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Definitions

• mGluR5 metabotropic glutamate receptor 5
• L-Glutamate is a major excitatory neurotransmitter in the central nervous system, which binds to neurons and activates cell surface receptors. L-Glutamate acts through two heterogeneous families of receptors: ionotropic and metatropic glutamate receptors (mGluR). mGluRs are G protein-coupled receptors that activate intracellular second messengers when bound to glutamate. Eight subtypes of mGluRs have been cloned and classified into three groups on the basis of sequence similarities and pharmacological properties.
• mGluRl and mGluR5 belong to Group I, which initiate cellular responses through a G-protein mediated mechanism and activate phospholipase C, leading to phosphoinositide hydrolysis and the mobilization of intracellular calcium (Schoepp, D.D., et al, Neuropharmacology 1999, 38, 1431).
• mGluR5 is expressed in both the central nervous system and the periphery (Chizh, B. A., et al, Amino Acids 2002, 23, 169). Therefore, modulation of mGluR5 activity is useful in the treatment of both peripheral and CNS disorders. With respect to peripheral disorders, mGluR5 negative modulators have shown efficacy in the treatment of gastrointestinal (GI) tract disorders, such as gastroesophageal reflux disease (GERD). [0005] In the CNS, excessive activation of mGluR5 has been implicated in a number of diseases, such as various pain states, psychiatric disorders such as anxiety and depression, and other neurological impairments such as drug addiction and drug withdrawal. For example, mGluR5 negative modulators are efficacious in the treatment of anxiety in a variety of animal models including stress-induced hyperthermia and fear- potentiated startle.
• Migraine is another CNS disorder relevant to mGluR5 modulation.
• Migraine is a chronic debilitating condition characterized by recurrent severe headaches that are often accompanied by a variety of other symptoms, such as nausea and fatigue.
• Pharmacologic therapies for the treatment of migraine may be divided into two classes, acute therapies for the treatment of symptoms when they arise, and chronic therapies designed to prevent the onset of migraine (prophylactics) (Goadsby, P. J., et al., N. Engl. J. Med. 2002, 346, 257).
• the best known therapeutics for the treatment of acute migraine are triptans, dual 5-HTi b /5-HTi ⁇ j agonists that exert their therapeutic effects through cranial vasoconstriction.
• ⁇ -blockers In contrast to the treatment for acute attacks, the current therapies for migraine prophylaxis may be subdivided into three classes: ⁇ -blockers, anticonvulsants, and antidepressants. All are moderately effective and carry substantial side-effects. Most prominent among the ⁇ -blockers is propranolol, whose side-effects include lethargy and hypotension. Valproate and topiramate are the most commonly used anticonvulsants, but, like the antidepressants, they cause side-effects such as fatigue. There is a clear medical need for a novel prophylactic therapy that is effective and free from the side-effects. Recently, an mGluR5 antagonist demonstrated efficacy in treating acute migraine in human clinical trials. The robust anxiolytic and antidepressant activities of mGluR5 antagonists should be beneficial to migraine patients, who often suffer anxiety and depression.
• mGluR5 modulation includes schizophrenia, neurodegenerative diseases, levodopa-induced dyskinesia, fragile X syndrome, substance abuse/addiction, epilepsy, inflammatory, visceral and neuropathic pain, and post-traumatic stress disorder. Therefore, there is a great need for effective mGluR5 modulators as therapeutics for the treatment of various disorders, such as neurological disorders. III. SUMMARY
• compositions and dosage forms comprising compounds provided herein.
• Compositions and dosage forms provided herein may comprise one or more additional active ingredients.
• Disorders that may be treated, prevented, and/or managed include, but are not limited to, migraine, anxiety, dental phobia, depression, pain, inflammatory pain, neuropathic pain, postoperative pain, acute thermal hyperalgesia, mechanical allodynia, visceral pain, chronic pain, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, amyotropic lateral sclerosis, epilepsy, seizure, psychosis, schizophrenia, substance abuse/addiction such as cocaine, nicotine, morphine, opioid, or alcohol abuse/addiction, bulimia, anorexia, smoking, obsessive compulsive disorder, aggression, post- traumatic stress disorder, autism, fragile X syndrome, excessive tactile sensitivity, sensory hyper-excitability, attention deficit hyperactivity disorder, bipolar disorder, mood disorder, cognitive disorder, mental retardation, Down syndrome, memory deficit, dementia, GERD, acid reflux, irritable bowel syndrome, lower urinary tract disorder
• provided herein is a method of modulating the activity of mGluR5.
• the method comprises contacting mGluR5 with a compound provided herein.
• the method comprises contacting mGluR5 with an antagonist or a negative allosteric modulator, such as a compound provided herein.
• the method comprises contacting the cell with a compound provided herein.
• the cell is a brain cell, such as, for example, a neuronal cell or a glial cell.
• alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents. In some embodiment, the alkyl may be optionally substituted with one or more halogen.
• alkyl also encompasses both linear and branched alkyl, unless otherwise specified.
• the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C 1-2 O), 1 to 15 (Ci-I 5 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3 _ 2 o), 3 to 15 (C 3-1S ), 3 to 12 (C 3 - I2 ), 3 to 10 (C 3 _io), or 3 to 6 (C 3-6 ) carbon atoms.
• linear Ci_ 6 and branched C 3 _ 6 alkyl groups are also referred as "lower alkyl.”
• alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, t- butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
• C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds.
• the alkenyl may be optionally substituted one or more substituents. In some embodiments, the alkenyl may be optionally substituted with one or more halogen.
• alkenyl also encompasses radicals having "cis” and “trans” configurations, or alternatively, "E” and “Z” configurations, as appreciated by those of ordinary skill in the art.
• alkenyl encompasses both linear and branched alkenyl, unless otherwise specified.
• C 2 - 6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2 - 10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
• alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
• alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bonds.
• the alkynyl may be optionally substituted one or more substituents. In some embodiments, the alkynyl may be optionally substituted with one or more halogen.
• alkynyl also encompasses both linear and branched alkynyl, unless otherwise specified.
• the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C2-10), or 2 to 6 (C 2-6 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C 3 _ 20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3 _ 6 ) carbon atoms.
• alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
• C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
• cycloalkyl refers to a cyclic saturated bridged and/or non-bridged monovalent hydrocarbon radical, which may be optionally substituted one or more substituents as described herein elsewhere.
• the cycloalkyl has from 3 to 20 (C 3 _ 2 o), from 3 to 15 (C 3-1S ), from 3 to 12 (C 3 - I2 ), from 3 to 10 (C 3-1 o), or from 3 to 7 (C 3 _ 7 ) carbon atoms.
• cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl.
• aryl refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C 6-2 o), from 6 to 15 (C 6-1 s), or from 6 to 10 (C 6-1 o) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
• Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
• aryl may also be optionally substituted with one or more substituents as described herein elsewhere.
• the term "arylalkyl” or “aralkyl” refers to a monovalent alkyl group substituted with aryl. In certain embodiments, both alkyl and aryl may be optionally substituted with one or more substituents as described herein elsewhere.
• heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one ring contains one or more heteroatoms independently selected from O, S, and N.
• Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
• the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
• monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
• bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl
• tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
• heteroaryl may be optionally substituted with one or more substituents as described herein elsewhere.
• heterocyclyl refers to a monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein at least one ring contains one or more heteroatoms independently selected from O, S, or N.
• the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
• the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
• the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
• heterocyclic radicals include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, ⁇ -carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrofuryl, dihydrobenzisoxazinyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithiany
• the heterocyclyl or heterocyclic may be optionally substituted with one or more substituents as described herein elsewhere.
• halogen refers to fluorine, chlorine, bromine, and/or iodine.
• the atoms of the compounds provided herein are meant to represent any stable isotope of that atom.
• hydrogen encompasses proton ( 1 H), deuterium ( 2 H), tritium ( 3 H), and/or mixtures thereof.
• a position is designated as "H” or "hydrogen”
• the position is understood to have hydrogen at its natural isotopic composition.
• the position is understood to have hydrogen at an isotopically enriched composition, i.e., an isotopic composition other than the natural isotopic composition of that atom.
• the compounds provided herein optionally comprise deuterium at one or more positions where hydrogen atoms are present, and wherein the deuterium composition of the atom or atoms is other than the natural isotopic composition.
• the compounds provided herein optionally comprise isotopes for other elements at one or more positions, including but not limited to, 13 C, 14 C, 33 S, 34 S, 36 S, 15 N, 17 O, and/or 18 O, and wherein the isotopic composition of the atom or atoms is other than the natural isotopic composition.
• the term "optionally substituted” refers to a group, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, which may be substituted with one or more substituents independently selected from, e.g., (a) C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 3 - 7 cycloalkyl, C ⁇ -u aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q 1 ; and (b) halo, cyano (-CN), nitro (-NO 2 ), -C(O)R a , -C(O)OR a , -C(0)NR b R c , - C(NR
• stereoisomer encompasses all enantiomerically/stereomerically pure and enantiomerically/ stereomerically enriched compounds provided herein.
• stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
• a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
• a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
• a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
• stereomerically enriched means a composition that comprises greater than about 55% by weight of one stereoisomer of a compound, greater than about 60% by weight of one stereoisomer of a compound, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.
• enantiomerically pure means a stereomerically pure composition of a compound having one chiral center.
• enantiomerically enriched means a stereomerically enriched composition of a compound having one chiral center.
• optically active refers to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
• the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
• R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
• the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
• the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
• (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
• sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
• the term "pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
• suitable non-toxic acids include inorganic and organic acids such as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, p-toluene
• solvate refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
• the term "pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
• each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
• the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
• active ingredient and active substance refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
• active ingredient and active substance may be an optically active isomer of a compound described herein.
• drug and “therapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
• the terms “treat,” “treating” and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agent, after the onset of symptoms of the particular disease.
• the terms “prevent,” “preventing” and “prevention” refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof.
• the terms refer to the treatment with or administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of disease or disorders provided herein.
• the terms encompass the inhibition or reduction of a symptom of the particular disease.
• Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments.
• patients who have a history of recurring symptoms are also potential candidates for the prevention.
• prevention may be interchangeably used with the term “prophylactic treatment.”
• the terms “manage,” “managing,” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a cure of the disease or disorder.
• the term “managing” encompasses treating a patient who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.
• a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
• a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or disorder.
• the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.
• a prophylactic ally effective amount of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence.
• a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
• the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
• the term "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In specific embodiments, the subject is a human.
• the term "metabotropic glutamate receptor ligand” or "mGluR ligand” refers to any compound, which binds to an mGluR receptor. Unless otherwise specified, the mGluR receptor includes, but is not limited to mGluR5.
• Ligands include endogenous ligands for a given metabotropic glutamate receptor as well as drug molecules and other compounds, such as synthetic molecules known to bind to a particular metabotropic glutamate receptor. In some embodiments, the ligand is an allosteric modulator.
• the ligands include those labeled with one or more radioisotopes, such as tritium or 11 C, or otherwise (e.g., fluorescently) labeled.
• the ligand is a positron- emission tomography (PET) ligand. It is within the abilities of the skilled person to select an appropriate ligand, for example, an agonist or an antagonist, for a given metabotropic glutamate receptor.
