyl, pyrrolidinyl,
  • tetrahydropyranyl (tetrahydropyranyl)methyl, (tetrahydropyranyl)ethyl, pyrazolidinyl, (pyrazolidinyl)methyl, (pyrazolidinyl)ethyl, imidazolinyl, (imidazolinyl)methyl,
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy is substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and Cl- C6 dialkylamino.
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy is substituted with 1-3 substituents selected from halogen, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and Cl- C6 dialkylamino.
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy is substituted with 1-2 substituents selected from halogen, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and Cl- C6 dialkylamino.
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein 2
  • Cy is substituted with 0-3 substituents independently selected from halogen, cyano,
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy is substituted with 0-3 substituents independently selected from F, hydroxyl, cyano, - NH 2 , -CH 3 , -CF 3 , -OCH 3 , and -NHCH 3 .
  • Cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, pyrazolidinyl, imidazolinyl, piperazinyl, and morpholinyl, and wherein Cy is unsubstituted.
  • m is selected from 0, 1, 2, and 3. In a further aspect, m is selected from 0, 1 and 2. In a still further aspect, m is selected from 0, 2 and 3. In a yet further aspect, n is selected from 0, 1, and 3. In an even further aspect, m is selected from 1, 2, and 3. In a still further aspect, m is selected from 0 and 1. In a yet further aspect, m is selected from 0 and 2. In an even further aspect, m is selected from 0 and 3. In a still further aspect, m is selected from 1 and 2. In a yet further aspect, m is selected from 1 and 3. In an even further aspect, m is selected from 2 and 3. In a still further aspect, m is 0. In a yet further aspect, n is 1. In an even further aspect, m is 2. In a still further aspect, m is 3.
  • n is selected from 0, 1, 2, and 3. In a further aspect, n is selected from 0, 1 and 2. In a still further aspect, n is selected from 0, 2 and 3. In a yet further aspect, n is selected from 0, 1, and 3. In an even further aspect, n is selected from 1, 2, and 3. In a still further aspect, n is selected from 0 and 1. In a yet further aspect, n is selected from 0 and 2. In an even further aspect, n is selected from 0 and 3. In a still further aspect, n is selected from 1 and 2. In a yet further aspect, n is selected from 1 and 3. In an even further aspect, n is selected from 2 and 3. In a still further aspect, n is 0. In a yet further aspect, n is 1. In an even further aspect, n is 2. In a still further aspect, n is 3.
  • q is selected from 0, 1, 2, and 3. In a further aspect, q is selected from 0, 1 and 2. In a still further aspect, q is selected from 0, 2 and 3. In a yet further aspect, q is selected from 0, 1, and 3. In an even further aspect, q is selected from 1, 2, and 3. In a still further aspect, q is selected from 0 and 1. In a yet further aspect, q is selected from 0 and 2. In an even further aspect, q is selected from 0 and 3. In a still further aspect, q is selected from 1 and 2. In a yet further aspect, q is selected from 1 and 3. In an even further aspect, q is selected from 2 and 3. In a still further aspect, q is 0. In a yet further aspect, q is 1. In an even further aspect, q is 2. In a still further aspect, q is 3.
  • leaving groups can be selected from halogens.
  • a halogen is fluoro, chloro, bromo or iodo.
  • halogen is fluoro, chloro, or bromo.
  • halogen is fluoro or chloro.
  • halogen is fluoro.
  • halogen is chloro or bromo.
  • halogen is chloro.
  • halogen is iodo.
  • halogen is bromo.
  • pseudohalogens e.g. triflate, mesylate, brosylate, etc.
  • leaving groups e.g. triflate, mesylate, brosylate, etc.
  • a compound can be present as:
  • a compound can be present as: [00322] In one aspect, a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as: or a subgroup thereof.
  • a compound is not present as:
  • a compound is not present as:
  • a compound is not present as:
  • the human metabotropic glutamate receptor 5 is a protein of 1212 amino acids encoded by the GRM5 gen.
  • the molecular weight of the unglycosylated protein is about 132 kDa and it is a transmembrane GPCR.
  • the family of metabotropic glutamate receptors are members of the GPCR Class C (also referred to as Class 3) family, or the glutamate receptor-like, which comprise receptor families such as the GABA receptors, the metabotropic glutamate receptors, potential taste receptors, and the retinoic acid-inducible orphan G protein-coupled receptors (RAIG).
  • the metabotropic glutamate receptors have the N-terminus oriented to the extracellular face of the membrane and the C-terminus located on the cytoplasmic face.
  • a schematic of the structure of a metabotropic glutamate receptor is shown in Figure 1 , with the transmembrane segments shown as cylindrical shapes (which span the lipid bilayer of the cell membrane).
  • the orthosteric binding for natural ligand, glutamate, for mGluRs is within a pocket located in the N-terminal extracellular domain as depicted in Figure 1.
  • HEK Human embryonic kidney
  • FDSS Functional Drug Screening System
  • HEK cells transfected with human mGluR5 were plated for assay in the FDSS.
  • the HEK cells transfected with human mGluR5 are the H10H cell line.
  • the HEK cells transfected with human mGluR5 are the H12H cell line. Rat assay results were found to correlate well with human assay results. The cells were loaded
  • mGluR5 agonist e.g., glutamate, 3,5- dihydroxyphenylglycine, or quisqualate
  • agonist here, glutamate
  • the above described assay can be 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 EC50 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 EC50 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 potentiate the agonist response (e.g., glutamate) of mGluR5.
  • the disclosed compounds and products of disclosed methods of making 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 a mammalian mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.
  • the human embryonic kidney cells can be transfected with a mammalian GluR5.
  • human embryonic kidney cells can be transfected with human mGluR5.
