COMBINATION THERAPIES INCLUDING METAL CHANNEL ACTIVATORS

CROSS-REFERENCE TO RELATED APPLICATION

[001] This international Patent Application claims priority to United States Provisional Patent Application No. 63/403,911, filed September 6, 2022, which is incorporated by reference in its entirety herein.

TECHNICAL FIELD

[002] The present invention relates to combination therapies for treatment of various medical conditions. Specifically, the present invention relates to a combination of a metal channer activator and a glutamate modulator for treatment of neurological and neurodegenerative disorders.

BACKGROUND

[003] Metal channel activators (openers) are associated with a wide range of physiological functions including the regulation of the electrical properties of excitable cells. Metal channels control the follow of metal ions such as Potassium (K ⁺ ) and Sodium (Na ⁺ ) across a cell membrane. A primary function of these channels in the brain is to regulate the neuronal action potential. Several neurologic disorders are potentially due to dysregulation of metal channels.

[004] Potassium (K ⁺ ) channels, present on the plasma membranes of most cell types, are the most diverse class of all ion channels. Potassium channels of the Kv7 family of voltage-gated potassium (K ⁺ ) channels are of particular therapeutic interest due to their importance in neurological conditions such as excitability disorders including Amyotrophic lateral sclerosis (ALS). There are five members of the Kv7 family of voltage-gated potassium (K ⁺ ) channels, including Kv7.1, Kv7.2, Kv7.3, Kv7.4, and Kv7.5.

[005] Metal channel activators have been reported to be useful for treatment of various neurological and neurodegenerative disorders. Thus far, only one metal channel activator, Retigabine, has been FDA approved. Retigabine is used as anticonvulsant for the treatment of epilepsy. Further Kv7 channel activators have been proposed for the treatment of many conditions including substance abuse and mood disorders (Vigil FA, Carver CM, Shapiro MS. Pharmacological Manipulation of K v 7 Channels as a New Therapeutic Tool for Multiple Brain Disorders. Front Physiol. 2020 Jun 19; 11 :688. doi:

10.3389/fphys.2020.00688). There remains a need, however, for new therapies utilizing Kv7. One solution is combining metal channel activators with other therapeutic agents to significantly improve treatment outcomes.

[006] Glutamate is a neurotransmitter associated with several types of receptors throughout the central nervous system. Some of these receptors include ionotropic receptors and metabotropic receptors. Ionotropic glutamate receptors include NMD A, AMPA and kainite. Metabotropic glutamate receptors include those from group 1 receptors including mGluRl and mGluR5; group II including mGluR2 and mGluR3; and group III including mGluR4, mGluR6, mGluR7, and mGluR8. Glutamate transporters may be expressed in glia or in neurons.

[007] Described herein are compositions and methods for combination therapies of Kv7 openers with glutamate modulators. The combination therapies have treatment capabilities greater than Kv7 openers or glutamate modulators alone, and may be particularly useful for depressive disorders and neurological or neurodegenerative diseases. Pharmaceutical compositions combining these agents may also be useful for treatment of a pain and related neurological or neurodegenerative conditions. These two agents target distinct molecular targets associated with depressive disorders, pain disorders, neurological diseases and neurodegenerative disorders. Specifically, the Kv7 channel opener reduces excitability, and glutamate modulators indirectly or directly affect various aspects of glutamate-associated receptors, for example in the glutamatergic synapse or other physiologically-relevant locations. We have found that combining Kv7 opener and an glutamate modulator will yield improved treatment outcomes as described herein.

SUMMARY

[008] The present invention is directed to combination therapies including a metal channel activator and a glutamate modulator.

[009] In an embodiment, provided is a pharmaceutical composition including a metal channel activator and a glutamate modulator.

[0010] In another embodiment, provided is a method of treating a depressive disorder, including administering the pharmaceutical composition. [0011] In another embodiment, provided is a method of treating a neurological or neurodegenerative disorder, including administering the pharmaceutical composition.

[0012] In another embodiment, provided is a method of treating a pain disorder, including administering the pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] These and/or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings in which:

[0014] FIG. 1 depicts a regression for determination of Kv7 activator ED50.

[0015] FIG. 2 depicts a regression for determination of glutamate modulator ED50.

[0016] FIG. 3 depicts an isobologram for Kv7 activator and glutamate modulator combination therapies.

[0017] FIG. 4 depicts a percent protection observed at varying Kv7 and glutamate modulator ratios.

DETAILED DESCRIPTION

[0018] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Exemplary embodiments will hereinafter be described in detail. However, these embodiments are only exemplary, and the present disclosure is not limited thereto but rather is defined by the scope of the appended claims. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure.

[0019] Accordingly, the embodiments are merely described below, by referring to structures and schemes, to explain aspects of the present description. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and/or." Expressions such as "at least one of," when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0020] It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers, and/or sections, these elements, components, regions, layers, and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below could be termed a second element, component, region, layer, or section without departing from the teachings of the present embodiments.

[0021] It is understood that the terms "comprises" and/or "comprising," or "includes" and/or "including" when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting. It will be further understood that the terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0023] As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present invention.

[0024] The articles "a" and "an" refer to one or to more than one (z.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0025] As used herein, when specific definition is not otherwise provided, the term "substituted" refers to a group substituted with deuterium, a halogen (-F, -Cl, -Br, -I), a hydroxy group (-OH), an amino group (-NH2), a carboxyl group (-CO2H), a substituted or unsubstituted C1-C10 amine group, a nitro group (-NO2), a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C12 aryl group, a Cl -CIO alkoxy group, a Cl to CIO trifluoroalkyl group such as a trifluorom ethyl group (-CF3) and the like, or a cyano group (-CN) instead of at least one hydrogen of a substituting group or compound. For example, if a compound is a substituted variant, or a substituted variant retaining glutamate modulatory activity, it should be appreciated that at least one, two, or three these substitutions are expressly contemplated. In the context of a given Formula, additional types of substitutions may be contemplated.

[0026] As used herein, “modulator”, “modulators”, and “modulating”, when describing compounds, describe compounds that may enact their effect through a number of mechanisms of action including but not limited to: binding to the active site of a protein, binding to a region of the protein away from the active site, causing relocalization of a protein, inducing degradation of a protein, inducing stabilization of a protein, causing a conformational change in a protein, decreasing the activation threshold for a protein, increasing the activation threshold for a protein, altering posttranslational modifications for a protein, reducing the transcription of a gene, increasing the transcription of a gene, reducing the translation of an mRNA transcript, increasing the translation of an mRNA transcript, disrupting an interaction between two proteins, and stabilizing an interaction between two proteins; wherein the protein may be the target of modulation or an intermediary protein which is associated with modulation of the target protein. Modulators of the targets described herein (i.e., Kv7 and glutamate receptor) may each or both be small molecule compounds, proteins, antibody fragments or antibodies, or any other construct effecting modulation.

[0027] As used herein, “neurological disease” refers to a disease or disorder which affects the brain and/or nerves found elsewhere in the body. Such neurologic diseases may include: Absence of the Septum Pellucidum, Acid Lipase Disease, Acute Disseminated Encephalomyelitis, Adrenoleukodystrophy, Agenesis of the Corpus Callosum, Agnosia, Aicardi Syndrome, Aicardi-Goutieres Syndrome, Alexander Disease, Alpers' Disease, Alternating Hemiplegia, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), Anencephaly, Angelman Syndrome, Antiphospholipid Syndrome, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis, Arteriovenous Malformation, Asperger Syndrome, Ataxia Telangiectasia, Ataxias and Cerebellar or Spinocerebellar Degeneration, Atrial Fibrillation and Stroke, Attention Deficit-Hyperactivity Disorder, Autism Spectrum Disorder, Back Pain, Barth Syndrome, Batten Disease, Behcet's Disease, Bell's Palsy, Benign Essential Blepharospasm, Binswanger's Disease, Brachial Plexus Injuries, Brain and Spinal Tumors, Brown-Sequard Syndrome, CADASIL, Canavan Disease, Carpal Tunnel Syndrome, Central Cord Syndrome, Central Pain Syndrome, Central Pontine Myelinolysis, Cephalic Disorders, Cerebellar Degeneration, Cerebellar Hypoplasia, Cerebral Aneurysms, Cerebral Arteriosclerosis, Cerebral Atrophy, Cerebral Cavernous Malformation, Cerebral Hypoxia, Cerebral Palsy, Cerebro-Oculo-Facio-Skeletal Syndrome (COFS), Charcot-Marie-Tooth Disease, Chiari Malformation, Chorea, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Pain, Coffin Lowry Syndrome, Colpocephaly, Coma, Complex Regional Pain Syndrome, Congenital Myasthenia, Congenital Myopathy, Corticobasal Degeneration, Craniosynostosis, Creutzfeldt-Jakob Disease, Cushing's Syndrome, Dandy-Walker Syndrome, Deep Brain Stimulation for Movement Disorders, Dementia, Dementia With Lewy Bodies, Dermatomyositis, Developmental Dyspraxia, Diabetic Neuropathy, Dravet Syndrome, Dysautonomia, Dysgraphia, Dyslexia, Dyssynergia Cerebellaris Myoclonica, Dystonia, Empty Sella Syndrome, Encephalitis Lethargica, Encephaloceles, Encephalopathy, Epilepsy, Erb-Duchenne and Dejerine-Klumpke Palsies, Essential Tremor, Fabry Disease, Fahr's Syndrome, Familial Periodic Paralyses, Farber's Disease, Febrile Seizures, Fibromuscular Dysplasia, Foot Drop, Friedreich Ataxia, Frontotemporal Dementia, Functional Neurologic Disorder, Gaucher Disease, Generalized Gangliosidoses, Gerstmann's Syndrome, Gerstmann-Straussler-Scheinker Disease, Giant Axonal Neuropathy, Glossopharyngeal Neuralgia, Guillain-Barre Syndrome, Headache, Hemicrania Continua, Hemifacial Spasm, Hereditary Neuropathies, Hereditary Spastic Paraplegia, Herpes Zoster Oticus, Holmes-Adie Syndrome, Holoprosencephaly, Huntington's Disease, Hydranencephaly, Hydrocephalus, Hydromyelia, Hypersomnia, Hypertonia, Hypotonia, Inclusion Body Myositis, Incontinentia Pigmenti, Infantile Neuroaxonal Dystrophy, Infantile Refsum Disease, Infantile Spasms, Inflammatory Myopathies, Iniencephaly, Isaacs' Syndrome, Joubert Syndrome, Kearns-Sayre Syndrome, Kennedy's Disease, Kleine-Levin Syndrome, Klippel-Feil Syndrome, Klippel-Trenaunay Syndrome (KTS), Kliiver-Bucy Syndrome, Krabbe Disease, Kuru, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome, Learning Disabilities, Leigh's Disease, Lennox-Gastaut Syndrome, Lesch-Nyhan Syndrome, Leukodystrophy, Lipid Storage Diseases, Lipoid Proteinosis, Lissencephaly, Locked-In Syndrome, Machado- Joseph Disease and Spinocerebellar Ataxia, Megalencephaly, Melkersson-Rosenthal Syndrome, Meningitis and Encephalitis, Menkes Disease, Meralgia Paresthetica, Metachromatic Leukodystrophy, Microcephaly, Migraine, Miller Fisher Syndrome, Mitochondrial Myopathies, Moebius Syndrome, Monomelic Amyotrophy, Motor Neuron Diseases, Moyamoya Disease, Mucolipidoses, Mucopolysaccharidoses, Multi-Infarct Dementia, Multifocal Motor Neuropathy, Multiple Sclerosis, Multiple System Atrophy, Multiple System Atrophy with Orthostatic Hypotension, Muscular Dystrophy, Myasthenia Gravis, Myoclonus, Myopathy, Myotonia, Myotonia Congenita, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with Brain Iron Accumulation, Neurofibromatosis, Neuroleptic Malignant Syndrome, Neurological Complications of AIDS, Neurological Complications of Lyme Disease, Neurological Consequences of Cytomegalovirus Infection, Neurological Sequelae Of Lupus, Neuromyelitis Optica, Neuronal Migration Disorders, Neurosarcoidosis, Neurosyphilis, Neurotoxicity, Niemann-Pick Disease, Normal Pressure Hydrocephalus, Occipital Neuralgia, Ohtahara Syndrome, Olivopontocerebellar Atrophy, Opsoclonus Myoclonus, Orthostatic Hypotension, Paraneoplastic Syndromes, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis, Paroxysmal Hemicrania, Parry-Romberg Syndrome, Pelizaeus-Merzbacher Disease, Peripheral Neuropathy, Periventricular Leukomalacia, Pervasive Developmental Disorders, Pinched Nerve, Piriformis Syndrome, Pituitary Tumors, Polymyositis, Pompe Disease, Porencephaly, Post-Polio Syndrome, Postural Tachycardia Syndrome, Primary Lateral Sclerosis, Progressive Multifocal Leukoencephalopathy, Progressive Supranuclear Palsy, Prosopagnosia, Pseudotumor Cerebri, Rasmussen's Encephalitis, Refsum Disease, Repetitive Motion Disorders, Restless Legs Syndrome, Rett Syndrome, Reye's Syndrome, Sandhoff Disease, Schilder's Disease, Schizencephaly, Septo-Optic Dysplasia, Shaken Baby Syndrome, Shingles, Sjogren's Syndrome, Sleep Apnea, Sotos Syndrome, Spasticity, Spina Bifida, Spinal Cord Infarction, Spinal Cord Injury, Spinal Muscular Atrophy, Stiff-Person Syndrome, Striatonigral Degeneration, Stroke, Sturge-Weber Syndrome, Subacute Sclerosing Panencephalitis, SUNCT Headache, Swallowing Disorders, Sydenham Chorea, Syncope, Syringomyelia, Tabes Dorsalis, Tardive Dyskinesia, Tarlov Cysts, Tay-Sachs Disease, Tethered Spinal Cord Syndrome, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Todd's Paralysis, Tourette Syndrome, Transient Ischemic Attack, Transmissible Spongiform Encephalopathies, Transverse Myelitis, Traumatic Brain Injury, Tremor, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Troyer Syndrome, Tuberous Sclerosis, Vasculitis Syndromes of the Central and Peripheral Nervous Systems, Von Hippel-Lindau Disease (VHL), Wallenberg's Syndrome, Wernicke-Korsakoff Syndrome, Whiplash, Whipple's Disease, Williams Syndrome, Wilson Disease, and Zellweger Syndrome.

[0028] As used herein, the term “metal channel activator” is construed to include both metal channel activator and pharmaceutically acceptable salt thereof.

[0029] As used herein, the term “glutamate modulator” is construed to include both glutamate modulator compounds and pharmaceutically acceptable salts thereof.

[0030] As used herein, the term “AUC” is the definite integral of the concentration of a drug in blood, cerebrospinal fluid, target organ, or any other physiologically relevant site after a dose is given as a function of time. AUC in this context is used to measure the total exposure to the drug across time. AUC can be evaluated over a definite time interval or estimated based on the integral drug concentrations measured over a time interval extrapolated to infinite time.

[0031] As used herein, the term “Cmax” is the highest concentration of a drug in the blood, cerebrospinal fluid, target organ, or any other physiologically relevant site after a dose is given.

[0032] As used herein, the term “Tmax” is the time taken after administration for a drug to reach its highest concentration in the blood, cerebrospinal fluid, target organ, or any other physiologically relevant site after a dose is given.

[0033] As used herein, the term “proteinopathies” refers to diseases characterized by an accumulation or aggregation of a single protein, or multiple proteins. Proteinopathies include but are not limited to: Creutzfeldt-Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, Amyotrophic lateral sclerosis (ALS), Frontotemporal Lobar Degeneration, and Lewy Body Dementia.

[0034] Additional aspects will be set forth in part of the description which follows and, in part, will be apparent from the description.

[0035] In the formulas set forth below, it is set out with substituents and definitions, and it should be clear to the reader that substituents and definitions are numbered (e.g., Rl, R2, Y, etc.) and are intended to apply within a given formula. Numberings that are repeated across formulas are intentional and should be each read within the context of each particular formula.

METAL CHANNEL ACTIVATOR

[0036] Examples of metal channel activators including Kv7 channel activators are disclosed in Formulas 1 - 171, the “Further embodiments” section, and in the corresponding referenced applications.

Formula 1

[0037] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 1. Such compounds are described in US Patent No 9,481,653, issued November 1, 2016, and corresponding to US Application No. 14/853,815 filed September 14, 2015; and US Publication No 20210188782A1, published June 24, 2021, and corresponding to US Application No. 17/127,231 filed December 18, 2020; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 1, these references incorporated by reference herein control.

[0038] In an embodiment, the Kv7 channel activator is a compound according to formula 1 : Formula 1 wherein D is optionally substituted C3-6 carbocyclyl, optionally substituted C2-5 heterocyclyl, isopropyl, or t-butyl; Bz is optionally substituted benzoimidazol-l,2-diyl; A is C1-8 alkyl; X is F; and Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0039] In further embodiments, D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t- butyl.

[0040] In further embodiments, D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t- butyl, wherein each substituent of D and Y, if present, independently has a molecular weight of 15 Da to 200 Da and consists of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0041] In another embodiment, the Kv7 channel activator is a compound according to formula 1 wherein, D is optionally substituted C3-6 carbocyclyl, optionally substituted C2-5 heterocyclyl, isopropyl, or t-butyl; Bz is optionally substituted benzoimidazol-l,2-diyl; A is C1-8 alkyl; X is H, F, CF3, optionally substituted phenyl, or optionally substituted pyridinyl; and Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0042] In further embodiments, D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t- butyl. [0043] In further embodiments, each substituent of D, X, and Y, if present, independently has a molecular weight of 15 Da to 200 Da and consists of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0044] In further embodiments, R ¹ is H, Cl, Br, CN, OCH3, CF3, — CO2CH2CH3, C1-4 alkyl, or Ci -4 hydroxy alkyl.

[0045] In further embodiments, X is optionally substituted phenyl.

[0046] In further embodiments, X is CF3.

[0047] In further embodiments, X is optionally substituted pyridinyl.

[0048] In further embodiments, X is H.

[0049] In further embodiments, Y is H.

[0050] In further embodiments, Y is OH.

[0051] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:

Formula 2

[0052] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 2. Such compounds are described in US Patent No. 9,481,653 issued November 1, 2016 and corresponding to US Application No. US14/853,815 filed September 14, 2015; US Patent No. 9,914,708, issued March 13, 2018 and corresponding to US Application No. 15/339,590 filed October, 31; US patent No 10,385,025, issued August 20, 2019 and corresponding to US Application No. 15/879,792 filed January 25, 2018; US Patent No. 10,906,877 issued on February 2, 2021 and corresponding to US Application No. 16/460,449 filed July 2, 2019; US Patent No. 10,851,067 issued on December 1, 2020 and corresponding to US Application No. 16/358,642 filed March 19, 2019; US Patent No. 11,261,162 issued on March 1, 2022 and corresponding to US Application No. 17/077,068 filed October 22, 2020; US Publication No. 20210188782A1, published June 24, 2021 and corresponding to US Application No. 17/127,231 filed December 18, 2020; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 2, these references incorporated by reference herein control.

[0053] In an embodiment, the Kv7 channel activator is a compound according to formula 2:

Formula 2 wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl; A is C2-8 alkyl;

X is H, F, CF3 optionally substituted phenyl, or optionally substituted pyridinyl; Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; R ¹ is F, Cl, Br, CN, OCH3, CHF ₂ , CF ₃ , C1-4— CO ₂ -alkyl, C1-4 alkyl, — CH ₂ CO ₂ H, — CH ₂ CO ₂ CH ₂ CH3 or — CH ₂ CON(CH3) ₂ , or C1-5 hydroxyalkyl; and R ² , R ³ , and R ⁴ are independently H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0054] In further embodiments, Y is H, F, CF3, OH, C1-5 O-alkyl, Co-6 alkylamino, optionally substituted tetrahydropyranyl, or Co-6 fluoroalkylamino.

[0055] In further embodiments R ¹ is Cl, Br, — OCH3, — CN, — CF3, — CH ₂ OH, — COOCH ₂ CH ₃ , — C(CH ₃ ) ₂ OH, — CHOHCH ₂ CH ₃ , — CHOHCH3, — CHF ₂ , — CH(CH ₃ ) ₂ , — C(CH ₂ CH ₃ ) ₂ OH, — CH ₂ COOCH ₂ CH ₃ , — CH ₂ C(CH ₃ ) ₂ OH, — CH ₂ COOH, or — CH ₂ CON(CH ₃ ) ₂ .

[0056] In further embodiments, R ² is H, F, — CH ₂ OH, — CO ₂ Me, or — C(CH3) ₂ OH.

[0057] In further embodiments, R ³ is H.

[0058] In further embodiments, R ⁴ is H, — CH3, or — CF3.

[0059] In further embodiments, R ¹ is Cl, Br, CN, OCH3, CF3, — CO ₂ CH ₂ CH3, Ci- ₄ alkyl, or Ci- ₄ hydroxy alkyl.

[0060] In further embodiments, X is optionally substituted phenyl.

[0061] In further embodiments, X is CF3.

[0062] In further embodiments, X is optionally substituted pyridinyl.

[0063] In further embodiments, X is H.

[0064] In further embodiments, Y is H.

[0065] In further embodiments, Y is OH.

[0066] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:

[0067] In further embodiments, the Kv7 channel activator is a compound according to formula 2 wherein, D is optionally substituted cyclobutyl, or t-butyl; A is C2-8 alkyl; X is H, CF3, or optionally substituted phenyl; Y is H or OH; R ¹ is CN or C1-4 hydroxyalkyl; and R ² , R ³ , and R ⁴ are independently H, or F.

[0068] In further embodiments, R ¹ is CN, — C(CH3)2OH, or — CH2C(CH3)2OH.

[0069] In further embodiments, R ² is F.

[0070] In further embodiments, R ³ is H.

[0071] In further embodiments, R ⁴ is H.

[0072] In further embodiments, R ¹ is CN. [0073] In further embodiments, R ¹ is C 1-4 hydroxy alkyl.

[0074] In further embodiments, X is optionally substituted phenyl.

[0075] In further embodiments, X is CF3.

[0076] In further embodiments, X is H.

[0077] In further embodiments, Y is H.

[0078] In further embodiments, Y is OH.

[0079] In further embodiments, the Kv7 channel activator is a compound according to formula 2 wherein, D is cyclobutyl; A is C1-8 alkyl; X is CF3; Y is H; R ¹ is H, Cl, Br, CN, 0CH3, CF ₃ , — CO2CH2CH3, C1-4 alkyl, or Ci- ₄ hydroxy alkyl; R ² is H, F, — CH ₂ OH, — CO2Me, or — C(CH3)2OH; R ³ is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and R ⁴ is H, — CH3, or — CF3; or

D is optionally substituted cyclobutyl; A is C1-8 alkyl; X is CF3; Y is H; R ¹ is H, Cl, Br, CN, OCH3, CF ₃ , — CO2CH2CH3, C1-4 alkyl, or Ci- ₄ hydroxy alkyl; R ² is H, F, — CH ₂ OH, — CO ₂ Me, or — C(CH ₃ ) ₂ OH; R ³ is H; and R ⁴ is H, — CH ₃ , or — CF _3; or

D is t-butyl; A is C1-8 alkyl; X is H; Y is H; R ¹ is Cl, Br, CN, OCH ₃ , CF ₃ , — CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R ² is H, F, — CH2OH, — CChMe, or — C(CH3)2OH; R ³ is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and R ⁴ is H, — CH3, or — CF3 ; or

D is t-butyl; A is C1-8 alkyl; X is CF ₃ ; Y is H; R ¹ is H, Cl, Br, CN, OCH ₃ , CF ₃ , — CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R ² is H, F, — CH2OH, — CChMe, or — C(CH3)2OH; R ³ is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and R ⁴ is H, — CH3, or — CF3; or

D is cyclobutyl; A is C1-8 alkyl; X is H; Y is methyl(2,2,2-trifluoroethyl)amino; R ¹ is H, Cl, Br, CN, OCH3, CF ₃ , — CO2CH2CH3, Ci- ₄ alkyl, or Ci- ₄ hydroxy alkyl; R ² is H, F, — CH2OH, — CO ₂ Me, or — C(CH ₃ ) ₂ OH; R ³ is H; and R ⁴ is H, — CH ₃ , or — CF ₃ ; or D is cyclobutyl; A is Ci-8 alkyl; X is CF3; Y is dimethylamino; R ¹ is H, Cl, Br, CN, 0CH3, CF ₃ , — CO2CH2CH3, C1-4 alkyl, or C 1-4 hydroxy alkyl; R ² is H, F, — CH ₂ OH, — CO ₂ Me, or — C(CH ₃ ) ₂ OH; R ³ is H; and R ⁴ is H, — CH ₃ , or — CF ₃ ; or

D is optionally substituted cyclobutyl, optionally substituted phenyl, or optionally substituted C2-5 alkyl, wherein the optional substituents are selected from — CH3 and F; A is Ci alkyl; X is substituted cyclobutyl, wherein the substituent is F;Y is H; R ¹ is selected from H, C3 hydroxyalkyl, CN, F, or Cl; R ² is selected from H, CN, F, Br, or — OCF3; R ³ is selected from H, F, or — OCH3; R ⁴ is H or F; and wherein when X is substituted with 2 fluorine atoms, the fluorine atoms are not geminal; or a pharmaceutically acceptable salt thereof; [0080] In an embodiment, the Kv7 channel activator is a compound according to formula 2. Wherein, R ¹ , R ² , R ³ , and R ⁴ are independently H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0081] In further embodiments, Y is H, F, CF3, OH, C1-5 O-alkyl, Co-6 alkylamino, optionally substituted tetrahydropyranyl, or Co-6 fluoroalkylamino.

[0082] In further embodiments, R ¹ is H, Cl, Br, — OCH3, — CN, — CF3, — CH2OH, — COOCH2CH3, — C(CH ₃ ) ₂ OH, — CHOHCH2CH3, — CHOHCH3, — CHF ₂ , — CH(CH ₃ ) ₂ , — C(CH ₂ CH ₃ )OH, — CH2COOCH2CH3, — CH ₂ C(CH ₃ )2OH, — CH2COOH, or — CH ₂ CON(CH ₃ )2.

[0083] In further embodiments, R ² is H, F, — CH2OH, — CO2Me, or — C(CH3)2OH.

[0084] In further embodiments, R ³ is H.

[0085] In further embodiments, R ⁴ is H, — CH3, or — CF3.

[0086] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

[0087] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. [0088] In further embodiments the Kv7 channel activator is a compound selected from the or a pharmaceutically acceptable salt thereof.

[0089] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0090] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0091] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0092] In further embodiments, the compound is: (Formula 2-3) or a pharmaceutically acceptable salt thereof.

[0093] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0094] In further embodiments, the compound is: (Formula 2-5) or a pharmaceutically acceptable salt thereof.

[0095] In further embodiments, the compound is: (Formula 2-6) or a pharmaceutically acceptable salt thereof.

[0096] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0097] In further embodiments, the compound is: (Formula 2-8) or a pharmaceutically acceptable salt thereof.

[0098] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[0099] In further embodiments, the compound is: (Formula 2-10) or a pharmaceutically acceptable salt thereof.

[00100] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [00101] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [00102] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:

[00103] In further embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

[00104] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[00105] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[00106] In further embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

[00107] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[00108] In further embodiments, the compound is: sfereoisomsr t or a pharmaceutically acceptable salt thereof.

[00109] In further embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

[00110] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[00111] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[00112] In further embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

[00113] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[00114] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof.

[00115] In an embodiment of Formula 2, D is optionally substituted cyclobutyl, or t-butyl; A is C 2-8 alkyl, X is H, CF3, or optionally substituted phenyl, Y is H or OH, R ¹ is CN or C1-4 hydroxyalkyl; and R ² , R ³ , and R ⁴ are independently H, or F. In a further embodiment, R ¹ is CN, -C(CH3)2OH, or -CH2C(CH3)2OH. In a further embodiment, R ² is F. In a further embodiment, R ³ is H. In a further embodiment, R ⁴ is H. In a further embodiment, R ¹ is CN. In a further embodiment, R ¹ is C1-4 hydroxyalkyl. In a further embodiment, X is optionally substituted phenyl. In a further embodiment, X is CF3. In a further embodiment, X is H. In a further embodiment, Y is H. In a further embodiment, Y is OH.

[00116] In an embodiment of Formula 2, D is cyclobutyl; A is C1-8 alkyl, X is CF3, Y is H, R ¹ is H, Cl, Br, CN, OCH ₃ , CF ₃ , -CO2CH2CH3, Ci- ₄ alkyl, or Ci- ₄ hydroxyalkyl; R ² is H, F, - CH2OH, -CO2Me, or -C(CH3)2OH; R ³ is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl or B; and R ⁴ is H, -CH3, or -CF3.

[00117] In an embodiment of Formula 2, D is optionally substituted cyclobutyl, A is C1-8 alkyl, X is CH ₃ , Y is H, R ¹ is H, Cl, Br, CN, OCH ₃ , CF ₃ , -CO2CH2CH3, Ci- ₄ alkyl, or Ci- ₄ hydroxyalkyl; R ² is H, F, -CH ₂ OH, -CO ₂ Me, or -C(CH ₃ ) ₂ OH; R ³ is H; and R ⁴ is H, -CH ₃ , or - CF ₃ .

[00118] In an embodiment of Formula 2, D is t-butyl; A is C1-8 alkyl; X is H; Y is H; R ¹ is Cl, Br, CN, OCH3, CF ₃ , -CO2CH2CH3, Ci- ₄ alkyl, or Ci- ₄ hydroxyalkyl; R ² is H, F, -CH ₂ OH, - CChMe, or -C(CH3)2OH; R ³ is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and R ⁴ is H, -CH3, or -CF3.

[00119] In an embodiment of Formula 2, D is t-butyl; A is C1-8 alkyl; X is CF3; Y is H; R ¹ is H, Cl, Br, CN, OCH3, CF ₃ , -CO2CH2CH3, Ci- ₄ alkyl, or Ci- ₄ hydroxyalkyl; R ² is H, F, - CH2OH, -CChMe, or -C(CH3)2OH; R ³ is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and R ⁴ is H, CH3, or CF3.

[00120] In an embodiment of Formula 2, D is cyclobutyl; A is C1-8 alkyl; X is H; Y is methyl(2,2,2-trifluoroethyl)amino; R ¹ is H, Cl, Br, CN, OCH3, CF3, -CO2CH2CH3, Ci- ₄ alkyl, or Ci- ₄ hydroxyalkyl; R ² is H, F, -CH ₂ OH, -CO ₂ Me, or -CH(CH ₃ ) ₂ OH; R ³ is H; and R ⁴ is H, - CH ₃ , or -CF ₃ .

[00121] In an embodiment of Formula 2, D is optionally substituted cyclobutyl, optionally substituted phenyl, or optionally substituted C2-5 alkyl, wherein the optional substituents are selected from -CH3 and F; A is Ci alkyl, X is substituted cyclobutyl, wherein the substituent is F; Y is H; R ¹ is selected from H, C3 hydroxyalkyl, CN, F, or Cl; R ² is selected from H, CN, F, Br, or -OCF3; R ³ is selected from H, F, or -OCH3; R ⁴ is H or F; and wherein when X is substituted with 2 fluorine atoms, the fluorine atoms are not geminal; or a pharmaceutically acceptable salt thereof. Formula 3

In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 3. Such compounds are described in US Patent No. 8,293,911 issued on October 23, 2012 and corresponding to US Application No. 11/894,877 filed August 22, 2007; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 3, this reference incorporated by reference herein controls.

[00122] In an embodiment, the Kv7 channel activator is a compound according to formula 3 : Formula 3 wherein, Ri and R2, vary independently, and are selected from the group consisting of H, CN, halogen, CH ₂ CN, OH, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , Ci-C ₆ alkyl, C(=O)Ci-C ₆ alkyl; NH— Ci- C ₆ alkyl; N(CI-C ₆ alkyl)-Ci-C ₆ alkyl, NHC(=O)CI-C ₆ alkyl, C(=O)N(CH ₃ ) ₂ , C(=O)N(Et) ₂ , C(=O)NH ₂ , C(=O)NH— Ci-C ₆ alkyl, SO ₂ NH ₂ , NHSO ₂ — Ci-C ₆ alkyl; C(=O)OCi-C ₆ alkyl, OC(=O)C1-C ₆ alkyl, OCi-C ₆ alkyl, SCi-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, (CH ₂ ) _m C ₃ -C ₆ cycloalkyl, C ₃ -Ce cycloalkenyl, (CH ₂ ) _m C ₃ -C6 cycloalkenyl, C ₂ -Ce alkenyl, C ₂ -Ce alkynyl, Ar, (CH ₂ ) _m thienyl, (CH ₂ ) _m imidazolyl, (CH ₂ ) _m pyrazyl, (CH ₂ ) _m oxazolyl, (CH ₂ ) _m isoxazolyl, (CH ₂ ) _m thiazolyl, (CH ₂ ) _m isothiazolyl, (CH ₂ ) _m phenyl, (CH ₂ ) _m pyrrolyl, (CH ₂ ) _m pyridyl, and (CH ₂ ) _m pyrimidyl, Wherein m=zero, 1, or 2; Ar is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; or Ri and R ₂ , together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring; wherein said fused ring may be saturated, unsaturated, or aromatic, and said fused ring optionally contains one or two heteroatoms selected independently from the group consisting of O, N, and S; R' is selected from the group consisting of H, halogen, phenyl, 2-(N,N-dimethylamino)ethyl, CF ₃ , OCi-C ₃ alkyl and Ci- C ₃ alkyl; R ₃ and R4 vary independently, and are selected from the group consisting of H, CN, halogen, CF ₃ , OCF ₃ , OCi-C ₃ alkyl, and Ci-C ₃ alkyl; X is O or S; Y is O or S; q=l or zero; and Rs is selected from the group consisting of Ci-Ce alkyl, (CHR6) _W C ₃ -C6 cycloalkyl, (CHRe)wCH ₂ C ₃ -C6 cycloalkyl, CH ₂ (CHR6) _W C ₃ -C6 cycloalkyl, CRe=CH — C ₃ -Ce cycloalkyl, CH=CRe — C ₃ -Ce cycloalkyl, (CHR^wCs-Ce cycloalkenyl, CH ₂ (CHR6) _W C5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHRe) _w Ar, CH2(CHRe) _w Ar, and (CHReJwCkbAr, wherein w=zero, 1, 2, or 3; Ar is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from the group consisting of N, O, and S; and Re is selected from the group consisting of H or C1-C3 alkyl; where all cycloalkyl and cycloalkenyl optionally contain one or two ring heteroatoms selected independently from N, O, and S; wherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in Ri, R2, R', R3, R4, Rs, Rs, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C1-C3 alkyl, halogen, OH, OEt, OMe, CN, CH2F, OCF3, and CF3; and wherein, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with a carbonyl group.

[00123] In further embodiments, Ri and R2, vary independently, and are selected from the group consisting ofH, halogen, CF3, Ci-Ce alkyl, C(=O)Ci-Ce alkyl, C(=O)OCi-Ce alkyl, OC(=O)Ci-C ₆ alkyl, OCi-C ₆ alkyl, SCH3, C ₃ -C ₆ cycloalkyl, (CH ₂ )mC3-C6 cycloalkyl, phenyl, pyridyl, pyrrolyl, thienyl, (CH2) _m phenyl, (CH2) _m pyrrolyl, and (CH2) _m pyridyl; wherein said cycloalkyl groups optionally contain one or two heteroatoms selected independently from the group consisting of O, N, and S; wherein said alkyl, cycloalkyl, phenyl, pyrrolyl, and pyridyl groups are optionally substituted with one or two groups selected, independently, from halogen, methyl, ethyl, or trifluoromethyl; and wherein m is zero, 1, or 2; R' is selected from the group consisting of H, halogen, phenyl, 2-(N,N-dimethylamino)ethyl, CF3, OC1-C3 alkyl and C1-C3 alkyl; R3 and R4vary independently, and are selected from the group consisting of H, halogen, CF3, OCF3, OC1-C3 alkyl, and C1-C3 alkyl; X is O or S; Y is O or S; q=l or 0; Rs is selected from the group consisting of Ci-Ce alkyl, (CHRe)wC3-C6 cycloalkyl, (CHRe) _w CH2C3-C6 cycloalkyl, CH2(CHRe)wC3-C6 cycloalkyl, CRe=CH — C3-C6 cycloalkyl, CH=CRe — C3-C6 cycloalkyl, (CHR^wCs-Ce cycloalkenyl, CH2(CHRe) _w C5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHRe) _w Ar, CH2(CHRe) _w Ar, and (CHR?)wCH2Ar; wherein w=0-3; Ar is selected from the group consisting of phenyl, pyrimidyl, or pyridyl, and a 5- member heteroaromatic ring; wherein said heteroaromatic ring contains 1 or 2 ring heteroatoms selected independently from the group consisting of N, O, and S; and Re is selected from the group consisting of H and methyl; wherein all cycloalkyl and cycloalkenyl groups in R5 optionally contain one or two ring heteroatoms selected independently from the group consisting of N, O, and S; and wherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in Ri, R2, R3, R4, Rs, Re, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C1-C3 alkyl, halogen, OEt, OMe, and trifluoromethyl.

[00124] In further embodiments, Ri and R2, vary independently, and are selected from the group consisting ofH, halogen, CF3, Ci-Ce alkyl, C(=O)Ci-Ce alkyl, C(=O)OCi-Ce alkyl, OC(=O)Ci-Ce alkyl, OCi-Ce alkyl, SCH3, (CH2) _m cyclopropyl, (CH2) _m cyclobutyl,

(CH2) _m cyclopentyl, (CH2) _m cyclohexyl, (CH2) _m oxazolyl, (CH2) _m isoxazolyl, (CH2) _m thiazolyl, (CH2) _m isothiazolyl, (CH2) _m phenyl, (CH2) _m pyrrolyl, (CH2) _m pyridyl, and (CH2) _m pyrimidyl; wherein said cyclopentyl and said cyclohexyl groups optionally contain one or two ring heteroatoms selected independently from the group consisting of O, N, and S; wherein said alkyl, cycloalkyl, phenyl, pyrrolyl, and pyridyl groups are optionally substituted with one or two groups selected, independently, from the group consisting of halogen, CH3, ethyl, and CF3; and m is zero, 1, or 2; R' is selected from the group consisting of H, halogen, CF3, and C1-C3 alkyl; R3 and R4vary independently, and are selected from the group consisting of H, halogen, CF3, OCF3, OC1-C3 alkyl, and C1-C3 alkyl; X is O or S; Y is O; q=l or 0; R5 is selected from the group consisting of Ci-Ce alkyl, (CHRe)wC3-C6 cycloalkyl, (CHR^wCEECs- Ce cycloalkyl, CH2(CHRe) _w C3-C6 cycloalkyl, CRe=CH — C3-C6 cycloalkyl, CH=CRe — C3- Ce cycloalkyl, (CHR^wCs-Ce cycloalkenyl, CH2(CHRe) _w C5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHRe)wAr, CH2(CHRe) _w Ar, and (CHRe^CEEAr; wherein w=0-3, Ar is selected from the group consisting of phenyl, pyridyl, and a 5-member heteroaromatic ring, wherein said heteroaromatic ring contains 1 or 2 ring heteroatoms selected independently from the group consisting of N, O, and S; Re is H or methyl; wherein all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from the group consisting of N, O, and S; and wherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in Ri, R2, R3, R4, Rs, Rs, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C1-C3 alkyl, halogen, OMe, OEt, and CF3. [00125] In further embodiments, Ri and R2, vary independently, and are selected from the group consisting of H, halogen, CF3, OC1-C3 alkyl, Ci-Ce alkyl, C(=O)OCi-C3 alkyl, OC(=O)Ci-C3 alkyl, and C(=O)Ci-C3 alkyl; R' is selected from the group consisting of H, F, CH3, and ethyl; R3 and R4vary independently, and are selected from the group consisting of H, F, Cl, CF ₃ , OCF3, OC1-C3 alkyl, and C1-C3 alkyl; and R ₅ is Ci-C ₆ alkyl, (CHR6) _W C ₃ - Ce cycloalkyl, (CHRs^CEECs-Ce cycloalkyl, CH2(CHRe)wC3-C6 cycloalkyl, or (CHRe)wAr, CH ₂ (CHR6) _w Ar, or (CHR ₆ ) _w CH ₂ Ar. [00126] In further embodiments, R ₂ is H or F; R' is H; R3 is selected from the group consisting of H, CH3, OCH3, CF3, OCF3, and Cl; RUs selected from the group consisting of CH3, OCH3, CF3, OCF3, and Cl; and R5 is C3-C6 alkyl or (CH ₂ ) _W C3-Ce cycloalkyl.

[00127] In further embodiments, Ri is halogen or CF3; R ₂ is H or F; R' is H; R3 and R4 vary independently, and are selected from the group consisting of H, CH3, OCH3, CF3, OCF3, or Cl; and R5 is selected from the group consisting of Ci-Ce alkyl, (CHR6)wC3-Ce cycloalkyl, (CHR6)WCH ₂ C3-C ₆ cycloalkyl, CH ₂ (CHR6) _W C3-C6 cycloalkyl, CRe=CH — C3-C6 cycloalkyl, CH=CRe — C3-C6 cycloalkyl, (CHR^wCs-Ce cycloalkenyl, CH ₂ (CHR6) _W C5-C6 cycloalkenyl, C ₂ -Ce alkenyl, C ₂ -Ce alkynyl, Ar, (CHRe)wAr, CH ₂ (CHR6) _w Ar, and (CHR6)wCH ₂ Ar.

[00128] In further embodiments, Ri is halogen or CF3; R ₂ is H or F; R' is H; R3 and R4 vary independently, and are selected from the group consisting of H, CH3, OCH3, CF3, OCF3, or Cl; and R5 is selected from the group consisting of Ci-Ce alkyl, (CHR6)wC3-Ce cycloalkyl, (CHR6)WCH ₂ C3-C ₆ cycloalkyl, CH ₂ (CHR6) _W C3-C6 cycloalkyl, CRe=CH — C3-C6 cycloalkyl, CH=CRe — C3-C6 cycloalkyl, (CHR^wCs-Ce cycloalkenyl, CH ₂ (CHR6) _W C5-C6 cycloalkenyl, C ₂ -Ce alkenyl, C ₂ -Ce alkynyl, Ar, (CHRe)wAr, CH ₂ (CHR6) _w Ar, and (CHR6)wCH ₂ Ar.

Formula 4

[00129] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 4. Such compounds are described in US Patent No. 8,293,911 issued on October 23, 2012 and corresponding to US Application No.

11/894,877; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 4, this reference incorporated by reference herein controls.

[00130] In an embodiment, the Kv7 channel activator is a compound according to formula 4:

Formula 4 wherein, Ri is selected from the group consisting of H, halogen, CN, CH2CN, CF3, Ci- C ₆ alkyl, OCH3, (C=O)OCH ₃ , O(C=O)CH ₃ , OCF ₃ , (CH ₂ ) _m C3-C6 cycloalkyl, phenyl, and pyridyl; R2 is selected from the group consisting of H, F, OCH3, CH3, and CF3; R3 and R4vary independently, and are selected from the group consisting of H, F, Cl, CF3, OCF3, OC1-C3 alkyl, or C1-C3 alkyl; and R5 is selected from the group consisting of Ci-Ce alkyl, (CHRe) _w C3-C6 cycloalkyl, (CHRe^CFBCs-Ce cycloalkyl, CH2(CHRe)wC3-Ce cycloalkyl, CRe=CH — C3-C6 cycloalkyl, CH=CRe — C3-C6 cycloalkyl, (CHRe^Cs-Ce cycloalkenyl, CH2(CHRe)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHRe) _w Ar, CH2(CHRe) _w Ar, (CHRe^CFFAr, and CH2-C(CH3)3; wherein w=0-3; Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl; and Re is C1-C3 alkyl; R' is selected from the group consisting of H, CH3, CH2CH3, or halogen; wherein all alkyl, cycloalkyl, aryl, and heteroaryl groups in Ri, R2, R3, R4, Rs, Rs, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C1-C3 alkyl, halogen, OCH3, OCH2CH3, CN, and CF ₃ .

[00131] In other embodiments, Ri is selected from the group consisting of H, F, Cl, Br, CF3, Ci-C ₆ alkyl, OCH3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, and OCH2CH3; R' is selected from the group consisting of H, CH3, CH2CH3, or halogen; R3 and R4 vary independently, and are selected from the group consisting of H, F, Cl, CF3, OCF3, OCH3, and CH3; and Rs is selected from the group consisting of Ci-Ce alkyl, CH2C3-C6 cycloalkyl, CH2CH2C3- Ce cycloalkyl, CH=CH — C3-C6 cycloalkyl, CH=CH — Cs-Ce cycloalkenyl, CH2C5- Ce cycloalkenyl, CH2CH2C5-C6 cycloalkenyl, C2-C6 alkenyl, and (CH2) _w Ar; wherein w=l or 2; Ar is selected from the group consisting of phenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furyl, thienyl, pyrrolyl, and pyridyl; wherein all alkyl, cycloalkyl, aryl, and heteroaryl groups in Ri, R2, R3, R4, Rs, Rs, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of CH3, halogen, OCH3, OCH2CH3, CN, and CF ₃ .