• PET positron- emission tomography
• neurodegenerative diseases e.g., Alzheimer's disease, Parkinson's disease, levodopa- induced dyskinesia, and amyotrophic lateral sclerosis
• neuropsychiatry diseases e.g., schizophrenia and anxiety, such as general anxiety disorder
• affective disorders e.g., depression, anxiety, and attention deficit disorder
• Exemplary neurological disorders include, but are not limited to, MLS (cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e.g., spinal cord injury and head injury), viral infection induced neurodegeneration, (e.g., AIDS, encephalopathies), epilepsy, benign forgetfulness, closed head injury, sleep disorders, depression (e.g., bipolar disorder), dementias, movement disorders, psychoses, alcoholism, post-traumatic stress disorder and the like.
• Neurological disorder also includes any condition associated with the disorder. For instance, a method of treating a neurodegenerative disorder includes methods of treating loss of memory and/or loss of cognition associated with a neurodegenerative disorder.
• Neurodegenerative disorder also includes any disease or condition that is implicated, at least in part, in monoamine (e.g., norepinephrine) signaling pathways (e.g., cardiovascular disease).
• adjective disorder includes depression, anxiety (e.g., generalized anxiety disorder (GAD)), attention deficit disorder, attention deficit disorder with hyperactivity, bipolar and manic conditions, obsessive-compulsive disorder, and the like.
• AD attention deficit disorder
• ADH attention deficit disorder with hyperactivity disorder
• AD/HD attention deficit/hyperactivity disorder
• depression includes all forms of depression including, but not limited to, major depressive disorder (MDD), bipolar disorder, seasonal affective disorder (SAD) and dysthymia.
• MDD major depressive disorder
• SAD seasonal affective disorder
• Depression may also includes any condition commonly associated with depression, such as all forms of fatigue (e.g., chronic fatigue syndrome) and cognitive deficits.
• the terms “substance abuse” and “eating disorders” are used herein in a manner consistent with their accepted meanings in the art. See, e.g., DSM-IVTM.
• the term "eating disorder,” as used herein, refers to abnormal compulsions to avoid eating or uncontrollable impulses to consume abnormally large amounts of food. These disorders may affect not only the social well-being, but also the physical well-being of sufferers. Examples of eating disorders include, but are not limited to, anorexia nervosa, bulimia, and binge eating.
• the term “pain” refers to an unpleasant sensory and emotional experience.
• pain refers to all categories of pain, including pain that is described in terms of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and neuropathic pain (abnormal response of a injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g., mild, moderate, or severe; and pain that is a symptom or a result of a disease state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic peripheral neuropathic pain (see, e.g., Harrison's Principles of Internal Medicine, pp.
• Pain includes pain resulting from dysfunction of the nervous system: organic pain states that share clinical features of neuropathic pain and possible common pathophysiology mechanisms, but are not initiated by an identifiable lesion in any part of the nervous system.
• somatic pain refers to a normal nerve response to a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer, and includes both cutaneous pain (e.g., skin, muscle or joint derived) and visceral pain (e.g., organ derived).
• a noxious stimulus such as injury or illness, e.g., trauma, burn, infection, inflammation, or disease process such as cancer
• cutaneous pain e.g., skin, muscle or joint derived
• visceral pain e.g., organ derived
• neuropathic pain refers to a heterogeneous group of neurological conditions that result from damage to the nervous system.
• the term also refers to pain resulting from injury to or dysfunctions of peripheral and/or central sensory pathways, and from dysfunctions of the nervous system, where the pain often occurs or persists without an obvious noxious input. This includes pain related to peripheral neuropathies as well as central neuropathic pain.
• diabetic neuropathy also called diabetic peripheral neuropathic pain, or DN, DPN, or DPNP
• PPN post-herpetic neuralgia
• TGN trigeminal neuralgia
• neuropathic pain involving damage to the brain or spinal cord, can occur following stroke, spinal cord injury, and as a result of multiple sclerosis, and is also encompassed by the term.
• Other types of pain that are meant to be included in the definition of neuropathic pain include, but are not limited to, pain from neuropathic cancer pain, HIV/ AIDS induced pain, phantom limb pain, and complex regional pain syndrome.
• neuropathic pain refers to the common clinical features of neuropathic pain including, but not limited to, sensory loss, allodynia (non-noxious stimuli produce pain), hyperalgesia and hyperpathia (delayed perception, summation, and painful after sensation). Pain is often a combination of nociceptive and neuropathic types, for example, mechanical spinal pain and radiculopathy or myelopathy.
• acute pain refers to the normal, predicted physiological response to a noxious chemical, thermal or mechanical stimulus typically associated with invasive procedures, trauma and disease. It is generally time-limited, and may be viewed as an appropriate response to a stimulus that threatens and/or produces tissue injury. The term also refers to pain which is marked by short duration or sudden onset.
• chronic pain encompasses the pain occurring in a wide range of disorders, for example, trauma, malignancies and chronic inflammatory diseases such as rheumatoid arthritis. Chronic pain may last more than about six months. In addition, the intensity of chronic pain may be disproportionate to the intensity of the noxious stimulus or underlying process. The term also refers to pain associated with a chronic disorder, or pain that persists beyond resolution of an underlying disorder or healing of an injury, and that is often more intense than the underlying process would predict. It may be subject to frequent recurrence.
• inflammatory pain is pain in response to tissue injury and the resulting inflammatory process. Inflammatory pain is adaptive in that it elicits physiologic responses that promote healing. However, inflammation may also affect neuronal function. Inflammatory mediators, including PGE 2 induced by the COX2 enzyme, bradykinins, and other substances, bind to receptors on pain-transmitting neurons and alter their function, increasing their excitability and thus increasing pain sensation. Much chronic pain has an inflammatory component. The term also refers to pain which is produced as a symptom or a result of inflammation or an immune system disorder.
• visceral pain refers to pain which is located in an internal organ.
• mixed etiology pain refers to pain that contains both inflammatory and neuropathic components.
• the term “dual mechanism pain” refers to pain that is amplified and maintained by both peripheral and central sensitization.
• central pain refers to pain initiated by a primary lesion or dysfunction in the central nervous system.
• hypoesthesia refers to increased sensitivity to stimulation, excluding the special senses.
• hypopathia refers to a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. It may occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia.
• dysesthesia refers to an unpleasant abnormal sensation, whether spontaneous or evoked.
• dysesthesia include hyperalgesia and allodynia.
• hypoalgesia refers to an increased response to a stimulus that is normally painful. It reflects increased pain on suprathreshold stimulation.
• allodynia refers to pain due to a stimulus that does not normally provoke pain.
• DPNP Neuropathic Pain
• DN diabetic neuropathy
• diabetic peripheral neuropathy refers to chronic pain caused by neuropathy associated with diabetes mellitus.
• the classic presentation of DPNP is pain or tingling in the feet that can be described not only as “burning” or “shooting” but also as severe aching pain. Less commonly, patients may describe the pain as itching, tearing, or like a toothache. The pain may be accompanied by allodynia and hyperalgesia and an absence of symptoms, such as numbness.
• Neuralgia also called “Postherpetic Neuralgia (PHN)” refers to a painful condition affecting nerve fibers and skin. Without being limited by a particular theory, it is a complication of shingles, a second outbreak of the varicella zoster virus (VZV), which initially causes chickenpox.
• VZV varicella zoster virus
• neurodegeneration pain refers to peripheral neuropathic pain as a result of cancer, and can be caused directly by infiltration or compression of a nerve by a tumor, or indirectly by cancer treatments such as radiation therapy and chemotherapy (chemotherapy-induced neuropathy).
• HIV/ AIDS peripheral neuropathy or "HIV/AIDS related neuropathy” refers to peripheral neuropathy caused by HIV/ AIDS, such as acute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as well as peripheral neuropathy resulting as a side effect of drugs used to treat HIV/AIDS.
• HIV/ AIDS peripheral neuropathy or "HIV/AIDS related neuropathy” refers to peripheral neuropathy caused by HIV/ AIDS, such as acute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as well as peripheral neuropathy resulting as a side effect of drugs used to treat HIV/AIDS.
• Pain refers to pain appearing to come from where an amputated limb used to be.
• Phantom limb pain can also occur in limbs following paralysis (e.g., following spinal cord injury). "Phantom Limb Pain" is usually chronic in nature.
• Neuralgia refers to a disorder of the fifth cranial (trigeminal) nerve that causes episodes of intense, stabbing, electric- shock-like pain in the areas of the face where the branches of the nerve are distributed (lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw). It is also known as the "suicide disease”.
• Pain Syndrome CRPS
• RSD Reflex Sympathetic Dystrophy
• fibromyalgia refers to a chronic condition characterized by diffuse or specific muscle, joint, or bone pain, along with fatigue and a range of other symptoms. Previously, fibromyalgia was known by other names such as fibrositis, chronic muscle pain syndrome, psychogenic rheumatism and tension myalgias.
• convulsion refers to a neurological disorder and is used interchangeably with “seizure,” although there are many types of seizure, some of which have subtle or mild symptoms instead of convulsions. Seizures of all types may be caused by disorganized and sudden electrical activity in the brain. In some embodiments, convulsions are a rapid and uncontrollable shaking during which the muscles contract and relax repeatedly.
• R 1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;
• R 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;
• L 1 is a bond, -S-, -SO-, -SO 2 -, -O-, -NR 9 -, -CR 5 R 6 -, -CR 5 R 6 -CR 7 R 8 -, optionally substituted cycloalkyl, optionally substituted heterocyclyl; optionally substituted aryl, or optionally substituted heteroaryl;
• L 2 is a bond, -O-, -NR 9 -, -CR 5 R 6 - or -CR 5 R 6 -CR 7 R 8 -;
• X is C or N
• Y is O, S, N, NR 10 , or CR 10 ;
• Z is O, S, N, NR 10 , or CR 10 ; wherein Y and Z are not both O or both S;
• R 9 and R 10 are each independently hydrogen or lower alkyl
• G is N, CH, CR', COR', or CNR'R";
• R' is lower alkyl
• R" is lower alkyl
• L 2 and R' or L 2 and R" may be combined to form a 3- to 10-membered ring; o is 0, 1, or 2; and p is 1 or 2.
• R 1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;
• R 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;
• L 1 is a bond, -S-, -SO-, -SO 2 -, -O-, -NR 9 -, -CR 5 R 6 -, -CR 5 R 6 -CR 7 R 8 -, optionally substituted cycloalkyl, optionally substituted heterocyclyl; optionally substituted aryl, or optionally substituted heteroaryl;
• L 2 is a bond, -O-, -NR 9 -, -CR 5 R 6 - or -CR 5 R 6 -CR 7 R 8 -;
• X is C or N
• Y is O, S, N, NR 10 , or CR 10 ;
• Z is O, S, N, NR 10 , or CR 10 ; wherein Y and Z are not both O or both S;
• R 9 and R 10 are each independently hydrogen or lower alkyl
• G is N or CH; o is 0, 1, or 2; and p is 1 or 2.