  • human embryonic kidney cells can be transfected with rat mGluR5.
  • transfected with a mGluR5 refers to transfection of the indicated cells with an appropriate expression construct comprising the nucleic acid sequence coding for the indicated mGluR5.
  • the nucleic acid sequence for an mGluR5 can be a cDNA sequence which is full-length or alternatively a partial cDNA sequence a subset of the full-length cDNA sequence.
  • Appropriate expression constructs are available to one skilled in the art, as are methods for manipulation of the desired cDNA sequence.
  • the disclosed compounds and products of disclosed methods of making are allosteric modulators of mGluR5, in particular, positive allosteric modulators of mGluR5.
  • the disclosed compounds can potentiate glutamate responses by binding to an allosteric site that is distinct from glutamate orthosteric binding site. The response of mGluR5 to a concentration of glutamate is increased when the disclosed compounds are present.
  • the disclosed compounds can have their effect substantially at mGluR5 by virtue of their ability to enhance the function of the receptor in response to the endogenous agonist, glutamate.
  • 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 mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.
  • the human embryonic kidney cells are transfected with rat mGluR5.
  • the human embryonic kidney cells are transfected with human mGluR5.
  • the potentiation is partial allosteric modulation.
  • the disclosed compounds exhibit potentiation of mGluR5 with an EC50 of less than about 10,000 nM.
  • the disclosed compounds exhibit potentiation of mGluR5 with an EC50 of less than about 5,000 nM. In an even further aspect, the disclosed compounds exhibit potentiation of mGluR5 with an EC50 of less than about 1,000 nM. In a still further aspect, the disclosed compounds exhibit potentiation of mGluR5 with an EC50 of less than about 500 nM. In a yet further aspect, the disclosed compounds exhibit potentiation of mGluR5 with an EC50 of less than about 100 nM.
  • the disclosed compounds and products of disclosed methods of making exhibit positive allosteric modulation of mGluR5 in the cell-based assay methods described herein, i.e. the disclosed compounds and disclosed products of making exhibit positive allosteric modulation of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with a mGluR5 (e.g. a mammalian, a rat, or a human mGluR5) in the presence of the compound, compared to the response to glutamate in the absence of the compound.
  • a mGluR5 e.g. a mammalian, a rat, or a human mGluR5
  • the disclosed compounds and products of disclosed methods of making can exhibit positive allosteric modulation of mGluR5 in a aforementioned cell-based assay with an EC50 of less than about 10,000 nM, of less than about 5,000 nM, of less than about 1,000 nM, of less than about 500 nM, or of less than about 100 nM.
  • the disclosed compounds and products of disclosed methods of making exhibit positive allosteric modulation of human mGluR5 in the H10H cell-line with an EC50 of less than about 10,000 nM, of less than about 5,000 nM. of less than about 1,000 nM, of less than about 500 nM, or of less than about 100 nM.
  • In vivo efficacy for disclosed compounds and products of disclosed methods of making can be measured in a number of preclinical rat behavioral model where known, clinically useful antipsychotics display similar positive responses.
  • disclosed compounds can reverse amphetamine-induced hyperlocomotion in male Sprague-Dawley rats at doses ranging from 1 to 100 mg/kg p.o.
  • the invention relates to methods of making compounds useful as positive allosteric modulators 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.
  • 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. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.
  • the disclosed compounds comprise the products of the synthetic methods described herein.
  • the disclosed compounds comprise a compound produced by a synthetic method described herein.
  • the invention comprises a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed methods and a pharmaceutically acceptable carrier.
  • the invention comprises a method for manufacturing a medicament comprising combining at least one compound of any of disclosed compounds or at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.
  • the compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person.
  • the compounds can be prepared according to the following synthesis methods.
  • pseudohalogens e.g. triflate, mesylate, brosylate, etc.
  • leaving groups in place of halogens in certain aspects.
  • the disclosed compounds may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of disclosed compounds may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of disclosed compounds involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • substituted 5-(prop-l-yn-yl)picolinamide analogs of the present invention can be prepared generically by the synthetic scheme as shown below.
  • Route I begins with a suitable substituted picolinic acid of type 1.1.
  • Suitable picolinic acids are commercially available or can be readily prepared by one skilled in the art.
  • the coupling reaction is carried out using an arene derivative (e.g., haloarene or aryl triflate/tosylate) and alkyne derivative (e.g., alk-l-yne or aryl acetylene) coupling methods known to one skilled in the art (e.g., Sonagashira reaction).
  • compounds of type 1.1 a suitable substituted alkyne derivative (R ⁇ CCH), appropriate Pd(0) and Cu(I) catalysts, and an appropriate base (e.g., diethylamine) are mixed in a suitable solvent such as DMF.
  • a suitable solvent such as DMF.
  • the mixture is heated (e.g., using a microwave reactor), at a suitable temperature, (e.g., about 90 °C) and time, (e.g., about 45 min), or for a time and at a temperature necessary to complete the reaction.
  • the product, a compound of type 1.2 is isolated by methods known to one skilled in the art (e.g., dilution with water, filtering, and purification if necessary).
  • amide compounds of type 1.3 can be prepared by the reaction of a substituted carboxylic acid of type 1.2 with a suitable amine [(R 2a )(R 2b )NH] under a standard coupling methods known to one skilled in the art.
  • compound 1.2, [(R 2a ) 2 NH, HATU, and N,N-diisopropylamine are mixed in a suitable solvent such as DMF at room temperature (e.g., about 15-30 °C). The mixture is allowed to stir for a period of time, (e.g., about 2 h) and temperature (e.g., room temperature or about 15-30 °C), or for a time and at a temperature necessary to complete the reaction.