[00132] In other embodiments, Ri is selected from the group consisting of H, F, Cl, Br, CF3, Ci-C ₆ alkyl, OCH3, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, and OCH2CH3; R' is selected from the group consisting of H, CH3, CH2CH3, or halogen; R3 and R4 vary independently, and are selected from the group consisting of H, F, Cl, CF3, OCF3, OCH3, and CH3; and Rs is selected from the group consisting of Ci-Ce alkyl, CH2C3-C6 cycloalkyl, CH2CH2C3- Ce cycloalkyl, CH=CH — C3-C6 cycloalkyl, CH=CH — Cs-Ce cycloalkenyl, CH2C5- Ce cycloalkenyl, CH2CH2C5-C6 cycloalkenyl, C2-C6 alkenyl, and (CH2) _w Ar; wherein w=l or 2; Ar is selected from the group consisting of phenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furyl, thienyl, pyrrolyl, and pyridyl; wherein all alkyl, cycloalkyl, aryl, and heteroaryl groups in Ri, R2, R3, R4, Rs, Rs, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of CH3, halogen, OCH3, OCH2CH3, CN, and CF3. Wherein, Ri is selected from the group consisting of F, CF3, Cl, CH ₃ , CH2CH3, SCH ₃ , 0CH3, CH2OCH3, CH2OCH2CH3, 0CF3, phenyl, thienyl, and H; R ₂ is selected from the group consisting of H, F, Cl, and OCH3; R' is selected from the group consisting of H, F, CH2CH3, and CH3; R3 and R4 vary independently, and are selected from the group consisting of H, Cl, CH3, CF3, OCH3, and OCF3; and R5 is selected from the group consisting of C4-C6 alkyl, (CH2) _w Ar, and (CH^wCs-Ce cycloalkyl; wherein w is 1, 2, or 3. [00133] In other embodiments, Ri is selected from the group consisting of F, CF3, Cl, CH3, OCH3, CH2OCH3, and H; R2 is selected from the group consisting of H, F, CH3, and Cl; R' is H; R3 is selected from the group consisting of H, Cl, CH3, CF3, OCH3, and OCF3; R4 is selected from the group consisting of Cl, OCH3, and CH3; and R5 is C4-C6 alkyl or 2- cyclopentyl ethyl.

[00134] In other embodiments, R3 and R4 are both CH3 or both OCH3; and R5 is C5-C6 alkyl. [00135] In other embodiments, R' and R2 are H; R3 and R4 are both methyl; and R5 is C5- Ce alkyl or (CH^wCs-Ce cycloalkyl; wherein w is 1, 2, or 3.

[00136] In other embodiments, the compound is selected from the group consisting of: N-(2- chloro-4-(3,4-dihydroisoquinolin-2(lH)-yl)-6-(trifluoromethy l)phenyl)-3,3- dimethylbutanamide; N-(4-(3,4-dihydroisoquinolin-2(lH)-yl)-2,6-dimethylphenyl)-3 ,3- dimethylbutanamide; N-(2-chloro-4-(3,4-dihydroisoquinolin-2(lH)-yl)-6- (trifluoromethyl)phenyl)-3-cyclopentylpropanamide; N-(2-chloro-4-(6-fluoro-3,4- dihydroisoquinolin-2(lH)-yl)-6-(trifluoromethylphenyl)-3,3-d imethylbutanamide; N-[2- chloro-4-(3,4-dihydro-lH-isoquinolin-2-yl)-6-methyl phenyl]-3,3-dimethylbutanamide; N-[2- chloro-4-(6-fluoro-3,4-dihydro-lH-isoquinolin-2-yl)-6-triflu oromethyl phenyl]-3- cyclopentylpropionamide; N-[2,6-dimethyl-4-(6-trifluoromethyl-3,4-dihydro-lH-isoquino lin- 2-yl)-phenyl]-3,3-dimethylbutanamide; N-[2-chloro-6-trifluoromethyl-4-(6-trifhioromethyl-

3.4-dihydro-lH-isoquinolin-2-yl)-phenyl]-3,3-dimethylbuta namide; N-[2-chloro-4-(6-chloro-

3.4-dihydro-lH-isoquinolin-2-yl)-6-trifluoromethyl phenyl]-3,3-dimethylbutanamide; N-[4- (6-chl oro-3, 4-dihydro-lH-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dime thylbutanamide; N-[4-(6-fluoro-3 ,4-dihy dro- 1 H-i soquinolin-2-yl)-2, 6-dimethyl phenyl]-3 , 3 - dimethylbutanamide; N-[2-chloro-4-(7-fluoro-3,4-dihydro-lH-isoquinolin-2-yl)-6- trifluoromethyl-phenyl]-3,3-dimethylbutanamide; N-[4-(7-fluoro-3,4-dihydro-lH- isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamid e; N-[2-chloro-4-(6-fluoro-

3.4-dihydro-lH-isoquinolin-2-yl)-6-methylphenyl]-3,3-dime thylbutanamide; N-[2-chloro-4- (7-fluoro-3,4-dihydro-lH-isoquinolin-2-yl)-6-methylphenyl]-3 ,3-dimethylbutanamide; N-[2- chloro-6-methyl-4-(6-trifluoromethyl-3,4-dihydro-lH-isoquino lin-2-yl)-phenyl]-3,3- dimethylbutanamide; N-[2-chloro-4-(6-chl oro-3, 4-dihydro- lH-isoquinolin-2 -yl)-6-methyl- phenyl]-3,3-dimethylbutanamide; N-[2-chloro-4-(6-fluoro-3, 4-dihydro- lH-isoquinolin-2 -yl)- phenyl]-3,3-dimethylbutanamide; N-[4-(6-fluoro-3, 4-dihydro- lH-isoquinolin-2 -yl)-2-methyl- phenyl]-3,3-dimethylbutanamide; N-[4-(6-fluoro-3,4-dihydro-lH-isoquinolin-2-yl)-2- trifluoromethylphenyl]-3,3-dimethylbutanamide; N-[2-chloro-4-(6-trifluoromethyl-3,4- dihy dro- 1 H-i soquinolin-2-yl)-phenyl] -3 , 3 -dimethylbutanamide; N- [4-(7 -fluoro-3 ,4-dihy dro- lH-isoquinolin-2-yl)-2-trifluoromethyl-phenyl]-3,3-dimethylb utanamide; 3,3-dimethyl-N-[2- trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-lH-isoquino lin-2-yl)-phenyl]butanamide; N-[4-(6-methoxy-3, 4-dihydro- lH-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3, 3- dimethylbutanamide; N-[4-(3, 4-dihydro- lH-isoquinolin-2 -yl)-2-methoxy-6-methyl-phenyl]- 3,3-dimethylbutanamide; N-[2-chloro-4-(3, 4-dihydro- lH-isoquinolin-2 -yl)-6- trifluoromethoxy-phenyl]-3,3-dimethylbutanamide; N-[4-(3,4-dihydro-M-isoquinolin-2-yl)- 2,6-dimethoxy-phenyl]-3,3-dimethylbutanamide; N-[2,6-dimethyl-4-(7-trifluoromethyl-3,4- dihydro-lH-isoquinolin-2-yl)-phenyl]-3,3-dimethyl butanamide; N-[2,6-Dimethyl-4-(6- trifluoromethyl-3,4-dihydro-lH-isoquinolin-2-yl)-phenyl]-3,3 -dimethyl-thiobutanamide; [2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-lH-isoquinoli n-2-yl)-phenyl]-carbamic acid ethyl ester; and N-[2,6-Dimethyl-4-(7-trifluoromethyl-3,4-dihydro-lH-isoquino lin-2-yl)- phenyl]-3, 3 -dimethyl butanamide.

Formula 5

In another embodiment, the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in US Patent No. 8,993,593 issued on March 31, 2015 and corresponding to US Application No. 12/698,070 filed February 1, 2010; US Publication No. US20220265634A1, published August 25, 2022 and corresponding to US Application No. 17/668,340 filed February 9, 2022;which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 5, these references incorporated by reference herein control.

[00137] In an embodiment, the Kv7 channel activator is a compound according to formula 5: Formula 5 optionally wherein the compound is substituted at any position.

Formula 6

[00138] In another embodiment, the Kv7 channel activator may be the following compound (ezogabine, also known as retigabine) or a pharmaceutically acceptable salt thereof.

Ezogabine is a compound according to formula 6: In the case of any conflict of terminology in the context of Formula 6, these references incorporated by reference herein control.

Formula 6 or, optionally, wherein the compound is substituted at any position.

Formula 7

In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 7. Such compounds are described in US Patent No. 10,526,328 issued on January 7, 2020 and corresponding to US Application No. 16/124,853 filed September 7, 2018; US Patent No. 10,106,536 issued on October 23, 2018 and corresponding to US Application No. 15/591,844 filed on May 10, 2017; US Patent No. 9,650,376 issued on May 16, 2017, and corresponding to US Application No. 14/776,271 filed March 17, 2014;; US Publication No. US20220060208A1, published February 24, 2022 and corresponding to US Application No. 17/277,145 filed January 14, 2019; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 7, these references incorporated by reference herein control.

[00139] In an embodiment, the Kv7 channel activator is a compound according to formula 7: wherein, L is CH2; R ¹ is optionally substituted cyclic C3H5, wherein the optional substituent of R ¹ is CF3; R ² is optionally substituted cyclobutyl; R ³ is optionally substituted C3 alkyl, wherein the optional substituent of R ³ is OH; R ⁴ is H; and R ⁵ is H; or wherein, L is CH ₂ ; R ¹ is optionally substituted C ₂ alkyl, wherein the optional substituents of R ¹ are independently CF3 or CH3; R ² is optionally substituted cyclobutyl; R ³ is optionally substituted C3 alkyl, wherein the optional substituent of R ³ is OH; R ⁴ is H; and R ⁵ is H; or wherein, wherein L is CH ₂ , CF ₂ , CHCH3, CH ₂ CH ₂ , C ₃ H ₆ , CH ₂ O, C ₂ H ₄ O, or C ₃ H ₆ O with the O of CH ₂ O, C ₂ H4O, or C3H5O bonded with R ¹ ; wherein R ¹ is optionally substituted Ci-2 alkyl, optionally substituted C5-10 cycloalkyl, optionally substituted C1-12 — O-alkyl, optionally substituted Ce-io aryl, optionally substituted Ce-io — O-aryl, or optionally substituted C ₂ -9 heterocyclyl, wherein the optional substituents of R ¹ are independently R ^A , F, Cl, CN, OR ^A , CF ₃ , NR ^A R ^B , COR ^A , CO ₂ R ^A , OCOR ^A , NR ^A COR ^B , CONR ^A R ^B , wherein R ^A and R ^B are independently H or C1-12 alkyl; wherein R ² is optionally substituted C _2.4 acyclic alkyl, optionally substituted cyclobutyl, optionally substituted Ce-io aryl, or optionally substituted C ₂ -9 heterocyclyl, wherein the optional substituents of R ² are independently F, Cl, Br, I, CN, C1-6 alkyl, C1-6 — O-alkyl, C 1-6 alkylamine, C1-6 aminoalkyl, C1-6 aminoacyl, C1-6 alkylthio, or C1-6 alkylsulfonyl; wherein R ³ , R ⁴ , and R ⁵ are independently H, F, Cl, Br, I, CN, optionally substituted C1.12 alkyl, optionally substituted C1-12 — O-alkyl, optionally substituted C ₂ .

9 heterocyclyl, optionally substituted Ce-io aryl, optionally substituted C ₂ -9 — O-heterocyclyl, optionally substituted Ce-io O-aryl, optionally substituted C1-12 acylamino, optionally substituted C1.12 aminoacyl, or optionally substituted CM ₂ aminoalkyl, wherein the optional substituents of R ³ , R ⁴ , or R ⁵ are independently F, Cl, Br, I, CN, C1-6 alkyl, C1-6 — O-alkyl, Ci- 6 alkylamine, C1-6 aminoalkyl, C1-6 aminoacyl, C 1-6 acylamino, C 1-6 alkylthio, or Ci- 6 alkylsulfonyl.

[00140] In further embodiments, R ² is optionally substituted C ₄ H9, optionally substituted cyclobutyl, optionally substituted Ce-io aryl, or optionally substituted C ₂ -9 heterocyclyl. [00141] In further embodiments, R ² is optionally substituted C4H9, or optionally substituted cyclobutyl.

[00142] In further embodiments, R ² is optionally substituted phenyl, or optionally substituted C2-9 heterocyclyl.

[00143] In further embodiments, R ¹ is optionally substituted phenyl.

[00144] In further embodiments, R ¹ is optionally substituted phenyl.

[00145] In further embodiments, R ¹ is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[00146] In further embodiments, R ¹ is C2-4 — O-alkyl.

[00147] In further embodiments, R ¹ is optionally substituted tetrahydrofuranyl or optionally sub stituted tetrahy dro-2H-pyranyl .

[00148] In further embodiments, R ¹ is selected from the group consisting of:

[00149] In further embodiments, R ² is selected from the group consisting of:

[00150] In further embodiments, R ³ is CF3, Cl, CN, OCH3, or H.

[00151] In further embodiments, R ¹ is selected from the group consisting of:

[00152] In further embodiments, R ⁴ is CHa, CF3, Cl, or H.

[00154] In further embodiments, the Kv7 channel activator is selected from the group consisting of:

[00155] In further embodiments, the Kv7 channel activator is selected from the group consisting of: Formula 8

In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 8. Such compounds are described in US Patent No. 9,650,376, published on February 4, 2014 and corresponding to US Application No. 14/776,271 filed March 17, 2014; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 8, this reference incorporated by reference herein controls.

[00156] In an embodiment, the Kv7 channel activator is a compound according to formula 8:

Formula 8 wherein, L is CH ₂ , CF ₂ , CHCH ₃ , CH ₂ CH ₂ , C ₃ H ₆ , CH ₂ O, C ₂ H ₄ O, or C ₃ H ₆ O with the O of CH ₂ O, C ₂ H ₄ O, or C ₃ HeO bonded with R ¹ ; wherein R ¹ is optionally substituted C1-2 alkyl, optionally substituted C5-10 cycloalkyl, optionally substituted C1-12 — O-alkyl, optionally substituted Ce-io aryl, optionally substituted Ce-io — O-aryl, or optionally substituted C ₂ .

9 heterocyclyl, wherein the optional substituents of R ¹ are independently R ^A , F, Cl, CN, OR ^A , CF ₃ , NR ^A R ^B , COR ^A , CO ₂ R ^A , OCOR ^A , NR ^A COR ^B , CONR ^A R ^B , wherein R ^A and R ^B are independently H or C1-12 alkyl; wherein R ² is optionally substituted C _2.4 acyclic alkyl, optionally substituted cyclobutyl, optionally substituted Ce-io aryl, or optionally substituted C ₂ -9 heterocyclyl, wherein the optional substituents of R ² are independently F, Cl, Br, I, CN, C1-6 alkyl, C1-6 — O-alkyl, C 1-6 alkylamine, C1-6 aminoalkyl, C1-6 aminoacyl, C1-6 alkylthio, or C1-6 alkylsulfonyl; wherein R ³ , R ⁴ , and R ⁵ are independently H, F, Cl, Br, I, CN, optionally substituted C1-12 alkyl, optionally substituted C1-12 — O-alkyl, optionally substituted C ₂ .

9 heterocyclyl, optionally substituted Ce-io aryl, optionally substituted C ₂ -9 — O-heterocyclyl, optionally substituted Ce-io O-aryl, optionally substituted C1-12 acylamino, optionally substituted C1-12 aminoacyl, or optionally substituted C1-12 aminoalkyl, wherein the optional substituents of R ³ , R ⁴ , or R ⁵ are independently F, Cl, Br, I, CN, C1-6 alkyl, C1-6 — O-alkyl, Cn 6 alkylamine, C1-6 aminoalkyl, C1-6 aminoacyl, C 1-6 acylamino, C 1-6 alkylthio, or Ci-

6 alkylsulfonyl.

[00157] In further embodiments, R ² is optionally substituted C H9, optionally substituted cyclobutyl, optionally substituted Ce-io aryl, or optionally substituted C ₂ -9 heterocyclyl. [00158] In further embodiments, R ² is optionally substituted C4H9, or optionally substituted cyclobutyl.

[00159] In further embodiments, R ² is optionally substituted phenyl, or optionally substituted C2-9 heterocyclyl.

[00160] In further embodiments, R ¹ is optionally substituted phenyl.

[00161] In further embodiments, R ¹ is optionally substituted phenyl.

[00162] In further embodiments, R ¹ is optionally substituted cyclopentyl or optionally substituted cyclohexyl.

[00163] In further embodiments, R ¹ is C2-4 — O-alkyl.

[00164] In further embodiments, R ¹ is optionally substituted tetrahydrofuranyl or optionally sub stituted tetrahy dro-2H-pyranyl .

[00165] In further embodiments, R ¹ is selected from the group consisting of:

[00166] In further embodiments, R ² is selected from the group consisting of:

[00167] In further embodiments, R ³ is CF3, Cl, CN, OCH3, or H.

[00168] In further embodiments, R ¹ is selected from the group consisting of:

[00169] In further embodiments, R ⁴ is CH3, CF3, Cl, or H. [00170] In further embodiments, R ² is selected from the group consisting of: Formula 9

[00171] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 9. Such compounds are described in International Publication No. WO2021023616A1, published February 11, 2021 and corresponding to International Application No. PCT/EP2020/071514 filed July 30, 2020; International Publication No. WO2019161877A1, published August 29, 2019 and corresponding to International Application No. PCT/EP2018/054057 filed February 20, 2018; US Publication No. US20220280455A1, published September 8, 2022 and corresponding to US Application No. 17/631,762 filed July 30, 2020; US Publication No. US20210032196A1, published February 4, 2021 and corresponding to US Application No. 16/943,872 filed July 30, 2020; US Publication No. US20210032196A1, published February 4, 2021 and corresponding to US Application No. 16/943,872 filed July 30, 2020;, , which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 9, these references incorporated by reference herein control.

[00172] In an embodiment, the Kv7 channel activator is a compound according to formula 9:

Formula 9 wherein, R1 is selected from the group consisting of Ci-Ce alkyl, CF3, CH2CF3, CF2CHF2, C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl may be substituted with 1 or 2 substituents selected from the group consisting of C1-C3 alkyl, F, CHF2 and CF3; and R2 is H, Ci-Ce alkyl or CF3; or R1 and R2 combine to form C3-C5 cycloalkyl optionally substituted with 1 or 2 F, CHF2 or CF3; and R3 is C1-C3 alkyl or QUO — C1-3 alkyl, said C1-C3 alkyl or QUO — C1-C3 is alkyl substituted with C=N, 3 F or C3-C5 cycloalkyl; R4 is selected from the group consisting of OCF ₃ , or OCHF2

[00173] In further embodiments, R4 is OCF3 or OCHF2.

[00174] In further embodiments, R3 is selected from the group consisting of QU — O — CF3, QU — O — cyclopropyl, QU — C=N.

[00175] In further embodiments R1 is C3-C4 cycloalkyl optionally substituted with 1 or 2 Ci- C ₃ alkyl, F, CHF ₂ or CF ₃ .

[00176] In further embodiments, R1 and R2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R4 is OCF3 or OCHF2. [00177] In further embodiments, theKv7 channel activator is selected from the group consisting of: (S) — N — ((R)-2-cy cl opropoxy-1 -(3 -(difluoromethoxy) phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide; (S) — N — ((R)-l -(3 -(difluorom ethoxy)phenyl)-2- (trifluoromethoxy)ethyl)-3 -hydroxy-4, 4-dimethylpentanamide; (S) — N — ((R)-l-(3- (tri fluoromethoxy )phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpe ntanamide; (S) — N — ((S)-2-cy ano- 1 -(3 -(tri fluoromethoxy)phenyl)ethyl)-3 -hydroxy-4, 4- dimethylpentanamide; (S) — N — ((S)-3 -cyano- 1 -(3 -(trifluorom ethoxy )phenyl) propylshydroxyl, 4-dimethylpentanamide; (R) — N-(2-cyclopropoxy-l -(3 -(trifluoromethoxy) phenyl)ethyl)-2-(3, 3 -difluoro- 1-hydroxycy cl obutyl)acetamide; (R) — N-(2-cy cl opropoxy-1 - (3 -(difluoromethoxy) phenyl)ethyl)-2-(3, 3 -difluoro- 1 -hydroxy cyclobutyl)acetamide; (R)-2- (3 , 3 -difluoro- 1 -hy droxy cy clobutyl)-N-( 1 -(3 -(difluorom ethoxy )phenyl)-2- (trifluoromethoxy)ethyl)acetamide; and (S) — N-(2-cyano-l -(3 -(trifluoromethoxy) phenyl)ethyl)-2-(3, 3 -difluoro- 1-hydroxycy cl obutyl)acetamide or a pharmaceutically acceptable salt of any of these compounds.

[00178] In further embodiments, the Kv7 channel activator is selected from the group consisting of (R) — N — ((R)-2-(difluoromethoxy)-l -(3 -(difluorom ethoxy)phenyl)ethyl)-3 -hydroxy-4, 4- dimethylpentanamide; (S) — N — ((R)-2-(difluoromethoxy)-l-(3- (difluoromethoxy)phenyl)ethyl)-3 -hydroxy-4, 4-dimethylpentanamide; (S)-3 -hydroxy -4,4- dimethyl-N — ((S)-l-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl) pentanamide; (R)-3 -hydroxy-4, 4- dimethyl-N — ((S)-l-(3-(2,2,2-trifluoroethoxy) phenyl)ethyl)pentanamide; (R) — N — ((R)-2- (difluorom ethoxy)- 1 -(3 -(difluorom ethoxy)phenyl)ethyl)-3 -hydroxy-3 -( 1 -(trifluoro- methyl)cyclopropyl)propanamide; (S) — N — ((R)-2-(difluoromethoxy)-l-(3- (difluoromethoxy)phenyl)ethyl)-3 -hydroxy-3 -(1 -(tri fluoro-methyl)cyclopropyl)propanamide; (R) — N — ((R)-2-(difluoromethoxy)- 1 -(3 -(trifluorom ethoxy)phenyl)ethyl)-3 -hydroxy-3 -( 1 - (trifluorom ethyl)cyclopropyl)propanamide; (S) — N — ((R)-2-(difluorom ethoxy)- 1 -(3- (trifluorom ethoxy )phenyl) ethyl)-3 -hydroxy-3 -(1 -(trifluorom ethyl)cy cl opropyl) propanamide; (R)-3 -(3 , 3 -difluorocy clobutyl)-N — ((R)-2-(difluorom ethoxy)- 1 -(3 -

(difluorom ethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3 -(3, 3 -difluorocy cl obutyl)-N — ((R)-2-(difluorom ethoxy)- 1 -(3 -(difluorom ethoxy )phenyl)ethyl)-3-hydroxypropanamide; (R)- 3-(3,3-difluorocyclobutyl)-N — ((R)-2-(difluorom ethoxy)- 1 -(3 -(trifluorom ethoxy)phenyl) ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N — ((R)-2-(difluoromethoxy)- 1 -(3 -(trifluorom ethoxy )phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)- N — ((S)- 1 -(3 -(difluorom ethoxy )phenyl)butyl)-3 -hy droxypropanamide; (R)-3 -(3,3- difluorocyclobutyl)-N — ((S)-l -(3 -(difluoromethoxy) phenyl)butyl)-3-hy droxypropanamide; (S) — N — ((R)-2-(difluorom ethoxy)- 1 -(3 -(difluoromethoxy)phenyl)ethyl)-3 -( 1 - ethylcyclopropyl)-3-hydroxypropanamide; (R) — N — ((R)-2-(difluorom ethoxy)- 1 -(3- (difluoromethoxy)phenyl) ethyl)-3-(l-ethylcyclopropyl)-3-hydroxypropanamide; (S) — N — ((S)-l -(3 -(difluoromethoxy )phenyl)butyl)-3 -hydroxy-4, 4-dimethylpentanamide; (S) — N — ((S)-l -(3 -(difluoromethoxy )phenyl)-4,4-difluorobutyl)-3 -hydroxy-4, 4-dimethylpentanamide; (S) — N — ((S)-l -(3 -(difluorom ethoxy )phenyl)-3, 3 -difluoropropyl)-3 -hydroxy-4, 4- dimethylpentanamide; (S) — N — ((S)-l -(3 -(difluoromethoxy) phenyl)ethyl)-3 -hydroxy-4, 4- dimethylpentanamide; (R)-2-(3, 3 -difluoro- 1-hydroxycy cl obutyl)-N-(2-(difluorom ethoxy)- 1- (3-(difluoromethoxy)phenyl) ethyl)acetamide; (R)-2-(3, 3 -difluoro- 1-hydroxycy cl obutyl)-N- (2-(difluoromethoxy)-l-(3-(trifluoromethoxy)phenyl)ethyl)ace tamide; (S)-2-(3, 3 -difluoro- 1- hydroxycyclobutyl)-N-(l-(3-(difluoromethoxy)phenyl)butyl)ace tamide; (S)-2-(3,3-difluoro- l-hydroxycyclobutyl)-N-(l-(3-(difluoromethoxy)phenyl)-4,4-di fluorobutyl)acetamide; (S)-2- (3,3-difluoro-l-hydroxycyclobutyl)-N-(l-(3-(trifluoromethoxy ) phenyl)propyl)acetamide;

(S) — N-(3 ,3 -difluoro- 1 -(3 -(trifluoromethoxy)phenyl)propyl)-2-(3 ,3 -difluoro- 1 - hydroxycyclobutyl)acetamide; (S) — N — ((R)-2-(difluorom ethoxy)- 1 -(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxy-4, 4-dimethylpentanamide; (R) — N — ((R)-2- (difluorom ethoxy)- 1 -(3 -(difluoromethoxy)phenyl)ethyl)-3 -( 1 -fluorocy clopropyl)-3 - hydroxybutanamide; (S) — N — ((R)-2-(difluorom ethoxy)- 1 -(3 -(difluoromethoxy)phenyl) ethyl)-3-(l -fluorocy cl opropyl)-3-hydroxybutanamide; (S) — N — ((R)-2-(difluoromethoxy)-l- (3 -(trifluoromethoxy)phenyl)ethyl)-3-(l -fluorocy cl opropyl)-3 -hydroxybutanamide; (R) — N — ((R)-2-(difluorom ethoxy)- 1 -(3 -(trifluoromethoxy)phenyl) ethyl)-3 -( 1 - fluorocy cl opropyl)-3 -hydroxybutanamide; (R)-3-cyclopropyl-N — ((R)-2-(difluoromethoxy)- 1 -(3 -(trifluorom ethoxy )phenyl) ethyl)-3 -hydroxybutanamide; (S)-3-cyclopropyl-N — ((R)-2- (difluorom ethoxy)- 1 -(3 -(trifluoromethoxy) phenyl)ethyl)-3 -hydroxybutanamide; (R) — N — ((R)-2-(difluorom ethoxy)- 1 -(3 -(difluoromethoxy )phenyl)ethyl)-5, 5,5 -trifluoro-3 -hydroxy-3 - methylpentanamide; (S) — N — ((R)-2-(difluorom ethoxy)- 1 -(3- (difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-m ethylpentanamide; (R) — N — ((R)-2-(difluorom ethoxy)- 1 -(3 -(difluorom ethoxy )phenyl)ethyl)-3 -hydroxy-3 , 5 - dimethylhexanamide; (S) — N — ((R)-2-(difluorom ethoxy)- 1 -(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanam ide; (S) — N — ((R)-2- (difluorom ethoxy)- 1 -(3 -(difluorom ethoxy)phenyl)ethyl)-3 -hydroxy-3 ,4- dimethylpentanamide; (R) — N — ((R)-2-(difluoromethoxy)-l-(3-

(difluoromethoxy)phenyl)ethyl)-3 -hydroxy-3, 4-dimethylpentanamide; (S) — N — ((R)-2- (difluorom ethoxy)- 1 -(3 -(difluorom ethoxy)phenyl)ethyl)-3 -(3 , 3 -dimethylcy clobutyl)-3 - hydroxypropanamide; (R) — N — ((R)-2-(difluoromethoxy)-l-(3- (difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3- hydroxypropanamide; (S)-3- cyclopentyl-N — ((R)-2-(difluorom ethoxy)- 1 -(3 -(difluoromethoxy )phenyl)ethyl)-3 - hydroxypropanamide; (R)-3-cyclopentyl-N — ((R)-2-(difluorom ethoxy)- 1 -(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(l-fluorocyclopropyl)-3- hy droxy-N — ((R)-2-m ethoxy- 1 -(3 -(trifluoromethoxy)phenyl)ethyl)butanamide; and (S)-3 -( 1 - fluorocy clopropyl)-3 -hy droxy-N — ((R)-2-m ethoxy- 1 -(3 - (trifluoromethoxy )phenyl)ethyl)butanamide; or a pharmaceutically acceptable salt of any of these compounds.

[00179] In further embodiments, the Kv7 channel activator is a compound according to formula 8 wherein R ¹ is selected from the group consisting of Ci-Ce alkyl, CF3, CH2CF3, CF2CHF2, C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl may be substituted with 1 or 2 F, CHF2 or CF3, and R ² is H, Ci-Ce alkyl or CF3; or R ¹ and R ² combine to form C3-C5 cycloalkyl optionally substituted with 1 or 2 F, CHF2 or CF3; R ³ is C1-C3 alkyl or CH2O — C1-3 alkyl, said C1-C3 alkyl or CH2O — C1-3 alkyl may optionally be substituted with 1 or 2 F; and R ⁴ is selected from the group consisting of OCF3, OCH2CF3 or OCHF2.

[00180] In further embodiments, R ⁴ is OCF3 or OCHF2.

[00181] In further embodiments, R ² is H or CH3.

[00182] In further embodiments, R ³ is CH2O — C1-3 alkyl.

[00183] In further embodiments, R ¹ is C3-C4 cycloalkyl optionally substituted with 1 or 2 F, CHF 2 or CF ₃ .

[00184] In further embodiments, R ¹ is t-butyl and R ² is H and R ⁴ is OCF3, OCH2CF3, OCHF2 or CF ₃ .

[00185] In further embodiments, R ¹ and R ² combine to form cyclobutyl optionally substituted with 1 or 2 F and R ⁴ is OCF3, OCH2CF3, OCHF2 or CF3.

[00186] In further embodiments, the Kv7 channel activator is selected from the group consisting of: (S)-3-hydroxy-4,4-dimethyl-N-[(lS)-l-[3- (trifluoromethoxy)phenyl]ethyl]pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-[(lS)-l-[3- (trifluoromethoxy)phenyl]ethyl]pentanamide, (S)-3 -hydroxy-4, 4-dimethyl-N-((S)-l -(3- (2,2,2- trifluoroethoxy)phenyl) ethyl)pentanamide, (R)-3 -hydroxy-4, 4-dimethyl-N-((S)-l -(3- (2,2,2- trifluoroethoxy)phenyl) ethyl)pentanamide, (S)-N-((S)-l-(3- (difluoromethoxy)phenyl)ethyl)-3- hydroxy -4, 4-dimethylpentanamide, (R)-N-((S)-l-(3- (difluoromethoxy)phenyl)ethyl)-3- hydroxy -4, 4-dimethylpentanamide, (S)-3-hydroxy-4,4- dimthyl-N-((S)-l-(3- (trifluoromethyl)phenyl)ethyl)pentanamide (R)-3 -hydroxy-4,4- dimethyl-N-((S)-l-(3- (trifluoromethyl)phenyl)ethyl)pentanamide, (S)-3 -hydroxy-4, 4- dimethyl-N-((S)-l-(3- (trifluorom ethoxy )phenyl)propyl)pentanamide, (R)-3 -hydroxy-4, 4- dimethyl-N-((S)-l-(3- (trifluorom ethoxy )phenyl)propyl)pentanamide, (S)-3-(3,3- difluorocy cl obutyl)-3 -hydroxy -N-((S)- 1 -(3 -(trifluorom ethoxy )phenyl)ethyl)propanamide,

(R)-3 -(3 , 3 -difluorocy clobutyl)-3 -hydroxy -N-((S)- 1 -(3 -

(trifluorom ethoxy )phenyl)ethyl)propanamide, (S)-3-hydroxy-4-methyl-N-((S)-l-(3-(2,2,2- trifluoroethoxy)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4-methyl-N-((S)-l-(3-(2,2,2- trifluoroethoxy)phenyl)ethyl)pentanamide, (S)-3 -( 1 -(difluorom ethyl)cy cl opropyl)-3 -hydroxy - N-((S)- 1 -(3 -(trifluoro- methoxy)phenyl)ethyl)propanamide, (R)-3 -( 1 -

(difluorom ethyl)cy cl opropyl)-3 -hydroxy- N-((S)-l-(3-

(trifluorom ethoxy )phenyl)ethyl)propanamide, (R)-3-hydroxy-N-((S)-l-(3-

(trifluoromethoxy)phenyl)ethyl)-3-(l- (trifluorom ethyl)cy cl opropyl)propanamide, (S)-3- hy droxy-N-((S)- 1 -(3 - (trifluoromethoxy )phenyl)ethyl)-3 -( 1 -

(trifluorom ethyl)cyclopropyl)propanamide, (S)- 3-hydroxy-4-methyl-N-((S)-l-(3-

(trifluorom ethoxy )phenyl)ethyl)pentanamide, (R)-3 -hydroxy -4-methyl-N-((S)-l -(3-

(trifluorom ethoxy )phenyl)ethyl)pentanamide, N-((R)-2-(difluoromethoxy)-l-(3-

(trifluorom ethoxy )phenyl)ethyl)-3-(R)-hydroxy- 4,4-dimethylpentanamide, N-((R)-2- (difluoromethoxy)-l-(3- (trifluoromethoxy) phenyl)ethyl)-3-(S)-hydroxy- 4,4- dimethylpentanamide, (S)-3 -hydroxy -N-((R)-2-methoxy-l -(3-

(trifluorom ethoxy )phenyl)ethyl)-4, 4- dimethylpentanamide, (R)-3 -hydroxy -N-((R)-2- methoxy-1 -(3 -(trifluoromethoxy) phenyl)ethyl)- 4,4-dimethylpentanamide, (S)-2-(3,3- difluoro-l-hydroxycyclobutyl)-N-(l-(3- (trifluoromethoxy)phenyl)ethyl)acetamide, (S)-2-(l- hydroxycyclobutyl)-N-(l-(3-(2,2,2- trifluoroethoxy)phenyl)ethyl)acetamide, (3R)-3 -hydroxy - 4-methyl-N-[(l S)-l-[3-(2,2,2- trifluoroethoxy)phenyl]ethyl]-3-

(trifluoromethyl)pentanamide, (3 S)-3 -hydroxy -4-methyl-N-[( IS)- 1 -[3 -(2,2,2- trifluoroethoxy)phenyl]ethyl]-3- (trifluoromethyl)pentanamide, 4,4,4-Trifluoro-3-hydroxy-N- [(1 S)-l-[3- (trifluoromethoxy )phenyl]ethyl]-3- (trifluoromethyl)butanamide, (R)-4, 4,5,5- tetrafluoro-3 -hydroxy-3 -methyl-N- ((S)-l-(3- (trifluorom ethoxy )phenyl)ethyl)pentanamide,

(S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N- ((S)-l-(3-

(trifluoromethoxy)phenyl)ethyl)pentanamide, (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-((S)- 1- (3-(trifluoromethoxy)phenyl)ethyl)pentanamide, (S)-5,5,5-trifluoro-3-hydroxy-3-methyl- N-((S)-1- (3-(trifluoro methoxy )phenyl)ethyl)pentanamide, (R)-3-(l-fluorocyclopropyl)-3- hydroxy-N-((S)-l- (3 -(trifluoromethoxy )phenyl)ethyl)butanamide, (S)-3-(l- fluorocyclopropyl)-3-hydroxy-N-((S)-l- (3-(trifluoro-methoxy)phenyl)ethyl)butanamide, (R)-2-( 1 -hydroxycyclopentyl)-N-(2-methoxy- 1 -(3 -

(trifluorom ethoxy )phenyl)ethyl)acetamide, (R)-3 -cyclopropyl-3 -hydroxy -N-((S)-1 -(3 -(2,2,2- trifluoroethoxy)phenyl)ethyl)butanamide, (S)-3 -cyclopropyl-3 -hydroxy -N-((S)-1 -(3 -(2,2,2- trifluoroethoxy)phenyl)ethyl)butanamide, (R)-4, 4, 4-trifluoro-3 -hydroxy-3 -methyl-N-((S)-l - (3 -(2,2,2- trifluoroethoxy)phenyl)ethyl)butanamide, and (S)-4, 4, 4-trifluoro-3 -hydroxy-3 - methyl-N-((S)-l- (3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide or a pharmaceutically acceptable salt of any of these compounds.

Formula 10

[00187] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 10. Such compounds are described in International Publication No. W02009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. W02004058739A1, published July 15, 2004 and corresponding to International Application No. PCT/DK2003/000906 filed December 18, 2003; US patent No. 7,368,472 issued May 6, 2008 and corresponding to US Application No. 10/540,075 filed December 18, 2003; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No. 12/671,505 filed July 31, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 8, these references incorporated by reference herein control.

[00188] In an embodiment, the Kv7 channel activator is a compound according to formula 10:

Formula 10 , wherein R ¹ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl and hydroxy-C3-8-Cycloalk(en)yl; R ² and R ² ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, aryl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl and hydroxy-C3-8- cycloalk(en)yl; R ³ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl-C3-6-alk(en/yn)yl, hydroxy- Ci-6-alk(en/yn)yl, aryl-C3-8-cycloalk(en)yl, NR ¹⁰ R ¹⁰ ' — Ci-4-alk(en/yn)yl, NR ¹⁰ R ¹⁰ ' — C3-8- Cycloalk(en)yl and hydroxy-C3-8-cycloalk(en)yl; wherein: R ¹⁰ and R ¹⁰ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ¹⁰ and R ¹⁰ ' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; X is CO or SO2; Z is O or NR ⁴ , wherein: R ⁴ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3- 8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms, and the ring formed by R ³ and R ⁴ and the nitrogen atom is optionally substituted with one or more substituents independently selected from Ci-6-alk(en/yn)yl, aryl and aryl-Ci-6-alk(en/yn)yl; q is 0 or 1; and Y represents a heteroaryl of one of the following formulas: wherein: W is O or S; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 0 or 1; and each R ⁵ is independently selected from the group consisting of Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl-Ci-6-alk(en/yn)yl, acyl, halogen, halo-Ci-6- alk(en/yn)yl, alk(en/yn)yloxy, — CO — NR ⁶ R ⁶ , cyano, nitro, — NR ⁷ R ⁴ , — S — R ⁸ , — SO2R ⁸ , and SO2OR ⁸ ; wherein: R ⁶ and R ⁶ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl and aryl; R ⁷ and R ⁷ ' are independently selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl and acyl; and R ⁸ is selected from the group consisting of Ci-6-alk(en/yn)yl, Ci-6-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl and NR ⁹ R ⁹ ; wherein: R ⁹ and R ⁹ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl and C3- 8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or a pharmaceutically acceptable salt thereof.

[00189] In further embodiments, the Kv7 channel activator is selected from the group consisting of: {2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-methyl-amino]-phe nyl}- carbamic acid ethyl ester; {2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}- carbamic acid ethyl ester; {2-Amino-4-[(5-methyl-thiophen-2-ylmethyl)-methyl-amino]- phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(5-bromo-thiophen-2-ylmethyl)-amino]- phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(6-chloro-3-methoxy-benzo[b]thiophen-2- ylmethyl)-amino]-phenyl} -carbamic acid ethyl ester; {(2-Amino-4-[(benzo[b]thiophen-2- ylmethyl)-amino]-phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(5-methyl-thiophen-2- ylmethyl)-amino]-phenyl} -carbamic acid ethyl ester; { 2- Amino-4-[(4-bromo-3 -methoxy - thiophen-2-ylmethyl)-amino]-phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(5-phenyl- thiophen-2-ylmethyl)-amino]-phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(3-chloro- thiophen-2-ylmethyl-amino]-phenyl}-carbamic acid ethyl ester; (2-Amino-4-{[4-(4-chloro- benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino}-phenyl )-carbamic acid ethyl ester; {2-Amino-4-[(3-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-ca rbamic acid ethyl ester; {2- Amino-4-[(5-fluoro-benzofuran-3-ylmethyl)-amino]phenyl}-carb amic acid ethyl ester; {2- Amino-4-[(thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-Amino-4-[(4- bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-Amino-4-[(5- ethyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-Amino-4- [(thiophen-3-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester; {2-Amino-4-[(5-chloro- thiophen-2-ylmethyl)-ethyl-amino]-phenyl}-carbamic acid ethyl ester; {2-Amino-4- [(benzo[b]thiophen-3-ylmethyl)-amino]-phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(5- dimethyl-amino-benzo[b]thiophen-3-ylmethyl)-amino]-phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(5-dimethyl-amino-3-methyl-benzo[b]thiophen-2-yl methyl)-amino]-phenyl}- carbamic acid ethyl ester; {2-Amino-4-[(5-fluoro-thiophen-2-ylmethyl)-amino]-phenyl}- carbamic acid ethyl ester; {2-Amino-4-[(benzo[b]thiophen-2-ylmethyl)-amino]-phenyl}- carbamic acid propyl ester; {2-Amino-4-[(benzo[b]thiophen-3-ylmethyl)-amino]-phenyl}- carbamic acid propyl ester; N-{2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)amino]phenyl}-2- (4-fluoro-phenyl)-acetamide; N-{2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)amino]phenyl}- 3,3-dimethyl-butyramide; and pharmaceutically acceptable salts thereof.

[00190] In further embodiments, the Kv7 channel activator is a compound according to the formula: or a pharmaceutically acceptable salt thereof.

[00191] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 2-Cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-aceta mide; N-(2,6- Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide; N-(4,6-Dimethyl-2- morpholin-4-yl-pyrimidin-5-yl)-2-(4-fluoro-phenyl)-acetamide ; Hexanoic acid (2,6-difluoro- 4-morpholin-4-yl-phenyl)-amide; 2-Cyclopentyl-N-(4,6-dimethyl-2-morpholin-4-yl- pyrimidin-5-yl)-acetamide; N-(2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)- propionamide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-3,3-dimethyl- butyramide; [2-Amino-4-(2,4,6-trimethyl-benzylamino)-phenyl]-carbamic acid ethyl ester; 2-Cyclopentyl- N-(2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide; and pharmaceutically acceptable salts thereof.

[00192] In further embodiments, the Kv7 channel activator is a compound according to formula 10 wherein: R ¹ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; R ² and R ² ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, aryl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl and hydroxy-C3-8- cycloalk(en)yl; R ³ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl-Ci-6-alk(en/yn)yl, hydroxy- Ci-6-alk(en/yn)yl, aryl-C3-8-cycloalk(en)yl, NR ¹⁰ R ¹⁰ ’ — Ci-6-alk(en/yn)yl, NR ¹⁰ R ¹⁰ ’ — C3-8- cycloalk(en)yl and hydroxy-C3-8-cycloalk(en)yl, wherein: R ¹⁰ and R ¹⁰ ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, or R ¹⁰ and R ¹⁰ ’ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; X is CO or SO2; Z is O or NR ⁴ , wherein: R ⁴ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3- 8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms, the ring formed by R ³ and R ⁴ and the nitrogen atom is optionally substituted with one or more substituents independently selected from Ci-6-alk(en/yn)yl, aryl and aryl-Ci-6-alk(en/yn)yl; q is 0 or 1; and Y represents a heteroaryl of formula: wherein: W is S; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 0 or 1; and each R ⁵ is independently selected from the group consisting of Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, aryl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl-Ci-6-alk(en/yn)yl, acyl, halogen, halo-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, — CO — NR ⁶ R ⁶ , cyano, nitro, — NR ⁷ R ⁷ ', — S — R ⁸ , — SO2R ⁸ , and SO2OR ⁸ , wherein: R ⁶ and R ⁶ ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl and aryl; R ⁷ and R ⁷ ’ are independently selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl and acyl; and R ⁸ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl and — NR ⁹ R ⁹ ', wherein: R ⁹ and R ⁹ ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3- 8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or a pharmaceutically acceptable salt thereof.

[00193] In further embodiments, R ¹ is selected from the group consisting of hydrogen and Ci-6-alk(en/yn)yl.

[00194] In further embodiments, at least one of the substituents R ² and R ² ’ is a hydrogen atom.

[00195] In further embodiments both R ² and R ² are hydrogen atoms.

[00196] In further embodiments, X is CO. [00197] In further embodiments, q is 0.

[00198] In further embodiments, q is 1 and Z is an oxygen atom.

[00199] In further embodiments, R ³ is selected from the group consisting of C1-6- alk(en/yn)yl and aryl-Ci-6-alk(en/yn)yl.

[00200] In further embodiments, R ³ is Ci-6-alk(en/yn)yl.

[00201] In further embodiments, R ³ is aryl-Ci-6-alk(en/yn)yl.

[00202] In further embodiments, W is a sulfur atom.