• R 1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;
• R 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;
• L 1 is a bond, -S-, -SO-, -SO 2 -, -O-, -NR 9 -, -CR 5 R 6 -, -CR 5 R 6 -CR 7 R 8 -, optionally substituted cycloalkyl, optionally substituted heterocyclyl; optionally substituted aryl, or optionally substituted heteroaryl;
• L 2 is a bond, -O-, -NR 9 -, or -CR 5 R 6 -;
• X is C or N
• Y is O, S, N, NR 10 , or CR 10 ;
• Z is O, S, N, NR 10 , or CR 10 ; wherein Y and Z are not both O or both S;
• R 9 and R 10 are each independently hydrogen or lower alkyl
• G is N or CH; o is 0, 1, or 2; and p is 1 or 2.
• R 1 is optionally substituted cycloalkyl. In another embodiment, R 1 is optionally substituted monocyclic cycloalkyl. In another embodiment, R 1 is optionally substituted heterocyclyl. In another embodiment, R 1 is optionally substituted monocyclic heterocyclyl. In another embodiment, R 1 is optionally substituted aryl. In another embodiment, R 1 is optionally substituted monocyclic aryl. In another embodiment, R 1 is optionally substituted heteroaryl. In another embodiment, R 1 is optionally substituted monocyclic heteroaryl.
• R 2 is optionally substituted cycloalkyl. In another embodiment, R 2 is optionally substituted monocyclic cycloalkyl. In another embodiment, R is optionally substituted heterocyclyl. In another embodiment, R is optionally substituted monocyclic heterocyclyl. In another embodiment, R is optionally substituted aryl. In another embodiment, R is optionally substituted monocyclic aryl.
• R is optionally substituted heteroaryl. In another embodiment,
• R 2 is optionally substituted monocyclic heteroaryl.
• R 3 is hydrogen. In another embodiment, R 3 is halogen.
• R 3 is lower alkyl
• R 4 is hydrogen. In another embodiment, R 4 is halogen.
• R 4 is lower alkyl.
• R 3 and R 4 are attached to the same carbon atom, R 3 and R 4 are combined with the carbon atom to which they are attached to form a
• L 1 is a bond. In another embodiment, L 1 is -S-. In another embodiment, L 1 is -SO-. In another embodiment, L 1 is -SO 2 -. In another embodiment, L 1 is -O- . In another embodiment, L 1 is -NR 9 -. In another embodiment, L 1 is -CR 5 R 6 -. In another embodiment, L 1 is -CR 5 R 6 -CR 7 R 8 -. In another embodiment, L 1 is optionally substituted cycloalkyl. In another embodiment, L 1 is optionally substituted heterocyclyl. In another embodiment, L 1 is optionally substituted aryl. In another embodiment, L 1 is optionally substituted heteroaryl. R 5 , R 6 , R 7 , R 8 , and R 9 are defined herein elsewhere.
• L 2 is a bond. In another embodiment, L 2 is -O- . In another embodiment, L 2 is -NR 9 -. In another embodiment, L 2 is -CR 5 R 6 -. In another embodiment, L 1 is -CR 5 R 6 -CR 7 R 8 -. R 5 , R 6 , R 7 , R 8 , and R 9 are defined herein elsewhere.
• R 5 is hydrogen. In another embodiment, R 5 is halogen.
• R 5 is lower alkyl
• R 6 is hydrogen. In another embodiment, R 6 is halogen.
• R 6 is lower alkyl
• R 5 and R 6 are combined with the carbon atom to which they are attached to form a 3- to 7-membered cycloalkyl.
• R 7 is hydrogen. In another embodiment, R 7 is halogen.
• R 7 is lower alkyl.
• R 8 is hydrogen. In another embodiment, R 8 is halogen. In another embodiment, R 8 is lower alkyl.
• R 7 and R 8 are combined with the carbon atom to which they are attached to form a 3- to 7-membered cycloalkyl.
• R 9 is hydrogen. In another embodiment, R 9 is lower alkyl.
• X is C. In another embodiment, X is N. [0092] In one embodiment, Y is O. In another embodiment, Y is S. In another embodiment, Y is N. In another embodiment, Y is NR 10 . In another embodiment, Y is CR 10 . R 10 is defined herein elsewhere.
• Z is O. In another embodiment, Z is S. In another embodiment, Z is N. In another embodiment, Z is NR 10 . In another embodiment, Z is CR 10 . R 10 is defined herein elsewhere.
• R 10 is hydrogen. In another embodiment, R 10 is lower alkyl.
• G is N. In another embodiment, G is CH. [0096] In one embodiment, G is CR' . In one embodiment, G is COR'. In one embodiment, G is CNR'R". In one embodiment, R' is lower alkyl. In one embodiment, R" is lower alkyl.
• L 2 and R' may be combined to form a 3- to 10- membered ring.
• R 9 and R' may be combined to form a 3- to 10-membered ring.
• L 2 when L 2 is -CR 5 R 6 - and R 5 is lower alkyl, R 5 and R' may be combined to form a 3- to 10 membered ring.
• R 6 and R' when L 2 is -CR 5 R 6 - and R 6 is lower alkyl, R 6 and R' may be combined to form a 3- to 10 membered ring.
• R 5 and R' when L 2 is -CR 5 R 6 - CR 7 R 8 and R 5 is lower alkyl, R 5 and R' may be combined to form a 3- to 10 membered ring. In one embodiment, when L 2 is -CR 5 R 6 -CR 7 R 8 and R 6 is lower alkyl, R 6 and R' may be combined to form a 3- to 10 membered ring. In one embodiment, when L 2 is -CR 5 R 6 -CR 7 R 8 and R 7 is lower alkyl, R 7 and R' may be combined to form a 3- to 10 membered ring.
• R 8 and R' may be combined to form a 3- to 10 membered ring.
• L and R" may be combined to form a 3- to 10- membered ring.
• L 9 and R" may be combined to form a 3- to 10-membered ring.
• R and R" may be combined to form a 3- to 10 membered ring. In one embodiment, when L 2 is -CR 5 R 6 - and R 6 is lower alkyl, R 6 and R" may be combined to form a 3- to 10 membered ring. In one embodiment, when L 2 is -CR 5 R 6 -
• CR 7 R 8 and R 5 is lower alkyl
• R 5 and R" may be combined to form a 3- to 10 membered ring.
• L 2 is -CR 5 R 6 -CR 7 R 8 and R 6 is lower alkyl
• R 6 and R" may be combined to form a 3- to 10 membered ring.
• L is
• R 7 and R" may be combined to form a 3- to 10 membered ring.
• L 2 is -CR 5 R 6 -CR 7 R 8 and R 8 is lower alkyl
• R 8 and R" may be combined to form a 3- to 10 membered ring.
• o is 0. In another embodiment, o is 1. In another embodiment, o is 2.
• p is 1. In another embodiment p is 2.
• Y, Z, G, o, and p are encompassed by this disclosure and specifically provided herein.
• L 1 is a bond or -CR 5 R 6 -, wherein R 5 and R 6 are each independently hydrogen or lower alkyl, or R 5 and R 6 may be combined with the carbon atom to which they are attached to form a 3- to 7-membered cycloalkyl.
• R 1 is aryl or heteroaryl, each of which is optionally substituted.
• R 2 is aryl or heteroaryl, each of which is optionally substituted.
• R 1 and R 2 are as defined herein elsewhere.
• L 1 is a bond.
• L 1 is -CH 2 -.
• L 1 is -C(CH 3 ) 2 -.
• L 2 is a bond.
• L 2 is -CH 2 -.
• L 2 is -C(O)-.
• L 2 is -CH 2 -C(O)-.
• L 1 is a bond, -CH 2 -, or -C(CHs) 2 -.
• L 2 is a bond, -CH 2 -, -C(O)-, or -CH 2 -C(O)-.
• R 3 is hydrogen or methyl. In one embodiment, R 4 is hydrogen or methyl. In one embodiment, R 3 and R 4 are both hydrogen. In one embodiment, R 3 and R 4 are both methyl. In one embodiment, one of R 3 and R 4 is methyl and the other is hydrogen. In one embodiment, R 3 is methyl and R 4 is hydrogen. [00106] In one embodiment, specific examples include, but are not limited to, the following compounds:
• R 1 is 5- or 6-membered aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted;
• R 2 is 5- or 6-membered aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted;
• R 3 is hydrogen or lower alkyl
• X is C or N
• Y is O, S, N, NR 10 , or CR 10 ;
• Z is O, S, N, NR 10 , or CR 10 ; wherein Y and Z are not both O or both S;
• R 10 is hydrogen or lower alkyl
• G is N or CH; o is 0, 1, or 2; and p is 1 or 2.
• R 1 is optionally substituted 5- or 6-membered aryl. In another embodiment, R 1 is optionally substituted 5- or 6-membered heteroaryl. In one embodiment, R 1 is optionally substituted phenyl. In another embodiment, R 1 is optionally substituted pyridyl. In another embodiment, R 1 is optionally substituted pyrimidinyl. In another embodiment, R 1 is optionally substituted pyrazinyl. In another embodiment, R 1 is optionally substituted pyridazinyl. In another embodiment, R 1 is optionally substituted triazinyl. In another embodiment, R 1 is optionally substituted furanyl. In another embodiment, R 1 is optionally substituted thienyl.
• R 1 is optionally substituted pyrrolyl. In another embodiment, R 1 is optionally substituted pyrazolyl. In another embodiment, R 1 is optionally substituted imidazolyl. In another embodiment, R 1 is optionally substituted thiazolyl. In another embodiment, R 1 is optionally substituted oxazolyl. In another embodiment, R 1 is optionally substituted isothiazolyl. In another embodiment, R 1 is optionally substituted isoxazolyl. In another embodiment, R 1 is optionally substituted oxadiazolyl. In another embodiment, R 1 is optionally substituted thiadiazolyl. In another embodiment, R 1 is optionally substituted triazolyl.
• R 1 is optionally substituted tetrazolyl. In another embodiment, R 1 is optionally substituted pyridine oxide.
• R 2 is optionally substituted 5- or 6-membered aryl. In another embodiment R 2 is optionally substituted 5- or 6-membered heteroaryl. In one embodiment, R 2 is optionally substituted phenyl. In another embodiment, R 2 is optionally substituted pyridyl. In another embodiment, R 2 is optionally substituted pyrimidinyl. In another embodiment, R 2 is optionally substituted pyrazinyl. In another embodiment, R 2 is optionally substituted pyridazinyl. In another embodiment, R 2 is optionally substituted triazinyl.
• R 2 is optionally substituted furanyl. In another embodiment, R is optionally substituted thienyl. In another embodiment, R is optionally substituted pyrrolyl. In another embodiment, R is optionally substituted pyrazolyl. In another embodiment, R 2 is optionally substituted imidazolyl. In another embodiment, R is optionally substituted thiazolyl. In another embodiment, R 2 is optionally substituted oxazolyl. In another embodiment, R 2 is optionally substituted isothiazolyl. In another embodiment, R 2 is optionally substituted isoxazolyl. In another embodiment, R 2 is optionally substituted oxadiazolyl. In another embodiment, R 2 is optionally substituted thiadiazolyl.
• R 2 is optionally substituted triazolyl. In another embodiment, R is optionally substituted tetrazolyl. In another embodiment, R 2 is optionally substituted pyridine oxide. [00111] In one embodiment, R 1 is substituted with one or more halogen. In another embodiment, R 1 is substituted with one or more CN. In another embodiment, R 1 is substituted with one or more lower alkyl. In another embodiment, R 1 is substituted with one or more methyl. In another embodiment, R 1 is substituted with one or more trifluoromethyl. In another embodiment, R 1 is substituted with one or more -O(lower alkyl). In another embodiment, R 1 is substituted with one or more -OMe.