  • the product (1.3) is isolated by methods known to one skilled in the art (e.g., extraction, washing, drying, concentration under a vacuum, and followed by purification, e.g., chromatography).
  • compounds of type 1.3 can be oxidized to N-oxide compounds of type 1.4.
  • a mixture of a suitable picolinamide derivative (1.3), a suitable reagent(s) for N-oxidation e.g., urea-hydrogen peroxide and TFAA
  • a suitable solvent e.g., dichloromethane.
  • the reaction mixture is stirred at room temperature (e.g., about 15-30 °C) and for a period of time (e.g., overnight, or about 8- 18 h), or for a time and at a temperature necessary to complete the reaction.
  • the product (1.4) is isolated by methods known to one skilled in the art [e.g., dilution with solvent, quench with a reducing agent (e.g., Na 2 S 2 0 3 ) if necessary, extraction, drying, concentration under a vacuum, and followed by purification, e.g., chromatography].
  • a reducing agent e.g., Na 2 S 2 0 3
  • substituted 5-(prop-l-yn-yl)picolinamide analogs of the present invention can be prepared generically by the synthetic scheme as shown below.
  • Route II begins with a suitable substituted picolinic acid derivative of type 2.1 that is commercially available or can be readily prepared by one skilled in the art.
  • Picolinamide derivatives of type 2.2 can be prepared by reaction of a substituted carboxylic acid of type 2.1 with a suitable amine [(R 2a )(R 2b )NH] under a standard coupling methods known to one skilled in the art.
  • compound 2.1, (R 2a ) 2 NH, HATU, and N,N- diisopropylamine are mixed in a suitable solvent such as DMF at room temperature (e.g., about 15-30 °C).
  • the mixture is allowed to stir for a period of time, (e.g., about 4 h) and temperature (e.g., room temperature or about 15-30 °C), or for a time and at a temperature necessary to complete the reaction.
  • the product (2.2) is isolated by methods known to one skilled in the art (e.g., extraction, washing, drying, concentration under a vacuum, and followed by purification if necessary).
  • picolinamide analogs of type 2.3 can be prepared by using typical coupling methods of an arene derivative (e.g., haloarene or aryl triflate/tosylate) and alkyne derivative (e.g., alk-l-yne or aryl acetylene) known to one skilled in the art (e.g., Sonagashira reaction).
  • an arene derivative e.g., haloarene or aryl triflate/tosylate
  • alkyne derivative e.g., alk-l-yne or aryl acetylene
  • compound of type 2.2, a suitable substituted alkyne derivative (R ⁇ CCH), appropriate Pd (0) and Cu (I) catalysts, and an appropriate base e.g.,
  • diethylamine are mixed in a suitable solvent such as DMF.
  • a suitable solvent such as DMF.
  • the mixture is heated (e.g., using a microwave reactor), at a suitable temperature, (e.g., about 90 °C) and time, (e.g., about 45 min), or for a time and at a temperature necessary to complete the reaction.
  • the product, a compound of type 2.3 is isolated by methods known to one skilled in the art (e.g., dilution with water, filtering, and purification, e.g., chromatography).
  • compounds of type 2.3 can be oxidized to N-oxide compounds of type 2.4.
  • a mixture of a suitable picolinamide derivative (2.3), a suitable reagent(s) for N-oxidation e.g., urea-hydrogen peroxide and TFAA
  • a suitable solvent e.g., dichloromethane.
  • the reaction mixture is stirred at room temperature (e.g., about 15-30 °C) and for a period of time (e.g., overnight, or about 8-18 h), or for a time and at a temperature necessary to complete the reaction.
  • the product (2.4) is isolated by methods known to one skilled in the art [e.g., dilution with solvent, quench with a reducing agent (e.g., Na 2 S 2 0 3 ) if necessary, extraction, drying, concentration under a vacuum, and followed by purification, e.g., chromatography].
  • a reducing agent e.g., Na 2 S 2 0 3
  • each disclosed methods can further comprise additional steps, manipulations, and/or components. It is also contemplated that any one or more step, manipulation, and/or component can be optionally omitted from the invention. It is understood that a disclosed methods can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed methods of using.
  • the compound produced exhibits positive allosteric modulation 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.
  • human embryonic kidney cells are transfected with human mGluR5.
  • human embryonic kidney cells are transfected with mammalian mGluR5.
  • the compound produced exhibits positive allosteric modulation of mGluR5.
  • the compound produced 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 rate mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.
  • the compound produced exhibits positive allosteric modulation of rat mGluR5 with an EC50 of less than about 10,000 nM, of less than about 5,000 nM. of less than about 1,000 nM, of less than about 500 nM, or of less than about 100 nM.
  • the compound produced 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 human mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.
  • the transfected cell line is the HI OH cell line.
  • the transfected cell line is the H12H cell line.
  • the compound produced exhibits positive allosteric modulation of human mGluR5 with an EC50 of less than about 10,000 nM, of less than about 5,000 nM. of less than about 1,000 nM, of less than about 500 nM, or of less than about 100 nM.
  • the compound produced exhibits activity in potentiating the mGluR5 receptor in the disclosed assays, generally with an EC50 for potentiation of less than about 10 ⁇ .
  • Preferred compounds within the present invention had activity in potentiating the mGluR5 receptor with an EC50 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 selective positive allosteric modulators (potentiators) of human and rat mGluR5 compared to the other seven subtypes of metabotropic glutamate receptors.
  • 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 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)
  • 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, ⁇ , ⁇ '- 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, trip
  • 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,
  • salts of the disclosed compounds are those wherein the counter ion is pharmaceutically acceptable.
  • salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.
  • acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,
  • inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids
  • organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the disclosed compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
  • primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the salt form can be converted by treatment with acid into the free acid form.
  • 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
  • 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.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • 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.
  • compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • 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), and then followed by chilling and shaping in molds.
  • 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.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • 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 form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated.
  • the compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.
  • the specific dose level for any particular patient will depend upon a variety of factors. Such factors include the age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the type and severity of the particular disease undergoing therapy.
  • the present invention is further directed to a method for the manufacture of a medicament for modulating glutamate receptor activity (e.g., treatment of one or more neurological and/or psychiatric disorder associated with glutamate dysfunction) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent.
  • the invention relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.
  • compositions can further comprise other ingredients
  • therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions.
  • compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a disclosed compound, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereochemically isomeric form thereof.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • compositions of this invention an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier or diluent, which carrier or diluent may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier or diluent which carrier or diluent may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as, for example, suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as, for example, starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
  • solid pharmaceutical media such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as, for example, suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as, for example, starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
  • oral administration is preferred, and tablets and capsules represent the most advantageous oral dosage unit forms in which
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a
  • transdermal patch as a spot-on, as an ointment.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • Formula (I) in pharmaceutical compositions it can be advantageous to employ ⁇ -, ⁇ - or ⁇ - cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2- hydroxypropyl-P-cyclodextrin or sulfobutyl-P-cyclodextrin.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invention in pharmaceutical compositions.
  • the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • suitable unit doses for the compounds of the present invention can, for example, preferably contain between 0.1 mg to about 1000 mg of the active compound.
  • a preferred unit dose is between 1 mg to about 500 mg.
  • a more preferred unit dose is between 1 mg to about 300 mg.
  • Even more preferred unit dose is between 1 mg to about 100 mg.
  • Such unit doses can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration.
  • a preferred dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
  • a typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time -release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
  • the time -release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the invention, and a pharmaceutically acceptable carrier. Additionally, the invention relates to a process for preparing such pharmaceutical composition, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the invention.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds according to the invention and one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which disclosed compounds or the other drugs may have utility as well as to the use of such a composition for the manufacture of a medicament.
  • the present invention also relates to a combination of a compound according to the present invention and an mGluR5 orthosteric agonist.
  • the present invention also relates to such a combination for use as a medicine.
  • the present invention also relates to a product comprising (a) a compound according to the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof, and (b) a mGluR5 orthosteric agonist, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 allosteric modulators, in particular positive mGluR5 allosteric modulators.
  • the different drugs of such a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.
  • amino acid L-glutamate (referred to herein simply as glutamate) is the principal excitatory neurotransmitter in the mammalian central nervous system (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.
  • synaptic plasticity e.g., long term potentiation (the basis of learning and memory)
  • motor control and sensory perception e.g., motor control and sensory perception.
  • Glutamate acts through two distinct receptors: ionotropic and metabotropic glutamate receptors.
  • the first class, the ionotropic glutamate receptors is comprised of multi-subunit ligand-gated ion channels that mediate excitatory post- synaptic currents.
  • 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, mGluR6, mGluR7 and mGluR8).
  • Group I mGluRs are coupled through Gaq/11 to increase inositol phosphate and metabolism and resultant increases in intracellular calcium.
  • Group I mGluRs are primarily located post-synaptically and have a modulatory effect on ion channel activity and neuronal excitability.
  • Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, 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 God 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.
  • 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.
  • NMDA receptor co-agonists can improve positive and negative symptoms.
  • a schematic of the NMDA receptor is shown in Figure 2.
  • Activation of mGluR5 potentiates NMDA receptor function as shown in Figure 3.
  • Orthosteric ligands lack subtype selectivity and can cause unwanted side effects.
  • Allosteric modulators see Figure 1) that can target transmembrane domains offer a pharmacologically attractive alternative. In one aspect, transmembrane domains can be significantly less conserved than extracellular loop regions.
  • 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
  • the subject compounds can be coadministered with ant-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, muscarinic agonists, muscarinic potentiators, HMG-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, GlyTl 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 GlyTl inhibitors and the like
  • GlyTl inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and
  • the subject compound can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor), anticholinergics such as biperiden, COMT inhibitors such as entacapone, A2a adenosine antagonists, cholinergic agonists, NMDA receptor antagonists and dopamine agonists.
  • anticholinergics such as biperiden
  • COMT inhibitors such as entacapone, A2a adenosine antagonists, cholinergic agonists, NMDA receptor antagonists and 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 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.
  • disorders associated with glutamate dysfunction include: acute and chronic neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS- induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary
  • incontinence substance tolerance
  • addictive behavior including addiction to substances (including opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal from such addictive substances (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), obesity, psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder.
  • addiction including opiates, nicotine, tobacco products, alcohol, benzodia
  • 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
  • anxiety and related disorders include: 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 the treatment of a neurological and/or psychiatric disorder associated with glutamate dysfunction in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alky -O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • Cy 1 is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; or wherein R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 2a and R 2b is independently selected from hydrogen,— Ar 2 , -(C1-C6 alkyl)-Ar 2
  • the compound administered is a disclosed compound or a product of a disclosed method of making a compound.
  • the glutamate dysfunction is associated with a mGluR5 dysfunction.
  • the method relates to treatment of a neurological and/or psychiatric disorder in a mammal by contacting at least one cell in a mammal, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one disclosed product in an amount effective to modulate mGluR5 activity in the at least one cell.
  • the compound is a modulator of mGluR5.
  • the compound is a potentiator of mGluR5.
  • the compound is a partial agonist of mGluR5.
  • the compound is a partial allosteric modulator of mGluR5.