[00203] In further embodiments, Y is of formula: wherein: W is S; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 0 or 1; and each R ⁵ is independently selected from the group consisting of Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, aryl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl-Ci-6-alk(en/yn)yl, acyl, halogen, halo-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, — CO — NR ⁶ R ⁶ , cyano, nitro, — NR ⁷ R ⁷ ', — S — R ⁸ , — SO2R ⁸ , and SO2OR ⁸ , wherein: R ⁶ and R ⁶ ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl and aryl; R ⁷ and R ⁷ ’ are independently selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl and acyl; and R ⁸ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl and — NR ⁹ R ⁹ ', wherein: R ⁹ and R ⁹ ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3- 8-cycloalk(en)yl-Ci-6-alk(en/yn)yl.

[00204] In further embodiments, Y is of formula:

wherein: W is S; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 0 or 1; and each R ⁵ is independently selected from the group consisting of Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, aryl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl-Ci-6-alk(en/yn)yl, acyl, halogen, halo-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, — CO — NR ⁶ R ⁶ , cyano, nitro, — NR ⁷ R ⁷ ', — S — R ⁸ , — SO2R ⁸ , and SO2OR ⁸ , wherein: R ⁶ and R ⁶ ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl and aryl; R ⁷ and R ⁷ ’ are independently selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl and acyl; and R ⁸ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, aryl and — NR ⁹ R ⁹ ', wherein: R ⁹ and R ⁹ ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3- 8-cycloalk(en)yl-Ci-6-alk(en/yn)yl.

Formula 11

In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 11. Such compounds are described in International Publication No. W02009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. W02004058739A1, published July 15, 2004 and corresponding to International Application No. PCT/DK2003/000906 filed December 18, 2003; US patent No. 7,368,472 issued May 6, 2008 and corresponding to US Application No. 10/540,075 filed December 18, 2003; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No. 12/671,505 filed July 31, 2008; International Publication No. W02004082677A1, published September 30, 2004 and corresponding to International Application No. PCT/DK2004/000186 filed March 18, 2004; International Publication No. W02004080950A1, published or issued September 23, 2004 and corresponding to International Application No. PCT/DK2004/000162 filed March 12, 2004; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 11, these references incorporated by reference herein control.

[00205] In an embodiment, the Kv7 channel activator is a compound according to formula 11 : Formula 11 wherein: s is 0 or 1; U is O, S, SO2, SO2NR ¹¹ , CO — O or CONR ¹¹ ; wherein: R ¹¹ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, and C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ² and R ¹¹ together with the nitrogen atom to which R ¹¹ is attached form a 5-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; q is 0 or 1; X is CO or SO2; with the proviso when X is SO2, then q is 0; Z is O or S; R ¹ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6- alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; R ² is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8-cycloalk(en)yl, Ar — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halogen, halo-Ci-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, NR ¹⁰ R ¹⁰ ' — Ci-6-alk(en/yn)yl, NR ¹⁰ R ¹⁰ ' — C3-8-cycloalk(en)yl and NR ¹⁰ R ¹⁰ ' — C3- 8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein: R ¹⁰ and R ¹⁰ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yl; or R ¹⁰ and R ¹⁰ ' together with the nitrogen atom to which they are attached form a 5-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; and provided that: when R ² is halogen or cyano, then s is 0; and when s is 1 and R ² is a hydrogen atom or acyl, then U is O or S; R ³ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, heterocycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3-s-cycloalk(en)yl, Ci-6-alk(en/yn)yl- heterocycloalk(en)yl, heterocycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8-cycloalk(en)yl, Ar-heterocycloalk(en)yl, Ar — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ar — Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, C1-6- alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-Ci-6-alk(en/yn)yl, C1-6- alk(en/yn)yloxy-C3-8-cycloalk(en)yl, Ci-6-alk(en/yn)yloxy-heterocycloalk(en)yl, Ar-oxy-Ci-6- alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-carbonyl-Ci- 6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-carbonyl-Ci-6-alk(en/yn)yl, C3-8-cycl oal k(en)yl-Ci-6- alk(en/yn)yl oxy-carbonyl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, hydroxy-Ci-6-alk(en/yn)yl- heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo- heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl-C3-8- cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl-Ar, halo- C3-8-cycloalk(en)yl-Ar, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl-Ar, halo-Ci-6-alk(en/yn)yl- C3-8-cycloalk(en)yl-Ar, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano- heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl- C3-8-cycloalk(en)yl, cyano-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, acyl-Ci-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, acyl-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-Ci-6-alk(en/yn)yl- heterocycloalk(en)yl, NR ¹² R ¹² , optionally substituted NR ¹² R ¹² ' — Ci-6-alk(en/yn)yl, optionally substituted NR ¹² R ¹² ' — C3-8-cycloalk(en)yl, and optionally substituted NR ¹² R ¹² ' — C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein: R ¹² and R ¹² ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8-cycloalk(en)yl, Ar — C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yl, Ar-heterocycloalk(en)yl, Ar-oxy-Ci-6-alk(en/yn)yl, Ar-oxy-C3-8- cycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar-oxy-heterocycloalk(en)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, halo-Ci-6-alk(en/yr)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ¹² and R ¹² ' together with the nitrogen atom to which they are attached form a 5-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; provided that: when R ³ is NR ¹² R ¹² , then q is 0; and Y represents a group of the following formulas: wherein: the line represents a bond attaching the group represented by Y to the carbon atom; W is O or S; V is N, C or CH; T is N, NH or O; a is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; c is 0 or 1; d is 0, 1, 2 or 3; e is 0, 1 or 2; f is 0, 1, 2, 3, 4 or 5; g is 0, 1, 2, 3 or 4; h is 0, 1, 2 or 3; j is 0, 1 or 2; k is 0, 1, 2 or 3; and each R ⁵ is independently selected from the group consisting of a Ci- 6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6- alk(en/yn)yl, Ar — C3-s-cycloalk(en)yl, Ar — C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar-oxy, Ar-oxy-Ci-6-alk(en/yn)yl, Ar-oxy-C3-s-cycloalk(en)yl, Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, Ci-6-alk(en/yn)yloxy, C3-8- cycloalk(en)yloxy, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, Ci-6-alk(en/yn)yloxy-carbonyl, halogen, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, — CO — NR ⁶ R ⁶ , cyano, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, NR ⁷ R ⁷ , S — R ⁸ and SO2R ⁸ ; or two adjacent

R ⁵ together with the aromatic group form a 5-8 membered ring that optionally contains one or two heteroatoms; wherein: R ⁶ and R ⁶ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl and Ar; R ⁷ and R ⁷ ' are independently selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, heterocycloalk(en)yl-Ci-6-alk(en/yn)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, heterocycloalk(en)yl-Ar and acyl; or R ⁷ and R ⁷ ' together with the nitrogen atom to which they are attached form a 5-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; and R ⁸ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, Cs-s-cycl oal k(en)yl, C3-s-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Ar and — NR ⁹ R ⁹ '; wherein R ⁹ and R ⁹ ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl and C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or a pharmaceutically acceptable salt thereof.

[00206] In further embodiments, the Kv7 channel activator is selected from the group consisting of: {4-[(Benzofuran-2-ylmethyl)-amino]-2-methylphenyl}-carbamic acid propyl ester; {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-ca rbamic acid ethyl ester; {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-car bamic acid ethyl ester; {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-c arbamic acid ethyl ester; [4- (4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid ethyl ester; [4-(4-Fluoro- benzylamino)-2-methylphenyl]-carbamic acid propyl ester; (4-{[4-(4-Chloro- benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino}-2-meth ylphenyl)-carbamic acid propyl ester; {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-ca rbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-car bamic acid propyl ester; {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-ca rbamic acid propyl ester; {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-car bamic acid propyl ester; {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-c arbamic acid propyl ester; [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid propyl ester; {4- [(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbam ic acid ethyl ester; {4-[(5- Chloro-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic acid ethyl ester; {4- [(Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbam ic acid ethyl ester; [2- Chloro-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid ethyl ester; [2-Chloro-4-(4- fluoro-benzylamino)-phenyl]-carbamic acid propyl ester; 2-Chloro-4-{[4-(4-chloro- benzenesulfonyl)-3-methyl-thi ophen-2 -ylmethyl]-amino)-phenyl} -carbamic acid propyl ester; {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-ca rbamic acid propyl ester; {4- [(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbam ic acid propyl ester; {2- Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carb amic acid propyl ester; {4- [(Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbam ic acid propyl ester; {4- [(Benzofuran-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic acid propyl ester; {4-[(5- Chloro-thiophen-2-ylmethyl)-amino]-2-cyanophenyl}-carbamic acid ethyl ester; {4- [(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carba mic acid methyl ester; {4- [(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carba mic acid isopropyl ester; {4-[(4-Fluoro-benzyl)-(methyl)amino]-2-methoxyphenyl}-carbam ic acid propyl ester; [4- (Benzo[b]thiophen-2-ylmethyl-(methyl)amino)-2-methoxy-phenyl ]-carbamic acid propyl ester; {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methoxy- phenyl}-carbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-methoxy-p henyl}- carbamic acid propyl ester; {2-Methoxy-4-[methyl-(5-methyl-thiophen-2-ylmethyl)-amino]- phenyl} -carbamic acid propyl ester; {4-[(4-Fluorobenzyl)-(methyl)-amino]-2- isopropoxyphenylj-carbamic acid ethyl ester; [4-(3-Fluorobenzylamino)-2-methoxyphenyl]- carbamic acid ethyl ester; [4-(4-Isopropylbenzylamino)-2-methoxyphenyl]-carbamic acid ethyl ester; {2-Methoxy-4-[(3-methylthiophen-2-ylmethyl)-amino]-phenyl}-c arbamic acid ethyl ester; [4-(2,4-Difluorobenzylamino)-2-methoxyphenyl]-carbamic acid ethyl ester; [2- Cyclopentyloxy-4-(4-methoxybenzylamino)-phenyl]-carbamic acid ethylester; [2- Cyclopentyloxy-4-(3-fluoro-2-methylbenzylamino)-phenyl]-carb amic acid ethyl ester; [4-(3- Fluoro-2-methylbenzylamino)-2-phenethyloxyphenyl]-carbamic acid ethyl ester; [2- Benzyloxy-4-(3-fluoro-2-methylbenzylamino)-phenyl]carbamic acid ethyl ester; [2- Benzyloxy-4-(4-methylsulfanylbenzylamino)-phenyl]-carbamic acid ethyl ester; {4- [(Benzo[b]thiophen-3-ylmethyl)-amino]-2-cyclopentyloxyphenyl }-carbamic acid ethyl ester; [4-(3-Fluoro-2-methylbenzylamino)-2-isopropoxyphenyl]-carbam ic acid ethyl ester; [2- Benzyloxy-4-(3-methoxybenzylamino)-phenyl]-carbamic acid ethyl ester; {4- [(Benzo[l,3]dioxol-5-ylmethyl)-amino]-2-isopropoxyphenyl}-ca rbamic acid ethyl ester; {4- [(5-Bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid propyl ester; {4-[(5-Chloro- thiophen-2-ylmethyl)-amino]-phenyl} -carbamic acid propyl ester; [2-Cyano-4-(4- isopropylbenzylamino)-phenyl]-carbamic acid ethyl ester; {4-[(5-Bromo-thiophen-2- ylmethyl)-(methyl)amino]-2-methyl phenyl} -carbamic acid propyl ester; {4-[(4- Isopropylbenzyl)-(methyl)amino]-2-methyl phenyl} -carbamic acid propyl ester; {2-Methyl- 4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-carbamic acid propyl ester; {2-Methyl- 4-[methyl-(4-methylsulfanyl-benzyl)-amino]-phenyl}-carbamic acid propyl ester; {4-[(4-tert- Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-carbamic acid ethyl ester; {2-Chloro-4- [methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl} -carbamic acid ethyl ester; {2-Chloro-4- [methyl-(4-methylsulfanyl-benzyl)-amino]-phenyl}-carbamic acid ethyl ester; {4-[(5-Bromo- thiophen-2-ylmethyl)-(methyl)amino]-2-chlorophenyl}-carbamic acid propyl ester; {2- Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phen yl}-carbamic acid propyl ester; {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-car bamic acid propyl ester; {2-Chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-carbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoro methyl-phenyl}-carbamic acid ethyl ester; {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluor omethyl- phenyl} -carbamic acid ethyl ester; {4-[(4-Isopropyl-benzyl)-(methyl)amino]-2- trifluoromethyl-phenyl} -carbamic acid ethyl ester; {4-[(4-tert-Butyl-benzyl)-(methyl)amino]- 2-trifluoromethyl-phenyl} -carbamic acid ethyl ester; {4-[Methyl-(4-trifluoromethyl-benzyl)- amino]-2-trifluoromethyl-phenyl}-carbamic acid ethyl ester; {4-[Methyl-(4-methylsulfanyl- benzyl)-amino]-2-trifluoromethyl-phenyl}-carbamic acid ethyl ester; {4-[(5-Bromo-thiophen- 2-ylmethyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbami c acid propyl ester; {4-[(5- Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-trifluoromethyl -phenyl} -carbamic acid propyl ester; {4-[(4-Isopropyl-benzyl)-(methyl)amino]-2-trifluoromethyl-ph enyl}-carbamic acid propyl ester; {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-trifluoromethyl-p henyl}- carbamic acid propyl ester; {4-[Methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluorometh yl- phenyl} -carbamic acid propyl ester; {4-[Methyl-(4-methylsulfanyl-benzyl)-amino]-2- trifluoromethyl-phenyl} -carbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)- (methyl)amino]-2-cyanophenyl) -carbamic acid propyl ester; {4-[(4-tert-Butyl-benzyl)- (methyl)amino]-2-cyanophenyl) -carbamic acid propyl ester; {2-Cyano-4-[methyl-(4- trifluoromethyl-benzyl)-amino]-phenyl}-carbamic acid propyl ester; {2-Bromo-4-[(5-bromo- thiophen-2-ylmethyl)-(methyl)amino]phenyl} -carbamic acid propyl ester; {2-Bromo-4-[(5- chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic acid propyl ester; {2-Bromo- 4-[(4-isopropylbenzyl)-(methyl)amino]-phenyl}-carbamic acid propyl ester; {2-Bromo-4-[(4- tert-butyl-benzyl)-(methyl)amino]-phenyl}-carbamic acid propyl ester; {2-Bromo-4-[methyl- (4-trifluoromethyl-benzyl-amino]-phenyl} -carbamic acid propyl ester; [2-Iodo-4-(4- isopropyl-benzylamino)-phenyl]-carbamic acid propyl ester; [4-(4-tert-Butyl-benzylamino)- 2-iodophenyl]-carbamic acid propyl ester; [2-Iodo-4-(4-trifluoromethyl-benzylamino)- phenyl]-carbamic acid propyl ester; [2-Iodo-4-(4-methylsulfanyl-benzylamino)-phenyl]- carbamic acid propyl ester; {2-Iodo-4-[4-(4-methylpiperazin-l-yl)-benzylamino]-phenyl}- carbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethylyamino]-2-trifluoromethyl- phenyl} -carbamic acid ethyl ester; {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2- trifluoromethyl-phenyl} -carbamic acid ethyl ester; [4-(4-tert-Butyl-benzylamino)-2- trifluoromethyl-phenyl]-carbamic acid ethyl ester; [4-(4-Methylsulfanyl-benzylamino)-2- trifluoromethyl-phenyl]-carbamic acid ethyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)- amino]-2-trifluoromethyl-phenyl}-carbamic acid propyl ester; [4-(4-Isopropylbenzylamino)- 2-trifluoromethyl-phenyl]-carbamic acid propyl ester; [4-(4-tert-Butyl-benzylamino)-2- trifluoromethyl-phenyl]-carbamic acid propyl ester; [2-Trifluoromethyl-4-(4-trifluoromethyl- benzylamino)-phenyl]-carbamic acid propyl ester; [4-(4-Dimethylamino-benzylamino)-2- trifluoromethyl-phenyl]-carbamic acid propyl ester; [4-(4-Methylsulfanyl-benzylamino)-2- trifluoromethyl-phenyl]-carbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)- amino]-2-cyanophenyl}-carbamic acid propyl ester; {4-[(5-Chloro-thiophen-2-ylmethyl)- amino]-2-cyanophenyl}-carbamic acid propyl ester; [2-Cyano-4-(4-trifluoromethyl- benzylamino)-phenyl]-carbamic acid propyl ester; {2-Bromo-4-[(5-bromo-thiophen-2- ylmethyl)-amino]-phenyl} -carbamic acid propyl ester; {2-Bromo-4-[(5-chloro-thiophen-2- ylmethyl)-amino]-phenyl} -carbamic acid propyl ester; [2-Bromo-4-(4- isopropylbenzylamino)-phenyl]-carbamic acid propyl ester; [2-Bromo-4-(4-tert-butyl- benzylamino)-phenyl]-carbamic acid propyl ester; [2-Bromo-4-(4-trifluoromethyl- benzylamino)-phenyl]carbamic acid propyl ester; [2-Bromo-4-(4-methylsulfanyl- benzylamino)-phenyl]-carbamic acid propyl ester; N-{4-[(5-Bromo-thiophen-2-ylmethyl)- amino]-2-methoxyphenyl}-butyramide; N-{4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2- m ethoxyphenyl} -butyramide; N-[4-(4-Isopropylbenzylamino)-2-methoxyphenyl]- butyramide; N-[4-(4-tert-Butyl-benzylamino)-2-methoxyphenyl]-butyramide; N-[2 -Methoxy - 4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide; {4-[(5-Chloro-thi ophen-2 -ylmethyl)- amino]-2-furan-2-yl-phenyl}-carbamic acid propyl ester; [2-Furan-2-yl-4-(4- isopropylbenzylamino)-phenyl]-carbamic acid propyl ester; [5-(4-Fluorobenzylamino)- biphenyl-2-yl]-carbamic acid propyl ester; {5-[(5-Chloro-thiophen-2-ylmethyl)-amino]- biphenyl-2-yl} -carbamic acid propyl ester; [5-(4-Isopropylbenzylamino)-biphenyl-2-yl]- carbamic acid propyl ester; N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino] - phenyl}-2-phenylacetamide; N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)- (methyl)amino]-phenyl) -3, 3 -dimethylbutyramide; N-{2-Chloro-4-[(5-chloro-thiophen-2- ylmethyl)-(methyl)amino]-phenyl} -3 -phenylpropionamide; N-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-butyramide; Pentanoic acid {2-chloro-4-[(5- chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide; Cyclopropanecarboxylic acid {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-p henyl}-amide;

Cyclobutanecarboxylic acid {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]- phenyl} -amide; Cyclopentanecarboxylic acid {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)- (methyl)amino]-phenyl) -amide; Cyclohexanecarboxylic acid {2-chloro-4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-amide; N-{2-Chloro-4-[(5-chloro-thi ophen-2 - ylmethyl)-(methyl)amino]-phenyl}-2-thiophen-2-yl-acetamide; N-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(3-methoxy-phe nyl)-acetamide, N-{2- Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phen yl)-2-(4-chloro-phenyl}- acetamide; N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino] -phenyl}-2-(4- methoxy-phenyl)-acetamide; N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)- (methyl)amino]-phenyl)-2-(4-fluoro-phenyl} -acetamide; N-{2-Chloro-4-[(5-chloro-thiophen- 2-ylmethyl)-(methyl)amino]-phenyl}-3-cyclohexylpropionamide; N-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-amino]-phenyl}-2,2-dimethylpropionamide ; N-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-amino]-phenyl}-2-phenoxyacetamide; N-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-amino]-phenyl}-2-phenyl acetamide; N-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-amino]-phenyl} -3, 3 -dimethylbutyramide; N-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-amino]-phenyl} -butyramide; Pentanoic acid {2-chloro-4-[(5-chloro- thiophen-2-ylmethyl)-amino]-phenyl}-amide;Cyclopropanecarbox ylic acid {2-chloro-4-[(5- chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide; Cyclobutanecarboxylic acid {2-chloro- 4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide; Cyclopentanecarboxylic acid {2- chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]phenyl}-amide ; Cyclohexanecarboxylic acid {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-a mide; N-{2-Chloro-4- [(5-chloro-thi ophen-2 -ylmethyl)-amino]-phenyl }-2 -thi ophen-2 -yl-acetamide; N-{2-Chloro-4- [(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(3-methoxyp henyl)-acetamide; N-{2- Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(4 -chlorophenyl)-acetamide; N- {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2 -(4-methoxyphenyl)- acetamide; N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl} -2-(4- fluorophenyl)-acetamide; 2,3-Dihydro-benzo[l,4]dioxine-6-carboxyl acid {2-chloro-4-[(5- chloro-thiophen-2-ylmethyl)-amino]-phenyl}-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid {2-chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-a mide; N-{2-Chloro-4- [(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-3-cyclohexylp ropionamide; N-{4-[(5- Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}- 2,2-dimethylpropionamide; N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl -phenyl}-2-phenyl acetamide; N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl -phenyl}-3,3- dimethylbutyramide; N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl - phenyl} -3 -phenylpropionamide; N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2- methyl-phenyl} -butyramide; 2,2,2-Trichloro-N-{4-[(5-chloro-thiophen-2-ylmethyl)- (methyl)amino]-2-methyl-phenyl} -acetamide; Cyclopropanecarboxylic acid {4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-2-methyl-phenyl}-amide; Cyclobutanecarboxylic acid {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methylph enyl}-amide;

Cyclopentanecarboxylic acid {4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl phenyl} -amide; Cyclohexanecarboxylic acid {4-[(5-chloro-thiophen-2-ylmethyl)- (methyl)amino]-2-methylphenyl} -amide; N-{4-[(5-Chloro-thiophen-2-ylmethyl)- (methyl)amino]-2-methylphenyl} -2 -thi ophen-2 -yl-acetamide; N-{4-[(5-Chloro-thiophen-2- ylmethyl)-(methyl)amino]-2-methylphenyl}-2-(3-methoxyphenyl) -acetamide; N-{4-[(5- Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-m ethyl phenyl }-malonamic acid methyl ester; 2-(4-Chlorophenyl)-N-{4-[(5-chloro-thiophen-2-ylmethyl)-(met hyl)amino]-2- methylphenyl} -acetamide; N-{4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2-methyl phenyl }-2-(4-methoxyphenyl)-acetamide; N-{4-[(5-Chloro-thiophen-2-ylmethyl)- (methyl)amino]-2-methyl phenyl }-2-(4-fluorophenyl)-acetamide; N-{4-[(5-Chloro-thiophen- 2-ylmethyl)-(methyl)amino]-2-methylphenyl}-3-cyclohexylpropi onamide; {2-Chloro-4-[(5- chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic acid phenyl ester; {2-Chloro- 4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-car bamic acid benzyl ester; {2- Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phen yl}-carbamic acid isobutyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-p henyl}-carbamic acid butyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-p henyl}-carbamic acid hexyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-p henyl}- carbamic acid 4-nitrobenzyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)- (methyl)amino]-phenyl} -carbamic acid but-3-enyl ester; {2-Chloro-4-[(5-chloro-thiophen-2- ylmethyl)-(methyl)amino]-phenyl} -carbamic acid but-2-ynyl ester; {2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic acid 2,2-dimethylpropyl ester; {2- Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phen yl}-carbamic acid 2- chlorobenzyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-p henyl}- carbamic acid 3 -chloropropyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)- (methyl)amino]-phenyl} -carbamic acid 2-benzyloxyethyl ester; 3-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino] -phenyl } - 1 -methyl- 1 -propyl-urea; 1 - { 2-Chl oro-4- [(5 - chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-(2-fluo rophenyl)-urea; N-{2-Chloro- 4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2,2 ,2-trifluoroacetamide; N-{2- Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2, 2-trifluoroacetamide; N-{5- [(5-Chloro-thiophen-2-ylmethyl)-amino]-4'-dimethylamino-biph enyl-2-yl}-2-(4- fluorophenyl)-acetamide; N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino] - phenyl}-2-(4-chlorophenyl)-acetamide; [4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2- methylphenyl]-carbamic acid ethyl ester; 2-(4-Fluorophenyl)-N-{2-methyl-4-[(6-p- tolyloxypyridin-3-ylmethyl)-amino]-phenyl}-acetamide; N-[2-Methyl-4-(4-trifluoromethyl- benzylamino)-phenyl]-butyramide; 2-(4-Fluorophenyl)-N-{2-methyl-4-[6- trifluoromethylpyridin-3-ylmethyl)-amino]-phenyl} -acetamide; Pentanoic acid {4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-2-methylphenyl}-amide; 3,3-Dimethyl-N-{2-methyl- 4-[(6-p-tolyloxypyridin-3-ylmethyl)-amino]-phenyl}-butyramid e; [2-Methyl-4-(4- trifluoromethyl-benzylamino)-phenyl]-carbamic acid ethyl ester; N-{2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-2-(4-chloropheny l)-propionamide; [4-(4- Chloro-benzylamino)-2-methylphenyl]-carbamic acid ethyl ester; {4-[(6-Methoxy- benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl} -carbamic acid propyl ester; {4- [(5=Chloro-thiophen-2-ylmethyl)-amino]-2-quinolin-3-yl-pheny l} -carbamic acid ethyl ester; {4-[(5-Dimethylamino-3-methyl-benzo[b]thiophen-2-ylmethyl)-a mino]-2-methylphenyl}- carbamic acid propyl ester; 3,3-Dimethyl-N-{2-methyl-4-[(6-trifluoromethylpyridin-3- ylmethyl)-amino]-phenyl} -butyramide; N-(4-{[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]- amino}-2-methylphenyl)-2-(4-fluorophenyl)-acetamide; {2-Benzyloxy-4-[(4-fluorobenzyl)- (methyl)amino]-phenyl}-thiocarbamic acid S-ethyl ester; {2-Cyclopentyloxy-4-[(4- fluorobenzyl)-(methyl)amino]-phenyl}-thiocarbamic acid S-ethyl ester; N-{4-[(6- Chloropyridin-3-ylmethyl)-amino]-2-methylphenyl}-2-(4-fluoro phenyl)-acetamide; {4-[(7- Dimethylamino-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylph enyl}-carbamic acid propyl ester; l-{2-Cyclopentyloxy-4-[(4-fluorobenzyl)-(methyl)amino]-pheny l}-3-ethyl-urea;

2-Amino-4-methyl-pentanoic acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]- amide; {4-[(6-Methoxy-benzo[b]thiophen-2-ylmethyl)-amino]-2-methylp henyl}-carbamic acid ethyl ester; 2-Amino-4-methyl-pentanoic acid [2-methyl-4-(4-trifluoromethyl- benzylamino)-phenyl]-amide; 2-(4-Fluorophenyl)-N-{2-methyl-4-[(4-methyl-2- phenylpyrimidin-5-ylmethyl)-amino]-phenyl}-acetamide, 3,3-Dimethyl-N-{2-methyl-4-[(2- phenylpyrimidin-5-ylmethyl)-amino]-phenyl}-butyramide; {4-[(5-Chloro-thiophen-2- ylmethyl)-amino]-2-pyridin-3-yl-phenyl} -carbamic acid ethyl ester; 1 -Aminocyclopropanecarboxylic acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide; {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-pyridin-4-yl-phe nyl}-carbamic acid ethyl ester; N-[2-Methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-pipe ridin-l-yl-acetamide;

N-(4-{[5-(4-Chlorophenoxy)-l,3-dimethyl-lH-pyrazol-4-ylme thyl]-amino}-2- methylphenyl)-2,2-dimethylpropionamide; 2,2-Dimethyl-N-{2-methyl-4-[(6-phenoxypyridin-

3-ylmethyl)-amino]-phenyl}-propionamide; N-[2-Methyl-4-(4-trifluoromethyl-benzylamino)- phenyl]-2-pyrrolidin-l-yl-acetamide; [4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-(6- methoxypyridin-3-yl)-phenyl]-carbamic acid ethyl ester; 4-[(3-Methyl-4- propoxycarbonylamino-phenyl amino)-methyl]-benzoic acid methyl ester; N-[2-Methyl-4-(4- trifluoromethyl-benzylamino)-phenyl]-2-morpholin-4-yl-acetam ide; 2,2-Dimethyl-N-{2- methyl-4- [(3 -methyl-5 -phenyli soxazol-4-ylmethyl)-amino] -phenyl } -propionamide; { 4- [(5 - Chloro-thiophen-2-ylmethyl-amino]-2-iodophenyl} -carbamic acid ethyl ester; N-{4-[(5- Chloro-thiophen-2-ylmethyl)-amino]-2-iodophenyl}-2-(4-fluoro phenyl)-acetamide; {4-[(5- Chloro-thiophen-2-ylmethyl)-amino]-2-quinolin-5-yl-phenyl}-c arbamic acid ethyl ester; and pharmaceutically acceptable salts thereof.

[00207] In further embodiments, the Kv7 channel activator is a compound according to formula 11, wherein: s is 0 or 1; U is O, S, SO2, SONR ¹¹ , or CONR ¹¹ ; wherein: R ¹¹ is hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, or C3-s-cycloalk(en)yl-Ci-6 -alk(en/yn)yl; or R ² and R ¹¹ taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms; q is 0 or 1; X is CO or SO2; with the proviso that q is 0 when X is SO2; Z is O or S; R ¹ is hydrogen, C1-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6 -alk(en/yn)yl, acyl, hydroxy-Ci-6- alk(en/yn)yl, hydroxy-C3-s-cycloalk(en)yl, hydroxy-C3-s -cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo -C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3-s-cycloalk(en) yl or cyano-C3-s -cycloalk(en)yl-Ci-6- alk(en/yn)yl; R ² is hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6 - alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-s-cycloalk(en)yl, Ar — C3-s-cycloalk(en)yl- Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-s-cycloalk (en)yl, hydroxy-C3- 8 -cycloalk(en)yl-Ci-6-alk(en/yn)yl, halogen, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk (en)yl, halo -C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, NR ¹⁰ R ¹⁰ ' — Ci-6-alk(en/yn)yl, NR ¹⁰ R ¹⁰ ' — C3-8 -cycloalk(en)yl or NR ¹⁰ R ¹⁰ ' — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein: R ¹⁰ and R ¹⁰ ' are each independently hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8-cycloalk(en)yl or cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ¹⁰ and R ¹⁰ ' taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms; with the proviso that: when R ² is halogen or cyano, then s is 0; and when s is 1 and R ² is a hydrogen atom or acyl, then U is O or S; R ³ is C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, heterocycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, heterocycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yloxy-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, C1-6- alk(en/yn)yloxy-heterocycloalk(en)yl, Ci-6-alk(en/yn)yloxy-carbonyl-Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yloxy-carbonyl-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy - carbonyl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy -heterocycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6- alk(en/yn)yl -C3-8-cycloalk(en)yl, hydroxy-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, halo -C3-8- cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo - Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, cyano-Ci- 6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3-8- cycloalk(en)yl -Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano-Ci-6- alk(en/yn)yl -heterocycloalk(en)yl, acyl-Ci-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl- heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl-Ci-6-alk(en/yn)yl-C3-8- cycloalk(en)yl, acyl-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, NR ¹² R ¹² , optionally substituted NR ¹² R ¹² '-Ci-6-alk(en/yn)yl, optionally substituted NR ¹² R ¹² '-C3-8-alk(en/yn)yl, or optionally substituted NR ¹² R ¹² '-C3-8-alk(en/yn)yl-Ci-6-alk(en/yn)yl; wherein: R ¹² and R ¹² ' are each independently hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8-cycloalk(en)yl, Ar — C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yl, Ar-heterocycloalk(en)yl, Ar-oxy-Ci-6-alk(en/yn)yl, Ar-oxy-C3-8- cycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar-oxy -heterocycloalk(en)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, or cyano -C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ¹² and R ¹² ' taken together with the nitrogen atom form a 5-8 membered saturated or unsaturated ring, which optionally contains 1, 2 or 3 further heteroatoms; with the proviso that when R ³ is NR ¹² R ¹² ' then q is 0; and Y is a group of formula: wherein: “|” represents a bond attaching the group represented by Y to the carbon atom; V is C or CH; and k is 0, 1, 2 or 3; and each R ⁵ is independently Ci-6-alk(en/yn)yl, Cs-s-cycloalk (en)yl, C3-s-cycloalk(en) yl-Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8- cycloalk(en)yl, Ar — C3-s-cycloalk (en)yl-Ci-6-alk(en/yn)yl , Ar-oxy, Ar-oxy-Ci-6alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, Ci-6-alk (en/yn)yl -heterocycloalk(en)yl, Ar-oxy-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, Ci-6-alk (en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, Ci-6-alk(en/yn)yloxy-carbonyl, halogen, halo-Ci-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, — CO — NR ⁶ R ⁶ ', cyano, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk (en)yl, cyano-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, NR ⁷ R ⁷ , S — R ⁸ or SO2R ⁸ ; or two adjacent R ⁵ groups taken together with the aromatic group form a 5-8 membered ring, which optionally contains one or two heteroatoms; wherein: R ⁶ and R ⁶ ' are each independently hydrogen, Ci-6-alk(en/yn)yl, C3- 8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl or Ar; R ⁷ and R ⁷ ' are each independently hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Ar, heterocycloalk(en)yl-Ci-6-alk (en/yn)yl, heterocycloalk(en)yl-C3-8- cycloalk(en)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl-Ci-6-alk (en/yn)yl, heterocycloalk(en)yl-Ar or acyl; or R ⁷ and R ⁷ taken together with the nitrogen atom form a 5- 8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms; and R ⁸ is hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yl, Ar or — NR ⁹ R ⁹ '; wherein: R ⁹ and R ⁹ ' are each independently hydrogen, Ci- 6-alk(en/yn)yl, C3-8-cycloalk(en)yl or C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or salts thereof. [00208] In further embodiments, R ¹ is Ci-6-alk(en/yn)yl or a hydrogen atom.

[00209] In further embodiments, s is 0.

[00210] In further embodiments, s is 1.

[00211] In further embodiments, U is an oxygen atom.

[00212] In further embodiments, R ² is hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, Ar, Ar — Ci-6-alk(en/yn)yl, halogen, halo-Ci-6-alk(en/yn)yl or cyano; with the provisos that when R ² is halogen or cyano, then s is 0; and when s is 1 and R ² is a hydrogen atom, then U is O or S.

[00213] In further embodiments, Z is an oxygen atom. [00214] In further embodiments, Z is a sulfur atom. [00215] In further embodiments, q is 0.

[00216] In further embodiments, q is 1. [00217] In further embodiments, X is CO. [00218] In further embodiments, R ³ is Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, heterocycloalk (en)yl-Ci -6-alk(en/yn)yl, heterocycloalk(en)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar-oxy-Ci-6-alk (en/yn)yl, Ar — C1-6- alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-carbonyl-Ci-6-alk(en/yn)yl, halo-Ci- 6 -alk(en/yn)yl, NR ¹² R ¹² , optionally substituted NR ¹² R ¹² ' — Ci-6-alk(en/yn)yl, or optionally substituted NR ¹² R ¹² ' — C3-s-cycloalk(en)yl.

[00219] In further embodiments, R ¹² and R ¹² ' are each independently hydrogen, Ci-6- alk(en/yn)yl or Ar.

[00220] In further embodiments, V is CH.

[00221] In further embodiments, each R ⁵ is independently Ci-6-alk(en/yn)yl, Ci-6- alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ci-6-alk(en/yn)yloxy, Ar-oxy, Ci-6-alk(en/yn)yloxy- carbonyl, halogen, halo-Ci-6-alk(en/yn)yl, NR ⁷ R ⁷ , S — R ⁸ or SO2R ⁸ ; or two adjacent R ⁵ groups taken together with the aromatic group form a 5-8 membered ring, which optionally contains one or two heteroatoms.

[00222] In further embodiments, both R ⁷ and R ⁷ ' are Ci-6-alk(en/yn)yl.

[00223] In further embodiments, R ⁸ is Ci-6-alk(en/yn)yl or Ar.

[00224] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 2-(4-Fluorophenyl)-N-{2-methyl-4-[(6-p-tolyloxypyridin-3-ylm ethyl)-amino]- phenyl} -acetamide; 2-(4-Fluorophenyl)-N-{2-methyl-4-[(6-trifluoromethylpyridin- 3- ylmethyl)-amino]-phenyl} -acetamide; 3,3-Dimethyl-N-{2-methyl-4-[(6-p-tolyloxypyridin-3- ylmethyl)-amino]-phenyl }-butyramide; 3,3-Dimethyl-N-{2-methyl-4-[(6- trifluoromethylpyridin-3-ylmethyl)-amino]-phenyl} -butyramide; N-(4-{[6-(4- Cyanophenoxy)-pyridin-3-ylmethyl]-amino}-2-methylphenyl)-2-( 4-fluorophenyl) - acetamide; N-{4-[(6-Chloropyridin-3-ylmethyl)-amino]-2-methylphenyl}-2- (4- fluorophenylj-acetamide; or 2,2-Dimethyl-N-{2-methyl-4-[(6-phenoxypyridin-3-ylmethyl)- amino]-phenyl }-proprionamide; or a salt thereof.

[00225] In further embodiments, the Kv7 channel activator is a compound according to formula 11 wherein: U is O, S or NR ² '; s is 0 or 1; X is CO or SO2; Z is O, S or NR ⁴ ; wherein R ⁴ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl and hydroxy-C3-s- cycloalk(en)yl; q is 0 or 1; R ¹ and R ¹ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-s-cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl and halo-C3-s- cycloalk(en)yl; R ² is selected from the group consisting of hydrogen, halogen, C1-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — C1-6- alk(en/yn)yl, Ar — C3-s-cycloalk(en)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-s- cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl and cyano; provided that: when R ² is halogen or cyano, then s is 0; and when s is 1 and U is NR ² ', then R ² ' is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-s-cycloalk(en)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-s-cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl and halo-C3-s- cycloalk(en)yl; or R ² and R ² ' together form a 5-8 membered saturated or unsaturated ring that optionally contains one further heteroatom; R ³ is selected from the group consisting of C1-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — C1-6- alk(en/yn)yl, Ar — C3-s-cycloalk(en)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-s- cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl and halo-C3-s-cycloalk(en)yl; and Y represents a group of the following formulas: wherein: the line represents a bond attaching the group represented by Y to the nitrogen atom; W is O or S; a is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; c is 0 or 1; d is 0, 1, 2 or 3; e is 0, 1 or 2; f is 0, 1, 2, 3, 4 or 5; g is 0, 1, 2, 3 or 4; h is 0, 1, 2 or 3; and each R ⁵ is independently selected from the group consisting of a Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, Ar, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yl, acyl, Ci-6-alk(an/en/yn)yloxy, halogen, halo-Ci-6-alk(en/yn)yl, — CO — NR ⁶ R ⁶ , cyano, nitro, — NR ⁷ R ⁷ , — S — R ⁸ and SO2OR ⁸ ; or two adjacent R ⁵ substituents together with the aromatic group form a 5-8 membered saturated or unsaturated ring that optionally contains one or two heteroatoms; wherein: R ⁶ and R ⁶ ' are independently selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl and Ar; R ⁷ and R ⁷ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar and acyl; and R ⁸ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Ar and — NR ⁹ R ⁹ '; wherein R ⁹ and R ⁹ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl; with the provisos that; when R ⁵ is SO2OR ⁸ then R ⁸ is not — NR ⁹ R ⁹ ; and when R ⁵ is SO2R ⁸ , then R ⁸ is not a hydrogen atom; or a pharmaceutically acceptable salt thereof; with the proviso that the compound of formula I is not: N-[4-[[(4- aminophenyl)amino]methyl]phenyl]-acetamide; N-[4-[[(4-amino-2- methylphenyl)amino]methyl]phenyl]-acetamide; N-[4-[[(4-amino-3- methylphenyl)amino]methyl]phenyl]-acetamide; 2-[[[4-(acetylamino)phenyl]methyl]amino]- 5-chloro-N-(5-chloro-2-pyridinyl)- benzamide; N- [4- [ [(3 ,4, 5- trimethoxyphenyl)amino]methyl]phenyl] -acetamide; N-[4-[[(5, 6,7, 8-tetrahydro-5, 5,8,8- tetramethyl-2- naphthalenyl)amino]methyl]phenyl]-acetamide; N-[4-[[[3-(lH-imidazol-l- ylmethyl)phenyl]amino]methyl]phenyl]- acetamide; N-[4-[[[2-(lH-imidazol-l- ylmethyl)phenyl]amino]methyl]phenyl]-acetamide; N-[4-[[(4-amino-3,5- dichlorophenyl)amino]methyl]phenyl]- acetamide; N-[4-[[(2,4-diamino-6- quinazolinyl)amino]methyl]phenyl]- acetamide; or N-[4-[[(2,4-diamino-6- quinazolinyl)amino]methyl]phenyl]- acetamide.

[00226] In further embodiments, R ¹ and R ¹ ' are independently selected from the group consisting of hydrogen and Ci-6-alk(en/yn)yl.

[00227] In further embodiments, at least one of R ¹ and R ¹ ' is a hydrogen atom.

In further embodiments, s is 1.

[00228] In further embodiments, s is 0. [00229] In further embodiments, R ² is selected from the group consisting of hydrogen, Ci-6- alk(en/yn)yl, Ar and halogen, provided that when R is halogen, then s is 0.

[00230] In further embodiments, U is NR ² ' and at least one of R and R ² ' is a hydrogen atom. [00231] In further embodiments, both R ² and R ² are hydrogen atoms.

[00232] In further embodiments, X is CO.

[00233] In further embodiments, q is 0.

[00234] In further embodiments, q is 1.

[00235] In further embodiments, Z is an oxygen atom.

[00236] In further embodiments, R ³ is Ci-6- alk(en/yn)yl.

[00237] In further embodiments, each R ⁵ is independently selected from the group consisting of a Ci-6-alk(en yn)yl, C3-8- cycloalk(en)yl, Ar, cyano, halogen, halo-Cr.6- alk(en/yn)yl and C1-6- alk(an/en/yn)yloxy or two adjacent substituents together form a 5-8 membered saturated or unsaturated ring which optionally contains one or two heteroatoms. [00238] In further embodiments, the Kv7 channel activator is selected from the group consisting of: {2-Amino-4-[(4-tert-butyl phenylamino)-methyl]-phenyl}-carbamic acid ethyl ester; (2-Amino-4-phenylaminomethyl-phenyl)-carbamic acid ethyl ester; [2-Amino-4- (aphthalene-2-ylaminomethyl)-phenyl]carbamic acid ethyl ester; [2-Amino-4-(p-tolylamino- methyl)-phenyl]carbamic acid ethyl ester; {2-Amino-4-[(4-trifluoromethylphenylamino)- methyl]-phenyl}-carbamic acid ethyl ester; {2-Amino-4-[(4-chlorophenylamino)-methyl]- phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(3-fluorophenylamino)-methyl]-phenyl}- carbamic acid ethyl ester; {2-Amino-4-[(4-fluorophenylamino)-methyl]-phenyl}-carbamic acid ethyl ester; {2-Amino-4-[(2-fluorophenylamino)-methyl]-phenyl}-carbamic acid ethyl ester; [2-Amino-4-(biphenyl-4-ylaminomethyl)-phenyl]-carbamic acid ethyl ester; {2-Amino- 4-[(2,4-difluorophenylamino)-methyl]-phenyl}-carbamic acid ethyl ester; {2-Amino-4-[(4- methoxyphenylamino)-methyl]-phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(4- cyclohexylphenylamino)-methyl]-phenyl}-carbamic acid ethyl ester; [2-Amino-4-(indan-5- ylaminomethyl-phenyl]-carbamic acid ethyl ester; {2-Amino-4-[(4-isopropylphenylamino)- methyl]-phenyl}-carbamic acid ethyl ester; {2-Amino-4-[(4-butylphenylamino)-methyl]- phenyl} -carbamic acid ethyl ester; {2-Amino-4-[(4-chloro-3- fluorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(2,4- dichlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(2,3- dichlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(3,5- dichlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(3,4- dichlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(3-

Ill trifluoromethylphenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(3- fluoro-4-trifluoromethylphenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4- [(3, 4-di chi orophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(4- cyanophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(4-fluoro-3- trifluoromethylphenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(3- chloro-4-methylphenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[(3- chlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; [2-Amino-4-(m- tolylaminomethyl)phenyl]carbamic acid ethyl ester; {2-Amino-4-[l-(4- chlorophenylamino)ethyl]phenyl} carbamic acid ethyl ester; {2-Amino-4-[l-(4- trifluoromethylphenylamino)ethyl]phenyl} carbamic acid ethyl ester; N-{2-Amino-4-[(3- fluorophenylamino)methyl]phenyl}-2,2-dimethylpropionamide; {4-[(4- Chlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {4-[(4- Trifluoromethylphenylamino)methyl]phenyl}carbamic acid ethyl ester; {4-[(4- Chlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {4-[(4- Fluorophenylamino)methyl]-2-methylphenyl}carbamic acid ethyl ester; {4-[(4- Chlorophenylamino)methyl]-2-methylphenyl}carbamic acid ethyl ester; {2-Methyl-4-[(4- trifluoromethylphenylamino)methyl]phenyl} carbamic acid ethyl ester; {4-[(3,4- Difluorophenylamino)methyl]-2-methylphenyl}carbamic acid ethyl ester; {4-[(3- Fluorophenylamino)methyl]-2-methylphenyl}carbamic acid ethyl ester; {2-Chloro-4-[(4- chlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Chloro-4-[(4- trifluoromethyl-phenylamino)-methyl]phenyl} -carbamic acid ethyl ester; {2-Chloro-4-[(4- fluorophenylamino)methyl]phenyl} -carbamic acid ethyl ester; {2-Chloro-4-[(3- fluorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Chloro-4-[(3,4- dichlorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {2-Chloro-4-[(4-chloro-3- fluorophenylamino)methyl]phenyl} carbamic acid ethyl ester; {4-[(4- Chlorophenylamino)methyl]-2-fluorophenyl}carbamic acid ethyl ester; {4-[(4-Chloro-3- fluorophenylamino)methyl]-2-fluorophenyl}carbamic acid ethyl ester; {2-Fluoro-4-[(4- trifluoromethylphenylamino)methyl]phenyl} carbamic acid ethyl ester; {4'-Dimethylamino-5- [(3 -fluorophenylamino)methyl]biphenyl-2-yl} carbamic acid ethyl ester; {4'-Dimethylamino- 5-[(4-trifluoromethylphenylamino)methyl]biphenyl-2-yl}carbam ic acid ethyl ester; {4'- Chloro-5-[(3-fluorophenylamino)methyl]biphenyl-2-yl}carbamic acid ethyl ester; {4'- Chloro-5-[(4-trifluoromethylphenylamino)methyl]biphenyl-2-yl }carbamic acid ethyl ester; N-{4-[(4-chlorophenylamino)methyl]phenyl}butyramide; N-{4-[(3,4- dichlorophenylamino)methyl]phenyl}butyramide; N-{4-[(4-chl oro-3- tluorophenylamino)methyl]phenyl } butyramide; N-{4-[(4-fluoro-phenylamino)methyl]-2- methyl phenyl Jbutyramide; N-{4-[(3-fluorophenylamino)methyl]-2- m ethylphenyl Jbutyramide; N-{4-[(4-chlorophenylamino)methyl]-2- m ethylphenyl Jbutyramide; N-{4-[(3,4-dichlorophenylamino)methyl]-2- m ethylphenyl Jbutyramide; N-{4-[(4-chloro-3-fluorophenylamino)methyl]-2-methyl phenyl Jbutyramide; N-{2-chloro-4-[(4- trifluoromethylphenylamino)methyl]phenyl}butyramide; N-{2-chloro-4-[(4- fluorophenylamino)methyl]phenyl}butyramide; N-{2-chloro-4-[(3- fluorophenylamino)methyl]phenyl}butyramide; N-{2-chloro-4-[(4- chlorophenylamino)methyl]phenyl}butyramide; N-{2-chloro-4-[(3,4- dichlorophenylamino)methyl]phenyl}butyramide; N-{2-chloro-4-[(4-chloro-3- fluorophenylamino)methyl]phenyl}butyramide; N-{2-fluoro-4-[(3- fluorophenylamino)methyl]phenyl}butyramide; N-{4-[(4-chlorophenylamino)methyl]-2- fluorophenyljbutyramide; N-{2-fluoro-4-[(4- trifluoromethylphenylamino)methyl]phenyl}butyramide; N-{-4-[(3,4- dichlorophenylamino)methyl]-2-fluorophenyl}butyramide; N-{4-[(4-chloro-3- fluorophenylamino)methyl]-2-fluorophenyl}butyramide; and pharmaceutically acceptable salts thereof.