• R 1 is substituted with one or more heterocyclyl. In another embodiment, R 1 is substituted with one or more morpholinyl. In another embodiment, R 1 is substituted with one or more aryl. In another embodiment, R 1 is substituted with one or more heteroaryl. In another embodiment, R 1 is substituted with one or more pyridine.
• R 2 is substituted with one or more halogen. In another embodiment, R 2 is substituted with one or more CN. In another embodiment, R 2 is substituted with one or more lower alkyl. In another embodiment, R 2 is substituted with one or more methyl. In another embodiment, R 2 is substituted with one or more trifluoromethyl. In another embodiment, R 2 is substituted with one or more -O(lower alkyl). In another embodiment, R 2 is substituted with one or more -OMe. In another embodiment, R is substituted with one or more heterocyclyl. In another embodiment,
• R 2 is substituted with one or more morpholine. In another embodiment, R 2 is substituted with one or more aryl. In another embodiment, R 2 is substituted with one or more heteroaryl. In another embodiment, R 2 is substituted with one or more pyridine.
• R 3 is hydrogen. In another embodiment, R 3 is lower alkyl. In one embodiment, R 3 is methyl. In another embodiment, R 3 is ethyl. In another embodiment, R 3 is propyl. In another embodiment, R 3 is isopropyl.
• X is C. In another embodiment, X is N.
• Y is O. In another embodiment, Y is S. In another embodiment, Y is N. In another embodiment, Y is NR 10 . In another embodiment, Y is
• R 10 is defined herein elsewhere.
• Z is O. In another embodiment, Z is S. In another embodiment, Z is N. In another embodiment, Z is NR 10 . In another embodiment, Z is
• R 10 is defined herein elsewhere.
• R 10 is hydrogen. In another embodiment, R 10 is lower alkyl. In one embodiment, R 10 is methyl. In another embodiment, R 10 is ethyl. In another embodiment, R 10 is propyl. In another embodiment, R 10 is isopropyl. In another embodiment, R 10 is butyl. In another embodiment, R 10 is isobutyl. In another embodiment, R 10 is t-butyl.
• G is N. In another embodiment, G is CH.
• o is 0. In another embodiment, o is 1. In another embodiment, o is 2.
• p is 1. In another embodiment p is 2.
• R 1 , R 2 , R 3 , X, Y, Z, o, and p are as defined herein elsewhere.
• R 3 , X, Y, Z, o, and p are as defined herein elsewhere.
• X is C, Y is N, and Z is S. In another embodiment, X is
• Y is N
• Z is NH
• X is N
• Y is CH
• Z is N
• X is N
• Y is N
• Z is N.
• R 1 is optionally substituted pyridyl or optionally substituted phenyl. In one embodiment, R 1 is pyridyl substituted with one or more halo or -CN. In another embodiment, R 1 is phenyl substituted with one or more halo or -CN.
• R is optionally substituted pyridyl or optionally substituted phenyl.
• R is pyridyl, substituted with one or more halo or -CN. In another embodiment, R is phenyl, substituted with one or more halo or -CN.
• R 1 is 5- or 6-membered aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted;
• R 2 is 5- or 6-membered aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted;
• R 3 is hydrogen or lower alkyl
• Y is O and Z is N; or Y is N and Z is O;
• G is N or CH; o is 0, 1, or 2; and p is 1 or 2.
• R 1 is optionally substituted 5- or 6-membered aryl. In another embodiment, R 1 is optionally substituted 5- or 6-membered heteroaryl. In one embodiment, R 1 is optionally substituted phenyl. In another embodiment, R 1 is optionally substituted pyridyl. In another embodiment, R 1 is optionally substituted pyrimidinyl. In another embodiment, R 1 is optionally substituted pyrazinyl. In another embodiment, R 1 is optionally substituted pyridazinyl. In another embodiment, R 1 is optionally substituted triazinyl. In another embodiment, R 1 is optionally substituted furanyl. In another embodiment, R 1 is optionally substituted thienyl.
• R 1 is optionally substituted pyrrolyl. In another embodiment, R 1 is optionally substituted pyrazolyl. In another embodiment, R 1 is optionally substituted imidazolyl. In another embodiment, R 1 is optionally substituted thiazolyl. In another embodiment, R 1 is optionally substituted oxazolyl. In another embodiment, R 1 is optionally substituted isothiazolyl. In another embodiment, R 1 is optionally substituted isoxazolyl. In another embodiment, R 1 is optionally substituted oxadiazolyl. In another embodiment, R 1 is optionally substituted thiadiazolyl. In another embodiment, R 1 is optionally substituted triazolyl.
• R 1 is optionally substituted tetrazolyl. In another embodiment, R 1 is optionally substituted pyridine oxide.
• R 2 is optionally substituted 5- or 6-membered aryl. In another embodiment R 2 is optionally substituted 5- or 6-membered heteroaryl. In one embodiment, R 2 is optionally substituted phenyl. In another embodiment, R 2 is optionally substituted pyridyl. In another embodiment, R 2 is optionally substituted pyrimidinyl. In another embodiment, R 2 is optionally substituted pyrazinyl. In another embodiment, R 2 is optionally substituted pyridazinyl. In another embodiment, R 2 is optionally substituted triazinyl.
• R is optionally substituted furanyl. In another embodiment, R is optionally substituted thienyl. In another embodiment, R is optionally substituted pyrrolyl. In another embodiment, R is optionally substituted pyrazolyl. In another embodiment, R 2 is optionally substituted imidazolyl. In another embodiment, R 2 is optionally substituted thiazolyl. In another embodiment, R 2 is optionally substituted oxazolyl. In another embodiment, R 2 is optionally substituted isothiazolyl. In another embodiment, R is optionally substituted isoxazolyl. In another embodiment, R 2 is optionally substituted oxadiazolyl. In another embodiment, R 2 is optionally substituted thiadiazolyl.
• R 2 is optionally substituted triazolyl. In another embodiment, R is optionally substituted tetrazolyl. In another embodiment, R 2 is optionally substituted pyridine oxide. [00131] In one embodiment, R 1 is substituted with one or more halogen. In another embodiment, R 1 is substituted with one or more CN. In another embodiment, R 1 is substituted with one or more lower alkyl. In another embodiment, R 1 is substituted with one or more methyl. In another embodiment, R 1 is substituted with one or more trifluoromethyl. In another embodiment, R 1 is substituted with one or more -O(lower alkyl). In another embodiment, R 1 is substituted with one or more -OMe.
• R 1 is substituted with one or more heterocyclyl. In another embodiment, R 1 is substituted with one or more morpholine. In another embodiment, R 1 is substituted with one or more aryl. In another embodiment, R 1 is substituted with one or more heteroaryl. In another embodiment, R 1 is substituted with one or more pyridine. [00132] In one embodiment, R 2 is substituted with one or more halogen. In another embodiment, R 2 is substituted with one or more CN. In another embodiment, R 2 is substituted with one or more lower alkyl. In another embodiment, R 2 is substituted with one or more methyl. In another embodiment, R 2 is substituted with one or more trifluoromethyl.
• R 2 is substituted with one or more -O(lower alkyl). In another embodiment, R 2 is substituted with one or more -OMe. In another embodiment, R is substituted with one or more heterocyclyl. In another embodiment, R 2 is substituted with one or more morpholine. In another embodiment, R 2 is substituted with one or more aryl. In another embodiment, R 2 is substituted with one or more heteroaryl. In another embodiment, R 2 is substituted with one or more pyridine. [00133] In one embodiment, R 3 is hydrogen. In another embodiment, R 3 is lower alkyl. In one embodiment, R 3 is methyl. In another embodiment, R 3 is ethyl. In another embodiment, R is propyl. In another embodiment, R is isopropyl. [00134] In one embodiment, Y is O and Z is N. In another embodiment, Y is N and Z is O.
• G is N. In another embodiment, G is CH. [00136] In one embodiment, o is 0. In another embodiment, o is 1. In another embodiment, o is 2.
• p is 1. In another embodiment p is 2. [00138] Any of the combinations of R 1 , R 2 , R 3 , Y, Z, G, o, and p are encompassed by this disclosure and specifically provided herein. [00139] In one embodiment, provided herein is a compound of formula (Ilia):
• R 1 , R 2 , R 3 , Y, Z, o, and p are as defined herein elsewhere.
• R 1 , R 2 , and R 3 are defined herein elsewhere.
• R 1 is optionally substituted pyridyl or optionally substituted phenyl.
• R 1 is pyridyl-oxide.
• R 1 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyridyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is phenyl substituted with one or more halo, CN, Me, CF 3 , or OMe. In one embodiment, R 1 is optionally substituted cyclohexyl. In one embodiment, R 1 is unsubstituted cyclohexyl. In another embodiment, R 1 is cyclohexyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is cyclohexyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is pyridyl, phenyl, or cyclohexyl, each of which is optionally substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrazinyl, or optionally substituted thiazolyl.
• R 2 is pyridyl substituted with one or more halo, CN, heterocyclyl, or heteroaryl.
• R 2 is pyridyl substituted with one or more halo, CN, morpholinyl, or pyridyl.
• R 2 is phenyl substituted with one or more halo, CN, heterocyclyl, or heteroaryl. In another embodiment, R 2 is phenyl substituted with one or more halo, CN, morpholinyl, or pyridyl. In another embodiment, R 2 is pyrazinyl substituted with one or more halo, CN, heterocyclyl, or heteroaryl. In another embodiment, R is pyrazinyl substituted with one or more halo, CN, morpholinyl, or pyridyl. In another embodiment, R 2 is thiazolyl substituted with one or more halo, CN, heterocyclyl, or heteroaryl.
• R 2 is thiazolyl substituted with one or more halo, CN, morpholinyl, or pyridyl.
• R 3 is hydrogen. In another embodiment, R 3 is methyl.
• R . 1 1 , ⁇ Ri 2 z , and R 3 are defined herein elsewhere.
• R 1 is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted isoxazolyl, optionally substituted oxazolyl, or optionally substituted thiazolyl.
• R 1 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyridyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is phenyl substituted with one or more halo, CN, Me, CF 3 , or OMe. In another embodiment, R 1 is pyrimidinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is pyrimidinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is pyrazinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is pyrazinyl substituted with one or more halo, CN, Me, CF 3 , or OMe. In another embodiment, R 1 is isoxazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is isoxazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is oxazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is oxazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe. In another embodiment, R 1 is thiazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is thiazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted thiazolyl.
• R 2 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is pyridyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is phenyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is pyrimidinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is pyrimidinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R is pyrazinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R is pyrazinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is thiazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is thiazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is optionally substituted naphthyl or optionally substituted indolyl.
• R 2 is unsubstituted naphthyl or unsubstituted indolyl.