  • the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 10,000 nM. In a still further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 5,000 nM. In an even further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 1,000 nM. In a further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 500 nM. In a yet further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 100 nM.
  • the mammal is a human.
  • the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.
  • the method further comprises the step of identifying a mammal in need of treatment of the disorder.
  • the disorder is a neurological and/or psychiatric disorder associated with mGluR5 dysfunction.
  • the disorder is selected from dementia, delirium, amnestic disorders, age-related cognitive decline, 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 invention relates to a method for the treatment of a disorder of uncontrolled cellular proliferation associated with glutamate dysfunction in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alky -O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • Cy 1 is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; or wherein R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 2a and R 2b is independently selected from hydrogen,— Ar 2 , -(C1-C6 alkyl)-Ar 2
  • the glutamate dysfunction is associated with a mGluR5 dysfunction.
  • the glutamate dysfunction is associated with a mGluR5 dysfunction.
  • the method relates to treatment of a disorder of uncontrolled cellular proliferation in a mammal by contacting at least one cell in a mammal, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one disclosed product in an amount effective to modulate mGluR5 activity in the at least one cell.
  • the compound is a modulator of mGluR5. In an even further aspect, the compound is a potentiator of mGluR5. In a yet further aspect, the compound is a partial agonist of mGluR5. In a still further aspect, the compound is a partial allosteric modulator of mGluR5.
  • the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 10,000 nM. In a still further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 5,000 nM. In an even further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 1,000 nM. In a further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 500 nM. In a yet further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 100 nM.
  • the mammal is a human.
  • the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.
  • the method further comprises the step of identifying a mammal in need of treatment of the disorder.
  • the disorder is a disease of uncontrolled cellular proliferation.
  • the disorder is cancer.
  • the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer.
  • the disorder is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma.
  • the invention relates to a method for potentiation of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alky -O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • Cy 1 is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; or wherein R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 2a and R 2b is independently selected from hydrogen,— Ar 2 , -(C1-C6 alkyl)-Ar 2
  • the method relates to potentiation of metabotropic glutamate receptor activity in a mammal by contacting at least one cell in a mammal, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one disclosed product in an amount effective to potentiate mGluR5 activity in the at least one cell.
  • potentiation increases activity.
  • the metabotropic glutamate receptor is mGluR5.
  • the compound is a partial agonist of mGluR5. In a still further aspect, the compound is a partial allosteric modulator of mGluR5.
  • the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 10,000 nM. In a still further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 5,000 nM. In an even further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 1,000 nM. In a further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 500 nM. In a yet further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC50 of less than about 100 nM.
  • the mammal is a human.
  • the mammal has been diagnosed with a need for potentiation of metabotropic glutamate receptor activity prior to the administering step.
  • the method further comprises comprising the step of identifying a mammal in need for potentiation of metabotropic glutamate receptor activity.
  • the metabotropic glutamate receptor is mGluR5.
  • the potentiation of metabotropic glutamate receptor activity treats a disorder associated with mGluR5 activity in the mammal.
  • the mammal has been diagnosed with a need for treatment of the disorder prior to the
  • treatment further comprises the step of identifying a mammal in need of treatment of the disorder.
  • potentiation of metabotropic glutamate receptor activity in a mammal is associated with the treatment of a neurological and/or psychiatric disorder associated with mGluR5 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.
  • potentiation of metabotropic glutamate receptor activity in a mammal is associated with the treatment of a disorder associated with uncontrolled cellular proliferation.
  • the disorder is cancer.
  • the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer.
  • the disorder is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma.
  • the invention relates to a method for enhancing cognition in a mammal comprising the step of administering to the mammal an effective amount of at least one compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alky -O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • the compound administered is a disclosed compound or a product of a disclosed method of making a compound.
  • an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.
  • the method relates to enhancing cognition in a mammal by contacting at least one cell in a mammal, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one disclosed product in an amount effective to modulate mGluR5 activity in the at least one cell.
  • the compound is a potentiator of mGluR5.
  • the compound is a partial agonist of mGluR5.
  • the compound is a partial allosteric modulator of mGluR5.
  • the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 10,000 11M. In a still further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 5,000 11M. In an even further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 1,000 11M. In a further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 500 11M. In a yet further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 100 11M.
  • the mammal is a human. In one aspect, the mammal has been diagnosed with a need for cognition enhancement prior to the administering step. In a still further aspect, the method further comprises the step of identifying a mammal in need of cognition enhancement prior to the administering step. In a further aspect, 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 performance of the Wisconsin Card Sorting Test. In a further aspect, the method further comprises the step of identifying a mammal in need of increasing mGluR5 activity.
  • the invention relates to a method for modulating metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal an effective amount of least one compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alkyfj-O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • the method relates to modulation of metabotropic glutamate receptor activity in a mammal by contacting at least one cell in a mammal, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one disclosed product in an amount effective to modulate mGluR5 activity in the at least one cell.
  • the compound administered is a disclosed compound or a product of a disclosed method of making a compound.
  • an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.
  • the metabotropic glutamate receptor is mGluR5.
  • modulating mGluR5 activity increases mGluR5 activity.
  • modulating mGluR5 activity potentiates mGluR5 activity.
  • the compound is a potentiator of mGluR5.
  • the compound is a partial agonist of mGluR5.
  • the compound is a partial allosteric modulator of mGluR5.
  • the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 10,000 11M. In a still further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 5,000 11M. In an even further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 1,000 11M. In a further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 500 11M. In a yet further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 100 11M.
  • the mammal is a human.
  • the mammal has been diagnosed with a need for modulating mGluR5 activity prior to the administering step.
  • the mammal has been diagnosed with a need for treatment of a disorder related to mGluR5 activity prior to the administering step.