[00239] In further embodiments, the Kv7 channel activator is a compound according to formula 11 wherein: U is O, S or C s is O or 1; X is CO or SO2; Z is O, S or NR. , wherein R ⁴ is selected from the group consisting of hydrogen, Cr-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en yn)yl and hydroxy-C3-s- cycloalk(en)yl; q is O or 1; R ¹ and R ¹ ' are independently selected from the group consisting of hydrogen, C\. 6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Cr.6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl and halo-C3-8-cycloalk(en)yl; R is selected from the group consisting of hydrogen, halogen, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Cr.6-alk(en/yn)yl, Ar, Ar-Ci-6- alk(en/yn)yl, Ar-C3-8-cycloalk(en)yl, acyl, hydroxy-Cr.6-alk(en/yn)yl, hydroxy- C3-8- cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and cyano; provided that when R ² is halogen or cyano then s is 0; when s is 1 and U is NR ² ' then R ² ' is selected from the group consisting of hydrogen, Ci-6-alk(en yn)yl, C -8-cycloalk(en)yl, C3-8-cycloallc(en)yl- Cr.6- alk(en/yn)yl, Ar, Ar-Ci-6-alk(en/yn)yl, Ar-C3-8-cycloalk(en)yl, acyl, hydroxy- .. 6- alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl and halo-C3-8- cycloalk(en)yl; or R ² and R ² ' together form a 5-8 membered saturated or unsaturated ring which optionally contains one further heteroatom; R ³ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Cr.6-alk(en/yn)yl, Ar, Ar-Ci-6- alk(en/yn)yl, Ar-C3-8- cycloalk(en)yl, hydroxy-Cr.6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, halo-Cj. 6-alk(en/yn)yl and halo-C3-8-cycloalk(en)yl; and Y is selected from groups according to a formula selected from the group consisting of: wherein: the line represents a bond attaching the group represented by Y to the nitrogen atom; W is O or S; a is 0, 1, 2 or 3; b is O, 1, 2, 3 or 4; c is 0 or 1; d is 0, 1, 2 or 3; e is 0, 1 or 2; f is O, 1, 2, 3, 4 or 5; g is 0, 1, 2, 3 or 4; h is 0, 1, 2 or 3; and each R ⁵ is independently selected from the group consisting of a Ci-6- alk(en yn)yl, C3-8-cycloalk(en)yl, Ar, C3-8- cycloalk(en)yl-Ci-6-alk(en yn)yl, Ar- Cr.6-alk(en/yn)yl, acyl, Ci-6-alk(an/en/yn)yloxy, halogen, halo-Cr.6-alk(en/yn)yl, -CO-NR ⁶ R ⁶ ', cyano, nitro, -NR ⁷ R ⁷ ', -S-R ⁸ , -SO2R ⁸ and SO2OR ⁸ , or two substituents together form a 5-8 membered saturated or unsaturated ring which optionally contains one or two heteroatoms; R ⁶ and R ⁶ ' are independently selected from the group consisting of hydrogen, C\. 6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl and Ar; R ⁷ and R ⁷ ' are independently selected from the group consisting of hydrogen, C\. 6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci- 6-alk(en/yn)yl, Ar and acyl; and R ⁸ is selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Cr.6-alk(en/yn)yl, Ar and -NR ⁹ R ⁹ ; wherein R ⁹ and R ⁹ ' are independently selected from the group consisting of hydrogen, C 6- alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; with the provisos that when R ⁵ is SO2OR ⁸ then R ⁸ is not -NR ⁹ R ⁹ ' and when R ⁵ is SO2R ⁸ , then R ⁸ is not a hydrogen atom; or salts thereof; with the proviso that the compound of formula I is not: 2- [[[4-(acetylamino)phenyl]methyl]amino]-5-chloro-N-(5-chloro- 2-pyridinyl)- benzamide; N- [4-[[(3,4,5-trimethoxyphenyl)amino]methyl]phenyl]-acetamide; N-[4-[[(5,6,7,8-tetrahydiO- 5,5,8,8-tetramethyl-2- naphthalenyl)amino]methyljphenyl]-acetamide; N- [4- [ [[3 -( 1 H- imidazol- 1 -ylmethyl)phenyl]amino]methyl]phenyl] - acetamide; N-[4-[[[2-(lH-imidazol-l- ylmethyl)phenyl]amino]methyl]phenyl]-acetamide; N-[4-[[[4-( IH-imidazol- 1 - ylmethyl)phenyl]amino]methyl]phenyl]- acetamide; N-[4-[[(4-amino-3,5- dichlorophenyl)ammo]methyl]phenyl]- acetamide; N-[4-[[(2,4-diamino-6- quinazolinyl)amino]methyl]phenyl]- acetamide; or N-[4-[[(2,4-diamino-6- quinazolinyl)amino]methyl]phenyl]- acetamide.

[00240] In further embodiments, the Kv7 channel activator is a compound according to formula 11 wherein: wherein U is O, S or NR ² s is O or 1; X is CO or SO2; Z is O, S or NR , wherein R is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-s-cycloaUc(en)yl-Cr.6-alk(en/yn)yl, hydroxy-Cr.6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; q is O or 1; 1 1 ' R and R are independently selected from the group consisting of hydrogen, Ct_ 6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl- Ci.6-alk(en/yn)yl, acyl, hydroxy-Cr.6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-Ci_.6- alk(en/yn)yl and halo-C3.8-cycloalk(en)yl; R is selected from the group consisting of hydrogen, halogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Cr.6-alk(en yn)yl, Ar, Ar-Cr.6- alk(en yn)yl, Ar-C3-8-cycloalk(en)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy- C3-8-cycloalk(en)yl, halo-Cr.6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and cyano; provided that when R ² is halogen or cyano then s is 0; when s is 1 and U is NR ² then R ² ' is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C -8-cycloalk(en)yl, C .8- cycloalk(en)yl-Ci-6- alk(en/yn)yl, Ar, Ar-Ci-6-alk(en/yn)yl, Ar-C3.8-cycloalk(en)yl, acyl, hydroxy-C ^A 6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl and halo-C3- 8- cycloalk(en)yl; or R and R together form a 5-8 membered saturated or unsaturated ring which optionally contains one further heteroatom; R ³ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en yn)yl, Ar, Ar-Ci-6- alk(en/yn)yl, Ar-C3-8- cycloalk(en)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, halo-Ci- 6-alk(en yn)yl and halo-C3-S-cycloalk(en)yl; and Y is selected from groups according to a formula selected from the group consisting of:

[00241] wherein, the line represents a bond attaching the group represented by Y to the nitrogen atom; W is O or S; a is 0, 1, 2 or 3; h is 0, 1, 2, 3 or 4; c is 0 or 1; d is 0, 1, 2 or 3; e is 0, 1 or 2; f is O, 1, 2, 3, 4 or 5; is 0, 1, 2, 3 or 4; h is 0, 1, 2 or 3; and each R ⁵ is independently selected from the group consisting of a Ch-6- alk(en/yn)yl, C3.s-cycloalk(en)yl, Ar, Cs-s-cycloall ^A ei ^A yl-Ci-e-all ^A en/ ^A yl, Ar- Ch-6-alk(en/yn)yl, acyl, Ci-6-alk(an/en/yn)yloxy, halogen, halo-Ci-6-alk(en/yn)yl, -CO-NR ⁶ R ⁶ , cyano, nitro, -NR ⁷ R ⁷ ', -S-R ⁸ , -SO2R ⁸ and SO2OR ⁸ , or two substituents together form a 5-8 membered saturated or unsaturated ring which optionally contains one or two heteroatoms; R ⁶ and R ⁶ are independently selected from the group consisting of hydrogen, C\. 6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl- Ci-6-alk(en/yn)yl and Ar; R ⁷ and R ⁷ ' are independently selected from the group consisting of hydrogen, Cj. 6-alk(en/yn)yl, C3-s-cycloalk(en)yl, Cs-s-cycloall ^A en 1- -e-all ^A en/yn 1, Ar and acyl; and R ⁸ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar and -NR ⁹ R ⁹ ; wherein R ⁹ and R ⁹ ' are independently selected from the group consisting of hydrogen, Q. 6-alk(en/yn)yl, C3-8- cycloalk(en)yl and C3-8-cycloalk(en)yl-Ch-6-alk(en yn)yl; with the provisos that when R ⁵ is SO2OR ⁸ then R ⁸ is not -NR ⁹ R ⁹ ' and when R ⁵ is SO2R ⁸ , then R ^s is not a hydrogen atom; or salts thereof for increasing ion flow in a potassium channel of a mammal such as a human.

Formula 12

[00242] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 12. Such compounds are described in International Publication No. W02009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. W02004096767A1, published November 11, 2004 and corresponding to International Application No. PCT/DK2004/000283 filed April 23, 2004; US Publication No. US20060264496A1 published November 23, 2006 and corresponding to US Application No. 10/551,738 filed April 23, 2003; US Publication No.

US20100256145A1, published October 7, 2010 and corresponding to US Application No. 12/671,505 filed July 31, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 12, these references incorporated by reference herein control.

[00243] In an embodiment, the Kv7 channel activator is a compound according to formula 12:

Formula 12 wherein, the dotted line represents an optional bond; R ¹ and R ¹ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-s-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ¹ and R ¹ together with the carbon atom to which they are attached form a 3-8 membered saturated or unsaturated ring that optionally contains 1 or 2 heteroatoms; s is 0 or 1; U is O, NR ¹¹ , S, SO2, SO2NR ¹¹ , CO — O or CO — NR ¹¹ ; wherein: R ¹¹ is selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-8-cycl oal k(en)yl, and C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ² and R ² ’ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; R ² is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8-cycloalk(en)yl, Ar — C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halogen, halo-Ci-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-C3-s-cycloalk(en)yl-Ci-6- alk(en/yn)yl, — NO2, NR ¹⁰ R ¹⁰ ' ^{— c} i-6-alk(en/yn)yl, NR ¹⁰ R ¹⁰ ' — C3-s-cycloalk(en)yl and NR ¹⁰ R ¹⁰ ' — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein: R ¹⁰ and R ¹⁰ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Cl— 6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ¹⁰ and R ¹⁰ ' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; with the proviso that; when R ² is NO2, halogen or cyano, then s is 0; and when R ² , R ² is a hydrogen atom or acyl and s is 1, then U is NR ¹¹ , O or S; wherein the group — (U) _s — R ² is linked to position 4 or 6 of the indole or indoline; q is 0 or 1; Z is O or S; X is CO or SO2; with the proviso that when q is 0, then X is SO2; R ³ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, heterocycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl- C3-8-cycloalk(en)yl, Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8-cycloalk(en)yl, Ar-heterocycloalk(en)yl, Ar — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ar — Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, C1-6- alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-Ci-6-alk(en/yn)yl, C1-6- alk(en/yn)yloxy-C3-8-cycloalk(en)yl, Ci-6-alk(en/yn)yloxy-heterocycloalk(en)yl, Ar-oxy-Ci-6- alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-carbonyl-Ci- 6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-carbonyl-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yloxy-carbonyl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, hydroxy-Ci-6-alk(en/yn)yl- heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo- heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl-C3-8- cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl-Ar, halo- C3-8-cycloalk(en)yl-Ar, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl-Ar, halo-Ci-6-alk(en/yn)yl- C3-8-cycloalk(en)yl-Ar, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano- heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl- C3-8-cycloalk(en)yl, cyano-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, acyl-Ci-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, acyl-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-Ci-6-alk(en/yn)yl- heterocycloalk(en)yl, — NR ^I2 R ¹² ', optionally substituted NR ¹² R ¹² ’ — Ci-6-alk(en/yn)yl, optionally substituted NR ¹² R ¹² ’ — C3-s-cycloalk(en)yl, and optionally substituted NR ¹² R ¹² ’ — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein: R ¹² and R ¹² ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl- Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-s-cycloalk(en)yl, Ar — C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ¹² and R ¹² ’ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring that optionally contains 1, 2 or 3 further heteroatoms; with the proviso that when R ³ is NR ¹² R ¹² , then q is 0; and Y represents a group of formula from the group: wherein: the line represents a bond attaching the group represented by Y to the carbon atom;

W is O or S; T is N, NE or O; L is N, C or CH; a is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; c is 0 or 1; d is 0, 1, 2 or 3; e is 0, 1 or 2; f is 0, 1, 2, 3, 4 or 5; g is 0, 1, 2, 3 or 4; h is 0, 1, 2 or 3; j is 0, 1, 2 or 3; with the provisos that: when T is a nitrogen atom, then j is 0, 1, 2 or 3; and when T is NH or an oxygen atom, then j is 0, 1 or 2; k is 0, 1, 2, 3 or 4; and each R ⁵ is independently selected from the group consisting of a Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar-thio, Ar-oxy, acyl, C1-6- alk(en/yn)yloxy, C3-s-cycloalk(en)yloxy, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, halogen, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, — CO — NR ⁶ R ⁶ , cyano, cyano-Ci-6-alk(en/yn)yl, cyano-C3-s-cycloalk(en)yl, cyano-C3-s- cycloalk(en)yl-Ci-6-alk(en/yn)yl, — NR ⁷ R ⁷ ', — S — R ⁸ and — SO2R ⁸ ; or two adjacent R ⁵ substituents together with the aromatic group to which they are attached form a 4-8 membered ring that optionally contains one or two heteroatoms; wherein: R ⁶ and R ⁶ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl and Ar; R ⁷ and R ⁷ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar and acyl; and R ⁸ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar and — NR ⁹ R ⁹ ; wherein R ⁹ and R ⁹ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; provided that when R ⁸ is — NR ⁹ R ⁹ , then R ⁵ is not — S — R ⁸ , or a pharmaceutically acceptable salt thereof, with the proviso that the compound of formula I is not: N-[l-(phenylmethyl)-lH- indol-5-yl]-Methanesulfonamide; N-[l-[(4-fluorophenyl)methyl]-lH-indol-5-yl]- Methanesulfonamide; N-[2,3-dihydro-l-(phenylmethyl)-lH-indol-5-yl]- Methanesulfonamide; N-[l -(phenylmethyl)- lH-indol-5-yl]-N'-4-quinolinyl-Urea; N-[l- (phenylmethyl)-lH-indol-5-yl]-N'-4-quinolinyl-Urea; or l-(l-benzyl-5-indolinyl)-3-phenyl- Urea; or salts thereof.

[00244] In further embodiments, least one of R ¹ or R ¹ is a hydrogen atom.

[00245] In further embodiments, R ¹ and R ¹ are hydrogen atoms.

[00246] In further embodiments, s is 0.

[00247] In further embodiments, s is 1.

[00248] In further embodiments, R ² is a hydrogen atom.

[00249] In further embodiments, R ² is NO2 or a halogen atom.

[00250] In further embodiments, U is NR ¹¹ .

[00251] In further embodiments, R ¹¹ is a hydrogen atom.

[00252] In further embodiments, X is CO. [00253] In further embodiments, X is SO2. [00254] In further embodiments, q is 0.

[00255] In further embodiments, q is 1.

[00256] In further embodiments, Z is an oxygen atom.

[00257] In further embodiments, R ³ is selected from the group consisting of Ci-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar-oxy-Ci-6-alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl and — NR ¹² R ¹² '; with the proviso that when R ³ is NR ¹² R ¹² ’ then q is 0.

[00258] In further embodiments, R ³ is NR ¹² R ¹² , q is 0 and R ¹² and R ¹² are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, Ar and Ar — Ci-6- alk(en/yn)yl, or R ¹² and R ¹² ' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms.

[00259] In further embodiments, each R ⁵ is independently selected from the group consisting of Ci-6-alk(en/yn)yl, Ar, Ar-thio, Ar-oxy, halogen and halo-Ci-6-alk(en/yn)yl or two adjacent R ⁵ together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms.

[00260] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[4-Chl oro-1 -(4-trifluoromethylbenzyl)-2, 3-dihy dro- lH-indol-5-yl]-3, 3- dimethylbutyramide; N-[4-Chl oro-1 -(5-chlorothi ophen-2 -ylmethyl)-2, 3-dihy dro-lH-indol-5- yl]-3,3-dimethylbutyramide; [l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-carbamic acid propyl ester; N-[l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-C-phenyl- methanesulfonamide; 4-Fluoro-N-[l -(4-fluorobenzyl)-2, 3-dihy dro- lH-indol-5-yl]- benzamide; N-[l-(4-Fluorobenzyl)-2, 3-dihy dro-lH-indol-5-yl]-3,3-dimethylbutyramide; N- [l-(4-Fluorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-thiophen-2- ylacetamide; N-[l-(4- Fluorobenzyl)-2, 3 -dihydro- 1 H-indol-5 -yl] -2-(4-fluorophenyl)-acetamide; 3 - [ 1 -(5 -

Chl orothiophen-2-ylmethyl)-2, 3-dihy dro-lH-indol-5-yl]- 1,1 -diisopropylurea; Morpholine-4- carboxylic acid [1 -(5-chlorothi ophen-2-ylmethyl)-2, 3-dihy dro-lH-indol-5-yl]-amide;

Pyrrolidine- 1 -carboxylic acid [1 -(5-chlorothi ophen-2-ylmethyl)-2, 3-dihy dro-lH-indol-5-yl]- amide; [l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]- carbamic acid 2- benzyloxy ethyl ester; 3-[l-(5-Chlorothiophen-2-ylmethyl)-2, 3-dihy dro- lH-indol-5-yl]-l- methyl- 1 -propylurea; [1 -(5-Chlorothiophen-2-ylmethyl)-2, 3-dihy dro- lH-indol-5-yl]- carbamic acid tert-butyl ester; N-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5- yl]-C-phenyl-methanesulfonamide; Butane- 1 -sulfonic acid [l-(5-chlorothiophen-2-ylmethyl)- 2, 3-dihy dro- lH-indol-5-yl]-amide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2, 3-dihy dro-lH- indol-5-yl]-4-fluorobenzamide; N-[l-(5-Chlorothi ophen-2 -ylmethyl)-2, 3-dihy dro-lH-indol- 5-yl]-2,2-dimethylpropionamide; N-[l-(5-Chlorothi ophen-2 -ylmethyl)-2, 3-dihy dro-lH-indol- 5-yl]-2-phenoxyacetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2, 3-dihy dro- lH-indol-5-yl]-

3.3-dimethylbutyramide; N-[l-(5-Chlorothiophen-2-ylmethyl)-2, 3-dihy dro-lH-indol-5-yl]- butyramide; Cyclopentanecarboxylic acid [l-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-lH- indol-5-yl]-amide; N-[l-(5-Chlorothi ophen-2 -ylmethyl)-2, 3-dihy dro-lH-indol-5-yl]-2- thiophen-2-ylacetamide; N-[l-(5-Chlorothi ophen-2 -ylmethyl)-2, 3-dihy dro- lH-indol-5-yl]- isonicotinamide; N-[ l-(5-Chlorothi ophen-2-ylmethyl)-2, 3-dihy dro-lH-indol-5-yl]-4- dimethylaminobenzamide; N-[ l-(5-Chlorothi ophen-2-ylmethyl)-2, 3-dihy dro- lH-indol-5-yl]- 2-(4-fluorophenyl)-acetamide; N-[l -(5-Chlorothi ophen-2-ylmethyl)-2, 3-dihy dro- lH-indol-5- yl]-6-trifluoromethylnicotinamide; l-tert-Butyl-3-[l-(5-chlorothiophen-2-ylmethyl)-2,3- dihydro-lH-indol-5-yl]-urea; l-[l-(5-Chlorothiophen-2-ylmethyl)-2, 3-dihy dro- lH-indol-5- yl]-3-ethyl urea; 1 -Benzyl-3-[l -(5-chlorothi ophen-2-ylmethyl)-2, 3-dihy dro- lH-indol-5-yl]- urea; l-[l-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl ]-3-phenethyl urea; 1-[1- (5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-t hiophen-2-ylurea; l-[l-(5- Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3-thio phen-3-ylurea; [l-(5- Chlorothiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-carbam ic acid propyl ester; 2,2- Dimethyl-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2, 3-dihy dro-lH-indol-5-yl]-propionamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2, 3-dihy dro- lH-indol-5-yl]-2, 2- dimethylpropionamide; 2-(4-Fluorophenyl)-N-[6-nitro-l-(4-trifluoromethylbenzyl)-2, 3- dihydro-lH-indol-5-yl]-acetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2, 3-dihy dro- lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[l-(5-Chlorothiophen-2-ylmethyl)-6-nitro-

2.3-dihy dro- lH-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amino-l -(5-chlorothi ophen-2- ylmethyl)-2, 3-dihy dro- lH-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amino-l-(4- trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-2,2-dimeth ylpropionamide; N-[6-Amino- 1 -(5-chlorothi ophen-2-ylmethyl)-2, 3-dihy dro- lH-indol-5-yl]-2,2-dimethylpropionamide; N- [6-Amino-l -(4-trifluoromethylbenzyl)-2, 3-dihy dro- lH-indol-5-yl]-2-(4-fluorophenyl)- acetamide; N-[6-Amino- l-(4-trifluoromethylbenzyl)-2, 3-dihy dro-lH-indol-5-yl]-3, 3- dimethylbutyramide, N-[6-Amino- l-(4-fluorobenzyl)-2, 3-dihy dro- lH-indol-5-yl]-3, 3- dimethylbutyramide; N-[6-Amino-l -(3-fluoro-4-trifluoromethylbenzyl)-2, 3-dihy dro- 1H- indol-5-yl]-3,3-dimethylbutyramide; N-[l-(5-Chlorothiophen-2-ylmethyl)-lH-indol-5-yl]-

3.3-dimethylbutyramide; N-[6-Bromo-l-(4-trifluoromethylbenzyl)-2, 3-dihy dro-lH-indol-5- yl]-3,3-dimethylbutyramide; N-[6-Bromo-l -(5-chlorothi ophen-2-ylmethyl)-2, 3-dihy dro- 1H- indol-5-yl]-3,3-dimethylbutyramide; N-[l-(4-Chlorobenzyl)-2, 3-dihy dro- lH-indol-5-yl]-3, 3- dimethylbutyramide; 3, 3-Dimethyl-N-[l -(4-trifluoromethylbenzyl)-2, 3-dihy dro-lH-indol-5- yl]-butyramide; N-[l-(4-Isopropylbenzyl)-2,3-dihydro-lH-indol-5-yl]-3,3- dimethylbutyramide; N-[l -(3-Fluoro-4-trifluoromethylbenzyl)-2, 3-dihy dro-lH-indol-5-yl]-

3.3-dimethylbutyramide; N-[l-(6-Chlorobenzo[l, 3]dioxol-5-ylmethyl)-2, 3-dihy dro-lH-indol- 5-yl]-3,3-dimethylbutyramide, N-[l-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethyl)-2,3- dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-[l-(2-Chloro-5-trifluoromethylbenzyl)-

2.3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; N-{l-[5-(4-Chlorophenoxy)-l,3- dimethyl-lH-pyrazol-4-ylmethyl]-2, 3-dihy dro-lH-indol-5-yl}-3,3-dimethylbutyramide; 3,3- Dimethyl-N-[l-(6-p-tolyloxy-pyridin-3-ylmethyl)-2,3-dihydro- lH-indol-5-yl]-butyramide; N-{l-[6-(4-Chlorophenyl sulfanyl)-pyridin-3-ylmethyl]-2, 3-dihy dro-lH-indol-5-yl}-3, 3- dimethylbutyramide, N-{l-[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-lH- indol- 5-yl}-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(6-trifluoromethylpyridin-3-ylmethyl)-

2.3-dihydro-lH-indol-5-yl]-butyramide; 3,3-Dimethyl-N-[l-(3-methyl-benzo[b]thiophen-2- ylmethyl)-2,3-dihydro-lH-indol-5-yl]-butyramide; N-[l-(6-Fluoro-4H-benzo[l,3]dioxin-8- ylmethyl)-2,3-dihydro-lH-indol-5-yl]-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[l-(6- phenoxypyridin-3-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-butyra mide; 3,3-Dimethyl-N-[l-(3- methyl-5-phenyl-isoxazol-4-ylmethyl)-2,3-dihydro-lH-indol-5- yl]-butyramide, N-(l- Benzo[b]thiophen-2-ylmethyl-2,3-dihydro-lH-indol-5-yl)-3,3-d imethylbutyramide; N-{ 1-[1- (4-Fluorophenyl)-5 -methyl- 1 H-pyrazol-4-ylmethyl] -2,3 -dihydro- 1 H-indol-5 -yl } -3 ,3 - dimethylbutyramide; 3,3-Dimethyl-N-[l-(5-methyl thi ophen-2 -ylmethyl)-2, 3-dihy dro-lH- indol-5-yl]-butyramide; 3, 3-Dimethyl-N-[l-(4-pyrrol-l-yl-benzyl)-2, 3-dihy dro-lH-indol-5- yl]-butyramide; N-[l-(4-Chlorobenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluoro phenyl)- acetamide; 2-(4-Fluorophenyl)-N-[ 1 -(4-trifluoromethylbenzyl)-2, 3-dihy dro-lH-indol-5-yl]- acetamide; 2-(4-Fluorophenyl)-N-[l-(4-isopropylbenzyl)-2,3-dihydro-lH-i ndol-5-yl]- acetamide; 2-(4-Fluorophenyl)-N-[l -(3-fluoro-4-trifluoromethylbenzyl)-2, 3-dihy dro-lH- indol-5-yl]-acetamide; N-[l-(6-Chlorobenzo[ 1 ,3]di oxol-5-ylmethyl)-2, 3-dihy dro-lH-indol-5- yl]-2-(4-fluorophenyl)-acetamide; N-[l-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethyl)-2,3- dihydro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[l-(2-Chloro-5- trifluoromethylbenzyl)-2,3-dihydro-lH-indol-5-yl]-2-(4-fluor ophenyl)-acetamide; N-{l-[5- (4-Chlorophenoxy)- 1, 3-dimethyl- lH-pyrazol-4-ylmethyl]-2, 3-dihy dro-lH-indol-5-yl}-2-(4- fluorophenyl)-acetamide; N-{l-[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-lH- indol-5-yl}-2-(4-fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-[l-(3-methyl- benzo[b]thiophen-2-ylmethyl)-2, 3-dihy dro-lH-indol-5-yl]-acetamide; N-[l-(6-Fluoro-4H- benzofl, 3]dioxin-8-ylmethyl)-2, 3-dihy dro-lH-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 2- (4-Fluorophenyl)-N-[l-(6-phenoxypyridin-3-ylmethyl)-2,3-dihy dro-lH-indol-5-yl]- acetamide; N-(l-Benzo[b]thiophen-2-ylmethyl-2,3-dihydro-lH-indol-5-yl)- 2-(4- fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N- { 1 -[ 1 -(4-fluorophenyl)-5-methyl- 1H- pyrazol-4-ylmethyl]-2,3-dihydro-lH-indol-5-yl}-acetamide; 2-(4-Fluorophenyl)-N-[l-(5- methylthiophen-2-ylmethyl)-2,3-dihydro-lH-indol-5-yl]-acetam ide; 2-(4-Fluorophenyl)-N- [ 1 -(4-pyrrol- 1 -yl-benzyl)-2, 3 -dihydro- lH-indol-5-yl]-acetamide; and pharmaceutically acceptable salts thereof.

Formula 13

[00261] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 13. Such compounds are described in International Publication No. W02009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No. 12/671,505 filed July 31, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 13, these references incorporated by reference herein control.

[00262] In an embodiment, the Kv7 channel activator is a compound according to formula 13. Formula 13 7 K6 wherein: q is 0 or 1; W is O or S; X is CO; Z is O; R1 is selected from the group consisting of halogen, cyano, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, C3-s-cycloalk(en)yloxy and C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy; R2 is selected from the group consisting of halogen, cyano, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-s- cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, C3-8- cycloalk(en)yloxy, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, optionally substituted phenyl and optionally substituted pyridyl; wherein the phenyl and pyridyl are optionally substituted with one or more substituents independently being halogen, Ci-6-alk(en/yr)yl, C3-8- cycloalk(en)yl or C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; R3 is selected from the group consisting of Ci-io-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yl, Ar — C3-s-cycloalk(en)yl, Ar — C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl and Ar; and each of R4, R5, R6 and R7 is independently selected from the group consisting of hydrogen and Ar; as the free base or a salt thereof.

[00263] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-(2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-(4-f luoro-phenyl)- acetamide; 2-Cyclopentyl-N-(2-bromo-6-trifluoromethyl-4-morpholin-4-yl- phenyl)- acetamide; N-(2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-3-cycl opentyl- propionamide; N-(2-Chloro-6-cyano-4-morpholin-4-yl-phenyl)-3-cyclohexyl-pr opionamide; 2-Cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-a cetamide; 2-Cyclopentyl-N- [2,6-dimethyl-4-(2-phenyl-morpholin-4-yl)-phenyl]-acetamide; 2-Cyclopentyl-N-[2,6- dimethyl-4-(2-phenyl-thiomorpholin-4-yl)-phenyl]-acetamide; 2-Cyclopentyl-N-[2,6- dimethyl-4-(3-pyridin-3-yl-thiomorpholin-4-yl)-phenyl]-aceta mide; 2-Cyclopentyl-N-{2,6- dimethyl-4-[2-(4-trifluoromethyl-phenyl)-thiomorpholin-4-yl] -phenyl}-acetamide; N-{4-[2- (2-Chloro-phenyl)-thiomorpholin-4-yl]-2,6-dimethyl-phenyl}-2 -cyclopentyl-acetamide; 2- Bicyclo[2.2.1]hept-2-yl-N-(2,6-dimethyl-4-morpholin-4-yl-phe nyl)-acetamide; 2- Cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamid e; 3-(3,4-Difluoro-phenyl)- N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propionamide; 2-Cyclopentyl-N-(2,6-dimethyl-4- morpholin-4-yl-phenyl)-acetamide; (2,6-Dimethyl-4-morpholin-4-yl-phenyl)-carbamic acid butyl ester; 2-(4-Chloro-phenyl)-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl) -acetamide; 2,3- Dihydro-benzofuran-2-carboxylic acid (2,6-dimethyl-4-morpholin-4-yl-phenyl)-amide; 3- Cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-propiona mide; 3-Cyclopentyl-N-(2,6- dimethyl-4-morpholin-4-yl-phenyl)-propionamide; N-(2,6-Dimethyl-4-morpholin-4-yl- phenyl)-2-(4-fluoro-phenyl)-acetamide; N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-2- thiophen-2-yl-acetamide; N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl- butyramide; Hexanoic acid (2,6-dimethyl-4-morpholin-4-yl-phenyl)-amide; 2-Cycloheptyl- N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide; (2,6-Dimethyl-4-morpholin-4-yl- phenyl)-carbamic acid benzyl ester; (2,6-Dimethyl-4-morpholin-4-yl-phenyl)-carbamic acid 2-chloro-benzyl ester; 3,5,5-Trimethyl-hexanoic acid (2,6-dimethyl-4-morpholin-4-yl- phenyl)-amide; Octanoic acid (2,6-dimethyl-4-morpholin-4-yl-phenyl)-amide; Heptanoic acid (2,6-dimethyl-4-morpholin-4-yl-phenyl)-amide; N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)- 2-phenyl-acetamide; 2-(3,4-Dichloro-phenyl)-N-(2,6-dimethyl-4-morpholin-4-yl-phe nyl)- acetamide; 2-(4-Allyloxy-3-chloro-phenyl)-N-(2,6-dimethyl-4-morpholin-4 -yl-phenyl)- acetamide; N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-2-(3-trifluoromethy l-phenyl)- acetamide; N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-2-naphthalen-2-yl-a cetamide; 3-(3- Chloro-phenyl)-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-prop ionamide; N-(2,6-Dimethyl-

4-morpholin-4-yl-phenyl)-2-(3,4-dimethyl-phenyl)-acetamid e; 2-(3-Bromo-phenyl)-N-(2,6- dimethyl-4-morpholin-4-yl-phenyl)-acetamide; 2-(3-Chloro-phenyl)-N-(2,6-dimethyl-4- morpholin-4-yl-phenyl)-acetamide; N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-2-p-tolyl- acetamide; N-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-2-m-tolyl-acetamide ; 2-(3,4-Difluoro- phenyl)-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide; N-(2,6-Dimethyl-4- morpholin-4-yl-phenyl)-2-(3-fluoro-phenyl)-acetamide; N-(2-Bromo-4-morpholin-4-yl-6- trifluoromethyl-phenyl)-3-cyclohexyl-propionamide; N-(2-Bromo-4-morpholin-4-yl-6- trifluoromethyl-phenyl)-2-(3-fluoro-phenyl)-acetamide; N-(2-Bromo-4-morpholin-4-yl-6- trifluoromethyl-phenyl)-propionamide; N-(2-Bromo-4-morpholin-4-yl-6-trifluoromethyl- phenyl)-butyramide; N-(2-Chloro-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-(3- fluoro- phenyl)-acetamide; N-(2-Chloro-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-cyc lopentyl- acetamide; 2-Cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl )-morpholin-4-yl]- phenyl} -acetamide; N-{4-[2-(2-Chloro-phenyl)-morpholin-4-yl]-2,6-dimethyl-pheny l}-2- cyclopentyl-acetamide; 2-Cyclopentyl-N-{4-[2-(4-fluoro-phenyl)-morpholin-4-yl]-2,6- dimethyl-phenyl} -acetamide; 2-(2-Chloro-phenyl)-N-(2,6-dimethyl-4-morpholin-4-yl- phenyl)-acetamide; Pentanoic acid (2,6-dimethyl-4-morpholin-4-yl-phenyl)-amide; 4-Methyl- pentanoic acid (2,6-dimethyl-4-morpholin-4-yl-phenyl)-amide; 2-Cyclopent-2-enyl-N-(2,6- dimethyl-4-morpholin-4-yl-phenyl)-acetamide; 5 -Methyl -hexanoic acid (2,6-dimethyl-4- morpholin-4-yl-phenyl)-amide; 3 -Methyl-pentanoic acid (2,6-dimethyl-4-morpholin-4-yl- phenyl)-amide; Hex-5-enoic acid (2,6-dimethyl-4-morpholin-4-yl-phenyl)-amide; 3-Ethyl- pentanoic acid (2,6-dimethyl-4-morpholin-4-yl-phenyl)-amide; 2-Cyclopentyl-N-(4- morpholin-4-yl-2-pyridin-3-yl-6-trifluoromethyl-phenyl)-acet amide; 2-Cyclopentyl-N-(5- morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide; 2-Cyclopentyl-N-(4'-fluoro-5- morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide; 2-Cyclopentyl-N-(4'-methyl-5- morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide, 2-Cyclopentyl-N-(3'-methyl-5- morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetamide; 2-Cyclopentyl-N-(3',4'-difluoro-

5-morpholin-4-yl-3-trifluoromethyl-biphenyl-2-yl)-acetami de; 2-(4-Fluoro-phenyl)-N-(4- morpholin-4-yl-2-pyridin-3-yl-6-trifluoromethyl-phenyl)-acet amide; 2-Cyclopentyl-N-(2,6- diethyl-4-morpholin-4-yl-phenyl)-acetamide; 2-Cyclopentyl-N-(2,6-diisopropyl-4-morpholin- 4-yl-phenyl)-acetamide; 2-Cyclopentyl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)-aceta mide; Hexanoic acid (2,6-difluoro-4-morpholin-4-yl-phenyl)-amide; N-(2,6-Difluoro-4-morpholin- 4-yl-phenyl)-3,3-dimethyl-butyramide; N-(2,6-Difluoro-4-morpholin-4-yl-phenyl)-2-(3- fluoro-phenyl)-acetamide; 2-Cyclopent-2-enyl-N-(2,6-difluoro-4-morpholin-4-yl-phenyl)- acetamide; 2-Bicyclo[2.2.1]hept-2-yl-N-(2,6-difluoro-4-morpholin-4-yl-p henyl)-acetamide; 2-Bicyclo[2.2.1]hept-2-yl-N-(2-methyl-4-morpholin-4-yl-6-tri fluoromethyl-phenyl)- acetamide; 5-Methyl-pentanoic acid (2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)- amide; 5 -Methyl -hexanoic acid (2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)- amide; 2-Cyclopent-2-enyl-N-(2-methyl-4-morpholin-4-yl-6-trifluorom ethyl-phenyl)- acetamide; 2-Cyclopentyl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl -phenyl)- acetamide; Hexanoic acid (2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-amide; 3,3- Dimethyl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-phen yl)-butyramide; 2-(3,4- Difluoro-phenyl)-N-(2-methyl-4-morpholin-4-yl-6-trifluoromet hyl-phenyl)-acetamide; Hexanoic acid (2-methoxy-6-methyl-4-morpholin-4-yl-phenyl)-amide; 2-Cyclopentyl-N-(2- methoxy-6-methyl-4-morpholin-4-yl-phenyl)-acetamide; N-(2-Methoxy-6-methyl-4- morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide; 2-(3,4-Difluoro-phenyl)-N-(2-methoxy-6- methyl-4-morpholin-4-yl-phenyl)-acetamide; 2-Cyclopent-2-enyl-N-(2-methoxy-6-methyl-4- morpholin-4-yl-phenyl)-acetamide; 2-(3-Fluoro-phenyl)-N-(2-methoxy-6-methyl-4- morpholin-4-yl-phenyl)-acetamide; 2-Bicyclo[2.2.1]hept-2-yl-N-(2-methoxy-6-methyl-4- morpholin-4-yl-phenyl)-acetamide; 4-Methyl-pentanoic acid (2-methoxy-6-methyl-4- morpholin-4-yl-phenyl)-amide; 5 -Methyl -Hexanoic acid (2-methoxy-6-methyl-4-morpholin- 4-yl-phenyl)-amide; N-(2-Chloro-6-methyl-4-morpholin-4-yl-phenyl)-2-(3-fluoro-ph enyl)- acetamide; and N-(2-Chloro-6-methyl-4-morpholin-4-yl-phenyl)-2-cyclopentyl- acetamide; as the free base or a pharmaceutically acceptable salt thereof.

Formula 14

[00264] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 14. Such compounds are described in International Publication No. W02009015667A1, published February 5, 2008 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. W02006029623A1, published March 23, 2006 and corresponding to International Application No. PCT/DK2005/000560 filed September 2, 2005; US Patent No. 7,601,870, issued October 13, 2009 and corresponding to US Application No. 11/312,664 filed December 20, 2005; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No. 12/671,505 filed July 31, 2008; which are incorporated by reference in their entirety herein.

In the case of any conflict of terminology in the context of Formula 14, these references incorporated by reference herein control.

[00265] In an embodiment, the Kv7 channel activator is a compound according to formula 14:

Formula 14 wherein, Z is O or S; q is 0 or 1; each of R ¹ and R ² is independently selected from the group consisting of halogen, cyano, amino, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, C3-s-heterocycloalk(en)yl, Aryl, Heteroaryl, halo-Ci-6- alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, C1-6- alk(en/yn)yloxy, C3-s-cycloalk(en)yloxy, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, and C3-8- heterocycloalk(en)yloxy; R ³ is selected from the group consisting of Ci-8-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl-Ci-6-alk(en/yn)yl, Aryl-C3-8- cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl-Ci-6- alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-Ci-6-alk(en/yn)y l, Heteroaryl-C alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl, Heteroaryl-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, amino-Ci-6-alk(en/yn)yl, amino-C3-8-cycloalk(en)yl, amino-C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-Ci-6- alk(en/yn)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, halo-Ci-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; and R ⁴ is selected from the group consisting of halogen, cyano, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl, Aryl, Heteroaryl, Aryl-Ci-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Aryl-C3-8-heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl- Ci-6-alk(en/yn)yl, NR ⁵ R ⁶ and R ⁷ NH — Ci-6-alk(en/yn)yl; wherein: R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, Aryl-Ci-6-alk(en/yn)yl, Aryl-C3-8- cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Heteroaryl-C i-6-alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl and Heteroaryl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, with the proviso that R ⁵ and R ⁶ are not hydrogen at the same time; and R ⁷ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Aryl-Ci-6-alk(en/yn)yl, Aryl-C3-s-cycloalk(en)yl and Heteroaryl; or a pharmaceutically acceptable salt thereof.