• R 2 is naphthyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R is naphthyl substituted with one or more halo, CN, Me, CF 3 , or OMe. In another embodiment, R 2 is indolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R is indolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is phenyl optionally substituted with one or more halo, CN, OH, lower alkyl, -O(lower alkyl), or heterocyclyl. In one embodiment, R 2 is phenyl substituted with one or more halo, CN, OH, lower alkyl, -O(lower alkyl), or heterocyclyl. In one embodiment, R 2 is phenyl substituted with one or more halo, CN, OH, Me, CF 3 , OMe, or morpholinyl.
• R is pyridyl, phenyl, pyrimidinyl, pyrazinyl, thiazolyl, naphthyl, or indolyl, each of which is optionally substituted with one or more halo, CN, OH, lower alkyl, -O(lower alkyl), or heterocyclyl.
• R 3 is hydrogen. In another embodiment, R 3 is methyl. [00150] Specific examples include, but are not limited to, the following compounds:
• R 1 is optionally substituted pyridyl or optionally substituted phenyl.
• R 1 is pyridyl substituted with one or more halo or CN.
• R 1 is phenyl substituted with one or more halo or CN.
• R 2 is optionally substituted pyridyl or optionally substituted phenyl.
• R 2 is pyridyl substituted with one or more halo or CN.
• R is phenyl substituted with one or more halo or CN.
• R 3 is hydrogen.
• R 1 is optionally substituted pyridyl or optionally substituted phenyl.
• R 1 is pyridyl substituted with one or more halo or CN.
• R 1 is phenyl substituted with one or more halo or CN.
• R 2 is optionally substituted pyridyl or optionally substituted phenyl.
• R 2 is pyridyl substituted with one or more halo or CN.
• R 2 is phenyl substituted with one or more halo or CN.
• R 3 is hydrogen.
• R 1 is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.
• R 1 is pyridyl substituted with one or more halo or CN.
• R 1 is phenyl substituted with one or more halo or CN.
• R 1 is pyrimidinyl substituted with one or more halo or CN.
• R is optionally substituted pyridyl or optionally substituted phenyl.
• R is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is pyridyl substituted with one or more halo, CN, Me, CF 3 or OMe.
• R 2 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is phenyl substituted with one or more halo, CN, Me, CF 3 or OMe.
• R is hydrogen.
• R 1 , R 2 , and R 3 are defined herein elsewhere.
• R 1 is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted thiazolyl.
• R 1 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyridyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is phenyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is pyrimidinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyrimidinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is pyrazinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyrazinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is thiazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is thiazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.
• R 2 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R is pyridyl substituted with one or more halo, CN, Me, CF 3 or OMe. In another embodiment, R 2 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R is phenyl substituted with one or more halo, CN, Me, CF 3 or OMe. In another embodiment, R 2 is pyrimidinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R is pyrimidinyl substituted with one or more halo, CN, Me, CF 3 or OMe.
• R 2 is thiazolyl optionally substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is thiazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is thiazolyl substituted with one or more halo, CN, Me, CF 3 , or -OMe.
• R is phenyl optionally substituted with one or more halo, CN, OH, lower alkyl, or -O(lower alkyl).
• R 2 is phenyl substituted with one or more halo, CN, OH, lower alkyl, or -O(lower alkyl).
• R 2 is phenyl substituted with one or more halo, CN, OH, Me, CF 3 , or OMe.
• R 2 is pyridyl, phenyl, pyrimidinyl, or thiazolyl, each of which is optionally substituted with one or more halo, CN, OH, lower alkyl, or -O(lower alkyl).
• R 3 is hydrogen. In another embodiment, R 3 is methyl.
• R 1 , R 2 , and R 3 are defined herein elsewhere.
• R 1 is optionally substituted pyridyl or optionally substituted phenyl.
• R 1 is pyridyl-oxide.
• R 1 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyridyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is phenyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrazinyl, or optionally substituted thiazolyl.
• R 2 is pyridyl substituted with one or more halo, CN, heterocyclyl, or heteroaryl.
• R 2 is pyridyl substituted with one or more halo, CN, morpholinyl, or pyridyl.
• R 2 is phenyl substituted with one or more halo, CN, heterocyclyl, or heteroaryl.
• R 2 is phenyl substituted with one or more halo, CN, morpholinyl, or pyridyl.
• R 2 is pyrazinyl substituted with one or more halo, CN, heterocyclyl, or heteroaryl.
• R is pyrazinyl substituted with one or more halo, CN, morpholinyl, or pyridyl.
• R 2 is thiazolyl substituted with one or more halo, CN, heterocyclyl, or heteroaryl.
• R 2 is thiazolyl substituted with one or more halo, CN, morpholinyl, or pyridyl.
• R 3 is hydrogen.
• R 3 is methyl.
• R 1 , R 2 , and R 3 are defined herein elsewhere.
• R 1 is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted isoxazolyl, optionally substituted oxazolyl, or optionally substituted thiazolyl.
• R 1 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyridyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is phenyl substituted with one or more halo, CN, Me, CF 3 , or OMe. In another embodiment, R 1 is pyrimidinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is pyrimidinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is pyrazinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is pyrazinyl substituted with one or more halo, CN, Me, CF 3 , or OMe. In another embodiment, R 1 is isoxazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is isoxazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is oxazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is oxazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe. In another embodiment, R 1 is thiazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 1 is thiazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted thiazolyl.
• R 2 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is pyridyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is phenyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is pyrimidinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is pyrimidinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R is pyrazinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R is pyrazinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is thiazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 2 is thiazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 3 is hydrogen.
• R 3 is methyl.
• R 1 is optionally substituted pyridyl or optionally substituted phenyl.
• R 1 is pyridyl substituted with one or more halo or CN.
• R 1 is phenyl substituted with one or more halo or CN.
• R 2 is optionally substituted pyridyl or optionally substituted phenyl.
• R 2 is pyridyl substituted with one or more halo or CN.
• R 2 is phenyl substituted with one or more halo or CN.
• R 3 is hydrogen. [00173] Specific examples include, but are not limited to, the following compounds:
• R 1 is optionally substituted pyridyl or optionally substituted phenyl.
• R 1 is pyridyl substituted with one or more halo or CN.
• R 1 is phenyl substituted with one or more halo or CN.
• R 2 is optionally substituted pyridyl or optionally substituted phenyl.
• R 2 is pyridyl substituted with one or more halo or CN.
• R 2 is phenyl substituted with one or more halo or CN.
• R 3 is hydrogen. [00175] Specific examples include, but are not limited to, the following compounds:
• R 1 is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.
• R 1 is pyridyl substituted with one or more halo or CN.
• R 1 is phenyl substituted with one or more halo or CN.
• R 1 is pyrimidinyl substituted with one or more halo or CN.
• R is optionally substituted pyridyl or optionally substituted phenyl.
• R is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R is pyridyl substituted with one or more halo, CN, Me, CF 3 or OMe. In another embodiment, R is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 2 is phenyl substituted with one or more halo, CN, Me, CF 3 or OMe. In one embodiment, R 3 is hydrogen. [00177] Specific examples include, but are not limited to, the following compounds:
• R 1 , R 2 , and R 3 are defined herein elsewhere.
• R 1 is optionally substituted pyridyl, optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted thiazolyl.
• R 1 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyridyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is phenyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is pyrimidinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyrimidinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is pyrazinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is pyrazinyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 1 is thiazolyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R 1 is thiazolyl substituted with one or more halo, CN, Me, CF 3 , or OMe.
• R 2 is optionally substituted pyridyl, optionally substituted phenyl, or optionally substituted pyrimidinyl.
• R 2 is pyridyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R 2 is pyridyl substituted with one or more halo, CN, Me, CF 3 or OMe. In another embodiment, R 2 is phenyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl). In another embodiment, R is phenyl substituted with one or more halo, CN, Me, CF 3 or OMe.
• R 2 is pyrimidinyl substituted with one or more halo, CN, lower alkyl, or -O(lower alkyl).
• R is pyrimidinyl substituted with one or more halo, CN, Me, CF 3 or OMe.
• R 3 is hydrogen.
• R 3 is methyl.
• the depicted structure is to be accorded more weight.
• the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
• the compound provided herein contains an alkenyl or alkenylene group
• the compound may exist as one or mixture of geometric cisl trans (or ZJE) isomers.
• structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers.
• the compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomer s, e.g., a racemic mixture of two enantiomer s; or a mixture of two or more diastereomers.
• a mixture of enantiomer s e.g., a racemic mixture of two enantiomer s; or a mixture of two or more diastereomers.
• administration of a compound in its (R) form is equivalent to administration of the compound in its (S) form.
• Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, by chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
• the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, e.g., Berge et ⁇ l., J. Ph ⁇ rm. ScL 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use, Stahl and Wermuth, ed.; Wiley- VCH and VHCA, Zurich, 2002).
• Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphor sulfonic acid, (+)-(15 r )-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glu
• Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, iV-methyl- glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)- morpholine, methylamine, piperidine, piperazine, propylamine, pyrrol
• the compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula I and is readily convertible into the parent compound in vivo.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
• the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
• a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See, e.g., Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al.
• Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
• KIE Kinetic Isotope Effect
• DKIE Deuterium Kinetic Isotope Effect
• the magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen.
• the DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen.
• High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy.
• tritium As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium ("T") for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements, including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 O or 18 O for oxygen, may lead to a similar kinetic isotope effect. [00196] For example, the DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride.
• the animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system.
• enzymes include the cytochrome P450 enzymes ("CYPs"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
• CYPs cytochrome P450 enzymes
• esterases esterases
• proteases proteases
• reductases reductases
• dehydrogenases dehydrogenases
• monoamine oxidases monoamine oxidases
• the resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. These drugs therefore often require the administration of multiple or high daily doses.
• isotopic enrichment at certain positions of a compound provided herein will produce a detectable KIE that will affect the pharmacokinetic, pharmacologic, and/or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition.
• a compound of formula (Ia) may be prepared by coupling a cyclic amine Ia-I with R 2 -L 2 -R ⁇ , wherein R 11 is halogen, such as Cl, Br, or I, or -OH, or other suitable leaving groups, such as -OMesylate, or -OTosylate (See Scheme 1).
• R 11 is halogen, such as Cl, Br, or I, or -OH, or other suitable leaving groups, such as -OMesylate, or -OTosylate
• further organic transformations may convert a certain set of L 1 , L 2 , R 1 and R 2 to a new set of L 1 , L 2 , R 1 and R 2 groups to prepare a specific compound of formula (Ia).
• the cyclic amine Ia-I may be coupled with an alkyl halide, such as a substituted benzyl bromide, under basic conditions, such as K 2 CO 3 or Na 2 CO 3 , in a solvent such as DMF or acetonitrile, to render a compound of formula (Ia) where L is -CH 2 - (See Scheme 2).
• an alkyl halide such as a substituted benzyl bromide
• basic conditions such as K 2 CO 3 or Na 2 CO 3
• a solvent such as DMF or acetonitrile
• the cyclic amine Ia-I may also be coupled with an acid chloride, or an acid in the presence of amide coupling reagents, such as EDCI and HOBt, with base such as TEA, in a solvent such as DCM, to render an amide (See Scheme 3).
• amide coupling reagents such as EDCI and HOBt
• base such as TEA
• a compound of formula (Ia) may be prepared according to Scheme 4 by coupling a cyclic amine Ia-I with aryl halide or heteroaryl halide, such as aryl or heteroaryl chlorides, bromides, or iodides, in the presence of suitable coupling reagents and under heating.