  • the method further comprises the step of identifying a mammal in need of increasing mGluR5 activity.
  • modulating mGluR5 activity in a mammal is associated with the treatment of a neurological and/or psychiatric disorder associated with mGluR5 dysfunction.
  • the disorder is selected from dementia, delirium, amnestic disorders, age-related cognitive decline, 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.
  • modulating mGluR5 activity in a mammal is associated with the treatment of a disorder associated with uncontrolled cellular proliferation.
  • the disorder is cancer.
  • the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer.
  • the disorder is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma.
  • the invention relates to a method for potentiation of mGluR5 activity in at least one cell, comprising the step of contacting the cell with an effective amount of at least one disclosed compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alkyfj-O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; or wherein R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 2a and R 2b is independently selected from hydrogen,—Ax 2 , -(C1-C6 alkyl)-Ar 2
  • the compound administered is a disclosed compound or a product of a disclosed method of making a compound.
  • potentiation is an increase in activity.
  • potentiation is partial agonism.
  • the compound is a partial agonist of mGluR5. In a still further aspect, the compound is a partial allosteric modulator of mGluR5.
  • the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 10,000 11M. In a still further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 5,000 11M. In an even further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 1,000 11M. In a further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 500 11M. In a yet further aspect, the compound exhibits positive allosteric modulation of mGluR5 with an EC 50 of less than about 100 11M.
  • the cell is mammalian. In a further aspect, the cell is human. In a further aspect, the cell has been isolated from a mammal prior to the contacting step.
  • contacting is via administration to a mammal.
  • the mammal has been diagnosed with a need for modulating mGluR5 activity prior to the administering step.
  • the mammal has been diagnosed with a need for treatment of a disorder related to mGluR5 activity prior to the administering step.
  • the present invention is further directed to administration of a metabotropic glutamate receptor potentiator for improving treatment outcomes in the context of cognitive or behavioral therapy to treat a psychiatric disorder. That is, in one aspect, the invention relates to a cotherapeutic method comprising the step of administering to a mammal an effective amount and dosage of at least one compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alkyfj-O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • administration improves treatment outcomes in the context of cognitive or behavioral therapy to treat a psychiatric disorder.
  • Administration in connection with cognitive or behavioral therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and/or after therapy.
  • cognitive or behavioral therapy can be provided within 1 , 2, 3, 4, 5, 6, 7 days before or after administration of the compound.
  • cognitive or behavioral therapy can be provided within 1 , 2, 3, or 4 weeks before or after administration of the compound.
  • cognitive or behavioral therapy can be provided before or after administration within a period of time of 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound. It is understood that the disclosed cotherapeutic methods can be used in connection with the disclosed compounds, compositions, kits, and uses.
  • the invention relates to a method for the manufacture of a medicament for potentiation of metabotropic glutamate receptor activity in a mammal comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
  • the invention relates methods for the manufacture of a medicament for modulating the activity of mGluR5 (e.g., treatment of one or more neurological and/or psychiatric disorder associated with mGluR5 dysfunction) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, with a
  • the invention relates to a medicament comprising one or more compounds having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alky -O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • Cy 1 is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; or wherein R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 2a and R 2b is independently selected from hydrogen,— Ar 2 , -(C1-C6 alkyl)-Ar 2
  • the invention relates to use of a compound having a structure represented by a formula:
  • R 1 is selected from— Ar 1 ,— (C1-C6 alkyl)- Ar 1 ,— (C1-C6 alky -O-Ar 1 , -Cy 1 , -(C1-C6 alkyfj-Cy 1 , -(C1-C6 alkyfj-O-Cy 1 , -C(OH)R 3 R 4 ,
  • Ar 1 is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • Cy 1 is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH 2 , C1-C6 alkyl, Cl- C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6
  • R is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; or wherein R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and CI -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R 2a and R 2b is independently selected from hydrogen,— Ar 2 , -(C1-C6 alkyl)-Ar 2
  • the use relates to a treatment of a disorder in a mammal.
  • the mammal is a human.
  • the use is characterized in that the disorder is a neurological and/or psychiatric disorder associated with metabotropic glutamate receptor dysfunction.
  • a use relates to enhancing cognition in a mammal.
  • the use relates to treatment of a disorder of uncontrolled cellular proliferation associated with metabotropic glutamate receptor dysfunction.
  • the invention relates to a process for preparing a
  • composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.
  • the invention relates to a process for preparing a
  • composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.
  • a use relates to the manufacture of a medicament for the treatment of a disorder associated with glutamate dysfunction in a mammal.
  • the disorder is a neurological and/or psychiatric disorder.
  • the disorder is a disease of uncontrolled cellular proliferation.
  • a use relates to treatment of a neurological and/or psychiatric disorder associated with glutamate dysfunction in a mammal.
  • a use relates to potentiation of metabotropic glutamate receptor activity in a mammal. In a yet further aspect, the use relates to positive allosteric modulation of metabotropic glutamate receptor activity in a mammal. In a further aspect, a use relates to partial agonism of metabotropic glutamate receptor activity in a mammal. In a further aspect, a use relates to modulating mGluR5 activity in a mammal. In a further aspect, a use relates to modulating mGluR5 activity in a cell.
  • the use relates to treatment of a neurological and/or psychiatric disorder 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.
  • a neurological and/or psychiatric disorder 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, narcole
  • the use relates to treatment of a disorder associated with
  • the disorder is cancer.
  • the cancer is selected from breast cancer, renal cancer, gastric cancer, and colorectal cancer.
  • the disorder is selected from lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, and malignant melanoma.