[00266] In further embodiments, the Kv7 channel activator is selected from the group consisting of: Hexanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide; N-(4-Bromo-2,6- dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide; N-(2-Bromo-4,6-dimethyl-phenyl)-2-(4- fluoro-phenyl)-acetamide; N-(2-Bromo-4,6-dimethyl-phenyl)-3,3-dimethyl-butyramide; N- (2-Bromo-4,6-dimethyl-phenyl)-2-cyclopentyl-acetamide; N-(2-Bromo-4,6-dichloro-phenyl)- 3,3-dimethyl-butyramide; N-(2-Bromo-4,6-dichloro-phenyl)-2-(4-fluoro-phenyl)-acetamid e; N-(2-Bromo-4,6-dichloro-phenyl)-2-cyclopentyl-acetamide; Heptanoic acid (4-bromo-2,6- dimethyl-phenyl)-amide; Cyclohexanecarboxylic acid (4-bromo-2,6-dimethyl-phenyl)-amide; N-(4-Bromo-2,6-dimethyl-phenyl)-2-thiophen-2-yl-acetamide; 2-Phenyl- cyclopropanecarboxylic acid (4-bromo-2,6-dimethyl-phenyl)-amide; N-(4-Bromo-2,6- dimethyl-phenyl)-2-(4-chloro-phenyl)-acetamide; Pentanoic acid (4-bromo-2,6-dimethyl- phenyl)-amide; Octanoic acid (4-bromo-2,6-dimethyl-phenyl)-amide; N-(4-Bromo-2,6- dimethyl-phenyl)-2-cyclopentyl-acetamide; 2-Bicyclo[2.2.1]kept-2-yl-N-(2,4-difluoro-6- morpholin-4-yl-phenyl)-acetamide; (S)-2-Amino-N-{2,6-dimethyl-4-[methyl-(4- trifhioromethyl-benzyl)-amino]-phenyl}-3- methyl-butyramide; (S)-2-Amino-4-methyl- pentanoic acid {2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-ph enyl}-amide; (4-Bromo-2,6-dimethyl-phenyl)-carbamic acid ethyl ester; (4-Bromo-2,6-dimethyl-phenyl)- carbamic acid propyl ester; N-(2-Amino-4-bromo-6-methyl-phenyl)-3,3-dimethyl- butyramide; 2-Cyclopentyl-N-{2,6-dimethyl-4-[2-(4-trifluoromethyl-phenyl )-pyrrolidin-l- yl]-phenyl}-acetamide; N-(4-Azepan-l-yl-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamid e; 2- Cyclopentyl-N-(2,6-dimethyl-4-pyrrol-l-yl-phenyl)-acetamide; N-(3'-Amino-3,5-dimethyl- biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide; N-(4'-Dimethylamino-3,5-dimethyl-biphenyl- 2-yl)-2-(4-fluoro-phenyl)-acetamide; N-(2,4-Dimethyl-6-quinolin-3-yl-phenyl)-2-(4-fluoro- phenyl)-acetamide; 2-(4-Fluoro-phenyl)-N-(4'-hydroxy-3'-methoxy-3,5-dimethyl-bi phenyl-2- yl)-acetamide; 2-(4-Fluoro-phenyl)-N-(3 '-hydroxy-3, 5-dimethyl-biphenyl-2-yl)-acetamide; 2- (4-Fluoro-phenyl)-N-(2'-methanesulfonylamino-3,5-dimethyl-bi phenyl-2-yl)-acetamide; N- (4'-Isopropyl-3,5-dimethyl-biphenyl-2-yl)-3,3-dimethyl-butyr amide; 2-Cyclopentyl-N-(3,5- dimethyl-biphenyl-2-yl)-acetamide; N-(4'-Fluoro-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro- phenyl)-acetamide; N-(3,5-Dimethyl-3',5'-bis-trifluoromethyl-biphenyl-2-yl)-2-( 4-fluoro- phenyl)-acetamide; N-(3'-Acetylamino-3,5-dimethyl-biphenyl-2-yl)-2-(4-fluoro-ph enyl)- acetamide; 2-(4-Fluoro-phenyl)-N-(2'-methoxy-3,5-dimethyl-biphenyl-2-yl )-acetamide; N- (3,5-Dimethyl-4'-vinyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-ac etamide; N-(3'-Cyano-3,5- dimethyl-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamide; N-(3,5-Dimethyl-3'- trifluoromethoxy-biphenyl-2-yl)-2-(4-fluoro-phenyl)-acetamid e; N-[2-(2,3-Dihydro- benzo[l,4]dioxin-6-yl)-4,6-dimethyl-phenyl]-2-(4-fluoro-phen yl)-acetamide; N-[2,4- Dimethyl-6-(2,2,5-trimethyl-2,3-dihydro-benzofuran-7-yl)-phe nyl]-2-(4-fluoro-phenyl)- acetamide; N-[2,6-Dimethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-ac etamide; N-{2,6- Dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl {-acetamide; {4-[(5-Chloro- thiophen-2-ylmethyl)-amino]-2,6-dimethyl-phenyl{-carbamic acid propyl ester; [4-(4-Fluoro- benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl ester; [2,6-Dimethyl-4-(4- trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester; [4-(3-Fluoro-4- trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl ester; {2,6- Dimethyl-4-[(4-methyl-2-phenyl-pyrimidin-5-ylmethyl)-amino]- phenyl {-carbamic acid propyl ester; {2,6-Dimethyl-4-[(6-p-tolyloxy-pyridin-3-ylmethyl)-amino]-ph enyl}-carbamic acid propyl ester; {4-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-2,6-dimethyl-pheny l{- carbamic acid propyl ester; {4-[(3-Fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-2,6- dimethyl-phenyl} -carbamic acid propyl ester; 2-Cyclopentyl-N-[2,6-dimethyl-4-(4- trifluoromethyl-benzylamino)-phenyl]-acetamide 2-Cyclopentyl-N-{2,6-dimethyl-4-[methyl- (4-trifluoromethyl-benzyl)-amino]-phenyl{ -acetamide; 2-Cyclopentyl-N-{2,6-dimethyl-4- [(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-phenyl {-acetamide; N-{2,6-Dimethyl-4-[(6- trifluoromethyl-pyridin-3-ylmethyl)-amino]-phenyl{-3,3-dimet hyl-butyramide; N-{2-Bromo- 4-[(5-chloro-thiophen-2-ylmethyl)-amino]-6-trifluoromethyl-p henyl{-3-cyclohexyl- propionamide; {4-[(3-Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl{-carb amic acid ethyl ester; {2,6-Dimethyl-4-[(4-trifluoromethyl-phenylamino)-methyl]-phe nyl {-carbamic acid ethyl ester; 2-Cyclopentyl-N-{4-[(3-fluoro-phenylamino)-methyl]-2,6-dimet hyl- phenyl{ -acetamide; N-{4-[(3-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl{-2- cyclopentyl-acetamide; 2-Cyclopentyl-N-{4-[(3-methoxy-phenylamino)-methyl]-2,6- dimethyl-phenyl{ -acetamide; N-{4-[(4-Chloro-phenylamino)-methyl]-2,6-dimethyl-phenyl{- 2-cyclopentyl-acetamide; 2-Cyclopentyl-N-{4-[(3,4-difluoro-phenylamino)-methyl]-2,6- dimethyl-phenyl{ -acetamide; 2-Cyclopentyl-N-{2,6-dimethyl-4-[(4-trifluoromethyl- phenylamino)-methyl]-phenyl{ -acetamide; 2-Cyclopentyl-N-[2,6-dimethyl-4-(p-tolylamino- methyl)-phenyl]-acetamide; 2-Cyclopentyl-N-{2,6-dimethyl-4-[(3-trifluoromethyl- phenylamino)-methyl]-phenyl{ -acetamide; 2-Cyclopentyl-N-{-4-[(3,5-difluoro- phenylamino)-methyl]-2,6-dimethyl-phenyl}-acetamide; {4-[(4-Fluoro-phenylamino)- methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester; {4-[(4-Chloro-phenylamino)- methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester; {2,6-Dimethyl-4-[(4- trifluoromethyl-phenylamino)-methyl]-phenyl}-carbamic acid propyl ester; {4-[(3,5- Difluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl} -carbamic acid propyl ester; {4-[(3- Fluoro-phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid propyl ester; N-(4- Bromo-2-methyl-6-morpholin-4-yl-phenyl)-3,3-dimethyl-butyram ide; {4-[(4- Methoxyphenylamino)-methyl]-2,6-dimethylphenyl}-carbamic acid propyl ester; (R)-2- Amino-4-methylpentanoic acid [2,6-dimethyl-4-(4-trifluoromethylbenzylamino)-phenyl]- amide; Pentanoic acid (4-[(4-chlorophenylamino)-methyl]-2,6-dimethylphenyl)-amide; 2-(4- Chlorophenyl)-N-[4-(4-chlorophenylamino)-methyl]-2,6-dimethy l phenyl)-acetamide; {2,6- Dimethyl-4-[(4-trifluoromethylphenylamino)-methyl]-phenyl}-c arbamic acid 2-methoxy ethyl ester; N-{4-[(5-Chl oro-pyri din-2 -ylamino)-methyl]-2, 6-dimethylphenyl }-2- cyclopentylacetamide; 2-Cyclopentyl-N-{4-[(2,6-dichloro-pyridin-4-ylamino)-methyl] -2,6- dimethylphenyl} -acetamide; N-{2-Chloro-6-methyl-4-[(6-trifluoromethyl-pyridin-3- ylmethyl)-amino]-phenyl}-2-(3-fluoro-phenyl)-acetamide; N-[2-Chloro-6-trifluoromethyl-4- (4-trifluoromethylbenzylamino)-phenyl]-2-cyclopentylacetamid e; [2-Amino-6-methyl-4-(4- trifluoromethylbenzylamino)-phenyl]-carbamic acid ethyl ester; 3,3-Dimethyl-N-{2-methyl- 6-morpholin-4-yl-4-(4-trifluoromethylbenzylamino)-phenyl} -butyramide; 2-Cyclopentyl-N- {2,6-dichloro-4-[(4-fluoro-phenylamino)-methyl]-phenyl}-acet amide; 2-Cyclopentyl-N-{2,6- dichloro-4-[(5-trifluoromethylpyridin-2-ylamino)-methyl]-phe nyl}-acetamide; and pharmaceutically acceptable salts thereof.

[00267] In further embodiments, Z is O or S; q is 0; R ¹ and R ² are each independently selected from the group consisting of halogen, cyano, amino, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl, halo-Ci-6-alk(en/yn)yl, halo-C3-s- cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, C3-8- cycloalk(en)yloxy, and C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy; R ³ is selected from the group consisting of Ci-8-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Aryl-Ci-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, amino-Ci-6-alk(en/yn)yl, amino-C3-8-cycloalk(en)yl, amino-C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-Ci-6- alk(en/yn)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, halo-Ci-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; and R ⁴ is selected from the group consisting of halogen, cyano, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl, Aryl-C3-s-cycloalk(en)yl, Aryl-C3- 8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, NR ⁵ R ⁶ and R ⁷ NH — Ci-6-alk(en/yn)yl; wherein: R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, Aryl-Ci-6- alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, and C3-8-cycloalk(en)yl-Ci-6alk(en/yn)yl, with the proviso that R ⁵ and R ⁶ can not both be hydrogen; and R ⁷ is selected from the group consisting of Ci-6- alk(en/yn)yl; C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl, halo-Ci-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl-Ci-6- alk(en/yn)yl, and Aryl-C3-8-cycloalk(en)yl; with the proviso that the compound of formula I is not N-(4-Bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide; or a pharmaceutically acceptable salt thereof.

[00268] In further embodiments, R ¹ and R ² are each independently selected from the group consisting of halogen, amino, Ci-6-alk(en/yn)yl, Aryl, and halo-Ci-6-alk(en/yn)yl.

[00269] In further embodiments, R ³ is selected from the group consisting of Ci-8- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl-Ci-6- alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, and amino-Ci-6-alk(en/yn)yl.

[00270] In further embodiments, R ⁴ is selected from the group consisting of halogen, Ci-6- alk(en/yn)yl, NR ⁵ R ⁶ and R ⁷ NH — Ci-6-alk(en/yn)yl, wherein R ⁵ , R ⁶ and R ⁷ are as previously defined.

[00271] In further embodiments, R ⁴ is NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen, Aryl-Ci-6-alk(en/yn)yl, and Ci-6-alk(en/yn)yl, with the proviso that R ⁵ and R ⁶ cannot both be hydrogen.

[00272] In further embodiments, R ⁴ is R ⁷ NH — Ci-6-alk(en/yn)yl, wherein R ⁷ is Aryl. [00273] In further embodiments, any Aryl is optionally substituted with one or more substituents independently selected from the group consisting of amino, halogen, cyano, Ci-6- alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, hydroxy, Ci-6-alk(en/yn)yloxy, halo-Ci-6- alk(en/yn)yloxy, di-(Ci-6-alk(en/yn)yl)amino, Ci-6-alk(en/yn)yl-CO — NH — and Ci-6- alk(en/yn)yl-sulfonamide; or two adjacent substituents may together with the Aryl group to which they are attached form a 4-8 membered ring, which is optionally substituted with one or more Ci-6-alk(en/yn)yl groups.

[00274] In further embodiments, the Kv7 channel activator is a compound according to formula 14, wherein: Z is O or S; q is 0; R ¹ and R ² are each independently selected from the group consisting of halogen, cyano, amino, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo- C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, and C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yloxy; R ³ is selected from the group consisting of C1-8- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl-Ci-6- alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, amino-Ci- 6-alk(en/yn)yl, amino-C3-8-cycloalk(en)yl, amino-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, C1-6- alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl and halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; and R ⁴ is selected from the group consisting of halogen, cyano, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-Ci- 6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, NR ⁵ R ⁶ and R ⁷ NH — Ci-6-alk(en/yn)yl; wherein: R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, Aryl-Ci-6-alk(en/yn)yl, Aryl- C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, and C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, with the proviso that R ⁵ and R ⁶ cannot both be hydrogen; and R ⁷ is selected from the group consisting of Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl, halo-Ci-6-alk(en/yn)yl, halo- C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Aryl-Ci-6-alk(en/yn)yl, and Aryl-C3-8-cycloalk(en)yl; with the proviso that the compound of formula I is not N-(4- Bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

Formula 15

[00275] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 15. Such compounds are described in International Publication No. W02009015667A1, published February 5, 2009 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. W02006092143A1, published September 8, 2006 and corresponding to International Application No. PCT/DK2006/000123 filed March 2, 2006; US Patent No. 7,812,020, issued October 12, 2010 and corresponding to US Application No. 11/817,340 filed March 2, 2006; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No. 12/671,505 filed July 31, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 15, these references incorporated by reference herein control.

[00276] In an embodiment, the Kv7 channel activator is a compound according to formula 15:

Formula 15 wherein, q is 0 or 1; each of R ¹ and R ² is independently selected from the group consisting of halogen, cyano, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, C3-s-cycloalk(en)yloxy and C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy; and R ³ is selected from the group consisting of Ci-8-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, optionally substituted Aryl-Ci-6-alk(en/yn)yl, optionally substituted Aryl-C3-8-cycloalk(en)yl, optionally substituted Aryl-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-Ci-6-alk(en/yn)y l, C3-8- heterocycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl-Ci-6- alk(en/yn)yl, Heteroaryl-Ci-6-alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl, Heteroaryl-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, NR ⁴ R ⁵ — Ci-6-alk(en/yn)yl, NR ⁴ R ⁵ — C3-8-cycloalk(en)yl NR ⁴ R ⁵ — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yloxy-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-Ci-6- alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yl; wherein each of R ⁴ and R ⁵ is independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl; as the free base or a pharmaceutically acceptable salt thereof.

[00277] In further embodiments, the Kv7 channel activator is selected from the group consisting of: (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-carbamic acid benzyl ester; (2,4- Dimethyl-6-morpholin-4-yl-pyri din-3 -yl)-carbamic acid 2-chloro-benzyl ester; 2-(4-Chloro- phenyl)-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-acetami de; 2-Phenyl- cyclopropanecarboxylic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-amide; N-(2,4- Dimethyl-6-morpholin-4-yl-pyri din-3 -yl)-2-thiophen-2-yl-acetamide; 3-Cyclohexyl-N-(2,4- dimethyl-6-morpholin-4-yl-pyridin-3-yl)-propionamide; (2,4-Dimethyl-6-morpholin-4-yl- pyri din-3 -yl)-carbamic acid isobutyl ester; 3-(3-Chloro-phenyl)-N-(2,4-dimethyl-6- morpholin-4-yl-pyri din-3 -yl)-propionamide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyri din-3 - yl)-2-(3,5-dimethyl-phenyl)-acetamide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-3-p- tolyl -propionamide; 2-(3 -Chi oro-phenyl)-N-(2,4-dimethyl-6-morpholin-4-yl-pyri din-3 -yl)- acetamide; 2-(3,4-Dichloro-phenyl)-N-(2,4-dimethyl-6-morpholin-4-yl-pyr i din-3 -yl)- acetamide; N-(2, 4-Dimethyl-6-morpholin-4-yl-pyri din-3 -yl)-2 -thi ophen-3 -yl-acetamide; N- (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-2-p-tolyl-aceta mide; 2-(3-Bromo-phenyl)-N- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-acetamide; N-(2,4-Dimethyl-6-morpholin-4-yl- pyridin-3-yl)-2-(3-trifluoromethyl-phenyl)-acetamide; N-(2,4-Dimethyl-6-morpholin-4-yl- pyridin-3-yl)-2-phenyl-acetamide; 3, 5, 5 -Trimethyl-hexanoic acid (2,4-dimethyl-6-morpholin- 4-yl-pyri din-3 -yl)-amide; Octanoic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-amide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-2-naphthalen- 2-yl-acetamide; Heptanoic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-amide; N-(2,4-Dimethyl-6-morpholin-4- yl-pyri din-3 -yl)-2-(3,4-dimethyl-phenyl)-acetamide; 2-Cyclohex-l-enyl-N-(2,4-dimethyl-6- morpholin-4-yl-pyri din-3 -yl)-acetamide; N-(2, 4-Dimethyl-6-morpholin-4-yl-pyri din-3 -yl)-2- (4-methoxy-3-methyl-phenyl)-acetamide; N-(2, 4-Dimethyl-6-morpholin-4-yl-pyri din-3 -yl)-2- (4-methoxy-phenyl)-acetamide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-3-(4- methoxy-phenyl)-propionamide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-2-m-tolyl- acetamide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-2-(4-fluoro-p henyl)-acetamide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-3,3-dimethyl- butyramide; N-(2,4-Dimethyl- 6-morpholin-4-yl-pyridin-3-yl)-2-(3-fluoro-phenyl)-acetamide ; 2-Bicyclo[2.2.1]kept-2-yl-N- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-acetamide; 2-(3,4-Difluoro-phenyl)-N-(2,4- dimethyl-6-m orpholin-4-yl-pyri din-3 -yl)-acetamide; 4-Methyl-pentanoic acid (2,4-dimethyl- 6-morpholin-4-yl-pyridin-3-yl)-amide; 2-Cyclopent-2-enyl-N-(2,4-dimethyl-6-morpholin-4- yl-pyri din-3 -yl)-acetamide; 2-Cy cl ohexyl-N-(2,4-dimethyl-6-morpholin-4-yl-pyri din-3 -yl)- acetamide; 5 -Methyl -hexanoic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-amide; 2- Cyclopentyl-N-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-a cetamide; 3-Cyclopentyl-N- (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-propionamide; Hexanoic acid (2,4-dimethyl-6- morpholin-4-yl-pyri din-3 -yl)-amide; N-(4-Chl oro-2-methoxy-6-morpholin-4-yl-pyri din-3 - yl)-2-cyclopentylacetamide; N-(2-Chloro-4-methoxy-6-morpholin-4-yl-pyridin-3-yl)-2- cyclopentylacetamide; N-(2-Chloro-4-methoxy-6-morpholin-4-yl-pyridin-3-yl)-3,3- dimethylbutyramide; N-(4-Chloro-2-methoxy-6-morpholin-4-yl-pyridin-3-yl)-3,3- dimethylbutyramide; N-(4-Chloro-2-methoxy-6-morpholin-4-yl-pyridin-3-yl)-propion amide; and pharmaceutically acceptable salts thereof. [00278] In further embodiments, q is 0 or 1; R ¹ and R ² each is independently selected from the group consisting of halogen, cyano, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3-s- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy, C3-s-cycloalk(en)yloxy and C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yloxy; and R ³ is selected from the group consisting of C1-8- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, optionally substituted aryl-Ci-6-alk(en/yn)yl, optionally substituted aryl-C3-8-cycloalk(en)yl, optionally substituted aryl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-Ci-6- alk(en/yn)yl, C3-8-heterocycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3-8- heterocycloalk(en)yl-Ci-6-alk(en/yn)yl, heteroaryl-Ci-6-alk(en/yn)yl, heteroaryl-C3-8- cycloalk(en)yl, heteroaryl-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, NR ⁴ R ⁵ — Ci-6-alk(en/yn)yl, NR ⁴ R ⁵ — C3-8-cycloalk(en)yl, NR ⁴ R ⁵ — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, C1-6- alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl and halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, wherein: R ⁴ and R ⁵ each is independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl and C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl.

Formula 16

[00279] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 16. Such compounds are described in International Publication No. W02009015667A1, published February 5, 2009 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; US Publication No. US20100256145A1, published October 7, 2010 and corresponding to US Application No. 12/671,505 filed July 31, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 16, these references incorporated by reference herein control.

[00280] In an embodiment, the Kv7 channel activator is a compound according to formula 16: Formula 16 wherein: q is 0 or 1; R ¹ and R ² are independently selected from the group consisting of hydrogen and optionally substituted aryl-Ci-6-alk(en/yn)yl, provided that R ¹ and R ² are not both hydrogen; or R ¹ and R ² together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further heteroatom; R ² and R ⁴ are independently selected from hydrogen, halogen, cyano, amino, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, halo- Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, Ci-6-alk(en/yn)yloxy, C3-s-cycloalk(en)yloxy, C3- 8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, halo-Ci-6-alk(en/yn)yloxy, halo-C3-s-cycloalk(en)yloxy and halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, provided that R ³ and R ⁴ are not both hydrogen; and R ⁵ is selected from the group consisting of Ci-io-alk(en/yn)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, optionally substituted aryl-Ci-6-alk(en/yn)yl and optionally substituted aryl; as the free base or a pharmaceutically acceptable salt thereof.

[00281] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimid in-5-yl]-2- cyclopentylacetamide; N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimid in-5- yl]-3,3-dimethylbutyramide; N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)- pyrimidin-5-yl]-2-(4-fluorophenyl)-acetamide; Hexanoic acid [4-amino-6-methyl-2-(4- trifhioromethylbenzylamino)-pyrimidin-5-yl]-amide; N-[4-Amino-6-methyl-2-(4- trifluoromethylbenzylamino)-pyrimidin-5-yl]-2-(3-chloropheny l)-acetamide; 2-Cyclopentyl- N-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-acetamide; N-(4,6-Dimethyl-2- morpholin-4-yl-pyrimidin-5-yl)-3,3-dimethylbutyramide; N-(4,6-Dimethyl-2-morpholin-4- ylpyrimidin-5-yl)-2-(4-fluorophenyl)-acetamide; 2-(3,4-Difluorophenyl)-N-(4,6-dimethyl-2- morpholin-4-ylpyrimidin-5-yl)-acetamide; N-(4,6-Dimethyl-2-morpholin-4-ylpyrimidin-5- yl)-2-(3-fluorophenyl)-acetamide; and Hexanoic acid (4,6-dimethyl-2-morpholin-4- ylpyrimidin-5-yl)-amide; as the free base or a pharmaceutically acceptable salt thereof.

Formula 17 In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 17. Such compounds are described in International Publication No. W02007065449A1, published June 14, 2007 and corresponding to International Application No. PCT/DK2006/050039 filed September 7, 2006; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 17, this reference incorporated by reference herein controls.

[00282] In an embodiment, the Kv7 channel activator is a compound according to formula 17:

Formula 17 wherein: q is 0 or 1; R ¹ and R ² are independently selected from the group consisting of hydrogen and optionally substituted aryl-Ci-6-alk(en/yn)yl, provided that R ¹ and R ² are not both hydrogen, or R ¹ and R ² together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further heteroatom;R ³ and R ⁴ are independently selected from hydrogen, halogen, cyano, amino, Ci-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, halo- Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, Ci-6-alk(en/yn)yloxy, C3-s-cycloalk(en)yloxy, C3- 8-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, halo-Ci-6-alk(en/yn)yloxy, halo-C3-s-cycloalk(en)yloxy and halo-C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yloxy, provided that R ³ and R ⁴ are not both hydrogen;R ⁵ is selected from the group consisting of Ci-io-alk(en/yn)yl, C3-8-cycloalk(en)yl- C1-6- alk(en/yn)yl, optionally substituted aryl-Ci-6-alk(en/yn)yl and optionally substituted aryl; as the free base or salts thereof.

[00283] In further embodiments, q is 0.

[00284] In further embodiments, q is 1.

[00285] In further embodiments, R ¹ and R ² are independently selected from hydrogen and optionally substituted aryl-Ci-6-alk(en/yn)yl, provided that R ¹ and R ² are not both hydrogen. [00286] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further hetero atom.

[00287] In further embodiments, said further hetero atom is oxygen.

[00288] In further embodiments, said ring is a 6 membered ring. [00289] In further embodiments, said ring is a morpholine ring. [00290] In further embodiments, R ³ and R ⁴ are independently selected from amino and Ci-6- alk(en/yn)yl, preferably methyl.

[00291] In further embodiments, R ⁵ is selected from the group consisting of Cnio- alk(en/yn)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, optionally substituted aryl-Ci-6- alk(en/yn)yl and optionally substituted aryl.

[00292] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimid in-5-yl]-2- cyclopentylacetamide, N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimid in-5- yl]-3,3- dimethylbutyramide, N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)- pyrimidin-5-yl]-2-(4- fluorophenyl)-acetamide, Hexanoic acid [4-amino-6-methyl-2-(4- trifluoromethylbenzylamino)-pyrimidin-5-yl]- amide, N-[4-Amino-6-methyl-2-(4- trifluoromethylbenzylamino)-pyrimidin-5-yl]-2-(3- chlorophenyl)-acetamide, 2-Cyclopentyl- N-(4,6-dimethyl-2-mo(pholin-4-yl-pyrimidin-5-yl)-acetamide, N-(4,6-Dimethyl-2-mocpholin- 4-yl-pyrimidin-5-yl)-3,3-dimethylbutyramide, N-(4,6-Dimethyl-2-mo(pholin-4-ylpyrimidin-5- yl)-2-(4-fluorophenyl)-acetamide, 2-(3,4-Difluorophenyl)-N-(4,6-dimethyl-2-morpholin-4- ylpyrimidin-5-yl)-acetamide, N-(4,6-Dimethyl-2-mo(pholin-4-ylpyrimidin-5-yl)-2-(3- fluorophenyl)-acetamide and Hexanoic acid (4,6-dimethyl-2-mo(pholin-4-ylpyrimidin-5-yl)- amide; as the free base or a salt thereof.

Formula 18

In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 18. Such compounds are described in International Publication No. W02004096767A1, published November 11, 2004 and corresponding to International Application No. PCT/DK2004/000283 filed April 23, 2004; US Publication No. US20060264496A1, published November 23, 2006 and corresponding to US Application No. 10/551,783 filed April 23, 2004; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 18, these references incorporated by reference herein control.

[00293] In an embodiment, the Kv7 channel activator is a compound according to formula 18: Formula 18 wherein, the dotted line represents an optional bond; R ¹ and R ¹ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-s-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ¹ and R ¹ ' together with the carbon atom to which they are attached form a 3-8 membered saturated or unsaturated ring which optionally contains 1 or 2 heteroatoms; s is 0 or 1; U is O, NR ¹¹ , S, SO2, SO2NR ¹¹ , CO — O or CO — NR ¹¹ ; wherein R ¹¹ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; or R ² and R ¹¹ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms; R ² is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8-cycloalk(en)yl, Ar — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, acyl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halogen, halo-Ci-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, — NO2, NR ¹⁰ R ¹⁰ ' — Ci-6-alk(en/yn)yl, NR ¹⁰ R ¹⁰ ' — C3-8-cycloalk(en)yl and NR ¹⁰ R ¹⁰ ' — C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein R ¹⁰ and R ¹⁰ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3- 8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, or R ¹⁰ and R ¹⁰ ' together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms; with the proviso that when R ² is NO2, halogen or cyano then s is 0; and with the proviso that when R ² is a hydrogen atom or acyl and s is 1 then U is NR ¹¹ , O or S; wherein the group — (U) _s — R ² is linked to position 4 or 6 of the indole or indoline; q is 0 or 1; Z is O or S; X is CO or SO2; with the proviso that q is 0 when X is SO2; R ³ is selected from the group consisting of C1-6- alk(en/yn)yl, C3-s-cycloalk(en)yl, heterocycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar — C1-6- alk(en/yn)yl, Ar — C3-s-cycloalk(en)yl, Ar-heterocycloalk(en)yl, Ar — C3-s-cycloalk(en)yl-Ci- 6-alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yl-C3-s-cycloalk(en)yl, Ar — Ci-6-alk(en/yn)yl- heterocycloalk(en)yl, Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yloxy-Ci-6- alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-C3-s-cycloalk(en)yl, Ci-6-alk(en/yn)yloxy- heterocycloalk(en)yl, Ar-oxy-Ci-6-alk(en/yn)yl, Ar — Ci-6-alk(en/yn)yloxy-Ci-6-alk(en/yn)yl, Ci-6-alk(en/yn)yloxy-carbonyl-Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yloxy-carbonyl-Ci-6- alk(en/yn)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy-carbonyl-Ci-6-alk(e n/yn)yl, hydroxy - Ci-6-alk(en/yn)yl, hydroxy-C3-s-cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3-s- cycloalk(en)yl-Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl-C3-s-cycloalk(en)yl, hydroxy-Ci- 6-alk(en/yn)yl-heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo- heterocycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl-C3-s- cycloalk(en)yl, halo-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-Ci-6-alk(en/yn)yl-Ar, halo- C3-8-cycloalk(en)yl-Ar, halo-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl-Ar, halo-Ci-6-alk(en/yn)yl- C3-8-cycloalk(en)yl-Ar, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano- heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl- C3-8-cycloalk(en)yl, cyano-Ci-6-alk(en/yn)yl-heterocycloalk(en)yl, acyl-Ci-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, acyl-Ci-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-Ci-6-alk(en/yn)yl- heterocycloalk(en)yl and — NR ^I2 R ¹² ', optionally substituted NR ¹² R ¹² ’ — Ci-6-alk(en/yn)yl, optionally substituted NR ¹² R ¹² ’ — C3-8-cycloalk(en)yl, optionally substituted NR ¹² R ¹² ’ — C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl; wherein R ¹² and R ¹² ’ are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6- alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar — C3-8-cycloalk(en)yl, Ar — C3-8-cycloalk(en)yl- Ci-6-alk(en/yn)yl, hydroxy-Ci-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, halo-Ci-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-Ci-6-alk(en/yn)yl, cyano-Ci-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, or R ¹² and R ¹² ’ together with the nitrogen atom to which they are attached form a 4-8 membered saturated or unsaturated ring which optionally contains 1, 2 or 3 further heteroatoms; with the proviso that when R ³ is

NR ¹² R ¹² ' then q is 0; and Y is selected from the groups according to the following formulas: wherein, W is O or S; T is N, NH or O; L is N, C or CH; a is 0, 1, 2 or 3; b is 0, 1, 2, 3 or 4; c is 0 or 1; d is 0, 1, 2 or 3; e is 0, 1 or 2; f is 0, 1, 2, 3, 4 or 5; g is 0, 1, 2, 3 or 4; h is 0, 1, 2 or 3; j is 0, 1, 2 or 3; with the proviso that when T is a nitrogen atom then j is 0, 1, 2 or 3; and when T is NH or an oxygen atom then j is 0, 1 or 2; k is 0, 1, 2, 3 or 4; and each R ⁵ is independently selected from the group consisting of a Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar, Ar — Ci-6-alk(en/yn)yl, Ar-thio, Ar-oxy, acyl, Ci-6- alk(en/yn)yloxy, C3-s-cycloalk(en)yloxy, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yloxy, halogen, halo-Ci-6-alk(en/yn)yl, halo-C3-s-cycloalk(en)yl, halo-C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, — CO — NR ⁶ R ⁶ , cyano, cyano-Ci-6-alk(en/yn)yl, cyano-C3-s-cycloalk(en)yl, cyano-C3-s- cycloalk(en)yl-Ci-6-alk(en/yn)yl, — NR ⁷ R ⁷ ', — S — R ⁸ and — SO2R ⁸ , or two adjacent R ⁵ together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms; R ⁶ and R ⁶ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl- Ci-6-alk(en/yn)yl and Ar; R ⁷ and R ⁷ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-s-cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar and acyl; and R ⁸ is selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-s-cycloalk(en)yl-Ci-6-alk(en/yn)yl, Ar and — NR ⁹ R ⁹ '; wherein R ⁹ and R ⁹ ' are independently selected from the group consisting of hydrogen, Ci-6-alk(en/yn)yl, C3-8- cycloalk(en)yl and C3-8-cycloalk(en)yl-Ci-6-alk(en/yn)yl; provided that when R ⁸ is — NR ⁹ R ⁹ then R ⁵ is not — S — R ⁸ ; or salts thereof.

Formula 19

In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 19. Such compounds are described in US Patent No. 9,248,122, issued February 2, 2016 and corresponding to US Application No. 14/091,395 filed November 27, 2013; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 19, this reference incorporated by reference herein controls.

[00294] In an embodiment, the Kv7 channel activator is a compound according to formula 19:

Formula 19 wherein, A ¹ , A ² and A ³ independently of each other represent CR ⁴ , N, O, S or N(CH3), A ⁴ represents CR ⁴ or N, and n denotes 0 or 1, with the proviso, that at least one of A ¹ , A ² , A ³ and A ⁴ does not represent CR ⁴ , and with the proviso, that if n denotes 0, then precisely one of A ¹ , A ² and A ³ represents O, S or N(CH3), or if n denotes 1, then A ¹ , A ² and

A ³ independently of each other represent CR ⁴ or N, R ¹ represents Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-8-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-8-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents F; Cl; Br; I; CN; CF3; C(=O)H; NO2; OCF3; SCF3; Ci-4-aliphatic residue, C(=0) — Ci-4-aliphatic residue, C(=0) — O — Ci-4-aliphatic residue, C(=O) — NH — Ci-4-aliphatic residue, C(=O) — N(Ci-4-aliphatic residue)2, O — Ci-4-aliphatic residue, O — C(=O) — Ci-4-aliphatic residue, S — Ci-4-aliphatic residue, S(=O)2 — Ci-4-aliphatic residue, S(=O)2 — O — Ci-4-aliphatic residue, wherein the Ci-

4-aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; C3-6- cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a C1-4- aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted;

R ³ represents C2-io-aliphatic residue, unsubstituted or mono- or polysubstituted; C3-10- cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a C1-8- aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted, or denotes

5 — R ⁵ , O — R ⁶ or N(R ⁷ R ⁸ ), wherein R ⁵ and R ⁶ in each case represent Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-s-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; with the proviso, that if R ⁵ or R ⁶ denote a 3 to 10 membered heterocycloaliphatic residue, than the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, R ⁷ represents Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-s-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; with the proviso that if R ⁷ denotes 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom; and R ⁸ denotes Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; or R ⁷ and

R ⁸ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted; and each

R ⁴ independently represents H, F; Cl; Br; I; CN; CF ₃ ; CHF ₂ ; CH ₂ F; OCF ₃ ; OCHF ₂ ; OCH ₂ F; SCF3; O — Ci-4-aliphatic residue, Ci-4-aliphatic residue or S(=O)2 — Ci-4-aliphatic residue; in which an “aliphatic group” and “aliphatic residue” may in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” may in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group”, an “aliphatic residue”, a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, NH — C(=0) —

C i-4aliphatic residue, N(Ci-4aliphatic residue)-C(=O) — C1-4 aliphatic residue, NH — S(=0)2 — Ci-4 aliphatic residue, N(CI-4 aliphatic residue)-S(=0)2 — C1-4 aliphatic residue, =0, OH, OCF3, O — Ci-4-aliphatic residue, O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, S — Cisaliphatic residue, S(=0)20H, S(=0)2 — Cis-aliphatic residue, S(=0)2 — O — Cis-aliphatic residue, S(=0)2 — NH(Ci-4-aliphatic residue), S(=0)2 — N(Ci-4-aliphatic residue^, CN, CF3, CHO, COOH, Ci-4-aliphatic residue, C(=0) — Cis-aliphatic residue, C(=0) — O — C1-4- aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, C(=0)NH2, a C(=0) — NH(Ci-4-aliphatic residue) and C(=0) — N(Ci-4-aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of -aliphatic residue),

N(Ci-4-aliphatic residue^, NH — C(=0) — Ci-4-aliphatic residue, N(CI-4 aliphatic residue)- C(=0) — C1-4 aliphatic residue, NH — S(=0)2 — C1-4 aliphatic residue, N(CI-4 aliphatic residue)-S(=0)2 — C1-4 aliphatic residue, OH, OCF3, O — Ci-4-aliphatic residue, O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, S — Ci-4-aliphatic residue, S(=0)20H, S(=0)2 — Cisaliphatic residue, S(=0)2 — O — Cis-aliphatic residue, S(=0)2 — NH(Ci-4-aliphatic residue), S(=0)2 — N(Ci-4-aliphatic residue^, CN, CF3, C(=0)H, C(=0)0H, Cis-aliphatic residue, C(=0) — Ci-4-aliphatic residue, C(=0) — O — Cis-aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=0)NH2, C(=0) — NH(Ci-4-aliphatic residue) and C(=0) — N(Ci-4-aliphatic residue^; in the form of an individual single stereoisomer or a mixture of the stereoisomers in any mixing ratio, and/or in the form of a free compound, a solvate and/or a physiologically acceptable salt.

[00295] In further embodiments, A ¹ , A ² and A ³ independently of each other represent CR ⁴ ,

N, O, S or N(CHi), A ⁴ represents CR ⁴ or N, and n denotes 0 or 1, with the proviso, that at least one of A ¹ , A ² , A ³ and A ⁴ does not represent CR ⁴ , and with the proviso, that if n denotes

O, then precisely one of A ¹ , A ² and A ³ represents O, S or N(CHi), or if n denotes 1, then A ¹ , A ² and A ³ independently of each other represent CR ⁴ or N, R ¹ denotes Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, or denotes C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0) — OH, C3-s-cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-8-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-s-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C(=0)CH ₃ , C(=O)C ₂ H ₅ , C(=0)0CH ₃ , C(=O)OC ₂ H ₅ , 03-8-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Ci-4-aliphatic residue, OCF ₃ , OCH2CH2OH, OCH2OCH3, SH, SCF ₃ , S— Ci- ₄ -aliphatic residue, CF ₃ , CN, Ci-4-aliphatic residue, C(=O)OH, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)OCH ₃ and C(=O)OC ₂ H ₅ , and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the aryl or the heteroaryl residue may in each case be optionally linked via a Ci-8-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN and C(=0)0H, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; Ci-4-aliphatic residue, S — Cis-aliphatic residue, O — Cis-aliphatic residue, wherein the Ci-4-aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue,

Or

C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a C1-4- aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN and C(=0)0H, R ³ denotes C2-io-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue,

Or denotes Cs-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(CI-4- aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-8-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H,

Or denotes S — R ⁵ , O — R ⁶ or N(R ⁷ R ⁸ ), wherein R ⁵ and R ⁶ in each case represent C1-10- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Cis-aliphatic residue, OCF3, SH, SCF3, S — C1-4- aliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Cisaliphatic residue, or in each case represent C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Cis-aliphatic residue, C(=0) — OH, C3-8- cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci- 4-aliphatic residue, and wherein the C3-8-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=O)OH, and wherein the Cs-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-8-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, on the condition that if R ⁵ or R ⁶ denote a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, R ⁷ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=O) — O — Cis-aliphatic residue and C(=O)OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=O)OH, C(=O) — O — Ci-4-aliphatic residue, C3-6-cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Oi-o-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Cis-aliphatic residue, C(=O) — O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, and/or

R ⁸ denotes Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=O)OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue,

Or

R ⁷ and R ⁸ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=O) — OH, C3-6-cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue,

And/or wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁷ and R ⁸ together with the nitrogen atom connecting them may optionally be condensed with aryl or heteroaryl, wherein the aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Cisaliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Cis-aliphatic residue, C(=O)OH, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)OCH ₃ and C(=O)OC ₂ H ₅ , C ₃ -6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Ci-4-aliphatic residue, OCF ₃ , OCH2CH2OH, OCH2OCH3, SH, SCF ₃ , S— Ci- ₄ -aliphatic residue, CF ₃ , CN, Ci-4-aliphatic residue, C(=O)OH, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)OCH ₃ and C(=O)OC ₂ H ₅ , and wherein the C3-6 cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0) — OH, and each R ⁴ independently represents H, F, Cl, Br, I, CN, CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , OCHF ₂ , OCH ₂ F, SCF3, O — Ci-4-aliphatic residue, Ci-4-aliphatic residue or S(=0)2 — Ci-4-aliphatic residue. In further embodiments, n denotes 1 and A ¹ represents N, A ² represents CR ⁴ , A ³ represents CR ⁴ and A ⁴ represents CR ⁴ ; or n denotes 1 and A ¹ represents CR ⁴ , A ² represents N, A ³ represents CR ⁴ and A ⁴ represents CR ⁴ ; or n denotes 1 and A ¹ represents CR ⁴ , A ² represents CR ⁴ , A ³ represents N and A ⁴ represents CR ⁴ ; or n denotes 1 and A ¹ represents CR ⁴ , A ² represents CR ⁴ , A ³ represents CR ⁴ and A ⁴ represents N; or n denotes 1 and A ¹ represents N, A ² represents N, A ³ represents CR ⁴ and A ⁴ represents CR ⁴ ; or n denotes 1 and A ¹ represents N, A ² represents CR ⁴ , A ³ represents N and A ⁴ represents CR ⁴ ; or n denotes 1 and A ¹ represents N, A ² represents CR ⁴ , A ³ represents CR ⁴ and A ⁴ represents N; or n denotes 1 and A ¹ represents CR ⁴ , A ² represents N, A ³ represents N and A ⁴ represents CR ⁴ ; or n denotes 1 and

A ¹ represents CR ⁴ , A ² represents N, A ³ represents CR ⁴ and A ⁴ represents N; or n denotes 1 and A ¹ represents CR ⁴ , A ² represents CR ⁴ , A ³ represents N and A ⁴ represents N; or n denotes 0 and A ¹ represents CR ⁴ , A ² represents CR ⁴ , and A ³ represents S; or n denotes 0 and

A ¹ represents N, A ² represents CR ⁴ , and A ³ represents S; or n denotes 0 and A ¹ represents S, A ² represents CR ⁴ and A ³ represents CR ⁴ ; or n denotes 0 and A ¹ represents S, A ² represents CR ⁴ and A ³ represents N. [00296] In further embodiments, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; Cn 4-aliphatic residue, S — Ci-4-aliphatic residue or O — Ci-4-aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH and O — Cisaliphatic residue.

[00297] In further embodiments, R ² represents Cis-aliphatic residue.

[00298] In further embodiments, each R ⁴ independently represents H; F; Cl; Br; CN; CF3; OCF3; CH ₃ , OCH3 or S(=O) ₂ CH ₃ .

[00299] In further embodiments, R ¹ represents the partial structure: wherein, m denotes 0, 1, or 2, R ^la and R ^lb each independently of one another represent H, F, Cl, Br, I, O — Ci-4-aliphatic residue or Cis-aliphatic residue, R ^lc denotes Cis-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and O — Ci-4-aliphatic residue, or denotes C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and O — Ci-4-aliphatic residue, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF ₃ , CN, Ci-4-aliphatic residue, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)OCH ₃ , C(=O)OC ₂ H ₅ , C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci-4-aliphatic residue, C(=O)CH3, C(=O)C ₂ Hs, C(=O)OCH3 and C(=O)OC ₂ Hs, and wherein the C3- 6 cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, CF3 C1-4- aliphatic residue and C(=0)0H.

[00300] In further embodiments, m denotes 1 or 2, R ^la and R ^lb represent H, R ^lc denotes C1-4- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and C1-4- aliphatic residue, or denotes C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, or m denotes 0 and R ^lc denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci- 4-aliphatic residue, C(=O)CH3, C(=O)C2Hs, C(=O)OCH3, C(=O)OC2Hs, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci-4-aliphatic residue, C(=O)CH3, C(=O)C2HS, C(=O)OCH3 and C(=O)OC2Hs, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, CF3, Ci-4-aliphatic residue and C(=O)OH.

[00301] In further embodiments, R ³ denotes a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN and Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and O — Ci-4-aliphatic residue, or denotes C3-6- cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, (=0) — O — Ci-4-aliphatic residue, S — Ci-4-aliphatic residue, CF3, CN and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-7-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3, CN and Ci-4-aliphatic residue, or R ³ denotes S — R ⁵ or O — R ⁶ , wherein R ⁵ and R ⁶ in each case denote Ci-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, NH(Ci-4-aliphatic residue), N(CI-4- aliphatic residue^, CF3 and Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and O — Ci-4-aliphatic residue, or in each case denote C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue may be linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, CF3, CN and Ci-4-aliphatic residue, on the condition that if R ⁵ or R ⁶ denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, or R ³ denotes N(R ⁷ R ⁸ ), wherein R ⁷ denotes Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, CF3 and O — Ci-4-aliphatic residue, or denotes C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue may in each case be linked, via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3, CN and Ci- 4-aliphatic residue, on the condition that if R ⁷ denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, and R ⁸ denotes Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3, CN and Ci-4-aliphatic residue, wherein the Ci -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, CF3 and O — Ci-4-aliphatic residue, or R ⁷ and R ⁸ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3, CN and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and O — Ci-4-aliphatic residue, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁷ and R ⁸ together with the nitrogen atom connecting them may optionally be condensed with aryl or heteroaryl, wherein the aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH,

O — Ci-4-aliphatic residue, OCF3, SCF3, CF3, ON, Ci-4-aliphatic residue, C(=0)0H, C3-

6 cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, and pyridyl, wherein the

Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and O — Ci-

4-aliphatic residue, and wherein benzyl, phenyl, thienyl, and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, O — Ci-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SCF3, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci-4-aliphatic residue and C(=0)0H.

[00302] In further embodiments, R ³ denotes C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, or denotes C3-6- cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and C1-4- aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or O — Ci-4-aliphatic residue, and wherein the C3-6- cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, or R ³ denotes S — R ⁵ or O — R ⁶ , wherein R ⁵ and R ⁶ in each case denote Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — C1-4- aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, CF3 and O — Ci-4-aliphatic residue, or in each case denote C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue in each case may be linked via an unsubstituted Ci-4-aliphatic group, on the condition that if R ⁵ or R ⁶ denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, or R ³ denotes N(R ⁷ R ⁸ ), wherein R ⁷ denotes Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, CF3 and O — Ci-4-aliphatic residue, or denotes C3-6- cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and C1-4- aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue is in each case linked via a unsubstituted Ci-4-aliphatic group, on the condition that if R ⁷ denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, and R ⁸ denotes unsubstituted Ci-4-aliphatic residue, or R ⁷ and R ⁸ form together with the nitrogen atom connecting them a 3 to 7 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3, CN and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, CF3 and O — Ci-4-aliphatic residue, and wherein the 3 to 7 membered heterocycloaliphatic residue formed by R ⁷ and R ⁸ together with the nitrogen atom connecting them may optionally be condensed with phenyl or pyridyl, wherein the phenyl or pyridyl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, benzyl, phenyl, and pyridyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH and O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, 0CH ₃ , OCF ₃ , OCH2CH2OH, OCH2CH2OCH3, SCF ₃ , CF ₃ and Ci-4-aliphatic residue.