• aryl halide or heteroaryl halide such as aryl or heteroaryl chlorides, bromides, or iodides
• Exemplary coupling reagents include, but are not limited to the following: (1) Pd(OAc) 2 , Xantphos, and CS 2 CO 3 in toluene; (2) Pd(OAc) 2 , Xantphos, and K 2 CO 3 in toluene; (3) Pd(OAc) 2 , Xantphos, and NaOfBu in toluene; (4) Pd 2 (dba) 3 , BINAP, and NaOfBu in t- BuOH or toluene; (5) Pd 2 (dba) 3 , ( ⁇ Bu) 3 P-BF 4 , and NaOfBu in toluene; or (6) Pd 2 (dba) 3 , Xantphos, and Cs 2 CO 3 in xylene.
• the heteroaryl halide is an electrophile, such as 2-chloropyridine
• the coupling reaction could be carried out in the presence of a base, such as DIEA, in
• the cyclic amine Ia-I may be prepared using the following specific schemes. Detailed reaction conditions are provided herein below for various specific examples. These specific schemes and specific examples of Ia-I are not limiting on the scope of this disclosure. One of ordinary skills of the art will understand that the following schemes may be modified with appropriate reagents, protecting groups, conditions, starting materials, or reaction sequences to suit the preparation of various other embodiments provided herein.
• the cyclic amine Ia-I is a 2-position substituted 4,5,6,7- tetrahydrooxazolo[5,4-c]pyridine, which may be prepared using procedures exemplified in Scheme 5.
• trans-Benzyl 4-amino-3-hydroxypiperidine-l-carboxylate is prepared according to procedures in WO 1994/20062, and coupled to an acid, such as picolinic acid, under standard amid coupling conditions, such as EDCI, HOBt, and TEA in DCM.
• the resulting hydroxy-amide compound is oxidized and subsequently cyclized to form the Cbz-protected 4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine.
• the Cbz protecting group may be removed by catalytic hydrogenation or by treatment with TMSI to render the desired cyclic amine Ia-I.
• the cyclic amine Ia-I is a 2-position substituted 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine, which may be prepared using procedures exemplified in Scheme 6.
• trans-Benzyl 3-amino-4-hydroxypiperidine-l-carboxylate is prepared according to procedures in WO 1994/20062, and coupled to an acid, such as picolinic acid, under standard amid coupling conditions, such as EDCI, HOBt, and TEA in DCM.
• the resulting hydroxy-amide compound is oxidized and subsequently cyclized to form the Cbz-protected 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine.
• the Cbz protecting group may be removed by catalytic hydrogenation or by treatment with TMSI to render the desired cyclic amine Ia-I.
• the cyclic amine Ia-I is 2-(oxazol-2-yl)-4,5,6,7-tetra- hydrooxazolo[4,5-c]pyridine, which may be prepared using procedures exemplified in Scheme 7.
• ⁇ raws-Benzyl 3-amino-4-hydroxypiperidine-l-carboxylate is prepared according to procedures in WO 1994/20062, and treated with oxalic acid diethyl ester, followed by oxidation to render a keto-amide.
• the keto-amide is cyclized to render 5- benzyl 2-ethyl 6,7-dihydrooxazolo[4,5-c]pyridine-2,5(4H)-dicarboxylate, which is coupled to 2,2-dimethoxy-ethylamine to yield an amide.
• the acetal amide is treated with TFA to render the corresponding aldehyde, which may be cyclized to form the oxazole.
• the Cbz protecting group is removed to provide the desired cyclic amine Ia-I.
• the cyclic amine Ia-I is a 2-position substituted 7- methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine, a 2-position substituted 7-methyl- 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine or a 2-position substituted 6-methyl-4,5,6,7- tetrahydrooxazolo[5,4-c]pyridine, which may be prepared using procedures exemplified in Schemes 8-11.
• the cyclic amine Ia-I is a 2-position substituted 5,6- dihydro-4H-pyrrolo[3,4- ⁇ i]oxazole, which may be prepared using procedures exemplified in Scheme 12. Pyrrole is reduced by Zn/ ⁇ Cl and protected with Cbz to yield benzyl 2,5-dihydro-lH-pyrrole-l-carboxylate, which is oxidized with m-CPBA to render the corresponding epoxide.
• the epoxide is treated with aqueous ammonia to yield benzyl 3-amino-4-hydroxypyrrolidine-l-carboxylate, which is coupled to an acid, such as picolinic acid, under standard amid coupling conditions, such as EDCI, ⁇ OBt, and TEA in DCM.
• the resulting hydroxy-amide compound is oxidized and subsequently cyclized to form the Cbz-protected 5,6-dihydro-4H-pyrrolo[3,4- ⁇ i]oxazole.
• the Cbz protecting group may be removed by treatment with TMSI to render the desired cyclic amine Ia-I.
• cyclic amine Ia-I is a 2-position substituted 5,6- dihydro-4H-pyrrolo[3,4- ⁇ i]oxazole
• a compound of formula (Ia) may be prepared using procedures exemplified in Scheme 13. Pyrrole is reduced by Zn/ ⁇ Cl and protected with Boc to yield tert-butyl 2,5-dihydro-lH-pyrrole-l-carboxylate, which is oxidized with m- CPBA to render the corresponding epoxide.
• the epoxide is treated with aqueous ammonia to yield tert-butyl 3-amino-4-hydroxypyrrolidine-l-carboxylate, which is coupled to an acid under standard amid coupling conditions, such as EDCI, ⁇ OBt, and TEA in DCM.
• the resulting hydroxy-amide is treated with TFA to remove the Boc protecting group.
• the resulting amine is coupled to a heteroaryl halide, such as 2- chloro-3-cyanopyridine under basic condition.
• the product is oxidized to the corresponding ketone and subsequently cyclized to form the desired 5,6-dihydro-4H- pyrrolo[3,4- ⁇ i]oxazole.
• the cyclic amine Ia-I is a 2-position substituted 5,6,7,8-tetrahydro-4H-oxazolo[5,4-(f]azepine, which may be prepared using procedures exemplified in Scheme 14.
• tert-Butyl 4-oxopiperidine-l-carboxylate is treated with ethyl diazoacetate in the presence of BF 3 etherate, to produce l-tert-buty ⁇ 3 -ethyl A- oxoazepane-l,3-dicarboxylate.
• the ester is decarboxylated under acidic conditions to render azepan-4-one, which is protected with Cbz and reduced to the corresponding alcohol.
• the alcohol is converted to the corresponding mesylate and treated with DBU to yield a mixture of benzyl 2,3,6,7-tetrahydro-lH-azepine-l-carboxylate and benzyl 2,3,4,7-tetrahydro-lH-azepine-l-carboxylate.
• the mixture is treated with m-CPBA to provide benzyl 8-oxa-4-azabicyclo[5.1.0]octane-4-carboxylate.
• the epoxide is treated with sodium azide.
• the resulting product is reduced with triphenylphosphine to render a hydroxy-amine, which is coupled to an acid, such as picolinic acid, under standard amid coupling conditions, such as EDCI, ⁇ OBt, and TEA in DCM.
• the resulting hydroxy- amide is oxidized and subsequently cyclized to form a Cbz-protected 5,6,7, 8-tetrahydro- 4H-oxazolo[5,4- ⁇ i]azepine.
• the Cbz protecting group may be removed by treatment with TMSI to render the desired cyclic amine Ia-I.
• the cyclic amine Ia-I is a 2-position substituted 5,6,7,8-tetrahydro-4H-oxazolo[5,4-c]azepine, which may be prepared using procedures exemplified in Scheme 15.
• Prop-2-en-l -amine is protected with Cbz and alkylated with 5-bromopent-l-ene.
• the resulting diene is treated with Grubb's catalysis and undergoes ring closing metathesis to yield benzyl 2,3,4,7-tetrahydro-lH-azepine-l-carboxylate, which is treated with m-CPBA to provide the corresponding epoxide.
• the epoxide is treated with sodium azide.
• the resulting product is reduced with triphenylphosphine to render a hydroxy-amine, which is coupled to an acid, such as picolinic acid, under standard amid coupling conditions, such as EDCI, ⁇ OBt, and TEA in DCM.
• the resulting hydroxy-amide is oxidized and subsequently cyclized to form a Cbz-protected 5,6,7,8-tetrahydro-4H-oxazolo[5,4-(f]azepine.
• the Cbz protecting group may be removed by treatment with TMSI to render the desired cyclic amine Ia-I .
• the cyclic amine Ia-I is a 2-position substituted 5,6,7,8-tetrahydro-4H-oxazolo[4,5-c]azepine, which may be prepared using procedures exemplified in Scheme 16.
• Benzyl 4-oxoazepane-l-carboxylate is brominated to yield a bromo-ketone, which is reduced to the corresponding bromo-alcohol.
• the bromo- alcohol is reacted with sodium azide.
• the resulting product is reduced with triphenylphosphine to render a hydroxy-amine, which is coupled to an acid, such as picolinic acid, under standard amid coupling conditions, such as EDCI, ⁇ OBt, and TEA in DCM.
• the resulting hydroxy-amide is oxidized and subsequently cyclized to form a Cbz-protected 5,6,7,8-tetrahydro-4H-oxazolo[4,5-c]azepine.
• the Cbz protecting group may be removed by treatment with TMSI to render the desired cyclic amine Ia-I.
• the cyclic amine Ia-I is a 2-position substituted 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine, which may be prepared using procedures exemplified in Scheme 17.
• tert-Butyl 4-oxopiperidine-l-carboxylate is brominated to yield a bromo-ketone, which is reacted with a suitable thioamide to render the 2- substituted 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.
• the cyclic amine Ia-I is a 2-position substituted 5,6,7,8-tetrahydroimidazo[l,2- ⁇ ]pyrazine, which may be prepared using procedures exemplified in Scheme 18.
• Cbz-protected glycine is reacted with a bromomethyl ketone to yield an imidazole intermediate, which is alkylated with ethyl bromoacetate.
• the resulting product is hydrogenate under acidic conditions to remove the Cbz protecting group and cyclize.
• the resulting cyclic amide is reduced with BH 3 in THF to render the 2-substituted 5,6,7,8-tetrahydroimidazo[l,2- ⁇ ]pyrazine.
• the cyclic amine Ia-I is a 2-position substituted 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and the compound of formula (Ia) may be prepared using procedures exemplified in Scheme 19. Benzyl 4-azido-3- hydroxypiperidine-1-carboxylate, which is prepared according to the procedures in WO 1994/20062, is converted to the corresponding mesylate, which is reacted with sodium azide to form a di-azide.
• the di-azide is reduced with triphenylphosphine, and the resulting di-amine is coupled with a suitable ethyl imidate to form the imidazoline intermediate, which is oxidized to the corresponding imidazole.
• the imidazole is protected with p ⁇ ra-methoxy benzyl (PMB) group, and the Cbz protecting group is removed via hydrogenation.
• PMB p ⁇ ra-methoxy benzyl
• the amine is coupled to a suitable aryl or heteroaryl halide and the PMB protecting group is removed by TFA to render the desired compound of formula (Ia).