  • the invention relates to the use of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, or a pharmaceutical composition, in combination with an additional pharmaceutical agent for use in the treatment or prevention of a central nervous system disorder selected from the group of psychotic disorders and conditions; anxiety disorders; movement disorders; drug abuse; mood disorders; neurodegenerative disorders; disorders or conditions comprising as a symptom a deficiency in attention and/or cognition; pain and diseases of uncontrolled cellular proliferation.
  • a central nervous system disorder selected from the group of psychotic disorders and conditions; anxiety disorders; movement disorders; drug abuse; mood disorders; neurodegenerative disorders; disorders or conditions comprising as a symptom a deficiency in attention and/or cognition; pain and diseases of uncontrolled cellular proliferation.
  • the invention relates to the use of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, or a pharmaceutical composition for use wherein the psychotic disorders and conditions are selected from the group of schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; substance-induced psychotic disorder;
  • the invention relates to the use of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, or a pharmaceutical composition for use wherein the anxiety disorders are selected from the group of panic disorder; agoraphobia; specific phobia; social phobia;
  • obsessive-compulsive disorder post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
  • the invention relates to the use of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, or a pharmaceutical composition for use wherein the movement disorders are selected from the group of Huntington's disease; dyskinesia; Parkinson's disease; restless leg syndrome and essential tremor; Tourette's syndrome and other tic disorders.
  • the invention relates to the use of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, or a pharmaceutical composition for use wherein the substance-related disorders are selected from the group of alcohol abuse; alcohol dependence; alcohol withdrawal; alcohol withdrawal delirium; alcohol-induced psychotic disorder; amphetamine dependence; amphetamine withdrawal; cocaine dependence; cocaine withdrawal; nicotine dependence; nicotine withdrawal; opioid dependence and opioid withdrawal.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dans un aspect, l'invention concerne des analogues de 5-(prop-1-yn-1-yl)picolinamide substitué, leurs dérivés et des composés apparentés, qui sont utile comme modulateurs allostériques positifs du récepteur de glutamate métabotrope sous-type 5 (mGluR5) ; des procédés de synthèse pour préparer les composés ; des compositions pharmaceutiques comprenant les composés ; et des procédés de traitement de troubles neurologiques et psychiatriques associés à un dysfonctionnement du glutamate au moyen des composés et compositions. Cet abrégé a pour vocation d'être un outil d'analyse à des fins de recherche dans le domaine particulier et n'est pas destiné à limiter la présente invention.
PCT/US2012/057395 2011-09-26 2012-09-26 Analogues de 5-(prop-1-yn-1-yl)picolinamide substitué comme modulateurs allostériques des récepteurs de mglur5 Ceased WO2013049255A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161539436P 2011-09-26 2011-09-26
US61/539,436 2011-09-26

Publications (1)

Publication Number Publication Date
WO2013049255A1 true WO2013049255A1 (fr) 2013-04-04

Family

ID=47996378

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/057395 Ceased WO2013049255A1 (fr) 2011-09-26 2012-09-26 Analogues de 5-(prop-1-yn-1-yl)picolinamide substitué comme modulateurs allostériques des récepteurs de mglur5

Country Status (1)

Country Link
WO (1) WO2013049255A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014060398A1 (fr) * 2012-10-18 2014-04-24 F. Hoffmann-La Roche Ag Dérivés d'éthynyle comme modulateurs de l'activité des récepteurs mglur5
WO2015027214A1 (fr) * 2013-08-23 2015-02-26 Vanderbilt University Analogues de thiéno[2,3-c]pyridazine-6-carboxamide substitués utilisés en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
JP2015534961A (ja) * 2012-10-18 2015-12-07 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｍｇｌｕｒ５受容体活性のモジュレーターとしてのエチニル誘導体
US9493481B2 (en) 2012-02-23 2016-11-15 Vanderbilt University Substituted 5-aminothieno[2,3—C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4
CN107531633A (zh) * 2015-04-15 2018-01-02 中国科学院上海药物研究所 5‑芳香炔基取代的苯甲酰胺类化合物及其制备方法、药物组合物和用途
JP2019077688A (ja) * 2013-08-16 2019-05-23 デューク ユニバーシティ 置換されたヒドロキサム酸化合物
WO2022025636A1 (fr) 2020-07-29 2022-02-03 주식회사 비보존 Double régulateur pour récepteurs mglur5 et 5-ht2a et utilisation de celui-ci
US11767310B2 (en) 2021-08-10 2023-09-26 Abbvie Inc. Nicotinamide RIPK1 inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090325964A1 (en) * 2008-05-23 2009-12-31 Wyeth Piperazine Metabotropic Glutamate Receptor 5 (MGLUR5) Negative Allosteric Modulators For Anxiety/Depression

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090325964A1 (en) * 2008-05-23 2009-12-31 Wyeth Piperazine Metabotropic Glutamate Receptor 5 (MGLUR5) Negative Allosteric Modulators For Anxiety/Depression