[00303] In further embodiments, A ¹ , A ² and A ³ independently of each other represent CR ⁴ ,

N, O, S or N(CH3), A ⁴ represents CR ⁴ or N, and n denotes 0 or 1, with the proviso, that at least one of A ¹ , A ² , A ³ and A ⁴ does not represent CR ⁴ , and with the proviso, that if n denotes

O, then precisely one of A ¹ , A ² and A ³ represents O, S or N(CH3), or if n denotes 1, then A ¹ , A ² and A ³ independently of each other represent CR ⁴ or N, R ¹ represents the partial structure: wherein: m denotes 0, 1, or 2, R ^la and R ^lb each independently of one another represent H, F, Cl, O — Ci-4-aliphatic residue or Ci-4-aliphatic residue, R ^lc denotes Ci-4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cnio — Ci-4 aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and O — Ci-4-aliphatic residue, or denotes C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, C1-10 — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and O — Ci-4-aliphatic residue, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci-4-aliphatic residue, C(=O)CH3, C(=O)C2HS, C(=O)OCH3, C(=O)OC2HS, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Cisaliphatic residue, OCF3, CF3, CN, Cis-aliphatic residue, C(=O)CH3, C(=O)C2Hs, C(=O)OCH3 and C(=O)OC2Hs, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, CF3 Cis-aliphatic residue and C(=O)OH, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; Cis-aliphatic residue, S — C1-4- aliphatic residue or O — Cis-aliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, =0, OH and O — Ci-4-aliphatic residue, R ³ denotes C2-6- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, or denotes C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, or R ³ denotes S — R ⁵ or O — R ⁶ , wherein R ⁵ and R ⁶ in each case denote Ci-s-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and C1-4- aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, CF3 and O — Ci-4-aliphatic residue, or in each case denote C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3 and Ci-4-aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and O — Cisaliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue in each case may be linked via an unsubstituted Cis-aliphatic group, on the condition that if R ⁵ or R ⁶ denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, or R ³ denotes N(R ⁷ R ⁸ ), wherein R ⁷ denotes C i-x-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — C1-4- aliphatic residue, OCF3, SCF3, CF3 and Cis-aliphatic residue wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, CF3 and O — Ci-4-aliphatic residue, or denotes C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, C(=0) — O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue is in each case linked via an unsubstituted Ci-4-aliphatic group, on the condition that if R ⁷ denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, and R ⁸ denotes unsubstituted Ci-4-aliphatic residue, or R ⁷ and R ⁸ form together with the nitrogen atom connecting them a 3 to 7 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, CF3, CN and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, CF3 and O — Cisaliphatic residue, and wherein the 3 to 7 membered heterocycloaliphatic residue formed by R ⁷ and R ⁸ together with the nitrogen atom connecting them may optionally be condensed with phenyl or pyridyl, wherein the phenyl or pyridyl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, O — Cis-aliphatic residue, OCF3, SCF3, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, benzyl, phenyl, and pyridyl, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, and O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OCH3, OCF3, OCH2CH2OH, O CH2CH2OCH3, SH, SCF ₃ , CF ₃ and Ci- ₄ -aliphatic residue; and each R ⁴ independently represents H, F, Cl, Br, CN, CF3, OCF3, CH3, OCH3 or S(=O) ₂ CH ₃ .

[00304] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 1 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-[l,5]na phthyridine-3- carboxylic acid amide; 2 2-Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl- [l,5]naphthyridine-3-carboxylic acid amide; 3-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-[l,6]naphthyridine-3-carboxylic acid amide; 4 2-Ethylsulfanyl-N-[(4-fluorophenyl)- methyl]-4-methyl-[l,6]naphthyridine-3-carboxylic acid amide; 5 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-[l,7]naphthyridine-3-carboxyl ic acid amide; 6- Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-[l,7]naph thyridine-3-carboxylic acid amide; 7 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-[l,8]na phthyridine-3- carboxylic acid amide; 8 2-Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl- [l,8]naphthyridine-3 -carboxylic acid amide; 9 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]- 4-methyl-7-(trifluoromethyl)-[l,8]naphthyridine-3-carboxylic acid amide; 102- Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-7-(triflu oromethyl)-[l,8]naphthyridine- 3-carboxylic acid amide; 11 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-7- (trifluoromethyl)-[l,6]naphthyridine-3-carboxylic acid amide; 122-Ethylsulfanyl-N-[(4- fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-[l,6]naph thyridine-3-carboxylic acid amide; 13 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trif luoromethyl)- [l,5]naphthyridine-3-carboxylic acid amide; 14 2-Ethylsulfanyl-N-[(4-fluorophenyl)- methyl]-4-methyl-7-(trifluoromethyl)-[l,5]naphthyridine-3-ca rboxylic acid amide; 15 5- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-methyl-thieno[3, 2-b]pyridine-6-carboxylic acid amide; 16 6-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-thieno[ 2,3-b]pyridine-5- carboxylic acid amide; 17 5-Ethoxy-N-[(3-fluorophenyl)-methyl]-7-methyl-2- (trifluoromethyl)-thieno[3,2-b]pyridine-6-carboxylic acid amide; 18 6-Ethoxy-N-[(3- fluorophenyl)-methyl]-4-methyl-2-(trifluoromethyl)-thieno[2, 3-b]pyridine-5-carboxylic acid amide; in the form of a free compound, a solvate and/or a physiologically acceptable salt.

Formula 20

In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 20. Such compounds are described in US Patent No. 9,284,286 issued March 15, 2016 and corresponding to US Application No. 14/091.373 filed November 27, 2013; International Publication No. WO2014082737A1, published June 5, 2014 and corresponding to International Application No. PCTZEP2013/003572 filed November 27, 2013; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 20, these references incorporated by reference herein control.

[00305] In an embodiment, the Kv7 channel activator is a compound according to formula 20: Formula 20 wherein: A ¹ represents CR ¹⁰ R ⁿ or S; A ² represents CR ¹² R ¹³ , C(=O), O, S, S(=O) or S(=O)2; A ³ , A ⁴ and A ⁵ independently of each other represent CR ⁷ , N, O, S or NR ⁸ , A ⁶ represents CR ⁷ or N, and n denotes 0 or 1, with the proviso, that if n denotes 0, then precisely one of A ³ , A ⁴ and A ⁵ represents O, S or NR ⁸ , or if n denotes 1, then A ³ , A ⁴ and A ⁵ independently of each other represent CR ⁷ or N; and with the proviso, that if n denotes 1 and A ³ , A ⁴ and A ⁵ each represent CR ⁷ , then A ⁶ does not represent N; R ¹ represents Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² , R ³ ; R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently of another represent H; F; Cl; Br; I; NO2; CF3; CN; OH; OCF3; SH; SCF3; Ci- 10-aliphatic residue, O — Ci-10-aliphatic residue or S — Ci-10-aliphatic residue, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; or C3-io-cycloaliphatic residue, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; or R ² and R ³ or R ⁴ and R ⁵ or R ¹⁰ and R ¹¹ or R ¹² and R ¹³ or R ² and R ¹¹ or R ² and R ⁴ or R ² and R ¹³ or R ⁴ and R ¹³ or R ⁴ and R ¹¹ or R ¹² and R ¹³ , together with the carbon atom(s) joining them, form a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted; wherein the remaining substituents R ² , R ³ ; R ⁴ ; R ⁵ ; R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in each case have the meaning given above; R ⁶ represents a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted; or represents an aryl or a heteroaryl, in each case unsubstituted or mono- or poly-substituted; each R ⁷ independently of each other represents H, F; Cl; CN; CF ₃ ; CHF ₂ ; CH ₂ F; OCF ₃ ; OCHF ₂ ; OCH ₂ F; SCF ₃ ; O— Ci- ₄ -aliphatic residue, Ci-4-aliphatic residue or S(=O)2 — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; and R ⁸ represents H or a Ci-4-aliphatic residue, wherein the aliphatic residue may be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; in which an “aliphatic group” and “aliphatic residue” may in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” may in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group”, an “aliphatic residue”, a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, NH — C(=O) — Ci-4aliphatic residue, N(Ci-4-aliphatic residue)-C(=O) — Ci-4-aliphatic residue, NH — S(=O)2 — Ci-4-aliphatic residue, N(Ci-4-aliphatic residue)-S(=O)2 — Ci-4-aliphatic residue, =0, OH, OCF3, O — Ci-4-aliphatic residue, O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, S — Ci-4-aliphatic residue, S(=0)20H, S(=0)2 — Ci-4-aliphatic residue, S(=0)2 — O — Cisaliphatic residue, S(=0)2 — NH(Ci-4-aliphatic residue), S(=0)2 — N(Ci-4-aliphatic residue^, CN, CF3, CHO, COOH, Ci-4-aliphatic residue, C(=0) — Cis-aliphatic residue, C(=0) — O — Ci-4-aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=0)NH2, a C(=0) — NH(Ci-4-aliphatic residue) and C(=0) — N(Ci-4-aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, -aliphatic residue), N(Ci-4-aliphatic residue)2, NH — C(=0) — Ci-4-aliphatic residue, N(CI-4 aliphatic residue)-C(=O) — Ci-

4 aliphatic residue, NH — S(=0)2 — C1-4 aliphatic residue, N(CI-4 aliphatic residue)-S(=0)2 — Ci-4 aliphatic residue, OH, OCF3, O — Ci-4-aliphatic residue, O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, S — Ci-4-aliphatic residue, S(=O)2OH, S(=O)2 — Ci-4-aliphatic residue, S(=O)2 — O — Ci-4-aliphatic residue, S(=O)2 — NH(Ci-4-aliphatic residue), S(=O)2 — N(CI-4- aliphatic residue^, CN, CF3, C(=O)H, C(=O)OH, Ci-4-aliphatic residue, C(=0) — C1-4- aliphatic residue, C(=0) — O — Ci-4-aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=0)NH2, C(=O) — NH(Ci-4-aliphatic residue) and C(=O) — N(Ci-4-aliphatic residue^; in the form of an individual single stereoisomer or a mixture of the stereoisomers in any mixing ratio, and/or in the form of a free compound, a solvate and/or a physiologically acceptable salt.

[00306] In further embodiments, A ¹ represents CR ¹⁰ R ⁿ or S; A ² represents CR ¹² R ¹³ , C(=O), O, S, S(=O) or S(=O)2; A ³ , A ⁴ and A ⁵ independently of each other represent CR ⁷ , N, O, S or NR ⁸ , A ⁶ represents CR ⁷ or N, and n denotes 0 or 1, with the proviso, that if n denotes 0, then precisely one of A ³ , A ⁴ and A ⁵ represents O, S or NR ⁸ , or if n denotes 1, then A ³ , A ⁴ and A ⁵ independently of each other represent CR ⁷ or N; and with the proviso, that if n denotes 1 and A ³ , A ⁴ and A ⁵ each represent CR ⁷ , then A ⁶ does not represent N; R ¹ denotes a C1-10- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=O)OH, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — C1-4- aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=O)OH, C3-6- cycloaliphatic residue and a 3 to 7 membered heterocycloaliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci- 4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=O)OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case be optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Ci- 4-aliphatic residue, CF3, CN, Cis-aliphatic residue, C(=0)0H, C(=0)CH3, C(=0)C2Hs, C(=0)0CH3, C(=0)0C2HS, C3-6 cycloaliphatic residue, 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O— Ci- ₄ -aliphatic residue, OCF ₃ , OCH2CH2OH, OCH2OCH3, SH, SCF ₃ , S— Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C(=0)CH3, C(=0)C2Hs, C(=0)0CH3, C(=0)0C2HS, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the aryl or the heteroaryl residue may in each case be optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN and C(=0)0H, R ² , R ³ , R ⁵ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently of the others represents H; F; Cl; Br; I; NO2; CF3; CN; OH; OCF3; SH; SCF3; Ci-4-aliphatic residue, O — Ci-4-aliphatic residue or S — Ci-4-aliphatic residue, in each case saturated or unsaturated, branched or unbranched, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-

4-aliphatic residue, or a C3-io-cycloaliphatic residue, saturated or unsaturated, branched or unbranched, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3,

5 — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci- 4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, or R ² and R ³ or R ⁴ and R ⁵ or R ¹⁰ and R ¹¹ or R ¹² and R ¹³ or R ² and R ¹¹ or R ² and

R ⁴ or R ² and R ¹³ or R ⁴ and R ¹³ or R ⁴ and R ¹¹ or R ¹² and R ¹³ , together with the carbon atom(s) joining them, form a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated and in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the remaining substituents R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in each case have the meaning given above; R ⁶ represents a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated and in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=O)OH, C3-6-cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Cis-aliphatic residue, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Cis-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, or represents an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C(=0)CH ₃ , C(=O)C ₂ H ₅ , C(=0)0CH ₃ , C(=O)OC ₂ H ₅ , C ₃ -6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Cisaliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S — Cis-aliphatic residue, CF ₃ , CN, Ci-4-aliphatic residue, C(=O)OH, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)OCH ₃ and C(=O)OC2HS, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the aryl or the heteroaryl residue may in each case be optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN and C(=0)0H, each R ⁷ independently of each other represents H, F; Cl; CN; CF3; CHF2; CH2F; OCF3; OCHF2; OCH2F; SCF3; a O — Ci-4-aliphatic residue, a Ci-4-aliphatic residue or a S(=0)2 — Cisaliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Cis-aliphatic residue, and R ⁸ represents H or Cis-aliphatic residue, wherein the Cis-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and O — Ci-4-aliphatic residue.

[00307] In further embodiments, A ¹ represents S; and A ² represents S, S(=O)2 or CR ¹² R ¹³ , wherein R ¹² and R ¹³ both represent H or both represent F.

[00308] In further embodiments, n denotes 1 and A ³ represents CR ⁷ , A ⁴ represents CR ⁷ , A ⁵ represents CR ⁷ and A ⁶ represents CR ⁷ ; or n denotes 1 and A ³ represents N, A ⁴ represents CR ⁷ , A ⁵ represents CR ⁷ and A ⁶ represents CR ⁷ ; or n denotes 1 and A ³ represents CR ⁷ , A ⁴ represents N, A ⁵ represents CR ⁷ and A ⁶ represents CR ⁷ ; or n denotes 1 and A ³ represents CR ⁷ , A ⁴ represents CR ⁷ , A ⁵ represents N and A ⁶ represents CR ⁷ ; or n denotes 1 and A ³ represents N, A ⁴ represents N, A ⁵ represents CR ⁷ and A ⁶ represents CR ⁷ ; or n denotes 1 and A ³ represents N, A ⁴ represents CR ⁷ , A ⁵ represents N and A ⁶ represents CR ⁷ ; or n denotes 1 and A ³ represents N, A ⁴ represents CR ⁷ , A ⁵ represents CR ⁷ and A ⁶ represents N; or n denotes 1 and A ³ represents CR ⁷ , A ⁴ represents N, A ⁵ represents CR ⁷ and A ⁶ represents N; or n denotes 1 and A ³ represents CR ⁷ , A ⁴ represents N, A ⁵ represents N and A ⁶ represents CR ⁷ ; or n denotes 1 and A ³ represents CR ⁷ , A ⁴ represents CR ⁷ , A ⁵ represents N and A ⁶ represents N; or n denotes 0 and A ³ represents S, A ⁴ represents CR ⁷ and A ⁵ represents CR ⁷ ; or n denotes 0 and A ³ represents S, A ⁴ represents CR ⁷ and A ⁵ represents N; or n denotes 0 and A ³ represents O, A ⁴ represents CR ⁷ and A ⁵ represents CR ⁷ , or n denotes 0 and A ³ represents O, A ⁴ represents CR ⁷ and A ⁵ represents N; or n denotes 0 and A ³ represents CR ⁷ , A ⁴ represents CR ⁷ and A ⁵ represents S; or n denotes 0 and A ³ represents N, A ⁴ represents CR ⁷ and A ⁵ represents S; or n denotes 0 and A ³ represents CR ⁷ , A ⁴ represents CR ⁷ and A ⁵ represents O; or n denotes 0 and A ³ represents N, A ⁴ represents CR ⁷ and A ⁵ represents O.

[00309] In further embodiments, R ¹ represents the partial structure: wherein: R ^14a and R ^14b each independently of the other represent H; F; Cl; Br; CF3; CN; OH; OCF3; NH2; Ci-4-aliphatic residue, O — Ci-4-aliphatic residue, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, OH and OCF3; or independently represent C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, Ci-4-aliphatic residue, OH, =0, O — Cisaliphatic residue, OCF3, NH2, NH(Ci-4-aliphatic residue) and N(Ci-4-aliphatic residue^; m represents 0, 1, 2 or 3; Y represents O or NR ¹⁵ , wherein R ¹⁵ represents H or Cis-aliphatic residue, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, Cis-aliphatic residue, OH, O — Cis-aliphatic residue, OCF3, NH2, NH(Ci-4-aliphatic residue) and N(Ci-4-aliphatic residue^; or C3-io-cycloaliphatic residue, saturated or unsaturated, unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, Ci-4-aliphatic residue, OH, O — Ci-4-aliphatic residue, OCF3, NH2, NH(Ci-4-aliphatic residue) and N(Ci-4-aliphatic residue^; o represents 0 or 1, B represents Ci-8-aliphatic residue, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, CN, OH, =0, O — Ci-4-aliphatic residue, OCF3, C(=0)0H, CF3, NH2, NH(Ci-4-aliphatic residue) and N(Ci-4-aliphatic residue^; or C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, CN, OH, O — Ci-4-aliphatic residue, OCF3, Ci-4-aliphatic residue, C(=O) — OH, CF3, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^ and SCF3; or aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, NO2, CN, OH, O — Cisaliphatic residue, OCF3, Cis-aliphatic residue, C(=O)OH, CF3, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, S — Cis-aliphatic residue, SCF3, benzyl, phenyl, pyridyl and thienyl, wherein benzyl, phenyl, pyridyl, thienyl can in each case be unsubstituted or mono- or poly-substituted by one or more substituents selected independently of one another from the group consisting of F, Cl, Br, NO2, CN, OH, O — Cis-aliphatic residue, OCF3, C1-4- aliphatic residue, C(=O) — OH, CF3, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, S — Cis-aliphatic residue and SCF3.

[00310] In further embodiments, R ^14a and R ^14b each independently of the other represents H; F; Cl; CH ₃ ; CH2CH3; (CH ₂ )2CH ₃ ; CH(CH ₃ ) ₂ ; (CH ₂ )3CH ₃ ; CH(CH) ₃ CH ₂ CH3; C(CH ₃ ) ₃ ; OH; OCH3; OCH2CH3; O(CH ₂ ) ₂ OCH3 or O(CH2)2OH; m represents 0, 1 or 2 and represents 0 and B represents CH ₃ ; CH2CH3; (CH ₂ )2CH ₃ ; CH(CH ₃ ) ₂ ; (CH ₂ )3CH ₃ ; CH(CH ₃ )CH ₂ CH3; C(CH ₃ ) ₃ ; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl; adamantyl; bicyclo[2.2.1]heptyl; bicyclo[2.2.2]octyl; phenyl, pyridyl or thienyl, in each case unsubstituted or mono-, di- or tri -substituted by one, two or three substituents each selected independently of one another from the group consisting of F, Cl, CN, OH, O — Ci-4-aliphatic residue, OCF3, Ci-4-aliphatic residue, CF3, NH2, NH(Ci-4-aliphatic residue) and N(Ci-4- aliphatic residue^.

[00311] In further embodiments, R ² ; R ³ ; R ⁴ ; R ⁵ ; R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently of the others represents H; F; Cl; CF ₃ ; CN; OH; OCF ₃ ; SCF ₃ ; CH ₃ ; CH2CH3; (CH ₂ )2CH ₃ ; CH(CH ₃ ) ₂ ; (CH ₂ )3CH ₃ ; CH(CH) ₃ CH ₂ CH3; C(CH ₃ ) ₃ ; OCH ₃ ; OCH2CH3; O(CH ₂ )2OCH ₃ ; O(CH2)2OH; SCH3; SCH2CH3; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or R ² and R ³ or R ⁴ and R ⁵ or R ¹⁰ and R ¹¹ or R ¹² and R ¹³ or R ² and R ¹¹ or R ² and R ⁴ or R ² and R ¹³ or R ⁴ and R ¹³ or R ⁴ and R ¹¹ or R ¹² and R ¹³ , together with the carbon atom(s) joining them, form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in each case unsubstituted; wherein the remaining substituents R ² , R ³ ; R ⁴ ; R ⁵ ; R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in each case have the meaning given above.

[00312] In further embodiments, each R ⁷ represents H, F; Cl; CN; CF3; CHF2; CH2F; OCF3; OCHF2; OCH2F; SCF ₃ ; CH ₃ ; CH2CH3; CH2CH2CH3; CH(CH ₃ ) ₂ ; OH2CH2CH2CH3; CH(CH) ₃ CH ₂ CH ₃ ; CH ₂ CH(CH ₃ ) ₂ ; O(CH ₃ ) ₃ ; OCH ₃ ; OCH ₂ CH ₃ ; O(CH ₂ ) ₂ OCH ₃ ; O(CH ₂ ) ₂ OH; S(=O) ₂ CH ₃ S(=O) ₂ CH ₂ CH ₃ S(=O) ₂ CH(CH ₃ ) ₂ or S(=O) ₂ CH ₂ CH ₂ CH ₃ ; and R ⁸ represents H or CH ₃ or CH ₂ CH ₃ or CH(CH ₃ ) ₂ .

[00313] In further embodiments, R ⁶ represents a C ₃ -io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, I, NO ₂ , CN, OH, =0, O — Ci-4-aliphatic residue, OCF ₃ , Ci-4-aliphatic residue, CF ₃ , SH, S — Ci-4-aliphatic residue and SCF ₃ ; or an aryl or a heteroaryl, in each case unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, I, NO ₂ , CN, OH, O — Ci-4-aliphatic residue, OCF ₃ , Ci-4-aliphatic residue, CF ₃ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , SH, S — Ci-4-aliphatic residue and SCF ₃ .

[00314] In further embodiments, R ⁶ represents phenyl, pyridyl or thienyl, in each case unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, CN, OH, O — Cisaliphatic residue, OCF ₃ , Cis-aliphatic residue, CF ₃ and SCF ₃ .

[00315] In further embodiments, A ¹ represents S; and A ² represents S, S(=O) ₂ or CR ¹² R ¹³ , wherein R ¹² and R ¹³ both represent H or both represent F; and R ¹ represents the partial structure: wherein: R ^14a and R ^14b each independently of the other represents H; F; Cl; CH ₃ ; CH ₂ CH ₃ ; (CH ₂ ) ₂ CH ₃ ; CH(CH ₃ ) ₂ ; (OH ₂ ) ₃ CH ₃ ; CH(CH) ₃ CH ₂ CH ₃ ; C(CH ₃ ) ₃ ; OH; OCH ₃ ; OCH ₂ CH ₃ ; O(CH ₂ ) ₂ OCH ₃ ; or O(CH ₂ ) ₂ OH; m represents 0, 1 or 2 and B represents phenyl or naphthyl or pyridyl or thienyl, in each case unsubstituted or mono- or di- or tri-substituted by one, two or three substituents each selected independently of one another from the group consisting of F, Cl, CN, OH, O-i-4-aliphatic residue, OCF ₃ , Ci-4-aliphatic residue, C(=O) — OH, CF ₃ , NH ₂ , NH(Ci-4-aliphatic residue) and N(Ci-4-aliphatic residue) ₂ ; R ² , R ³ , R ⁴ ; R ⁵ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently of the others represent H; F; Cl; Br; I; NO2; CF3; CN; OH; OCF3; SH; SCF ₃ ; CH ₃ ; CH2CH3; CH2CH2CH3; CH(CH ₃ ) ₂ ; CH2CH2CH2CH3; CH(CH) ₃ CH ₂ CH3; CH ₂ CH(CH ₃ )2; C(CH ₃ ) ₃ ; OCH ₃ ; OCH2CH3; O(CH ₂ )2OCH ₃ ; O(CH ₂ ) ₂ OH; SCH ₃ ; SCH2CH3; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or R ² and R ³ or R ⁴ and R ⁵ or R ¹⁰ and R ¹¹ or R ¹² and R ¹³ or R ² and R ¹¹ or R ² and R ⁴ or R ² and R ¹³ or R ⁴ and R ¹³ or R ⁴ and R ¹¹ or R ¹² and R ¹³ , together with the carbon atom(s) joining them, form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in each case unsubstituted; wherein the remaining substituents R ² , R ³ ; R ⁴ ; R ⁵ ; R ¹⁰ , R ¹¹ , R ¹² and R ¹³ in each case have the meaning given above; R ⁶ represents phenyl, in each case unsubstituted or mono- or poly-substituted by one or more substituents each selected independently of one another from the group consisting of F, Cl, Br, I, CN, OH, OCH3, OCH2CH3, OCF3, CH ₃ , CH2CH3, CH(CH ₃ ) ₂ and CF ₃ ; each R ⁷ represents H, F; CI; CN; CF ₃ ; CHF ₂ ; CH ₂ F; OCF ₃ ; OCHF ₂ ; OCH ₂ F; SCF ₃ ; CH ₃ ; CH2CH3; CH2CH2CH3; CH(CH ₃ ) ₂ ; CH2CH2CH2CH3; CH(CH)3CH ₂ CH ₃ ; CH ₂ CH(CH ₃ )2; C(CH ₃ ) ₃ ; OCH ₃ ; OCH2CH3; O(CH ₂ ) ₂ OCH ₃ ; O(CH ₂ ) ₂ OH; S(=O) ₂ CH ₃ S(=O) ₂ CH ₂ CH3, S(=O) ₂ CH(CH ₃ )2 or S(=O)2CH ₂ CH ₂ CH3; and R ⁸ represents H or CH ₃ or CH2CH3 or CH(CH ₃ ) ₂ .

[00316] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 1 2-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-me thyl-butyl)- benzamide; 2 N-(3,3-Dimethyl-butyl)-2-[3-(4-fluorophenyl)-propylsulfanyl] -benzamide; 3 3- [[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-meth yl-butyl)-pyridine-2-carboxylic acid amide; 4 3-[2-(Benzenesulfonyl)-ethylsulfanyl]-N-(thiophen-2-yl-methy l)-pyridine-2- carboxylic acid amide; 5 4-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-me thyl- butyl)-pyridine-3 -carboxylic acid amide; 6 4-[[3,3-Difluoro-3-(4-fluorophenyl)- propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-pyridine-3-carb oxylic acid amide; 7 3-[[3,3- Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-but yl)-pyridine-4-carboxylic acid amide; 8 3-[2-(Benzenesulfonyl)-ethylsulfanyl]-N-(thiophen-2-yl-methy l)-pyridine-4- carboxylic acid amide; 9 3-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-me thyl- butyl)-pyrazine-2-carboxylic acid amide; 10 4-[[3,3-Difluoro-3-(4-fluorophenyl)- propyl]sulfanyl]-N-(3-methyl-butyl)-pyrimidine-5-carboxylic acid amide; 11 4-[[3,3- Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophe nyl)-methyl]-pyrimidine-5- carboxylic acid amide; 12 3-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-me thyl- butyl)-pyridazine-4-carboxylic acid amide; 13 3-[[3,3-Difluoro-3-(4-fluorophenyl)- propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-pyridazine-4-ca rboxylic acid amide; 14 4- [[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-flu orophenyl)-methyl]-thiazole-5- carboxylic acid amide; 15 4-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4- fluorophenyl)-methyl]-2-methyl-thiazole-5-carboxylic acid amide; in the form of a free compound, a solvate and/or a physiologically acceptable salt.

Formula 21

[00317] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in US Publication No.

US20140148454A1, published May 29, 2014 and corresponding to US Application No. 14/091,378 filed November 27, 2013; International Publication No. WO2014082739A1, published June 5, 2014 and corresponding to International Application No.

PCT/EP2013/003574 filed November 27, 2013; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 21, these references incorporated by reference herein control.

[00318] In an embodiment, the Kv7 channel activator is a compound according to formula 21 :

Formula 21 wherein, A ¹ represents CR ⁵ or N; A ² represents CR ⁶ , N, O, S or NR ⁷ ; A ³ represents CR ⁸ or N, and n denotes 0 or 1, on the condition, that if n denotes 0, then A ² represents O, S or NR ⁷ , or if n denotes 1, then A ² represents CR ⁶ or N, wherein R ⁵ is selected from F, Cl, Br, CN, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , C ₂ H ₅ , SCH ₃ , OCF ₃ , OCHF ₂ or OCH ₂ F; R ⁶ is selected from H, F,

Cl, Br, CN, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , C ₂ H ₅ , SCH ₃ , OCF ₃ , OCHF ₂ or OCH ₂ F;

R ⁷ represents Ci-4-aliphatic residue or C ₃ -5-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; R ⁸ is selected from H, F, Cl, Br, CN, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , C ₂ HS, SCH ₃ , OCF ₃ , OCHF ₂ or OCH ₂ F; with the proviso, that, if n denotes 1, then at least one of A ¹ , A ² and A ³ denotes N, with the proviso, that if n denotes 1 and A ³ denotes N, then A ¹ and/or A ² denotes N, and with the proviso, that if n denotes 1 and A ² denotes N and A ¹ denotes CR ⁵ and A ³ denotes CR ⁸ , then R ⁵ denotes F, Cl, CH ₃ , CF ₃ , CHF ₂ or CH ₂ F;

R ¹³ represents H or Ci-4-aliphatic residue, R ¹ represents Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; or Cs-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-e-cycloaliphatic residue or a 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, or denotes S — R ⁹ , O — R ¹⁰ or N(R ⁿ R ¹² ), wherein R ⁹ and R ¹⁰ in each case represent Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted; C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; with the proviso, that if R ⁹ or R ¹⁰ denote a 3 to 7 membered heterocycloaliphatic residue, than the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, R ¹¹ represents Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted; C3-6-cycloaliphatic residue or a 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; with the proviso that if R ¹¹ denotes a 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom; and R ¹² denotes Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted; or R ¹¹ and R ¹² form together with the nitrogen atom connecting them a 3 to 7 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted;

R ³ represents Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; or C3-10- cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a C1-4- aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ³ denotes a 3 to 10 membered heterocycloaliphatic residue or a heteroaryl, the 3 to 10 membered heterocycloaliphatic residue or the heteroaryl is linked via a carbon atom; and R ⁴ denotes H or Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; or R ³ and R ⁴ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted; in which an “aliphatic group” and “aliphatic residue” may in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” may in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group”, an “aliphatic residue”, a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, NH — C(=O) — Ci-4-aliphatic residue, N(Cis aliphatic residue)-C(=O) — C1-4 aliphatic residue, NH — S(=O)2 — C1-4 aliphatic residue, N(Cis aliphatic residue)-S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, O — Ci-4-aliphatic residue, O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, S — Ci- 4-aliphatic residue, S(=0)20H, S(=0)2 — Ci-4-aliphatic residue, S(=0)2 — O — Ci-4-aliphatic residue, S(=0)2 — NH(Ci-4-aliphatic residue), S(=0)2 — N(Ci-4-aliphatic residue^, CN, CF3, CHO, COOH, Ci-4-aliphatic residue, C(=0) — Ci-4-aliphatic residue, C(=0) — O — Cisaliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, C(=0)NH2, a C(=0) — NH(Ci-4-aliphatic residue) and C(=0) — N(Ci-4-aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of -aliphatic residue),

N(Ci-4-aliphatic residue^, NH — C(=0) — Cis-aliphatic residue, N(Cis aliphatic residue)- 0(=0) — C1-4 aliphatic residue, NH — S(=0)2 — C1-4 aliphatic residue, N(Cis aliphatic residue)-S(=0)2 — C1-4 aliphatic residue, OH, OCF3, O — Ci-4-aliphatic residue, O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, S — Ci-4-aliphatic residue, S(=0)20H, S(=0)2 — Cisaliphatic residue, S(=0)2 — O — Cis-aliphatic residue, S(=0)2 — NH(Ci-4-aliphatic residue), S(=0)2 — N(Ci-4-aliphatic residue^, CN, CF3, C(=0)H, C(=0)0H, Cis-aliphatic residue, C(=0) — Ci-4-aliphatic residue, C(=0) — O — Cis-aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=0)NH2, C(=0) — NH(Ci-4-aliphatic residue) and C(=0) — N(Ci-4-aliphatic residue^; in the form of an individual single stereoisomer or a mixture of the stereoisomers in any mixing ratio, and/or in the form of a free compound, a solvate and/or a physiologically acceptable salt. [00319] In further embodiments, A ¹ represents CR ⁵ or N; A ² represents CR ⁶ , N, O, S or NR ⁷ ; A ³ represents CR ⁸ or N, and n denotes 0 or 1, on the condition, that if n denotes 0, then A ² represents O, S or NR ⁷ , or if n denotes 1, then A ² represents CR ⁶ or N, wherein R ⁵ is selected from F, Cl, Br, CN, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , C ₂ H ₅ , SCH ₃ , OCF ₃ , OCHF ₂ or OCH ₂ F; R ⁶ is selected from H, F, Cl, Br, CN, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , C ₂ H ₅ , SCH ₃ , OCF ₃ , OCHF ₂ or OCH ₂ F; R ⁷ represents Ci-4-aliphatic residue or C ₃ -5-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(CI-4- aliphatic residue) ₂ , OH, =0, O — Ci-4-aliphatic residue, OCF ₃ , SH, SCF ₃ , S — Ci-4-aliphatic residue, CF ₃ , CN, Ci-4-aliphatic residue and C(=O)OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF ₃ , CF ₃ and unsubstituted O — Cisaliphatic residue, R ⁸ is selected from H, F, Cl, Br, CN, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , C ₂ H>, SCH ₃ , OCF ₃ , OCHF ₂ or OCH ₂ F; with the proviso, that, if n denotes 1, then at least one of A ¹ , A ² and A ³ denotes N, with the proviso, that if n denotes 1 and A ³ denotes N, then A ¹ and/or A ² denotes N, and with the proviso, that if n denotes 1 and A ² denotes N and A ¹ denotes CR ⁵ and A ³ denotes CR ⁸ , then R ⁵ denotes F, Cl, CH ₃ , CF ₃ , CHF ₂ or CH ₂ F; R ¹³ represents H or Ci-4-aliphatic residue, R ¹ denotes Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , OH, =0, O — Ci-4-aliphatic residue, OCF ₃ , SH, SCF ₃ , S — Ci-4-aliphatic residue, CF ₃ , CN, Ci-4-aliphatic residue and C(=O)OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF ₃ , CF ₃ and unsubstituted O — Ci-4-aliphatic residue, or denotes C ₃ -io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , OH, =0, O — Cisaliphatic residue, OCF ₃ , SH, SCF ₃ , S — Cis-aliphatic residue, CF ₃ , CN, Cis-aliphatic residue, C(=O)OH, C ₃ -6-cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF ₃ , CF ₃ and unsubstituted O — Cis-aliphatic residue, and wherein the C ₃ -6- cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — C1-4 aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue,

C(=0)0H, C(=0)CH ₃ , C(=O)C ₂ H ₅ , C(=0)0CH ₃ , C(=O)OC ₂ H ₅ , C ₃ -6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Cisaliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S — Cis-aliphatic residue, CF ₃ , CN, a Ci-4-aliphatic residue, C(=O)OH, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)— OCH ₃ and C(=O) — OC2H5, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Ci-4-aliphatic residue), an N(Ci-4-aliphatic residue^, OH, =0, O — C1-4- aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, and wherein the aryl or the heteroaryl residue may in each case be optionally linked via a Cis-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN and C(=O)OH, R ² denotes C1-6- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Cis-aliphatic residue, or denotes C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6- cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, or denotes S — R ⁹ , O — R ¹⁰ or N(R ⁿ R ¹² ); wherein R ⁹ and R ¹⁰ in each case represent Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, or in each case represent C3-6-cycloaliphatic residue or 3 to 7 membered heterocyclo-aliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue) ₂ , OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C3-6-cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6- cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), an N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue may in each case optionally linked via a Ci- 4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, on the condition that if R ⁹ or R ¹⁰ denote a 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, R ¹¹ denotes Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0) — O — Ci-4-aliphatic residue, and C(=0)0H, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, or denotes C3-6-cycloaliphatic residue or 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C(=0) — O — Ci-4-aliphatic residue, C3-6-cycloaliphatic residue, and a 3 to 7 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=O) — OH, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Cisaliphatic residue, C(=O) — O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, on the condition that if R ¹¹ denotes a 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, and R ¹² denotes Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — C1-4- aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4aliphatic residue, or R ¹¹ and R ¹² form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0) — OH, C3-6-cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ¹¹ and R ¹² together with the nitrogen atom connecting them may optionally be condensed with aryl or heteroaryl, wherein the aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— 0CH ₃ and e, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Cisaliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S — Cis-aliphatic residue, CF ₃ , CN, Ci-4-aliphatic residue, C(=O)OH, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)OCH ₃ and C(=O)OC2HS, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, R ³ denotes C 1-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0) — O — Ci-4-aliphatic residue and C(=0)0H, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, or denotes C3-10- cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C(=0) — O — Ci-4-aliphatic residue, C3-6- cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — C1-4- aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, C(=0) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, on the condition that if R ³ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(CI-4- aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C(=O)CH3, C(=O)C2HS, C(=O)OCH3, C to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Ci-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=O)OH, C(=O)CH3, C(=O)C2HS, C(=O)OCH3 and C(=O)OC2Hs, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), an N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=O)OH, and wherein the aryl or the heteroaryl residue may in each case be optionally linked via a Ci-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN and C(=0)0H, R ⁴ denotes H or Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Cisaliphatic residue, CF3, CN, Cis-aliphatic residue and C(=0)0H, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — C 1-4-al iphatic residue, or R ³ and R ⁴ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C3-6-cycloaliphatic residue and 3 to 7 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6- cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue)2, OH, =0, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue and C(=0)0H, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ³ and R ⁴ together with the nitrogen atom connecting them may optionally be condensed with aryl or heteroaryl, wherein the aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=0)0H, C(=0)CH ₃ , C(=O)C ₂ H ₅ , C(=0)0CH ₃ , C(=O)OC ₂ H ₅ , C ₃ -6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ³ and R ⁴ together with the nitrogen atom connecting them may optionally be condensed with a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, wherein the Cs-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, =0, OH, O — Ci-4-aliphatic residue, OCF3, SH, SCF3, S — Ci-4-aliphatic residue, CF3, CN, Ci-4-aliphatic residue, C(=O)OH, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)OCH ₃ , C(=O)OC ₂ H ₅ , C ₃ -6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, O — Cisaliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S — Cis-aliphatic residue, CF ₃ , CN, Ci-4-aliphatic residue, C(=O)OH, C(=O)CH ₃ , C(=O)C ₂ H ₅ , C(=O)OCH ₃ and C(=O)OC2HS, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, NH(Ci-4-aliphatic residue), N(Ci-4-aliphatic residue^, OH, =0, O — Cis-aliphatic residue, OCF3, SH, SCF3, S — Cis-aliphatic residue, CF3, CN, Cis-aliphatic residue and C(=O)OH.

[00320] In further embodiments, the compound is according to formula 21 wherein n denotes 0 and is according to the formula:

wherein, A ² represents O and A ³ represents CR ⁸ ; or A ² represents S and A ³ represents CR ⁸ ; or A ² represents NR ⁷ and A ³ represents CR ⁸ ; or A ² represents O and A ³ represents N; or A ² represents S and A ³ represents N; or A ² represents NR ⁷ and A ³ represents N.

[00321] In further embodiments, the compound is according to formula 21 wherein n denotes 1 and is according to the formula: wherein: A ¹ represents N and A ² represents CR ⁶ and A ³ represents CR ⁸ ; or A ¹ represents

CR ⁵ and A ² represents N and A ³ represents CR ⁸ ; or A ¹ represents N and A ² represents N and

A ³ represents CR ⁸ ; or A ¹ represents N and A ² represents CR ⁶ and A ³ represents N; or

A ¹ represents CR ⁵ and A ² represents N and A ³ represents N; or A ¹ represents N and

A ² represents N and A ³ represents N.

[00322] In further embodiments, R ⁵ denotes F, Cl, CHa, OCH3 or CH2CH3; and/or R ⁶ denotes H; and/or R ⁷ denotes CH3, CH2CH3 or cyclopropyl; and/or R ⁸ denotes H.

[00323] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, or 2, R ^la and R ^lb each independently of one another represent H, F, Cl, Br, I, O — Ci-4-aliphatic residue or Ci-4-aliphatic residue, R ^lc denotes Ci-4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and O — Ci-4-aliphatic residue, or denotes C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and unsubstituted O — Ci-4-aliphatic residue, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci-4-aliphatic residue, C(=O)CH3, C(=O)C2Hs, C(=O)OCH3, C(=O)OC2HS, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci- 4-aliphatic residue, C(=O)CH3, C(=O)C2Hs, C(=O)OCH3 and C(=O)OC2Hs, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, CF3C1-4- aliphatic residue and C(=O)OH.

[00324] In further embodiments, m denotes 1 or 2, R ^la and R ^lb represent H, R ^lc denotes C1-4- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and C1-4- aliphatic residue, or denotes C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, or m denotes 0 and R ^lc denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci- 4-aliphatic residue, C(=0)CH3, C(=O)C2Hs, C(=0)0CH3, C(=O)OC2Hs, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci-4-aliphatic residue, C(=0)CH3, C(=O)C2HS, C(=0)0CH3 and C(=O)OC2Hs, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, CF3Ci-4-aliphatic residue and C(=0)0H. [00325] In further embodiments, R ² is selected from the group consisting of CH3, C2H5, CH2CH2CH3, CH(CH ₃ ) ₂ , CH2CH2CH2CH3, CH ₂ CH(CH ₃ )2, CH(CH ₃ )CH ₂ CH3, C(CH ₃ ) ₃ , CH ₂ -cyclopropyl, 0CH ₃ , OC ₂ H ₅ , OCH2CH2CH3, OCH(CH ₃ ) ₂ , O-cyclopropyl, SCH ₃ , SC ₂ H ₅ , SCH2CH2CH3, SCH(CH3)2, S-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N(CH ₃ ) ₂ , N(CH ₃ )C ₂ H ₅ , N(CH3)CH ₂ CH ₂ CH3, N(CH ₃ )CH(CH ₃ )2, N(CH ₃ )-cyclopropyl, N(C ₂ H ₅ ) ₂ , N(C2H ₅ )CH2CH ₂ CH3, N(C ₂ H ₅ )CH(CH ₃ )2, N(C ₂ H ₅ )-cyclopropyl, N-aziridinyl, N- azetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl, in each case unsubstituted or mono- or polysubstituted with F, OH and/or OCH3.

[00326] In further embodiments, R ³ represents the partial structure: wherein: o denotes 0, 1, 2 or 3, R ^3a and R ^3b each independently of one another represent H, F, Cl, Br, I, O — Ci-4-aliphatic residue or Ci-4-aliphatic residue or together denote =0, and

R ^3c denotes Ci-4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and O — Ci-4-aliphatic residue, or denotes C3-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and unsubstituted O — C1-4- aliphatic residue, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci-4-aliphatic residue, C(=O)CH3, C(=O)C2HS, C(=O)OCH3, C(=O)OC2HS, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, CF3, Ci-4-aliphatic residue and C(=O) — OH, and R ⁴ denotes H or unsubstituted Ci-4-aliphatic residue or Ci-4-aliphatic residue, monosubstituted with OCH3, or R ³ and R ⁴ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, C(=0)0H, O — Cisaliphatic residue, OCF3, SCF3, S — Cis-aliphatic residue, CF3, Cis-aliphatic residue, cyclopropyl, cyclobutyl and cyclopentyl, wherein the Cis-aliphatic residue is in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, CF3 and O — Cis-aliphatic residue, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ³ and R ⁴ together with the nitrogen atom connecting them may optionally be condensed with phenyl or pyridyl, wherein the phenyl or pyridyl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, SCF3, S — Cisaliphatic residue, CF3, Cis-aliphatic residue, C(=0)0H and C3-6-cycloaliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and unsubstituted O — Cis-aliphatic residue, and wherein the C3-6-cycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, O — Ci-4-aliphatic residue, OCF3, SCF3, S — Ci-4-aliphatic residue, CF3, Ci-4-aliphatic residue and C(=0)0H, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ³ and R ⁴ together with the nitrogen atom connecting them may optionally be condensed with a C3-6- cycloaliphatic residue, or a 3 to 7 membered heterocycloaliphatic residue, wherein the C3-6- cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, O — Ci-4-aliphatic residue, OCF ₃ , SCF ₃ , CF ₃ , CN, Ci- ₄ -aliphatic residue, C(=0)0H, C(=0)CH ₃ , C(=O)C ₂ H ₆ , C(=0)0CH ₃ and C(=O)OC ₂ H ₆ .