• the cyclic amine Ia-I is a 2-position substituted 5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5- ⁇ ]pyrazine, which may be prepared using procedures exemplified in Scheme 20.
• Cbz-protected glycine is reacted with ethyl chloroformate in the presence of 4-methylmorpholine to yield an acyl hydrazine, which is coupled with a suitable ethyl imidate to form a triazole intermediate, which is alkylated with ethyl bromoacetate.
• the resulting product is hydrogenate to remove the Cbz protecting group and cyclize.
• the resulting cyclic amide is reduced with BH 3 in THF to render the 2-substituted 5,6,7, 8-tetrahydro-[l,2,4]triazolo[l,5- ⁇ ]pyrazine.
• a compound of formula (Ib) may be prepared following Scheme 21, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 22, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 23, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 24, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 25, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 26, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 27, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 28, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 29, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 30, using suitable starting material known in the art and/or available from a commercial source.
• Scheme 30 :
• a compound of formula (Ib) may be prepared following Scheme 31, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (Ib) may be prepared following Scheme 32, using suitable starting material known in the art and/or available from a commercial source.
• Scheme 32 :
• a compound of formula (Ib) may be prepared following Scheme 33, using suitable starting material known in the art and/or available from a commercial source.
• a compound of formula (I) is prepared as a mixture of two or more stereoisomers or diastereoisomers.
• the stereoisomers or diastereoisomers are separated using techniques known to those skilled in the art, including but not limited to, chiral column chromatography and chiral resolution by forming a salt with a suitable chiral counterion.
• the compound of formula (I) is prepared following one or more stereoselective reaction(s).
• the compound of formula (I) is prepared as a substantially pure stereoisomer.
• the method comprises contacting mGluR with a compound provided herein.
• a method of modulating the activity of mGluR5 via the binding of an mGluR5 ligand to mGluR5. comprises contacting mGluR5 with a compound provided herein.
• the ligand is L-glutamate.
• the ligand is a drug molecule or another small molecule known to have binding affinity to mGluR5.
• the mGluR5 ligand is a radioactively labeled compound, known to bind to mGluR5.
• binding to metabotropic glutamate receptor may be assessed using PET imaging known in the art, e.g. utilizing appropriate PET ligands.
• the ligand is an allosteric modulator, antagonist, or inverse agonist of mGluR5.
• a method of modulating e.g., inhibiting or augmenting the activity of a metabotropic glutamate receptor, such as mGluR5.
• the method comprises contacting the receptor, such as mGluR5, with a compound provided herein, in vitro or in vivo.
• mGluR5 is contacted with a compound provided herein by administering to a subject a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or solvate thereof.
• the subject may be a human.
• the compound provided herein inhibits or reduces the activity of metabotropic glutamate receptor, such as mGluR5.
• Inhibition of mGluR5 activity may be measured using assays known in the art.
• the activity of mGluR5 is inhibited or reduced by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, as compared with the activity obtained without contacting with the compounds provided herein.
• the inhibition or reduction of receptor activity is dose-dependent.
• Exemplary assay methods include, but are not limited to, in vitro functional assays as described herein elsewhere.
• the functional assay utilizes an appropriate cell-line expressing the desired metabotropic glutamate receptor, such as mGluR5.
• the functional assay utilizes synaptosomes isolated from brain tissue of an appropriate organism.
• inhibition of metabotropic glutamate receptor activity may be assessed using receptor binding experiments known in the art, e.g. utilizing appropriate membrane preparations.
• the assay involves treatment of a test subject (e.g. a mice or a rat) with a compound provided herein as well as a reference compound, followed by isolation of brain tissue and ex vivo analysis of receptor occupancy.
• mGluR5 metabotropic glutamate receptor
• a subject e.g., human
• administering to the subject an effective amount of a compound provided herein.
• the activity of mGluR5 is inhibited or reduced by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, when measured using an assay known in the art.
• a method of inhibiting or reducing the activity of a metabotropic glutamate receptor, such as mGluR5, by a metabotropic glutamate receptor ligand comprises contacting mGluR5 receptor with an antagonist, an inverse agonist, or an allosteric modulator of the mGluR5 receptor.
• an antagonist, an inverse agonist, or an allosteric modulator of the mGluR5 receptor is a compound provided herein.
• provided herein is a method of treating, preventing, and/or managing a disorder related to mGluR5, such as a neurological, psychiatric, or neuromuscular disorder.
• the treatment, prevention, and/or management is done by inhibiting or reducing the activity of mGluR5 using a composition or a compound provided herein.
• provided herein is the use of a compound or a composition provided herein in the manufacture of a medicament for the treatment, prevention, and/or management of a disorder related to mGluR5, such as a neurological, psychiatric, or neuromuscular disorder provided herein.
• the method comprises administering to a subject (e.g., human) a therapeutically or prophylactically effective amount of a composition or a compound provided herein.
• the subject is a human.
• the compound provided herein inhibits the activity of mGluR5.
• the compounds provided herein are allosteric modulators of mGluR5.
• the compounds provided herein are antagonists of mGluR5.
• the compounds provided herein are selective for mGluR5 over other CNS -related targets.
• the compounds provided herein are highly brain penetrable in animals, such as rodents, and human.
• inhibition of mGluR5 activity may be assessed by functional assays as described herein elsewhere.
• the efficacious concentration of the compounds provided herein is less than 10 nM, less than 100 nM, less than 1 ⁇ M, less than 10 ⁇ M, less than 100 ⁇ M, or less than 1 mM.
• compound's activity may be assessed in various art-recognized animal models.
• mGluR5 modulators may be effective in the treatment and prevention of migraine in human, and may have comparable efficacy to triptans in treating migraine. See, e.g., Jaeschke, G., et al, Expert Opin. Ther. Pat. 2008, 18, 123.
• a method of treating, preventing, and/or managing a disorder related to anxiety comprising administering to a subject an effective amount of a compound provided herein.
• a disorder related to anxiety e.g., general anxiety disorder
• mGluR5 modulators may be effective in treating anxiety, and efficacious in a variety of animal models including stress-induced hyperthermia and fear-potentiated startle test. See e.g., Pecknold, J.C., et al, J. Clin. Neuropharmacol. 1982, 2, 129; Cosford, N.D.P., et al, J. Med. Chem. 2003, 46, 204.
• mGluR5 modulators may be effective in treating depression, and efficacious in a variety of animal models for depression. See, e.g., Jaeschke, G., et al, Expert Opin. Ther. Pat. 2008, 18, 123.
• a method of treating, preventing, and/or managing GERD comprising administering to a subject an effective amount of a compound provided herein.
• mGluR5 modulators may be effective in treating GERD in human. See, e.g., Jaeschke, G., et al, Expert Opin. Ther. Pat. 2008, 18, 123; Bolea C, et al, WO 2004/78728 Al.
• a method of treating, preventing, and/or managing a neurodegenerative disease including but not limited to, Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Alzheimer's disease, and amyotropic lateral sclerosis, comprising administering to a subject an effective amount of a compound provided herein.
• mGluR5 modulators may be effective in treating Parkinson's disease, and efficacious in a variety of animal models for Parkinson's disease. See, e.g., Jaeschke, G., et al, Expert Opin. Ther. Pat.
• provided herein is a method of treating, preventing, and/or managing pain, including but not limited to, inflammatory pain, neuropathic pain, postoperative pain, acute thermal hyperalgesia, mechanical allodynia, visceral pain, and chronic pain, comprising administering to a subject an effective amount of a compound provided herein. See e.g., Jaeschke, G., et al, Expert Opin. Ther. Pat. 2008, 18, 123; Cosford, N.D.P., et al, WO 2003/51315 A2.
• provided herein is a method of treating, preventing, and/or managing post-traumatic stress disorder, comprising administering to a subject an effective amount of a compound provided herein. See e.g., Bach, P., et al, Expert Opin. Ther. Patents 2007, 17, 371.
• provided herein is a method of treating, preventing, and/or managing schizophrenia, comprising administering to a subject an effective amount of a compound provided herein. See e.g., Bach, P., et al, Expert Opin. Ther. Patents 2007, 17, 371; Jaeschke, G., et al, Expert Opin. Ther. Pat. 2008, 18, 123.
• a method of treating, preventing, and/or managing fragile X syndrome comprising administering to a subject an effective amount of a compound provided herein. See e.g., Jaeschke, G., et al, Expert Opin. Ther. Pat. 2008, 18, 123.
• provided herein is a method of treating, preventing, and/or managing substance abuse/addiction, including but not limited to the abuse/addiction of cocaine, morphine, opioid, nicotine, and alcohol, comprising administering to a subject an effective amount of a compound provided herein. See e.g., Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123.
• provided herein is a method of treating, preventing, and/or managing epilepsy, comprising administering to a subject an effective amount of a compound provided herein. See e.g., Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123.
• provided herein is a method of treating, preventing, and/or managing a neurological disorder as defined herein elsewhere, comprising administering to a subject an effective amount of a compound provided herein.
• a method of treating, preventing, and/or managing a lower urinary tract disorder as defined herein elsewhere comprising administering to a subject an effective amount of a compound provided herein.
• a method of treating, preventing, and/or managing cancer including but not limited to, oral cancer and glioneuronal cancer, comprising administering to a subject an effective amount of a compound provided herein.
• the compounds provided herein are active in at least one model, which can be used to measure the activity of the compounds and estimate their efficacy in treating a disorder related to mGluR5.
• the model is for depression ⁇ e.g., mean immobility
• the compounds are active when they inhibit mean immobility of a test subject by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, or more, when compared to vehicle.
• the compounds provided herein produce a similar disparity in measured endpoint between treated animals and animals administered vehicle.
• a method of effecting a therapeutic effect as described herein elsewhere comprises administering to a subject ⁇ e.g., a mammal) a therapeutically effective amount of a compound or a composition provided herein.
• a subject e.g., a mammal
• the particular therapeutic effects may be measured using any model system known in the art or described herein, such as those involving an animal model of a disease.
• the disorder related to mGluR5 is migraine, anxiety (e.g., general anxiety disorder, social anxiety disorder, panic disorder, and dental phobia), depression (e.g., major depressive disorder, bipolar disorder, unipolar disorder, dysthymia and seasonal affective disorder), pain (e.g., inflammatory pain, neuropathic pain, postoperative pain, acute thermal hyperalgesia, mechanical allodynia, visceral pain, and chronic pain), neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, levodopa- induced dyskinesia, Huntington's disease, and amyotropic lateral sclerosis), epilepsy, seizure, psychosis, schizophrenia, substance abuse/addiction (e.g., cocaine, nicotine, morphine, opioid, or alcohol abuse/addiction), bulimia, anorexia, obsessive compulsive disorder, aggression, post-traumatic stress disorder, autism, fragile X syndrome, excessive
• Neurological disorders include cerebral function disorders, including without limitation, senile dementia, Alzheimer's type dementia, cognition, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, Lennox syndrome, autism, and hyperkinetic syndrome.
• Neuropathic pain includes without limitation post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy/causalgia or nerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy arising from chronic alcohol use).