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9493481B2 (en) 2012-02-23 2016-11-15 Vanderbilt University Substituted 5-aminothieno[2,3—C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4
US9868746B2 (en) 2012-02-23 2018-01-16 Vanderbilt University Substituted 5-aminothieno[2,3-C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4
JP2015534961A (ja) * 2012-10-18 2015-12-07 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｍｇｌｕｒ５受容体活性のモジュレーターとしてのエチニル誘導体
US9227959B2 (en) * 2012-10-18 2016-01-05 Hoffman-La Roche Inc. Ethynyl derivatives
EA025667B1 (ru) * 2012-10-18 2017-01-30 Ф. Хоффманн-Ля Рош Аг ПРОИЗВОДНЫЕ ЭТИНИЛА В КАЧЕСТВЕ МОДУЛЯТОРОВ АКТИВНОСТИ РЕЦЕПТОРА mGluR5
AU2013333988B2 (en) * 2012-10-18 2017-03-09 F. Hoffmann-La Roche Ag Ethynyl derivatives as modulators of mGluR5 receptor activity
WO2014060398A1 (fr) * 2012-10-18 2014-04-24 F. Hoffmann-La Roche Ag Dérivés d'éthynyle comme modulateurs de l'activité des récepteurs mglur5
JP2019077688A (ja) * 2013-08-16 2019-05-23 デューク ユニバーシティ 置換されたヒドロキサム酸化合物
WO2015027214A1 (fr) * 2013-08-23 2015-02-26 Vanderbilt University Analogues de thiéno[2,3-c]pyridazine-6-carboxamide substitués utilisés en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4
US9637498B2 (en) 2013-08-23 2017-05-02 Vanderbilt University Substituted thieno[2,3-C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4
CN107531633A (zh) * 2015-04-15 2018-01-02 中国科学院上海药物研究所 5‑芳香炔基取代的苯甲酰胺类化合物及其制备方法、药物组合物和用途
CN107531633B (zh) * 2015-04-15 2020-11-06 中国科学院上海药物研究所 5-芳香炔基取代的苯甲酰胺类化合物及其制备方法、药物组合物和用途
WO2022025636A1 (fr) 2020-07-29 2022-02-03 주식회사 비보존 Double régulateur pour récepteurs mglur5 et 5-ht2a et utilisation de celui-ci
KR20220014854A (ko) 2020-07-29 2022-02-07 주식회사 비보존 mGluR5 및 5-HT2A 수용체의 이중 조절제 및 이의 용도
US12060339B2 (en) 2020-07-29 2024-08-13 Vivozon Inc. Dual modulator of mGluR5 and 5-HT2A receptor, and use thereof
US12435051B2 (en) 2020-07-29 2025-10-07 Vivozon, Inc. Dual modulator of mGluR5 and 5-HT2A receptor, and use thereof
US11767310B2 (en) 2021-08-10 2023-09-26 Abbvie Inc. Nicotinamide RIPK1 inhibitors

Similar Documents

Publication Publication Date Title
AU2012328476B2 (en) Substituted 2-(4-heterocyclylbenzyl)isoindolin-1-one analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M1
US8901125B2 (en) Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mGluR5 receptors
US20130345204A1 (en) Substituted bicyclic cycloalkyl pyrazole lactam analogs as allosteric modulators of mglur5 receptors
WO2013049255A1 (fr) Analogues de 5-(prop-1-yn-1-yl)picolinamide substitué comme modulateurs allostériques des récepteurs de mglur5
WO2013103931A1 (fr) Analogues de 1-benzylindolin-2-one substitués en tant que modulateurs allostériques positifs des récepteurs m1 de l'acétylcholine muscarinique
US9550778B2 (en) Substituted 6-aryl-imidazopyridine and 6-aryl-triazolopyridine carboxamide analogs as negative allosteric modulators of mGluR5
US9012445B2 (en) Substituted 4-(1H-pyrazol-4-yl)benzyl analogues as positive allosteric modulators of mAChR M1 receptors
US20130345205A1 (en) Substituted bicyclic aralkyl pyrazole lactam analogs as allosteric modulators of mglur5 receptors
EP2648723A1 (fr) Utilisation de composés bicycliques de pyrazole en tant que modulateurs allostériques des récepteurs mglur5
WO2013192346A1 (fr) Analogues de pyrazole alcoxy bicycliques substitués en tant que modulateurs allostériques des récepteurs mglur5
WO2015080904A1 (fr) Analogues substitués du 4-benzyl-3,4-dihydro-2h-benzo[b] [1,4] oxazine-2-carboxamide, utilisés comme modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m1
US20160102090A1 (en) Substituted 3-benzylquinoxalin-4(3h)-one analogs as positive allosteric modulators of muscarinic acetycholine receptor m1
WO2012092530A1 (fr) Analogues de naphthyridinone utilisés comme modulateurs allostériques positifs de mglur5
CN103037693A (zh) 作为mglur5正向变构调节剂的取代的6-甲基烟酰胺
EP2685825A1 (fr) Imadazapyrinidin-5(6h)-ones substituées en tant que modulateurs allostériques des récepteurs mglur5
WO2011035324A1 (fr) Analogues du o-benzylnicotinamide en tant que modulateurs allostériques positifs du mglur5
US10221175B2 (en) Substituted pyrrolo[3,4-e]indolizines, imidazo[1,2-a]pyrrolo[3,4-e]pyridines, pyrrolo[3,4-e][1,2,4]triazolo[1,5-a]pyridines and pyrrolo[3,4-e][1,2,4]triazolo[4,3-a]pyridines as positive allosteric modulators of muscarinic acetylcholine receptor M1
US8710074B2 (en) Dihydronaphthyridinyl(organo)methanone analogs as positive allosteric mGluR5 modulators
US8865725B2 (en) Substituted imidazopyrimidin-5(6H)-ones as allosteric modulators of MGLUR5 receptors
US9527834B2 (en) Substituted 1-benzylquinoxalin-2(1H)-one analogs as positive allosteric modulators of muscarinic acetylcholine receptor M1
US20130252943A1 (en) Bicyclic oxazole lactams as allosteric modulators of mglur5 receptors
WO2024059216A2 (fr) Composés à noyau 6,6 southwestern utilisés en tant que modulateurs allostériques négatifs du mglu5 et leurs méthodes de production et d'utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12836754

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12836754

Country of ref document: EP

Kind code of ref document: A1