[00327] In further embodiments, R ³ represents the partial structure:

Wherein, o denotes 0, 1, 2 or 3, R ^3a and R ^3b each independently of one another represent H, F, CH3 or OCH3, or together denote =0, R ^3c denotes Ci-4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, O — Ci-4-aliphatic residue, and CF3, or denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, and Ci-4-aliphatic residue, and R ⁴ denotes H, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ OCH ₃ or CH ₂ CH ₂ CH ₂ OCH ₃ , or R ³ and R ⁴ form together with the nitrogen atom connecting them a heteroaliphatic residue, selected from the group consisting of morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazepanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, azepanyl, tetrahydroimidazof 1 ,2-a]pyrazinyl, octahydropyrrolof 1 ,2-a]pyrazinyl, dihydroindolinyl, or dihydroisoindolyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, C(=0)0H, OCH3, OCH2CH3, 0CF3, SCF ₃ , CF ₃ , C(=O)CH ₃ , C(=O)OCH ₃ , CH2CF3, CH2OH, CH2OCH3, CH2CH2OCH3, CH ₃ , CH2CH3, CH2CH2CH3, CH(CH ₃ ) ₂ and cyclopropyl.

[00328] In further embodiments, A ¹ represents CR ⁵ , N; A ² represents CR ⁶ , N, O, S or NR ⁷ ; A ³ represents CR ⁸ or N, and n denotes 0 or 1, on the condition, that if n denotes 0, then A ² represents O, S or NR ⁷ , or if n denotes 1, then A ² represents CR ⁶ or N, wherein R ⁵ denotes F, Cl, CH3, OCH3 or CH2CH3; and/or R ⁶ denotes H; and/or R ⁷ denotes CH3, CH2CH3 or cyclopropyl; and/or R ⁸ denotes H; with the proviso, that, if n denotes 1, then at least one of A ¹ , A ² and A ³ denotes N, with the proviso, that if n denotes 1 and A ³ denotes N, then A ¹ and/or A ² denotes N, and with the proviso, that if n denotes 1 and A ² denotes N and A ¹ denotes CR ⁵ and A ³ denotes CR ⁸ , then R ⁵ denotes F, Cl, CH3, CF3, CHF2 or CH2F;

R ¹³ represents H or CH3; R ¹ represents the partial structure: wherein, m denotes 1 or 2, R ^la and R ^lb represent H and R ^lc denotes Ci-4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, or denotes Cs-io-cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, or wherein m denotes 0 and R ^lc denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, Ci-4-aliphatic residue, C(=O) — CH3, C(=O)C2HS, C(=O)OCH3, C(=O)OC2HS, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, O — Cisaliphatic residue, OCF3, CF3, CN, Cis-aliphatic residue, C(=O)CH3, C(=O)C2Hs, C(=O)OCH3 and C(=O)OC2Hs, and wherein the C3-6-cycloaliphatic residue and the 3 to 7 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Cis-aliphatic residue, OCF3, CFsCis-aliphatic residue and C(=O)OH; R ² is selected from the group consisting of CH3, C2H5, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH ₂ CH(CH ₃ )2, CH(CH ₃ )CH ₂ CH3, C(CH ₃ ) ₃ , CH ₂ -cyclopropyl, 0CH ₃ , OC ₂ H ₅ , OCH2CH2CH3, OCH(CH ₃ ) ₂ , O-cyclopropyl, SCH3, SC ₂ H ₅ , SCH2CH2CH3, SCH(CH ₃ ) ₂ , S- cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N(CH3)2, N(CH3)C2Hs, N(CH3)CH ₂ CH ₂ CH3, N(CH ₃ )CH(CH ₃ )2, N(CH ₃ )-cyclopropyl, N(C ₂ H ₅ ) ₂ , N(C ₂ H ₅ )CH2CH ₂ CH3, N(C ₂ H ₅ )CH(CH3) ₂ , N(C2H5)-cyclopropyl, N-aziridinyl, N-azetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl, in each case unsubstituted or mono- or polysubstituted with F, OH and/or OCH3; R ³ represents the partial structure: wherein: denotes 0, 1, 2 or 3, R ^3a and R ^3b each independently of one another represent H, F, CHa or OCH3, or together denote =0, R ^3c denotes Ci-4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, O — Ci-4-aliphatic residue, and CF3, or denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O — Ci-4-aliphatic residue, CF3 and Ci-4-aliphatic residue, or denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, OH, O — Ci-4-aliphatic residue, OCF3, CF3, CN, and Ci-4-aliphatic residue, and R ⁴ denotes H, CH ₃ , CH2CH3, CH2CH2OCH3 or CH2CH2CH2OCH3, or R ³ and R ⁴ form together with the nitrogen atom connecting them a morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazepanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, azepanyl, tetrahydroimidazo[l,2-a]pyrazinyl, octahydropyrrolo[l,2-a]-pyrazinyl, dihydroindolinyl, or dihydroisoindolyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, C(=0)0H, OCH3, OCH2CH3, 0CF3, SCF ₃ , CF ₃ , C(=0)CH ₃ , C(=0)0CH ₃ , CH2CF3, CH2OH, CH2OCH3, CH2CH2OCH3, CH ₃ , CH2CH3, CH2CH2CH3, CH(CH ₃ ) ₂ and cyclopropyl. [00329] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[(4-Chlorophenyl)-methyl]-4-ethylsulfanyl-6-methyl-2-morph olin-4-yl- pyrimidine-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4,6-dimethoxy-2- morpholin-4-yl-pyrimidine-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4- ethylsulfanyl-2-methyl-6-morpholin-4-yl-pyridine-3-carboxyli c acid amide; N-[(4- Chlorophenyl)-methyl]-2-methyl-6-morpholin-4-yl-4-propyl-pyr idine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-ethoxy-2-methyl-6-morpholin-4-yl-p yridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-[(3R)-3-fluoro-pyrrolidin-l-yl]-2- methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-3-isopropyl- 5-morpholin-4-yl-pyrazine-2-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-3- isopropyl-5-morpholin-4-yl-pyridine-2-carboxylic acid amide; 4-Isopropyl-2-(methyl- tetrahydro-pyran-4-yl-amino)-N-[l-[3-(trifluoromethyloxy)-ph enyl]-ethyl]-thiazole-5- carboxylic acid amide; 4-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-methyl-2-morph olin- 4-yl-pyrimidine-5-carboxylic acid amide; 4-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-2- methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 4-Ethylsulfanyl-N-[(4- fluorophenyl)-methyl]-2-methyl-6-morpholin-4-yl-pyridine-3-c arboxylic acid amide; N-(4,4- Dimethyl-pentyl)-4-ethylsulfanyl-2-methyl-6-morpholin-4-yl-p yridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-ethylsulfanyl-2-methyl-6-[(3R) -3-methyl-morpholin-

4-yl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-ethylsulfanyl-2-methyl-6- [(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)- methyl]-4-cyclopropyl-2-methyl-6-morpholin-4-yl-pyridine-3-c arboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-4-isopropyl-2-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-ethoxy-2-methyl-6-morpholin-4- yl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-dimethylamino-2-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-3-(l-methyl- propyl)-5-morpholin-4-yl-pyrazine-2-carboxylic acid amide; N-(2-Cyclopentyl-ethyl)-3-(l- methyl-propyl)-5-morpholin-4-yl-pyrazine-2-carboxylic acid amide; 4-Isopropyl-2-[methyl- (tetrahydro-pyran-4-yl-methyl)-amino]-N-[l-[3-(trifluorometh yloxy)-phenyl]-ethyl]-thi azole-

5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-isopropyl-2-(methyl-tetrahydro - pyran-4-yl-amino)-thiazole-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4- isopropyl-2-[methyl-(tetrahydro-pyran-4-yl-methyl)-amino]-th iazole-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-isopropyl-2-morpholin-4-yl-thi azole-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-isopropyl-2-piperidin-l-yl-thi azole-5-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-isopropyl-2-piperidin-l-yl-thiazol e-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-isopropyl-2-([l,4]oxazepan-4-y l)-thiazole-5- carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-isopropyl-2-([l,4]oxazepan-4-yl)-t hiazole- 5-carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2-morpholin-4-yl-4-propyl- thiazole-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-isopropyl-2-morpholin-4- yl-oxazole-5-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-isopropyl-2-morpholin-4-yl- oxazole-5-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-5-isopropyl-3-methyl-2- morpholin-4-yl-3H-imidazole-4-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-5- isopropyl-3-methyl-2-morpholin-4-yl-3H-imidazole-4-carboxyli c acid amide; 2-(Methyl- tetrahydro-pyran-4-yl-amino)-4-(trifluoromethyl)-N-[l-[3-(tr ifluoromethyloxy)-phenyl]- ethyl]-thiazole-5-carboxylic acid amide; 2-(Methyl-tetrahydro-pyran-4-yl-amino)-4- (trifluoromethyl)-N-[[3-(trifluoromethyloxy)-phenyl]-methyl] -thiazole-5-carboxylic acid amide; N-[l-(4-Chlorophenyl)-ethyl]-2-(methyl-tetrahydro-pyran-4-yl -amino)-4- (trifluoromethyl)-thiazole-5-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-(methyl- tetrahydro-pyran-4-yl-amino)-4-(trifluoromethyl)-thiazole-5- carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-[methyl-(tetrahydro-pyran-4-yl-methy l)-amino]-4- (trifluoromethyl)-thiazole-5-carboxylic acid amide; 2-Morpholin-4-yl-4-(trifluoromethyl)-N- [[3-(trifluoromethyloxy)-phenyl]-ethyl]-thiazole-5-carboxyli c acid amide; 2-Morpholin-4-yl- 4-(trifluoromethyl)-N-[l-[3-(trifluoromethyloxy)-phenyl]-eth yl]-thiazole-5-carboxylic acid amide; N-[l-(4-Chlorophenyl)-ethyl]-2-morpholin-4-yl-4-(trifluorome thyl)-thiazole-5- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-morpholin-4-yl-4-(trifluoromet hyl)- thiazole-5-carboxylic acid amide; 2-Morpholin-4-yl-4-(trifluoromethyl)-N-[l-[3- (trifluoromethyl)phenyl]-ethyl]-thiazole-5-carboxylic acid amide; in the form of a free compound, a solvate and/or a physiologically acceptable salt.

Formula 22

In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 22. Such compounds are described in Patent No. 9,278,103 issued March 8, 2016 and corresponding to US Application No. 14/230,572 filed March 31, 2014; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 22, this reference incorporated by reference herein controls.

[00330] In an embodiment, the Kv7 channel activator is a compound according to formula 22: Formula 22 wherein, R ¹ represents a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents F; Cl; Br; I; CN; CF3; C(=O)H; NO2; OCF3; SCF3; a C1-4- aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — C1-4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the Ci- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, wherein the Cn 4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted;

R ³ represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a Ci-4-aliphatic residue, a O — C1-4- aliphatic residue, a S — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ⁶ represents a C2-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁶ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or denotes, O — R ⁸ , wherein R ⁸ represents a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁸ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, in which an “aliphatic group” and an “aliphatic residue” can in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” can in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group” and an “aliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=O)2 — Cisaliphatic residue, a S(=O)2 — O — Cis-aliphatic residue, a S(=O)2 — NH — Cis-aliphatic residue, CN, CF3, CHO, COOH, a Cis-aliphatic residue, a C(=O) — Cis-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH2, a C(=O) — NH(CI-4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, a S(=O)2 — NH — Ci-4-aliphatic residue, CN, CF3, CHO, COOH, a Ci-4-aliphatic residue, a C(=O) — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH2, a C(=O) — NH(Ci- 4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of aliphatic residue), an N(CI-4 aliphatic residue) ₂ , an NH — C(=0) — C1-4 aliphatic residue, an NH — S(=0) ₂ — C1-4 aliphatic residue, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — C1-4- aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O) ₂ OH, a S(=O) ₂ — Cisaliphatic residue, a S(=O) ₂ — O — Cis-aliphatic residue, a S(=O) ₂ — NH — Cis-aliphatic residue, CN, CF3, C(=O)H, C(=O)OH, a Cis-aliphatic residue, a C(=O) — Cis-aliphatic residue, a C(=O) — O — Cis-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=O) — NH ₂ , a C(=O) — NH(CI-4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue) ₂ ; said compound being in the form of a free compound, the racemate, a mixture of enantiomers, diastereomers, or of enantiomers and diastereomers in any mixing ratio, or of an individual enantiomer or diastereomer, or in the form of a salt of physiologically acceptable acids or bases.

[00331] In further embodiments, R ¹ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue) ₂ , OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=O) ₂ — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue) ₂ , OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue) ₂ , OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn

4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) —

OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH)CI-4 aliphatic residue), an N(CI-4 aliphatic residue, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, CF3, CN, a

Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and cycloaliphatic benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C ₂ H ₅ , and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the aryl or the heteroaryl residue may in each case be optionally bridged via a Cn 8 aliphatic group, preferably a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent sleeted from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN and C(=0) — OH, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, or a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Cisaliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Cis-aliphatic residue and an O — Ci-4-aliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue, R ³ represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue, R ⁶ denotes a C2-io-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, on the condition that if R ⁶ denotes a 3 to 10 membered heterocycloaliphatic residue, the binding is carried out via a carbon atom of the 3 to 10 membered heterocycloaliphatic residue, or R ⁶ denotes O — R ⁸ , wherein R ⁸ represents a CMO- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Cn 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Cisaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Cis-aliphatic residue, or represent a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, on the condition that if R ⁸ denotes a 3 to 10 membered heterocycloaliphatic residue, the binding is carried out via a carbon atom of the 3 to 10 membered heterocycloaliphatic residue.

[00332] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R ^12a and R ^12b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Cn 4 aliphatic residue or C(=O) — OH, or together denote =0, and R ^12c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, a S(=O)2 — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a S(=0)2 — C1-4 aliphatic residue, CF3, CN, a C1-4 aliphatic residue, C(=0) — OH, C(=0) — CH3, C(=0) — C2H5, C(=0) — O — CH3 and C(=0 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH. [00333] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, or 2 or 3, R ^12a and R ^12b each independently of one another represent H, F, Cl, Br, I, OH, an O — C1-4 aliphatic residue or a C1-4 aliphatic residue or together denote =0, and R ^12c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci- 4 aliphatic residue, CN, a S(=O)2 — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Cisaliphatic residue, or an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, OCF2H, CF3, CN, a Cis-aliphatic residue, CH2 — aliphatic residue) ₂ , , C(=O)— O— CH ₃ and C(=O)— O—

C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted, preferably unsubstituted or mono- or disubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, preferably with at least one substituent selected from the group consisting of F, Cl, CH3, O — CH3, CF3 and OCF3, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, CF3 a Ci-4-aliphatic residue and C(=O) — OH.

[00334] In further embodiments, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, or a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, or piperidinyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue, and wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl or piperidinyl may in each case be optionally bridged via an C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue.

[00335] In further embodiments, R ³ represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, or a S — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — C1-4 aliphatic residue.

[00336] In further embodiments, R ⁶ denotes a C2-s-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a C(=O) — O — Ci-4-aliphatic residue, a S — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-

4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁶ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R ⁶ denotes O — R ⁸ wherein R ⁸ denotes a Ci-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, CF3, a C(=O) — O — Ci-4-aliphatic residue, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may be bridged via a C1-8 aliphatic group, preferably a Cn 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-

4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁸ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00337] In further embodiments, R ⁶ denotes a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case is unsubstituted, or denotes a Cs-io-cycloaliphatic residue, or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a unsubstituted C1-4 aliphatic group, on the condition that if R ⁶ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R ⁶ denotes O — R ⁸ wherein R ⁸ denotes a Ci-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, an NH(Ci-4 aliphatic residue), an N(CI-4 aliphatic residue^, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — C1-4 aliphatic residue, or in each case denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue in each case may be bridged via an unsubstituted C1-8 aliphatic group, on the condition that if R ⁷ or R ⁸ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00338] In further embodiments, R ¹ represents the partial structure: wherein: m is 0, 1 or 2, and R ^12a and R ^12b each independently of one another represent H, F, OH, CH3 or OCH3, or together denote =0, R ^12c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, CN, OH, S(=O)2 — CH3, an unsubstituted O — C1-4 aliphatic residue, and CF3, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or wherein m is 0 or 2, and R ^12a and R ^12b each independently of one another represent H, F, OH, CH3 or OCH3; and R ^12c denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic H ₂ — OCH ₃ , S(=O) ₂ — CH ₃ , SCF ₃ , NO ₂ , N(CH ₃ ) ₂ , i-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5,

C(=0) — O — CH, C(=0) — 0 — C2H5 and phenyl, wherein phenyl may be unsubstituted or mono- or polysubstituted, preferably unsubstituted or mono- or disubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH ₃ and C(=O)— O— C ₂ H ₅ , R ² represents F; Cl; Br; I; CN; CF ₃ ; NO ₂ ; OCF ₃ ; SCF ₃ ; methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec. -butyl; tert.-butyl; CH2 — OH; CH2 — O — CH3; CH ₂ — CH ₂ — OH; CH ₂ — CH ₂ — OCH ₃ ; O-methyl; O-ethyl; O— (CH ₂ ) ₂ — O— CH ₃ ; O— (CH2)2 — OH; S-Methyl; S-Ethyl; cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, R ³ represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; methyl; ethyl; n-propyl; isopropyl; n-butyl; sec. -butyl; tert.-butyl; O-methyl; O-ethyl; O — (CH2)2 — O — CH3; O — (CH2)2 — OH; S-Methyl; or S-Ethyl, R ⁶ denotes ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH3)(C2Hs), C(CH ₃ )2(C ₂ H ₅ ), CH ₂ — OCH3, C2H4— OCH3, C ₃ H ₆ — OCH3, cyclopropyl, cyclobutyl, or tetrahydropyranyl, ethenyl or propenyl ( — CH2CH 2H2, — CH=CH — CH3, — C((=CH2) — CH3), in each case unsubstituted, or R ⁶ denotes O — R ⁸ wherein R ⁸ denotes methyl, ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, or n- hexyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, N(CI-4 aliphatic residue) and an O — C1-4- aliphatic residue, or in each case denote CH2-cyclopropyl or oxetanyl, wherein the Cisaliphatic residue in each case is unsubstituted.

[00339] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[(3,5-Difluoro-phenyl)-methyl]-2-methoxy-4-methyl-6-morpho lin-4-yl- pyridine-3 -carboxylic acid amide; 9 N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4- yl-2-[(E)-prop-l-enyl]-pyridine-3-carboxylic acid amide; 10 N-[(3-Fluorophenyl)-methyl]-4- methyl-6-morpholin-4-yl-2-propyl-pyridine-3-carboxylic acid amide; 19 N-[(3- Fluorophenyl)-methyl]-2-methoxy-4-methyl-6-morpholin-4-yl-py ridine-3-carboxylic acid amide; N-[3-Fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4-methyl-6-m orpholin-4-yl- pyridine-3 -carboxylic acid amide; 2-Ethyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-2-isopropyl- 4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]- 4-methyl-6-morpholin-4-yl-2-[(E)-prop-l-enyl]-pyridine-3-car boxylic acid amide; N-[(4- Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl-pyr idine-3-carboxylic acid amide 2-Ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4- yl-pyridine-3- carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-2-methoxy-4-methyl-6-morpholin-4 -yl- pyridine-3 -carboxylic acid amide; 2-Ethoxy-N-[(4-fluorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-methoxy-4- methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-[(3,4-Difluoro-phenyl)- methyl]-2-methoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carbo xylic acid amide; 2- Methoxy-4-methyl-6-morpholin-4-yl-N-[(2-phenyl-phenyl)-methy l]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethoxy-4-methyl-6-morpholin-4-yl-p yridine-3- carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2-ethoxy-4-methyl-6-morphol in-4- yl-pyridine-3 -carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2-ethoxy-4-methyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2 -Ethoxy -4-methyl-6-morpholin-4-yl-N- [(2-phenyl-phenyl)-methyl]-pyridine-3-carboxylic acid amide; 2-Butoxy-N-[(3- fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-c arboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propoxy-py ridine-3-carboxylic acid amide; 2-Methoxy-4-methyl-6-morpholin-4-yl-N-[[4-(trifluoromethyl)- phenyl]-methyl]- pyridine-3 -carboxylic acid amide; 2-Ethoxy-4-methyl-6-morpholin-4-yl-N-[[4- (trifluoromethyl)-phenyl]-methyl]-pyridine-3-carboxylic acid amide; 2-Ethoxy-4-methyl-6- morpholin-4-yl-N-(4, 4, 4-trifluoro-butyl)-pyridine-3 -carboxylic acid amide; 2-Methoxy-4- methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-butyl)-pyridine-3 -carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-methoxy-4-methyl-6-morpholin-4-yl-py ridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-ethoxy-4-methyl-6-morpholin-4- yl-pyridine-3- carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-2-isopropyl-4-methyl-6-[(3R)-3-m ethyl- morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-2-methoxy- 4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxy lic acid amide; 2-Ethoxy-N- [(4-fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpholi n-4-yl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-isopropyl-4-methyl-6-[(3R)-3-methy l-morpholin-4- yl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-methoxy-4-methyl-6-[(3R)- 3-methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2- ethoxy-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3- carboxylic acid amide; N-[(4- Fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpholin-4- yl]-2-(l-methyl-propyl)- pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-methyl-6-[(3R)-3-methyl- morpholin-4-yl]-2-(l-methyl-propyl)-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N- [(4-fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpholi n-4-yl]-pyridine-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpho lin-4-yl]-2- propyl-pyridine-3 -carboxylic acid amide; 2-Cyclopropyl-N-(4,4-dimethyl-pentyl)-4-methyl- 6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl- pentyl)-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-2-propyl-p yridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-2-methoxy-4-methyl-6-[(3R)-3-met hyl-morpholin-4- yl]-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-methoxy-4-methyl-6- [(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)- methyl]-4-methyl-2-(l-methyl-propyl)-6-morpholin-4-yl-pyridi ne-3-carboxylic acid amide; 2-tert-Butyl-N-(4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4- yl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-methyl-2-(l-methyl-propyl)-6-morph olin-4-yl-pyridine-3- carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2-methoxy-4-methyl-6-[(3R)- 3- methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)- methyl]-2-methoxy-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]- pyridine-3-carboxylic acid amide; 2-Methoxy-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-N-(4,4,4 -trifluoro-butyl)- pyridine-3 -carboxylic acid amide; 2-Methoxy-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]- N-[[4-(trifluoromethyl)-phenyl]-methyl]-pyridine-3-carboxyli c acid amide; 2-tert-Butyl-N- [(3 -fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N- [(4-Chlorophenyl)-methyl]-2-isopropyl-4-methyl-6-[(3R)-3-met hyl-morpholin-4-yl]- pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl- morpholin-4-yl]-2-propyl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2- (2-fluoro-ethoxy)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-(2,2-difluoro-ethoxy)-4-methyl-6-mor pholin-4-yl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-(cyclopropyl-methoxy)-4-methyl -6- morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-(2,2-Difluoro-ethoxy)-N-[(4- fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-c arboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-ethoxy-4-methyl-6-[(3R)-3-methyl-mor pholin-4-yl]-pyridine-3- carboxylic acid amide; 2-(Cyclopropyl-methoxy)-N-[(4-fluorophenyl)-methyl]-4-methyl -6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-isopropyl- 6-[(3S)-3-(methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine- 3-carboxylic acid amide; N- (4,4-Dimethyl-pentyl)-4-methyl-2-(2-methyl-butyl)-6-morpholi n-4-yl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(l, l-dimethyl-propyl)-4-methyl-6-morpholin-4-yl- pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-cyclopropyl-4-methyl-6- [(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)- methyl]-2-(2-dimethylaminoethyloxy)-4-methyl-6-morpholin-4-y l-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-isopropyl-6-[(2S)-2-(methoxyme thyl)-morpholin-4- yl]-4-methyl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-cyclopropyl- 6-[(2S)-2-(methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine- 3-carboxylic acid amide; N- [(4-Fluorophenyl)-methyl]-2-isopropyl-4-methyl-6-morpholin-4 -yl-pyridine-3-carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2-isopropyl-4-methyl-6-morp holin-4-yl- pyridine-3 -carboxylic acid amide; 2-Isopropyl-4-methyl-6-morpholin-4-yl-N-[[4- (trifluoromethyl)-phenyl]-methyl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl- pentyl)-4-methyl-6-morpholin-4-yl-2-propyl-pyridine-3 -carboxylic acid amide; N-(4,4- Dimethyl-pentyl)-2-isopropyl-4-methyl-6-morpholin-4-yl-pyrid ine-3-carboxylic acid amide;

2-Isopropyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro- butyl)-pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2-isopropyl-4-methyl-6-morp holin-4-yl-pyridine-3- carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-(oxe tan-

3 -yloxy)-pyridine-3 -carboxylic acid amide; 4-Methyl-6-morpholin-4-yl-2-propyl-N-(4,4,4- trifluoro-butyl)-pyridine-3-carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-4- methyl-6-morpholin-4-yl-2-propyl-pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro- phenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl-pyridine- 3 -carboxylic acid amide; 4- Methyl-6-morpholin-4-yl-2-propyl-N-[[4-(trifluoromethyl)-phe nyl]-methyl]-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-prop yl- pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-isopropyl-4-methyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-Cyclopropyl-N-(4,4-dimethyl-pentyl)-4- methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-Cyclopropyl-4-methyl-6- m orpholin-4-yl-N-(4, 4, 4-trifluoro-butyl)-pyridine-3 -carboxylic acid amide; 2-Cyclopropyl- N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridi ne-3-carboxylic acid amide; 2-Cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morphol in-4-yl-pyridine-3- carboxylic acid amide; 2-Cyclopropyl-N-[(3,4-difluoro-phenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-[(3,5-difluoro-phenyl)- methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-4- methyl-6-morpholin-4-yl-N-[[4-(trifluoromethyl)-phenyl]-meth yl]-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-cyclopropyl-4-methyl-6-morphol in-4-yl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-2-(l-methyl-propyl)-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(2-methoxy- ethoxy)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-[[4- fluoro-3-(methoxymethyl)-phenyl]-methyl]-4-methyl-6-morpholi n-4-yl-pyridine-3- carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(3 -methoxy -propyl)-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-[[3-fluoro-4- (methoxymethyl)-phenyl]-methyl]-4-methyl-6-morpholin-4-yl-py ridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-2-(methoxymethyl)-4-methyl-6-mor pholin-4-yl- pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2,4-diisopropyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(2-methoxy- ethyl)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)- methyl]-2,4-diethyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; and N-(4,4- Dimethyl-pentyl)-4-methyl-6-morpholin-4-yl-2-tetrahydro-pyra n-4-yl-pyridine-3-carboxylic acid amide, respectively in the form of free compounds; racemic mixtures; mixtures of the enantiomers, diastereomers, or enantiomers and diastereomers in any mixing ratio, or an individual enantiomer or diastereomer; or in the form of the salts of physiologically acceptable acids or bases.

Formula 23

[00340] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 23. Such compounds are described in US Patent No. 9,168,259 issued March 8, 2016 and corresponding to US Application No. 13/449,472 filed April 18, 2012; US Patent No. 8,552,200 issued December 12, 2013 and corresponding to US Application No. 13/276,464 filed October 19, 2011; International Publication No. WO2012052167A1, published April 26, 2012 and corresponding to International Application No. PCTZEP2011/005265 filed April 26, 2012; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 23, these references incorporated by reference herein control.

[00341] In an embodiment, the Kv7 channel activator is a compound according to formula 23:

Formula 23 wherein, R ¹ represents a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents F; Cl; Br; I; CN; CF3; C(=O)H; NO2; OCF3; SCF3; a C1-4- aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — C1-4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the Ci- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, wherein the Cn 4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted;

R ³ represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a Ci-4-aliphatic residue, a O — C1-4- aliphatic residue, a S — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ⁴ represents a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁴ denotes a 3 to 10 membered heterocycloaliphatic residue or a heteroaryl, the 3 to 10 membered heterocycloaliphatic residue or the heteroaryl is linked via a carbon atom; R ⁵ denotes H or a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; or R ⁴ and R ⁵ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted; R ⁶ represents a C2-10- aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁶ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or denotes S — R ⁷ , O — R ⁸ or N(R ⁹ R ¹⁰ ), wherein R ⁷ and R ⁸ in each case represent a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Cn 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁷ or R ⁸ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, R ⁹ represents a C1-10- aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁹ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom; R ¹⁰ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; or R ⁹ and R ¹⁰ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted; in which an “aliphatic group” and an “aliphatic residue” can in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” can in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group” and an “aliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=0)20H, a S(=0)2 — Ci-4-aliphatic residue, a S(=0)2 — O — Ci-4-aliphatic residue, a S(=0)2 — NH — Ci-4-aliphatic residue, CN, CF3, CHO, COOH, a Ci-4-aliphatic residue, a C(=0) — Ci-4-aliphatic residue, a C(=0) — O — Cisaliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0) — NH2, a C(=0) — NH(CI-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue)2; in which “mono- or polysubstituted” with respect to a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=0) — C1-4 aliphatic residue, a NH — S(=0)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=0)20H, a S(=0)2 — Cisaliphatic residue, a S(=0)2 — O — Cis-aliphatic residue, a S(=0)2 — NH — Cis-aliphatic residue, CN, CF3, CHO, COOH, a Cis-aliphatic residue, a C(=0) — Cis-aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0) — NH2, a C(=0) — NH(CI-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Ci-

4 aliphatic residue^, an NH — C(=0) — C1-4 aliphatic residue, an NH — S(=0)2 — C1-4 aliphatic residue, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, a S(=O)2 — NH — Ci-4-aliphatic residue, CN, CF3, C(=O)H, C(=O)OH, a Ci-4-aliphatic residue, a C(=0) — Ci-4-aliphatic residue, a C(=0) — O — C1-4- aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=O) — NH2, a C(=O) — NH(C 1-4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue^; said compound being in the form of a free compound, the racemate, a mixture of enantiomers, diastereomers, or of enantiomers and diastereomers in any mixing ratio, or of an individual enantiomer or diastereomer, or in the form of a salt of physiologically acceptable acids or bases.

[00342] In further embodiments, R ¹ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C ₂ H ₅ , and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the aryl or the heteroaryl residue may in each case be optionally bridged via a Cn 8 aliphatic group, preferably a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN and C(=0) — OH, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, or a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Cisaliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and an O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, and wherein the Cs-e-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a Ci-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue, R ³ represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue, R ⁴ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, and C(=0) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C(=O) — O — Ci-4-aliphatic residue a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the

Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or monoor polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn

4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, a

C(=0) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, on the condition that if R ⁴ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— hatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the aryl or the heteroaryl residue may in each case be optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN and C(=0) — OH, R ⁵ denotes H or a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or R ⁴ and R ⁵ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁴ and R ⁵ together with the nitrogen atom connecting them may optionally be condensed with aryl or heteroaryl, wherein the aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue, C(=O) — OH, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and

C(=O) — O — C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁴ and R ⁵ together with the nitrogen atom connecting them may optionally be condensed with a C3-10 cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, wherein the C3-10 cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, =0, OH, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, R ⁶ denotes a C2-io-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue^, OH, =0, an O — Cisaliphatic residue, OCF3, SH, SCF3, a S — Cis-aliphatic residue, CF3, CN, a Cis-aliphatic residue and C(=0) — OH, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Cis-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, and C(=0) — OH, wherein the Cisaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Cis-aliphatic residue, and and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(Cis aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, on the condition that if R ⁶ denotes a 3 to 10 membered heterocycloaliphatic residue, the binding is carried out via a carbon atom of the 3 to 10 membered heterocycloaliphatic residue, or R ⁶ denotes S — R ⁷ , O — R ⁸ or N(R ⁹ R ¹⁰ ), wherein R ⁷ and R ⁸ in each case represent a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Cisaliphatic residue, CF3, CN, a Cis-aliphatic residue and C(=O) — OH, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Cis-aliphatic residue, or in each case represent a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, on the condition that if R ⁷ or R ⁹ denotes a 3 to 10 membered heterocycloaliphatic residue, the binding is carried out via a carbon atom of the 3 to 10 membered heterocycloaliphatic residue, R ⁹ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Cisaliphatic residue, OCF3, SH, SCF3, a S — Cis-aliphatic residue, CF3, CN, a Cis-aliphatic residue, a C(=O) — O — Cis-aliphatic residue, and C(=O) — OH, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Cis-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C(=O) — O — Ci-4-aliphatic residue a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Cisaliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cis aliphatic residue), an N(Cis aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Cis-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, on the condition that if R ⁹ denotes a 3 to 10 membered heterocycloaliphatic residue, the binding is carried out via a carbon atom of the 3 to 10 membered heterocycloaliphatic residue, R ¹⁰ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or R ⁹ and R ¹⁰ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci-

4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁹ and R ¹⁰ together with the nitrogen atom connecting them may optionally be condensed with aryl or heteroaryl, wherein the aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue, C(=O) — OH, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O to 6 membered heterocycloaliphatic residu , benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH.

[00343] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R ^12a and R ^12b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Cn 4 aliphatic residue or C(=O) — OH, or together denote =0, and R ^12c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, a S(=0)2 — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a S(=0)2 — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, C(=0) — CH3, C(=0) — C2H5, C(=0) — O — CH3 and C(=0) — O — C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C ₂ H ₅ , and wherein the C ₃ - 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH.

[00344] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, or 2 or 3, R ^12a and R ^12b each independently of one another represent H, F, Cl, Br, I, OH, an O — C1-4 aliphatic residue or a C1-4 aliphatic residue or together denote =0, and R ^12c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci- 4 aliphatic residue, CN, a S(=O)2 — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Cisaliphatic residue, or an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, OCF2H, CF3, CN, a Cis-aliphatic residue, CH2 — OH, CH ₂ — 0CH ₃ , S(=0) ₂ — CH ₃ , SCF ₃ , N0 ₂ , N(CI-4 aliphatic residue) C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— C ₂ H ₅ , a C _3.6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted, preferably unsubstituted or mono- or disubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF ₃ , CF ₃ , CN, a Ci-4-aliphatic residue, C(=0) — CH ₃ , C(=0) — C ₂ H>, C(=0) — O — CH ₃ and C(=0) — O — C2H5, preferably with at least one substituent selected from the group consisting of F, Cl, CH ₃ , O — CH ₃ , CF ₃ and OCF ₃ , and wherein the C ₃ -6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF ₃ , CF ₃ a Ci-4-aliphatic residue and C(=0)— OH.

[00345] In further embodiments, R ² represents F; Cl; Br; I; CN; CF ₃ ; NO ₂ ; OCF ₃ ; SCF ₃ ; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, or a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted aliphatic residue, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, or piperidinyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue, and wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl or piperidinyl may in each case be optionally bridged via an C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted aliphatic residue.

[00346] In further embodiments, R ³ represents H; F; Cl; Br; I; CN; CF ₃ ; SCF ₃ ; NO ₂ ; OCF ₃ ; a Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, or a S — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue.

[00347] In further embodiments, R ⁴ represents the partial structure: wherein: n denotes 0, 1, 2, or 3, R ^13a and R ^13b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4 aliphatic residue or C(=O) — OH, or together denote =0, and R ^13c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— e, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, R ⁵ denotes H or a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or R ⁴ and R ⁵ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, C(=0) — OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a C1-4- aliphatic residue, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, CF3 and an unsubstituted O — Ci-4-aliphatic residue, wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁴ and R ⁵ together with the nitrogen atom connecting them may optionally be condensed with aryl or heteroaryl, wherein the aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, and pyridyl, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁴ and R ⁵ together with the nitrogen atom connecting them may optionally be condensed with a C3-10 cycloaliphatic residue, preferably cyclopropyl, cyclobutyl or cycclopentyl, or a 3 to 10 membered heterocycloaliphatic residue, preferably oxetanyl or oxiranyl, wherein the C3-10 cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, =0, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C ₂ H ₅ , wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, and C(=O) — OH, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH.

[00348] In further embodiments, R ⁴ represents the partial structure: wherein: n denotes 0, 1, 2 or 3, R ^13a and R ^13b each independently of one another represent H, F, Cl, Br, I, an O — Ci-4 aliphatic residue or a Ci-4 aliphatic residue or together denote =0, and R ^13c denotes a Ci-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, an O — Ci-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a C1-4- aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted, preferably unsubstituted or mono- or disubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci- 4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, preferably with at least one substituent selected from the group consisting of F, Cl, CH3, O — CH3, CF3 and OCF3, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, CF3 a Ci-4-aliphatic residue and C(=0) — OH, R ⁵ denotes H or an unsubstituted Ci-4-aliphatic residue or a Ci-4-aliphatic residue monosubstituted with O-methyl, or R ⁴ and R ⁵ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, C(=0) — OH, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, cyclopropyl, cyclobutyl and cyclopentyl, wherein the Ci-4-aliphatic residue is in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁴ and R ⁵ together with the nitrogen atom connecting them may optionally be condensed with phenyl or pyridyl, wherein the phenyl or pyridyl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, CF3, a C1-4- aliphatic residue, C(=0) — OH, and a C3-6 cycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — Ci- 4 aliphatic residue, CF3, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁴ and R ⁵ together with the nitrogen atom connecting them may optionally be condensed with a C3-6 cycloaliphatic residue, preferably cyclopropyl, cyclobutyl or cyclopentyl, or a 4 to 7 membered heterocycloaliphatic residue, preferably oxetanyl or oxiranyl, wherein the C3-6 cycloaliphatic residue or the 4 to 7 membered heterocycloaliphatic residue condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an O — C1-4 aliphatic residue, OCF3, SCF3, CF ₃ , CN, a Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— C ₂ H ₅ .

[00349] In further embodiments, R ⁶ denotes a C ₂ -8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a C(=0) — O — Ci-4-aliphatic residue, a S — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-

4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁶ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R ⁶ denotes S — R ⁷ or O — R ⁸ wherein R ⁷ and R ⁸ in each case denote a Ci-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, an NH(Ci-4 aliphatic residue), an N(Cn 4 aliphatic residue^, CF3, a C(=O) — O — Ci-4-aliphatic residue, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or in each case denote a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — Ci- 4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may be bridged via a C1-8 aliphatic group, preferably a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁷ or R ⁸ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R ⁶ denotes N(R ⁹ R ¹⁰ ), wherein R ⁹ denotes a Cns-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, a C(=O) — O — Ci-4-aliphatic residue, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Cn 4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case be bridged, preferably is bridged, via a Cn 8 aliphatic group, preferably a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁹ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, and R ¹⁰ denotes a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or R ⁹ and R ¹⁰ form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R ⁹ and R ¹⁰ together with the nitrogen atom connecting them may optionally be condensed with aryl or heteroaryl, preferably with phenyl or pyridyl, wherein the aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3,

CN, a Ci-4-aliphatic residue, C(=O) — OH, residue, benzyl, phenyl, thienyl, and pyridyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , OH, an O—C1-4 aliphatic residue, OCF ₃ , O— CH ₂ — OH, O— CH ₂ — O— CH ₃ , SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, and C(=O) — OH. [00350] In further embodiments, R ⁶ denotes a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case is unsubstituted, or denotes a C3-io-cycloaliphatic residue, or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a unsubstituted C1-4 aliphatic group, on the condition that if R ⁶ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R ⁶ denotes S — R ⁷ or O — R ⁸ wherein R ⁷ and R ⁸ in each case denote a C1-8- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, an NH(CI-4 aliphatic residue), an N(Cn

4 aliphatic residue^, a C(=0) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or in each case denotes a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — Ci- 4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue in each case may be bridged via an unsubstituted C1-8 aliphatic group, on the condition that if R ⁷ or R ⁸ denotes a

3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R ⁶ denotes N(R ⁹ R ¹⁰ ), wherein R ⁹ denotes a C1-8- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — Ci-

4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue is in each case bridged via a unsubstituted C1-8 aliphatic group, preferably an unsubstituted C1-4 aliphatic group, on the condition that if R ⁹ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, and

R ¹⁰ denotes an unsubstituted Ci-4-aliphatic residue, or R ⁹ and R ¹⁰ form together with the nitrogen atom connecting them a 3 to 6 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the 3 to 6 membered heterocycloaliphatic residue formed by R ⁹ and R ¹⁰ together with the nitrogen atom connecting them may optionally be condensed with phenyl or pyridyl, wherein the phenyl or pyridyl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, residue, benzyl, phenyl, and pyridyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OCH3, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, CF3, and a Ci-4-aliphatic residue.

[00351] In further embodiments, R ¹ represents the partial structure: wherein: m is 0, 1 or 2, and R ^12a and R ^12b each independently of one another represent H, F, OH, CH3 or OCH3, or together denote =0, R ^12c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, CN, OH, S(=O)2 — CH3, an unsubstituted O — C1-4 aliphatic residue, and CF3, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or wherein m is 0 or 2, and R ^12a and R ^12b each independently of one another represent H, F, OH, CH3 or OCH3; and R ^12c denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic H ₂ — OCH ₃ , S(=O) ₂ — CH ₃ , SCF ₃ , NO ₂ , N(CH ₃ ) ₂ , -4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5,

C(=0) — O — CH3, C(=0) — 0 — C2H5 and phenyl, wherein phenyl may be unsubstituted or mono- or polysubstituted, preferably unsubstituted or mono- or disubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH ₃ and C(=O)— O— C ₂ H ₅ , R ² represents F; Cl; Br; I; CN; CF ₃ ; NO ₂ ; OCF ₃ ; SCF ₃ ; methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec. -butyl; tert.-butyl; CH2 — OH; CH2 — O — CH3;

CH ₂ — CH ₂ — OH; CH ₂ — CH ₂ — OCH ₃ ; O-methyl; O-ethyl; O— (CH ₂ ) ₂ — O— CH ₃ ; O— (CH2)2 — OH; S-Methyl; S-Ethyl; cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, R ³ represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; methyl; ethyl; n-propyl; isopropyl; n-butyl; sec. -butyl; tert.-butyl; O-methyl; O-ethyl; O — (CH2)2 — O — CH3; O — (CH2)2 — OH; S-Methyl; or S-Ethyl, R ⁴ represents the partial structure (T2)

(T2) wherein n denotes 0, 1, 2 or 3, R ^13a and R ^13b each independently of one another represent H, F, CH3 or OCH3, or together denote =0,

R ^13c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, an unsubstituted O — C1-4 aliphatic residue, and CF3, or denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyranyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, and a C1-4- aliphatic residue, R ⁵ denotes H, methyl or ethyl, C2H4OCH3 or C3H5OCH3, or R ⁴ and R ⁵ form together with the nitrogen atom connecting them a morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazepanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, azepanyl, tetrahydroimidazof 1 ,2- a]pyrazinyl, octahydropyrrolo[l,2-a]pyrazinyl, dihydroindolinyl, or dihydroisoindolyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, =0, C(=0)— OH, O-methyl, O-ethyl, OCF ₃ , SCF3, CF ₃ , C(=0)— CH ₃ , C(=0)— 0CH ₃ , CH2CF3, CH2OH, CH2 — OCH3, CH2CH2 — OCH3, methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, and cyclobutyl, R ⁶ denotes ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.- butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH3)(C2Hs), C(CH ₃ )2(C ₂ H ₅ ), CH ₂ — OCH3, C2H4— OCH3, C ₃ H ₆ — OCH3, cyclopropyl, cyclobutyl, or tetrahydropyranyl, ethenyl or propenyl ( — CH2CH 2H2, — CH=CH — CH3, — C((=CH2) — CH3), in each case unsubstituted, or R ⁶ denotes S — R ⁷ or O — R ⁸ wherein R ⁷ and R ⁸ in each case denote methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n- pentyl, isopentyl, neopentyl, or n-hexyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, N(CI-4 aliphatic residue) and an O — Ci-4-aliphatic residue, or in each case denote CH2- cyclopropyl or oxetanyl, wherein the Ci-4-aliphatic residue in each case is unsubstituted, or R ⁶ denotes N(R ⁹ R ¹⁰ ), wherein R ⁹ denotes methyl, C(=0) — CH3, ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl, R ¹⁰ denotes methyl or ethyl, or R ⁹ and R ¹⁰ form together with the nitrogen atom connecting them a morpholinyl, piperidinyl, pyrrolidinyl, or azetidinyl, in each case unsubstituted.