• exemplary diseases and conditions that may be treated, prevented, and/or managed using the methods, compounds, and/or compositions provided herein include, but are not limited to: obesity; migraine or migraine headache; urinary incontinence, including without limitation involuntary voiding of urine, dribbling or leakage of urine, stress urinary incontinence (SUI), urge incontinence, urinary exertional incontinence, reflex incontinence, passive incontinence, and overflow incontinence; and sexual dysfunction, in men or women, including without limitation sexual dysfunction caused by psychological and/or physiological factors, erectile dysfunction, premature ejaculation, vaginal dryness, lack of sexual excitement, inability to obtain orgasm, and psycho-sexual dysfunction, including without limitation, inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction.
• the neurological disorder is cognitive impairment.
• the neurological disorder is mood disorders.
• the neurological disorder is movement disorders.
• the neurological disorder is schizophrenia.
• the neurological disorder is attention disorders.
• the neurological disorder is anxiety disorder.
• the neurological disorder is seizure.
• the neurological disorder is epilepsy.
• the neurological disorder is vertigo.
• the neurological disorder is pain.
• the neurological disorder is neuropathic pain.
• the neuropathic pain is diabetic neuropathy.
• the neurological disorder is a neurodegenerative disease.
• the neurodegenerative disease is Parkinson's disease.
• the neurodegenerative disorder is levodopa-induced dyskinesia.
• the neurodegenerative disorder is Alzheimer's disease.
• the neurodegenerative disorder is Huntington's disease.
• the compounds described herein treat, prevent, and/or manage a central nervous disorder, without causing addiction to said compounds.
• Any suitable route of administration can be employed for providing the patient with a therapeutically or prophylactic ally effective dose of an active ingredient.
• oral, mucosal e.g., nasal, sublingual, buccal, rectal, vaginal
• parenteral e.g., intravenous, intramuscular
• transdermal, and subcutaneous routes can be employed.
• routes of administration include oral, transdermal, and mucosal.
• Suitable dosage forms for such routes include, but are not limited to, transdermal patches, ophthalmic solutions, sprays, and aerosols.
• Transdermal compositions can also take the form of creams, lotions, and/or emulsions, which can be included in an appropriate adhesive for application to the skin or can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• An exemplary transdermal dosage form is a "reservoir type” or “matrix type” patch, which is applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient.
• the patch can be replaced with a fresh patch when necessary to provide constant administration of the active ingredient to the patient.
• the amount to be administered to a patient to treat, prevent, and/or manage the disorders described herein will depend upon a variety of factors including the activity of the particular compound employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount required. For example, the physician or veterinarian could start doses of the compounds employed at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• a suitable daily dose of a compound provided herein will be that amount of the compound which is the lowest dose effective to produce a therapeutic or prophylactic effect. Such an effective dose will generally depend upon the factors described above.
• oral, intravenous, intracerebroventricular, and subcutaneous doses of the compounds provided herein for a patient will range from about 0.005 mg per kilogram to about 5 mg per kilogram of body weight per day.
• the oral dose of a compound provided herein will range from about 10 mg to about 300 mg per day.
• the oral dose of a compound provided herein will range from about 20 mg to about 250 mg per day.
• the oral dose of a compound provided herein will range from about 100 mg to about 300 mg per day.
• the oral dose of a compound provided herein will range from about 10 mg to about 100 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 25 mg to about 50 mg per day. In another embodiment, the oral dose of a compound provided herein will range from about 50 mg to about 200 mg per day.
• Each of the above -recited dosage ranges may be formulated as a single or multiple unit dosage formulations. [00267] In some embodiments, the compounds disclosed herein may be used in combination with one or more second active agents to treat, prevent, and/or manage disorders described herein. 4. Pharmaceutical Compositions and Dosage Forms
• compositions can be used in the preparation of individual, single unit dosage forms.
• Pharmaceutical compositions and dosage forms provided herein comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, clathrate, or prodrug thereof.
• Pharmaceutical compositions and dosage forms can further comprise one or more excipients.
• compositions and dosage forms provided herein can also comprise one or more additional active ingredients. Examples of optional second, or additional, active ingredients are also disclosed herein.
• Single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient.
• mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
• parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
• topical e.g., eye drops or other ophthalmic preparations
• transdermal or transcutaneous administration e.g., transcutaneous administration to a patient.
• dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in- water emulsions, or a water-in- oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
• suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in- water emul
• compositions, shape, and type of dosage forms will typically vary depending on their use.
• a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
• a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease.
• Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water.
• lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
• Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002).
• lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
• lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
• anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
• water e.g., 5%
• water e.g., 5%
• water and heat accelerate the decomposition of some compounds.
• the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
• Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
• Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
• anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are, in one embodiment, packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
• compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
• Such compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
• antioxidants such as ascorbic acid, pH buffers, or salt buffers.
• the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
• dosage forms comprise a compound provided herein in an amount of from about 0.10 to about 500 mg.
• dosage forms comprise a compound provided herein in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
• dosage forms comprise the second active ingredient in an amount of 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg.
• the specific amount of the second active agent will depend on the specific agent used, the diseases or disorders being treated or managed, and the amount(s) of a compound provided herein, and any optional additional active agents concurrently administered to the patient.
• compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
• dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).
• Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
• excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
• excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
• oral dosage forms are tablets or capsules, in which case solid excipients are employed.
• tablets can be coated by standard aqueous or non-aqueous techniques.
• Such dosage forms can be prepared by any of the methods of pharmacy.
• pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
• a tablet can be prepared by compression or molding.
• Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
• Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
• Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.
• microcrystalline cellulose examples include, but are not limited to, the materials sold as AVICEL-PH- 101, AVICEL-PH-103 AVICEL RC-581, AVICEL- PH- 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
• An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC- 581.
• Suitable anhydrous or low moisture excipients or additives include AVICEL-PH- 103TM and Starch 1500 LM.
• fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
• the binder or filler in pharmaceutical compositions is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
• Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one embodiment, pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, or from about 1 to about 5 weight percent of disintegrant.
• Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
• Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
• hydrogenated vegetable oil e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil
• zinc stearate ethyl oleate, ethyl laureate, agar, and mixtures thereof.
• Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
• AEROSIL200 syloid silica gel
• a coagulated aerosol of synthetic silica marketed by Degussa Co. of Piano, TX
• CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
• lubricants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
• a solid oral dosage form comprises a compound provided herein, and optional excipients, such as anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
• excipients such as anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
• Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference.
• Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
• Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active agents provided herein.
• provided are single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
• controlled-release pharmaceutical products improve drug therapy over that achieved by their non-controlled counterparts.
• use of a controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
• Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
• controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
• the controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
• the drug in order to maintain a constant level of drug in the body, the drug can be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
• Controlled- release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
• Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial.
• administration of a parenteral dosage form bypasses patients' natural defenses against contaminants, and thus, in these embodiments, parenteral dosage forms are sterile or capable of being sterilized prior to administration to a patient.
• parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
• Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
• aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
• Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms.
• cyclodextrin and its derivatives can be used to increase the solubility of a compound provided herein. See, e.g., U.S. Patent No. 5,134,127, which is incorporated herein by reference.
• Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
• excipients e.g., carriers and diluents
• excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable.
• Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms. Examples of additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990).
• the pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients.
• the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
• Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
• stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, or as a delivery-enhancing or penetration-enhancing agent.
• salts, solvates, prodrugs, clathrates, or stereoisomers of the active ingredients can be used to further adjust the properties of the resulting composition.
• active ingredients provided herein are not administered to a patient at the same time or by the same route of administration.
• kits which can simplify the administration of appropriate amounts of active ingredients.
• kits comprises a dosage form of a compound provided herein.
• Kits can further comprise one or more second active ingredients as described herein, or a pharmacologically active mutant or derivative thereof, or a combination thereof.
• kits can further comprise devices that are used to administer the active ingredients.
• devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
• Kits can further comprise cells or blood for transplantation as well as pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
• the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
• Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water- miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
• water for Injection USP Water for Injection USP
• aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
• water- miscible vehicles such as
• Me means methyl
• Et means ethyl
• Ac means acetyl
• BINAP means 2,2'-bis(diphenylphosphino)-l,l'- binaphthyl
• Dess-Martin reagent means l,l,l-tris(acetyloxy)-l,l-dihydro-l,2- benziodoxol-3-(lH)-one
• DCM means dichloromethane
• DIEA means diisopropylethylamine
• DMF means dimethylformamide
• EDCI means N-(3- dimethylaminopropyl)-iV'-ethylcarbodiimide hydrochloride
• EtOAc means ethyl acetate
• EtOH means ethanol
• ⁇ OBt means hydroxybenzotriazole
• the title compound was prepared via the procedure used for Compound 60, using benzyl 2-(3-cyanophenyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylate instead of benzyl 2-m-tolyl-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate.
• Benzyl 2-(3-cyanophenyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylate was prepared via the procedure used for 1-1.3, using 3-cyanobenzoic acid instead of picolinic acid.
• the title compound was prepared via the procedure used for Compound 63, using 2-(2-chlorophenyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine instead of 3-(4,5,6,7- tetrahydro-oxazolo[4,5-c]pyridin-2-yl)-benzonitrile.
• 2-(2-Chlorophenyl)-4,5,6,7- tetrahydrooxazolo[5,4-c]pyridine was prepared via the procedure used for 1-1.4, using 2- chlorobenzoic acid instead of picolinic acid.
• Compound 70 2-(4-Chlorophenyl)-5-(pyridin-2-yl)-4,5,6,7- tetrahvdrooxazolo [5 ,4-c] pyridine
• the title compound was prepared via the procedure used for Compound 60, using benzyl 2-(4-chlorophenyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylate instead of benzyl 2-m-tolyl-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate.
• Benzyl 2-(4-chlorophenyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylate was prepared via the procedure used for 1-1.3, using 4-chlorobenzoic acid instead of picolinic acid.
• the title compound was prepared via the procedure used for Compound 64, using 2-(pyridin-4-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine instead of 3-(4,5,6,7- tetrahydro-oxazolo[4,5-c]pyridin-2-yl)benzonitrile.
• 2-(Pyridin-4-yl)-4,5,6,7-tetrahydro- oxazolo[5,4-c]pyridine was prepared via the procedure used for 1-1.4, using isonicotinic acid instead of picolinic acid.
• the title compound was prepared via the procedure used for Compound 76, using benzyl 2-(pyridin-3-yl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylate instead of benzyl 2-(4-methylpyridin-2-yl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)- carboxylate.
• Benzyl 2-(pyridin-3-yl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)- carboxylate was prepared via the procedure used for 1-1.3, using nicotinic acid instead of picolinic acid.
• the title compound was prepared via the procedure used for Compound 76, using benzyl 2-(pyridin-4-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate instead of benzyl 2-(4-methylpyridin-2-yl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)- carboxylate.
• Benzyl 2-(pyridin-4-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)- carboxylate was prepared via the procedure used for 1-23.3, using isonicotinic acid instead of picolinic acid.
• the title compound was prepared via the procedure used for Compound 60, using benzyl 2-(3-methylisoxazol-5-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)- carboxylate instead of benzyl 2-m-tolyl-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)- carboxylate.
• Benzyl 2-(3-methylisoxazol-5-yl)-6,7-dihydrooxazolo[4,5-c]pyridine- 5(4H)-carboxylate was prepared via the procedure used for 1-23.3 using 3- methylisoxazole-5-carboxylic acid instead of picolinic acid.

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