[00352] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[(3,5-Difluoro-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6- morpholin-4-yl- pyridine-3 -carboxylic acid amide; Ethylsulfanyl-N-[(3-fhiorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2- methoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N- [(4-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine -3-carboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[methyl -(tetrahydro-pyran-2-yl- methyl)-amino]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-6-(3-methoxy-azetidin-l-yl)-4-methyl-pyridine-3-carb oxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(3-hydroxy-azeti din-l-yl)-4-methyl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(4-fluorophen yl)- methylamino]-4-methyl-pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4- methyl-6-morpholin-4-yl-2-[(E)-prop-l-enyl]-pyridine-3 -carboxylic acid amide; N-[(3- Fluorophenyl)methyl]-4-methyl-6-morpholin-4-yl-2-propyl-pyri dine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-morpholin-4-yl -4-(trifluoromethyl)- pyridine-3 -carboxylic acid amide; N-[(3-Fluorophenyl)methyl]-4-methyl-2,6-dimorpholin-4- yl-pyridine-3 -carboxylic acid amide; l-[6-Ethylsulfanyl-5-[(3-fluorophenyl)-methyl- carbamoyl]-4-methyl-pyridin-2-yl]-piperidine-4-carboxylic acid methyl ester; l-[6- Ethylsulfanyl-5-[(3-fluorophenyl)-methyl-carbamoyl]-4-methyl -pyridin-2-yl]-piperidine-4- carboxylic acid; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(4-hydroxy-pip eridin-l-yl)- 4-methyl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(4-oxo-piperidin-l-yl)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(4- fluoro-2-methoxy-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-p yridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(4-fluoro-2-hydroxy-phenyl)-methyl]-4-met hyl-6-morpholin-4-yl- pyridine-3 -carboxylic acid amide; N-[(3-Fluorophenyl)methyl]-2-methoxy-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-2-(2- methoxy-ethoxy)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-Ethyl-N- [(3 -fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N- [(3-Fluorophenyl)methyl]-2-isopropyl-4-methyl-6-morpholin-4- yl-pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)methyl]-4-methyl-6-morpholin-4-yl-2-pyrro lidin-l-yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-pyrro lidin- l-yl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(l,2,3,4-tetrahydro-isoquinolin-2-yl)-pyridine-3-ca rboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[6-(tri fluoromethyl)-l,2,3,4- tetrahydro-isoquinolin-2-yl]-pyridine-3-carboxylic acid amide; N-[(4-Fluorophenyl)methyl]- 4-methyl-6-morpholin-4-yl-2-[(E)-prop-l-enyl]-pyridine-3-car boxylic acid amide; N-[(4- Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl-pyr idine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(3-methoxy-pyr rolidin-l-yl)-4- methyl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(4-methyl-piperazin-l-yl)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-piperidin-l-yl-pyridine-3-c arboxylic acid amide; 6- Dimethylamino-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-methy lamino-pyridine- 3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(2-methoxy-eth yl- methyl-amino)-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-6-(2-methoxy-ethylamino)-4-methyl-pyri dine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-2-(isopropylsulfanyl)-4-methyl-6 -morpholin-4-yl- pyridine-3 -carboxylic acid amide; 2-Ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-2-methoxy- 4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]- 4-methyl-2-methylsulfanyl-6-morpholin-4-yl-pyridine-3-carbox ylic acid amide; N-[(3,4- Difluoro-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6-morpholi n-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-N-(3-methyl-butyl)-6-morpholin-4-yl -pyridine-3- carboxylic acid amide; N-(Cyclopentyl-methyl)-2-ethylsulfanyl-4-methyl-6-morpholin- 4-yl- pyridine-3 -carboxylic acid amide; N-(2-Cyclopentyl-ethyl)-2-ethylsulfanyl-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(6-fluoro-pyridin-2- yl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N- [(5-fluoro-pyri din-2 -yl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-(2,2-Dimethyl-propyl)-2-ethylsulfanyl-4-methyl-6-morpholin -4-yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(2-me thyl- morpholin-4-yl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-6-(4-methoxy-piperidin-l-yl)-4-methyl-pyridine-3-car boxylic acid amide; 2- Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-[(2-phenyl-phenyl) -methyl]-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-[[2-(trifluorome thyl)- phenyl]-methyl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-6-[(4-fluorophenyl)-methyl-methyl-amino]-4-methyl-py ridine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(3-phenyl-propyl )-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-phenethyl-pyridi ne-3- carboxylic acid amide; N-Benzyl-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine- 3- carboxylic acid amide N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2- (propylsulfanyl)-pyridine-3-carboxylic acid amide; 2-(Butylsulfanyl)-N-[(3-fluorophenyl)- methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-5- fluoro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl -pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-[[3-(trifluorome thyl)phenyl]-methyl]- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-[[4- (trifluoromethyl)-phenyl]-methyl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-[methyl-(tetrahydro-pyran-4 -yl-methyl)-amino]-pyridine- 3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-2-(2-methyl- propylsulfanyl)-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)- methyl]-2-(2-methoxy-ethylsulfanyl)-4-methyl-6-morpholin-4-y l-pyridine-3-carboxylic acid amide; 2-Ethoxy-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morpholin-4- yl-pyridine-3- carboxylic acid amide; 2-Dimethylamino-N-[(3-fluorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; 6-(2,6-Dimethyl-morpholin-4-yl)-2- ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine- 3-carboxylic acid amide; N- (4,4-Dimethyl-pentyl)-2-ethylsulfanyl-4-methyl-6-morpholin-4 -yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(2-tetrahydro-py ran-2-yl-ethyl)- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(tetrahydro- pyran-2-yl-methyl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-4-methyl-6-(4-methyl-piperidin-l-yl)-pyridine-3-carb oxylic acid amide; 2- Ethylsulfanyl-N-[[2-(4-fluorophenyl)-phenyl]methyl]-4-methyl -6-morpholin-4-yl-pyridine-3- carboxylic acid amide; 2-[[6-Ethylsulfanyl-5-[(3-fluorophenyl)-methyl-carbamoyl]-4- methyl- pyridin-2-yl]-methyl-amino]-acetic acid ethyl ester; 6-(4-Cyclopropyl-piperazin-l-yl)-2- ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine- 3-carboxylic acid amide; 6- (4,4-Dimethyl-piperidin-l-yl)-2-ethylsulfanyl-N-[(3-fluoroph enyl)-methyl]-4-methyl- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-[[4- (trifluoromethylsulfanyl)-phenyl]-methyl]pyridine-3-carboxyl ic acid amide; N-(Cyclohexyl- methyl)-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-N-(2-methoxy-ethyl)-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-(3-methoxy-propyl)-4-methyl-6-morpholin-4- yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-N-(4-methyl-pentyl)-6-morpholin-4-y l- pyridine-3 -carboxylic acid amide; N-Butyl-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-pentyl- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[[4-fluoro-3-(trifluoromethyl)- phenyl]methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxyl ic acid amide; N-(2-tert- Butoxy-ethyl)-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyri dine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro -butyl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[[4-fluoro-2-(4-fluorophenyl)-phenyl]methy l]-4-methyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-methoxy-4- methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-[(3,4-Difluoro-phenyl)- methyl]-2-methoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carbo xylic acid amide; 2- Methoxy-4-methyl-6-morpholin-4-yl-N-[(2-phenyl-phenyl)-methy l]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethoxy-4-methyl-6-morpholin-4-yl-p yridine-3- carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2-ethoxy-4-methyl-6-morphol in-4- yl-pyridine-3 -carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2-ethoxy-4-methyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-Ethoxy-4-methyl-6-morpholin-4-yl-N- [(2-phenyl-phenyl)-methyl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[[3-fluoro- 5-(trifluoromethyl)-phenyl]methyl]-4-methyl-6-morpholin-4-yl -pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[[2-fluoro-3-(trifluoromethyl)-phenyl]meth yl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[[2-fluoro-5- (trifluoromethyl)-phenyl]methyl]-4-methyl-6-morpholin-4-yl-p yridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-([l,4 ]oxazepan-4-yl)- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-[[4- (trifluoromethyloxy)-phenyl]-methyl]pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)- methyl]-2-methoxy-4-methyl-6-([l,4]oxazepan-4-yl)-pyridine-3 -carboxylic acid amide; 2- Ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-6-([l,4]oxazepan -4-yl)-pyridine-3 -carboxylic acid amide; N-[(2,3-Difluoro-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6- morpholin-4-yl- pyridine-3 -carboxylic acid amide; N-[(2,5-Difluoro-phenyl)-methyl]-2-ethylsulfanyl-4- methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-[(3-Cyano-phenyl)-methyl]-2- ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxyli c acid amide; 2-Ethylsulfanyl- N-(2-isopropoxy-ethyl)-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid amide; N- (3,3-Dimethyl-butyl)-2-ethylsulfanyl-4-methyl-6-morpholin-4- yl-pyridine-3-carboxylic acid amide; N-(3-Cyclopentyl-propyl)-2-ethylsulfanyl-4-methyl-6-morpholi n-4-yl-pyridine-3- carboxylic acid amide; N-(2-Cyclohexyl-ethyl)-2-ethylsulfanyl-4-methyl-6-morpholin- 4-yl- pyridine-3 -carboxylic acid amide; N-[(2,4-Difluoro-phenyl)-methyl]-2-ethylsulfanyl-4- methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[3-(4- fluorophenyl)-propyl]-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(3-pyridin-2-yl-pr opyl)-pyridine-3-carboxylic acid amide; 2-Butoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4- yl-pyridine-3- carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-prop oxy- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- (3 -oxo-azetidin-l-yl)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[3-(3- fluorophenyl)-propyl]-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(3-pyridin-3-yl-pr opyl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(3-pyridin-4-yl- propyl)-pyridine- 3-carboxylic acid amide; N-(5,5-Dimethyl-hexyl)-2-ethylsulfanyl-4-methyl-6-morpholin- 4- yl-pyridine-3 -carboxylic acid amide; 2-Methoxy-4-methyl-6-morpholin-4-yl-N-[[4- (trifluoromethyl)-phenyl]-methyl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-[methyl-(pyridin-4-yl-methy l)-amino]-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[meth yl- (pyridin-3-yl-methyl)-amino]-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-6-[(4- fluoro-benzoyl)-methyl-amino]-N-[(3-fluorophenyl)-methyl]-4- methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[meth yl-(pyridin-2-yl- methyl)-amino]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-4-methyl-6-(pyridin-3-yl-methylamino)-pyridine-3-car boxylic acid amide; 6- (Acetyl-methyl-amino)-2-ethylsulfanyl-N-[(3-fluorophenyl)-me thyl]-4-methyl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-ethylsulfanyl-4-methyl-6-morph olin- 4-yl-pyridine-3 -carboxylic acid amide; N-[(3-Chlorophenyl)-methyl]-2-ethylsulfanyl-4- methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 6-[Bis(2-methoxy-ethyl)-amino]- 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridin e-3-carboxylic acid amide; 2- (Ethyl-methyl-amino)-N-[(3-fluorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(3-methoxy-pro pyl- methyl-amino)-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[3-(2- fluorophenyl)-propyl]-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-[[3-(trifluorometh yloxy)-phenyl]- methyl]pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[[3-(methoxymethyl)- phenyl]methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxyl ic acid amide; 2-Ethoxy-4- methyl-6-morpholin-4-yl-N-[[4-(trifluoromethyl)-phenyl]-meth yl]-pyridine-3-carboxylic acid amide; 2-Ethoxy-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-butyl) -pyridine-3-carboxylic acid amide; N-(l,3-Benzodioxol-5-yl-methyl)-2-ethylsulfanyl-4-methyl-6-m orpholin-4-yl- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[[2-fluoro-4-(trifluoromethyl)- phenyl]methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxyl ic acid amide; 6-(Azepan-l- yl)-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyr idine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(4-methoxyphenyl)-methyl]-4-methyl-6-morp holin-4-yl-pyridine-3- carboxylic acid amide; (2S)-2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- (2- methyl-morpholin-4-yl)-pyridine-3-carboxylic acid amide; (2R)-2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-(2-methyl-morpholin-4-yl)-p yridine-3-carboxylic acid amide; 2-Methoxy-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-butyl )-pyridine-3- carboxylic acid amide; N-(3-Cyclopropyl-propyl)-2-ethylsulfanyl-4-methyl-6-morpholi n-4- yl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[[3-fluoro-4-(trifluoromethyl)- phenyl]methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxyl ic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo- piperazin-l-yl)-pyridine-3- carboxylic acid amide; 6-(4-Acetyl-piperazin-l-yl)-2-ethylsulfanyl-N-[(3-fluorophen yl)- methyl]-4-methyl-pyridine-3-carboxylic acid amide; N-[(4-Cyano-phenyl)-methyl]-2- ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxyli c acid amide; 2-Ethylsulfanyl- N-[[4-(methoxymethyl)-phenyl]methyl]-4-methyl-6-morpholin-4- yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[[3-fluoro-4-(methoxymethyl)-phenyl]methyl ]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Dimethylaminophenyl)-methyl]-2- ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxyli c acid amide; 2-Ethylsulfanyl- N-[[4-fluoro-3-(methoxymethyl)-phenyl]methyl]-4-methyl-6-mor pholin-4-yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(4-me thyl- 3 -oxo-piperazin- l-yl)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-(6-oxa-2-azaspiro[3.3]hepta n-2-yl)-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-methyl-2-methylsulfanyl-6-morpholi n-4-yl-pyridine-

3-carboxylic acid amide; 4-Methyl-2-methylsulfanyl-6-morpholin-4-yl-N-(4,4,4-trifluor o- butyl)-pyridine-3 -carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl-2- methylsulfanyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3,4-Difluoro- phenyl)-methyl]-4-methyl-2-methylsulfanyl-6-morpholin-4-yl-p yridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-4-methyl-2-methylsulfanyl-6 -morpholin-4-yl- pyridine-3 -carboxylic acid amide; 4-Methyl-2-methylsulfanyl-6-morpholin-4-yl-N-[[4- (trifluoromethyl)-phenyl]-methyl]pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-(6-oxo-2,3,4,7,8,8a-hexahyd ro-lH-pyrrolo[l,2-a]pyrazin- 2-yl)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(3-oxa-6-azabicyclo[2.2.1]heptan-6-yl)-pyridine-3-c arboxylic acid amide; N-(3- Cyano-propyl)-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyri dine-3-carboxylic acid amide;

2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(p-tolyl-meth yl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-N-(3-methylsulfonyl-propyl)-6-morph olin-4-yl-pyridine-3- carboxylic acid amide; N-(4-Cyano-butyl)-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(m-tolyl- methyl)-pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-methoxy-4- methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2- ethoxy-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 6-(2-Ethyl-morpholin-

4-yl)-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methy l-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-2-methylsulfanyl-6-morp holin-4-yl-pyridine-

3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-2-isopropyl-4-methyl-6-[(3R)-3- methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-(methyl-pyri din-2 -yl-amino)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(meth yl-pyridin-3-yl- amino)-pyridine-3 -carboxylic acid amide; 2-Dimethylamino-N-[(4-fluorophenyl)-methyl]-4- methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxyli c acid amide; 2-(Ethyl- methyl-amino)-N-[(4-fluorophenyl)-methyl]-4-methyl-6-[(3R)-3 -methyl-morpholin-4-yl]- pyridine-3 -carboxylic acid amide; 2-(Ethyl-methyl-amino)-N-[(4-fluorophenyl)-methyl]-4- methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-[methyl-(tetrahydro-pyran-3 -yl-methyl)-amino]-pyridine- 3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl- morpholin-4-yl]-2-methylsulfanyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(4- fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpholin-4- yl]-pyridine-3-carboxylic acid amide; 6-(3-Ethyl-morpholin-4-yl)-2-ethylsulfanyl-N-[(3-fluoropheny l)-methyl]-4- methyl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6- [(3R)-3-(methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3- carboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3S)-3-(methoxy methyl)-morpholin-4-yl]-4- methyl-pyridine-3 -carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-2-methoxy-4- methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxyli c acid amide; 2-Ethoxy-N- [(4-fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpholi n-4-yl]-pyridine-3-carboxylic acid amide; 2-Dimethylamino-N-(4,4-dimethyl-pentyl)-4-methyl-6-[(3R)-3-m ethyl- morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(ethyl-methyl- amino)-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3- carboxylic acid amide; N- (4,4-Dimethyl-pentyl)-2-isopropyl-4-methyl-6-[(3R)-3-methyl- morpholin-4-yl]-pyridine-3- carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-methoxy-4-methyl-6-[(3R)-3-methyl- morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethoxy-4- methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxyli c acid amide; 2-(Ethyl- methyl-amino)-4-methyl-6-morpholin-4-yl-N-[[4-(trifluorometh yl)-phenyl]-methyl]pyridine- 3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(ethyl-methyl-amino)-4-methyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-(Ethyl-methyl-amino)-4-methyl-6- morpholin-4-yl-N-(4, 4, 4-trifluoro-butyl)-pyridine-3 -carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-(ethyl-methyl-amino)-4-methyl-6-morp holin-4-yl-pyridine-3- carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-methyl-6-[(3R)-3-methyl-morpholin- 4-yl]- 2-methylsulfanyl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2- ethylsulfanyl-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyri dine-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpho lin-4-yl]-2-(l -methyl- propyl)-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-methyl-6-[(3R)-3- methyl-morpholin-4-yl]-2-(l-methyl-propyl)-pyridine-3 -carboxylic acid amide; 2- Cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-m ethyl-morpholin-4-yl]- pyridine-3 -carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl- morpholin-4-yl]-2-propyl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-(4,4-dimethyl- pentyl)-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3 -carboxylic acid amide; N- (4,4-Dimethyl-pentyl)-4-methyl-6-[(3R)-3-methyl-morpholin-4- yl]-2-propyl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(meth yl- pyridin-4-yl-amino)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(4-fluoro-3- methyl-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid amide; 2- Ethylsulfanyl-N-(2-hydroxy-3-phenyl-propyl)-4-methyl-6-morph olin-4-yl-pyridine-3- carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2-(ethyl-methyl-amino)-4-me thyl- 6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2- (ethyl-methyl-amino)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Dimethylamino-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morphol in-4-yl-pyridine-3- carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2-dimethylamino-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2- ethylsulfanyl-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyri dine-3-carboxylic acid amide; N-[(3,5-Dimethyl-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6- morpholin-4-yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-heptyl-4-methyl-6-morpholin-4-yl-pyridine- 3- carboxylic acid amide; 6-Dimethylamino-N-(4,4-dimethyl-pentyl)-2-ethylsulfanyl-4-me thyl- pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethylsulfanyl-6-(2-methoxy- ethyl-methyl-amino)-4-methyl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2- ethylsulfanyl-6-(3-methoxy-propyl-methyl-amino)-4-methyl-pyr idine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-pr opyl-morpholin-4-yl)- pyridine-3 -carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-2-methoxy-4-methyl-6- [(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)- methyl]-2-methoxy-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]- pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-2-(l-methyl-propyl)-6-m orpholin-4-yl- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-hexyl-4-methyl-6-morpholin-4-yl- pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethylsulfanyl-4-methyl-6- (methyl-tetrahydro-furan-3-yl-amino)-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl- pentyl)-2-ethylsulfanyl-4-methyl-6-(2-methyl-morpholin-4-yl) -pyridine-3-carboxylic acid amide; 2-tert-Butyl-N-(4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4- yl-pyridine-3- carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-methyl-2-(l-methyl-propyl)-6-morph olin- 4-yl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)-pyridine-3-carbox ylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(2R)-2-(methoxy methyl)-morpholin-4-yl]-4- methyl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6- [(2S)-2-(methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3- carboxylic acid amide; N- [(3,4-Difluoro-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6-[( 3R)-3-methyl-morpholin-4-yl]- pyridine-3 -carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2-methoxy-4-methyl-6- [(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-(3- hydroxy-3-phenyl-propyl)-4-methyl-6-morpholin-4-yl-pyridine- 3 -carboxylic acid amide; 2- Ethylsulfanyl-N-(2-hydroxy-4-methyl-pentyl)-4-methyl-6-morph olin-4-yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[2-(2-methoxy- ethyl)- morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-(5-hydroxy- 4, 4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-4-methyl-N-[(3-methylsulfonyl-phenyl)-methyl]- 6-morpholin-4-yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[2- (trifluoromethyl)-5,6,7,8-tetrahydro-[l,6]naphthyridin-6-yl] pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6- [(3R)-3-methyl-morpholin-4- yl]-pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2-methoxy-4- methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxyli c acid amide; 2-Ethylsulfanyl- 4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-N-(4,4,4-trifluoro -butyl)-pyridine-3-carboxylic acid amide; 2-Methoxy-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-N-(4,4,4 -trifluoro- butyl)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-[(3R)-3-methyl- morpholin-4-yl]-N-[[4-(trifluoromethyl)-phenyl]-methyl]pyrid ine-3-carboxylic acid amide;

2-Methoxy-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-N-[[4 -(trifluoromethyl)-phenyl]- methyl]pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[3- (methoxymethyl)-azetidin-l-yl]-4-methyl-pyridine-3 -carboxylic acid amide; 6-(2,5- Dimethyl-morpholin-4-yl)-2-ethylsulfanyl-N-[(3-fluorophenyl) -methyl]-4-methyl-pyridine-3- carboxylic acid amide; 2-Dimethylamino-4-methyl-6-morpholin-4-yl-N-[[4- (trifluoromethyl)-phenyl]-methyl]pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro- phenyl)-methyl]-2-dimethylamino-4-methyl-6-morpholin-4-yl-py ridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[2-(t rifluoromethyl)-5, 6,7,8- tetrahydro-imidazo[l,2-a]pyrazin-7-yl]-pyridine-3-carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-dimethylamino-4-methyl-6-morpholin-4 -yl-pyridine-3-carboxylic acid amide; 2-Dimethylamino-N-(4,4-dimethyl-pentyl)-4-methyl-6-morpholin -4-yl-pyridine-

3 -carboxylic acid amide; 2-Dimethylamino-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro - butyl)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-N-[(4-methylsulfonyl- phenyl)-methyl]-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(4- fluorophenyl)-methyl]-6-[(3R)-3-(methoxymethyl)-morpholin-4- yl]-4-methyl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-6-[(3S)-3- (methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3 -carboxylic acid amide; 2-tert-Butyl- N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridi ne-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[4-(2 ,2,2-trifluoro-ethyl)-piperazin- l-yl]-pyridine-3-carboxylic acid amide; 6-(2,2-Dimethyl-morpholin-4-yl)-2-ethylsulfanyl-N- [(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N- [(3-fluorophenyl)-methyl]-4-methyl-6-[methyl-(2-oxo-propyl)- amino]-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-ethylsulfanyl-6-[(2R)-2-(metho xymethyl)- morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2- ethylsulfanyl-6-[(2S)-2-(methoxymethyl)-morpholin-4-yl]-4-me thyl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-ethylsulfanyl-6-[(3R)-3-(metho xymethyl)- morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2- ethylsulfanyl-6-[(3S)-3-(methoxymethyl)-morpholin-4-yl]-4-me thyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(meth yl-tetrahydro- pyran-4-yl-amino)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-6-[(4-methoxy-cyclohexyl)-methyl-amino]-4-methyl-pyr idine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[2-(t rifluoromethyl)- morpholin-4-yl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-4-methyl-6-(methyl-tetrahydro-pyran-3-yl-amino)-pyri dine-3-carboxylic acid amide; 6-(3,5-Dimethyl-morpholin-4-yl)-2-ethylsulfanyl-N-[(3-fluoro phenyl)-methyl]-4-methyl- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3S)-3- (hydroxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3-carboxyl ic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3R)-3-(hydroxy methyl)-morpholin-4-yl]-4- methyl-pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-isopropyl-4- methyl-6-[(3R)-3-methyl-morpholin-4-yl]-pyridine-3-carboxyli c acid amide; N-[(4- Chlorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpholin-4- yl]-2-propyl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6 - morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Cyano-3-fluoro-phenyl)-methyl]-2- ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxyli c acid amide; N-[(4- Chlorophenyl)-methyl]-2-(2-fluoro-ethoxy)-4-methyl-6-morphol in-4-yl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-(2,2-difluoro-ethoxy)-4-methyl -6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2- (cy cl opropyl-methoxy)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-(2,2- Difluoro-ethoxy)-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morp holin-4-yl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-ethoxy-4-methyl-6-[(3R)-3-meth yl- morpholin-4-yl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethylsulfanyl- 4-methyl-6-[(2S)-2-methyl-morpholin-4-yl]-pyridine-3-carboxy lic acid amide; N-(4,4- Dimethyl-pentyl)-2-ethylsulfanyl-4-methyl-6-[(2R)-2-methyl-m orpholin-4-yl]-pyridine-3- carboxylic acid amide; 2-(Cyclopropyl-methoxy)-N-[(4-fluorophenyl)-methyl]-4-methyl -6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-isopropyl- 6-[(3S)-3-(methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine- 3-carboxylic acid amide; N- (4,4-Dimethyl-pentyl)-4-methyl-2-(2-methyl-butyl)-6-morpholi n-4-yl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(l, l-dimethyl-propyl)-4-methyl-6-morpholin-4-yl- pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethylsulfanyl-4-methyl-6- (methyl-tetrahydro-pyran-3-yl-amino)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4- methyl-6-morpholin-4-yl-N-[(4-nitrophenyl)-methyl]-pyridine- 3-carboxylic acid amide; N- [(4-Chlorophenyl)-methyl]-2-cyclopropyl-4-methyl-6-[(3R)-3-m ethyl-morpholin-4-yl]- pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-(2- dimethylaminoethyloxy)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-N-[(4-fluoro-3-methoxy-phenyl)-methyl]-4-methy l-6-morpholin-4-yl-pyridine- 3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-isopropyl-6-[(2S)-2- (methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-N-(3-hydroxy-4-methyl-pentyl)-4-methyl-6-morph olin-4-yl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluoro-4-methoxy-phenyl)-methyl]-4-met hyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[[4-(Difluoro-methoxy)-phenyl]- methyl]-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N- (l,3-Dihydro-isobenzofuran-5-yl-methyl)-2-ethylsulfanyl-4-me thyl-6-morpholin-4-yl- pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-cyclopropyl-6-[(2S)-2- (methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(2S)-2-(hydroxy methyl)-morpholin-4-yl]-4- methyl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6- [(2R)-2-(hydroxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3- carboxylic acid amide; 6- (Benzyl-methyl-amino)-2-ethylsulfanyl-N-[(3-fluorophenyl)-me thyl]-4-methyl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[meth yl- (tetrahydro-furan-2-yl-methyl)-amino]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N- [(3-fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl-morpholi n-4-yl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[(3 S)-3-methyl- morpholin-4-yl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-4-methyl-6-[methyl-[[4-(trifluoromethyl)-phenyl]-met hyl]-amino]-pyridine-3- carboxylic acid amide; 6-(l,l-Dioxo-[l,4]thiazinan-4-yl)-2-ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide; 6-(Azetidin-l-yl)-2- ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine- 3-carboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(methyl -tetrahydro-furan-3-yl- amino)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(N-methyl-anilino)-pyridine-3-carboxylic acid amide; 6-(2,3-Dihydro-lH-isoindol-

2-yl)-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methy l-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(l,2, 3,4-tetrahydro- quinolin-l-yl)-pyridine-3 -carboxylic acid amide; 6-(2,3-Dihydro-lH-indol-l-yl)-2- ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine- 3-carboxylic acid amide; 2- Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(2,4,4-trimethyl-p entyl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3-methoxy-cy clohexyl)-methyl- amino]-4-methyl-pyridine-3-carboxylic acid amide; N-(4,4-Difluoro-pentyl)-2-ethylsulfanyl- 4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]- 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3,4-Difluoro- phenyl)-methyl]-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridi ne-3-carboxylic acid amide;

2-Isopropyl-4-methyl-6-morpholin-4-yl-N-[[4-(trifluoromet hyl)-phenyl]-methyl]-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-ox o- morpholin-4-yl)-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-methyl-6- morpholin-4-yl-2-propyl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2- isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Isopropyl-4- methyl-6-morpholin-4-yl-N-(4, 4, 4-trifluoro-butyl)-pyridine-3 -carboxylic acid amide; N- [(3,5-Difluoro-phenyl)-methyl]-2-isopropyl-4-methyl-6-morpho lin-4-yl-pyridine-3- carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-(oxe tan-

3 -yloxy)-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-(4-methoxy-4-methyl-pentyl)-

4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-(4-fluoro-4- methyl-pentyl)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 4-Methyl-6- morpholin-4-yl-2-propyl-N-(4,4,4-trifluoro-butyl)-pyridine-3 -carboxylic acid amide; N-[(3,4- Difluoro-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl- pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-2 -propyl-pyridine-3- carboxylic acid amide; 4-Methyl-6-morpholin-4-yl-2-propyl-N-[[4-(trifluoromethyl)-p henyl]- methyl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-2-oxo-pentyl)-2-ethylsulfanyl-4- methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-(8-oxa-3-azabicyclo[3.2.1]o ctan-3-yl)-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-prop yl- pyridine-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-isopropyl-4-methyl-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-Cyclopropyl-N-(4,4-dimethyl-pentyl)-4- methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-Cyclopropyl-4-methyl-6- morpholin-4-yl-N-(4, 4, 4-trifluoro-butyl)-pyridine-3 -carboxylic acid amide; 2-Cyclopropyl- N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridi ne-3-carboxylic acid amide;

2-Cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morp holin-4-yl-pyridine-3- carboxylic acid amide; 2-Cyclopropyl-N-[(3,4-difluoro-phenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-[(3,5-difluoro-phenyl)- methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-4- methyl-6-morpholin-4-yl-N-[[4-(trifluoromethyl)-phenyl]methy l]-pyridine-3-carboxylic acid amide;N-[(4-Chlorophenyl)-methyl]-2-cyclopropyl-4-methyl-6-m orpholin-4-yl-pyridine-3- carboxylic acid amide;2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methoxy- 6-morpholin- 4-yl-pyridine-3 -carboxylic acid amide;N-(4,4-Dimethyl-pentyl)-2-(2-methoxy-ethylsulfanyl)- 4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide;2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-6-[(4-fluorophenyl)-methyl-(3-methoxy- propyl)-amino]-4-methyl- pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(3,4,4- trimethyl-pentyl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-6-[3-(2-methoxy-ethyl)-morpholin-4-yl]-4-methyl-pyri dine-3-carboxylic acid amide;

2-(Acetyl-methyl-amino)-N-[(3-fluorophenyl)-methyl]-4-met hyl-6-morpholin-4-yl-pyridine-

3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(4-fluorophen yl)- methyl-(2-methoxy-ethyl)-amino]-4-methyl-pyridine-3-carboxyl ic acid amide;2- Ethylsulfanyl-4-methyl-N-[3-(3-methyl-oxetan-3-yl)-propyl]-6 -morpholin-4-yl-pyridine-3- carboxylic acid amide; N-(4,4-Dimethyl-pent-2-ynyl)-2-ethylsulfanyl-4-methyl-6-morp holin-

4-yl-pyridine-3 -carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-pyridine-3-ca rboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-(methoxymethyl)- 6-morpholin-4-yl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-2-(l-methyl-propyl)-6- morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-hexyl)-2-ethylsulfanyl-4- methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(2- methoxy-ethoxy)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Ethylsulfanyl-4-methyl-N-[3-(l-methyl-cyclopropyl)-propyl]-6 -morpholin-4-yl-pyridine-3- carboxylic acid amide; 2-Cyclopropyl-N-[[4-fluoro-3-(methoxymethyl)-phenyl]-methyl] -4- methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[[4-fluoro-3- (methoxymethyl)-phenyl]methyl]-4-methyl-6-[(3R)-3-methyl-mor pholin-4-yl]-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[[4-fluoro-3-(hydroxymethyl)-phenyl]methyl ]-4- methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(3- methoxy-propyl)-4-methyl-6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2- Cyclopropyl-N-[[3-fluoro-4-(methoxymethyl)-phenyl]-methyl]-4 -methyl-6-morpholin-4-yl- pyridine-3 -carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-2-(methoxymethyl)-4- methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]- 2,4-diisopropyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl- pentyl)-2-(2-methoxy-ethyl)-4-methyl-6-morpholin-4-yl-pyridi ne-3 -carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2,4-diethyl-6-morpholin-4-yl-pyr idine-3-carboxylic acid amide; and N-(4,4-Dimethyl-pentyl)-4-methyl-6-morpholin-4-yl-2-tetrahyd ro-pyran-4-yl- pyridine-3 -carboxylic acid amide, respectively in the form of free compounds; racemic mixtures; mixtures of the enantiomers, diastereomers, or enantiomers and diastereomers in any mixing ratio, or an individual enantiomer or diastereomer; or in the form of the salts of physiologically acceptable acids or bases.

Formula 24

[00353] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 24. Such compounds are described in US Patent No. 9,168,259 issued March 8, 2016 and corresponding to US Application No. 13/449,472 filed April 18, 2012; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 24, this reference incorporated by reference herein controls.

[00354] In an embodiment, the Kv7 channel activator is a compound according to formula 24: Formula 24 wherein, X ¹ represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted; or a Cs-e-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and in each case optionally bridged via a Cn 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or represents OX ⁶ , wherein X ⁶ represents a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted; or a C3-6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted; X ² and X ³ independently of one another represent H; F; Cl; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a Ci-4-aliphatic residue, or an O — C1-4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, X ⁴ and X ⁵ independently of one another represent H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if X ⁴ and/or X ⁵ denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X ² and X ³ and/or X ⁴ and X ⁵ in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and the respective remaining substituents of X ² and X ³ each independently of one another represent H; F; Cl; Br; I; CN; CH ₂ F; CHF ₂ ; CF ₃ ; OH; OCH ₂ F; OCHF ₂ ; OCF ₃ ; SCF3; a Ci-4-aliphatic residue, or an O — C1-4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a Cs-e- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, and the respective remaining substituents of X ⁴ and X ⁵ each independently of one another represent H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if X ⁴ and/or X ⁵ denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X ² and X ⁴ together with the carbon atoms connecting them, form a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and X ³ represents H; F; Cl; Br; I; CN; CH ₂ F; CHF ₂ ; CF ₃ ; OH; OCH ₂ F; OCHF ₂ ; OCF ₃ ; SCF ₃ ; a Ci- ₄ -aliphatic residue, or an O— Ci- 4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; and X ⁵ represents H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if X ⁵ denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, in which an “aliphatic group” and an “aliphatic residue” can in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” can in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group” and an “aliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a N(Ci-4-aliphatic residue)- C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, a N(Ci-4-aliphatic residue)-S(=O)2 — C1-4 aliphatic residue, =0, OH, OCH2F, OCHF2, OCF3, a O — Cisaliphatic residue, a O — C(=O) — Cis-aliphatic residue, SH, SCF3, a S — Cis-aliphatic residue, S(=O) ₂ OH, a S(=O) — Ci-4-aliphatic residue, a S(=O)2 — Cis-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, a S(=O)2 — NH — Cis-aliphatic residue, a S(=O)2 — N(Cis- aliphatic residue^, CN, CH2F, CHF2, CF3, CHO, COOH, a Cis-aliphatic residue, CH2OH, CH ₂ — OCH3, C2H4— OH, C2H4— OCH3 CH ₂ — CF ₃ , a C(=O)— Cis-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH2, a C(=O) — NH(CI-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a N(Ci-4-aliphatic residue)-C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, a N(Ci-4-aliphatic residue)-S(=O)2 — C1-4 aliphatic residue, =0, OH, OCH2F, OCHF2, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Cisaliphatic residue, SH, SCF3, a S — Cis-aliphatic residue, S(=0)20H, a S(=0) — Cis-aliphatic residue, a S(=0)2 — Cis-aliphatic residue, a S(=0)2 — O — Cis-aliphatic residue, a S(=0)2 — NH — Ci-4-aliphatic residue, a S(=0)2 — N(Ci-4-aliphatic residue^, CN, CH2F, CHF2, CF3, CHO, COOH, a Cis-aliphatic residue, CH ₂ 0H, CH ₂ — 0CH ₃ , C ₂ H ₄ — OH, C ₂ H ₄ — OCH3 CH2 — CF3, a C(=0) — Ci-4-aliphatic residue, a C(=0) — O — Cis-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0) — NH2, a C(=0) — NH(Ci-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; said compound being in the form of a free compound, the racemate, a mixture of enantiomers, diastereomers, or of enantiomers and diastereomers in any mixing ratio, or of an individual enantiomer or diastereomer, or in the form of a salt of physiologically acceptable acids or bases.

[00355] In further embodiments, X ¹ represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=O) — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or represents a C3-6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=0) — Cisaliphatic residue, a S(=0)2 — Cis-aliphatic residue, CN, and a Cis-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Cis-aliphatic residue, and wherein the Cs-e-cycloaliphatic residue may optionally be bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or represents OX ⁶ , wherein X ⁶ represents a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue; wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, X ² and X ³ independently of one another represent H; F; Cl; Br; I; CN; CH ₂ F; CHF ₂ ; CF ₃ ; OH; OCH ₂ F; OCHF ₂ ; OCF ₃ ; SCF3; a Ci-4-aliphatic residue, or an O — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or represent a Cs-e- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Ci-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci- 4-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH ₂ F, OCHF ₂ , OCF ₃ , CH ₂ F, CHF ₂ , CF ₃ and an unsubstituted O — Ci-4-aliphatic residue, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, X ⁴ and X ⁵ independently of one another represent H; CH2F; CHF2; CF3; or a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or represent a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4- aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, on the condition that if X ⁴ and/or X ⁵ denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the Ci- 4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or X ² and X ³ and/or X ⁴ and X ⁵ in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=O) — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and the respective remaining substituents of X ² and X ³ each independently of one another represent H; F; Cl; Br; I; CN; CH ₂ F; CHF ₂ ; CF ₃ ; OH; OCH ₂ F; OCHF ₂ ; OCF ₃ ; SCF ₃ ; a Ci- ₄ -aliphatic residue, or an O — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH ₂ F, OCHF ₂ , OCF ₃ , CH ₂ F, CHF ₂ , CF ₃ and an unsubstituted O — Ci-4-aliphatic residue, or represent a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Cisaliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Cis-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Cis-aliphatic residue, CN, and a Cis-aliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Cis-aliphatic residue, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, and the respective remaining substituents of X ⁴ and X ⁵ each independently of one another represent H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or represent a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Cisaliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Cis-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Cis-aliphatic residue, CN, and a Cis-aliphatic residue, on the condition that if X ⁴ and/or X ⁵ denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the Ci- 4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Cis-aliphatic residue, or X ² and

X ⁴ together with the carbon atoms connecting them, form a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Cisaliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Cis-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Cis-aliphatic residue, CN, and a Cis-aliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Cis-aliphatic residue, and the remaining substituent X ³ represents H; F; Cl; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a Ci-4-aliphatic residue, or an O — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or represents a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH ₂ F, OCHF ₂ , OCF ₃ , CH ₂ F, CHF ₂ , CF ₃ and an unsubstituted O — Ci-4-aliphatic residue, and the remaining substituent X ⁵ represents H; CH ₂ F; CHF ₂ ; CF ₃ ; OCH ₂ F; OCHF ₂ ; OCF ₃ ; SCF ₃ ; a Ci-4-aliphatic residue, wherein the C1-4- aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH ₂ F, OCHF ₂ , OCF ₃ , CH ₂ F, CHF ₂ , CF ₃ and an unsubstituted O — Ci-4-aliphatic residue, or represents a C ₃ -6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue) ₂ , OH, =0, an O — Ci-4-aliphatic residue, OCH ₂ F, OCHF ₂ , OCF ₃ , SH, SCF ₃ , a S — Ci- 4-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0) ₂ — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, on the condition that if X ⁵ denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH ₂ F, OCHF ₂ , OCF ₃ , CH ₂ F, CHF ₂ , CF ₃ and an unsubstituted O — Ci-4-aliphatic residue.

[00356] In further embodiments, X ¹ represents a C ₂ -6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue) ₂ , OH, =0, an O — Ci-4-aliphatic residue, OCH ₂ F, OCHF ₂ , OCF ₃ , SH, SCF ₃ , a S — Ci-4-aliphatic residue, a S(=O) — Ci-4-aliphatic residue, a S(=O) ₂ — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH ₂ F, OCHF ₂ , OCF ₃ , CH ₂ F, CHF ₂ , CF ₃ and an unsubstituted O — Ci-4-aliphatic residue, or represents a C ₃ -6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue) ₂ , OH, =0, an O — Ci-4-aliphatic residue, OCH ₂ F, OCHF ₂ , OCF ₃ , SH, SCF ₃ , a S — Ci-4-aliphatic residue, a S(=0) — Cisaliphatic residue, a S(=0) ₂ — Cis-aliphatic residue, CN, and a Cis-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH ₂ F, OCHF ₂ , OCF ₃ , CH ₂ F, CHF ₂ , CF ₃ and an unsubstituted O — Cis-aliphatic residue, or represents OX ⁶ , wherein X ⁶ represents a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Cisaliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Cis-aliphatic residue, a S(=O) — Ci-4-aliphatic residue, a S(=O)2 — Cis-aliphatic residue, CN, and a Cis-aliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O — Cis-aliphatic residue.

[00357] In further embodiments, X ¹ represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=O) — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue is in each case unsubstituted, or represents a C3-6- cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue is in each case unsubstituted, or represents OX ⁶ , wherein X ⁶ represents a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a S(=0) — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, CN, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue is in each case unsubstituted.

[00358] In further embodiments, X ¹ represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or represents a C3-6- cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or represents OX ⁶ , wherein X ⁶ represents a Ci-4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue. [00359] In further embodiments, X ¹ represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH ₃ )(C2Hs), C(CH ₃ )2(C ₂ H ₅ ), ethenyl or propenyl (— CH ₂ CH=CH ₂ , — CH=CH— CH ₃ , — C(=CH ₂ )— CH ₃ ), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OX ⁶ , wherein X ⁶ represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, CH2OH, CH ₂ OCH ₃ , CH2CH2OH, CH ₂ CH ₂ OCH ₃ , and CH(OH)CH ₂ OH.

[00360] In further embodiments, X ² and X ³ independently of one another represent H; F; Cl; Br; I; CH ₂ F; CHF ₂ ; CF ₃ ; OH; OCH ₂ F; OCHF ₂ ; OCF ₃ ; a Ci- ₄ -aliphatic residue, or an O— Cn 4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or represent a C ₃ -6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, CH2F, CHF2, CF ₃ , OCH2F, OCHF2, OCF ₃ , and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, X ⁴ and X ⁵ independently of one another represent H; CH2F; CHF2; CF ₃ ; a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or represent a C ₃ -6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O— Ci-4-aliphatic residue, CH ₂ F, CHF ₂ , CF ₃ , OCH ₂ F, OCHF ₂ , OCF ₃ , and a Ci- ₄ - aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, on the condition that if X ⁴ and/or X ⁵ denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X ² and X ³ and/or X ⁴ and X ⁵ in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C ₃ -io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, CH2F, CHF2, CF ₃ , OCH2F, OCHF2, OCF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, and the respective remaining substituents of X ² and X ³ each independently of one another represent H; F; Cl; Br; I; CH ₂ F; CHF ₂ ; CF ₃ ; OH; OCH ₂ F; OCHF ₂ ; OCF ₃ ; a Ci- ₄ - aliphatic residue, or an O — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or represent a C ₃ -6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, CH2F, CHF2, CF ₃ , OCH2F, OCHF2, OCF ₃ , and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, and the respective remaining substituents of X ⁴ and X ⁵ each independently of one another represent H; CH2F; CHF2; CF ₃ ; a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or represent a C ₃ -6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, CH2F, CHF2, CF ₃ , OCH2F, OCHF2, OCF ₃ , and a Ci-4-aliphatic residue, on the condition that if X ⁴ and/or X ⁵ denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or X ² and X ⁴ together with the carbon atoms connecting them, form a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, CH2F, CHF2, CF ₃ , OCH2F, OCHF2, OCF ₃ , and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, and the remaining substituent X ³ represents H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a Ci-4-aliphatic residue, or an O — C1-4 aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or represents a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Cisaliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a Cis-aliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — C 1.4-al iphatic residue, and the remaining substituent

X ⁵ represents H; CH2F; CHF2; CF3; a Cis-aliphatic residue, wherein the Cis-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue, or represents a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a Ci-4-aliphatic residue, on the condition that if X ⁵ denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted O — Ci-4-aliphatic residue.

[00361] In further embodiments, X ² and X ³ independently of one another represent H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; a Ci-4-aliphatic residue, or an O — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue is in each case unsubstituted, or represent a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, X ⁴ and X ⁵ independently of one another represent H; CH2F; CHF2; CF3; a C1-4- aliphatic residue, wherein the Ci-4-aliphatic residue is unsubstituted, or represent a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, on the condition that if X ⁴ and/or X ⁵ denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X ² and X ³ and/or X ⁴ and X ⁵ in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, CH2F, CHF2, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue is in each case unsubstituted, and the respective remaining substituents of X ² and X ³ each independently of one another represent H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; a Ci-4-aliphatic residue, or an O — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue is in each unsubstituted, or represent a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, and the respective remaining substituents of X ⁴ and X ⁵ each independently of one another represent H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue is unsubstituted, or represent a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, on the condition that if X ⁴ and/or X ⁵ denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X ² and X ⁴ together with the carbon atoms connecting them, form a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, CH2F, CHF2, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue is in each case unsubstituted, and the remaining substituent X ³ represents H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; a Ci-4-aliphatic residue, or an O — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue is in each case unsubstituted, or represents a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, and the remaining substituent X ⁵ represents H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue is unsubstituted, or represents a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, on the condition that if X ⁵ denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom.

[00362] In further embodiments, X ² and X ³ independently of one another represent H; OH; an unsubstituted Ci-4-aliphatic residue, or an unsubstituted O — C1-4 aliphatic residue, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, X ⁴ and X ⁵ independently of one another represent H; CH2F; CHF2; CF3; an unsubstituted C1-4- aliphatic residue, or X ² and X ³ or X ⁴ and X ⁵ in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-io-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CH2F, CHF2, CF3, an unsubstituted O — Ci-4-aliphatic residue, and an unsubstituted Ci-4-aliphatic residue, and the respective remaining substituents of X ² and X ³ each independently of one another represent H; OH; an unsubstituted C1-4- aliphatic residue, or an unsubstituted O — C1-4 aliphatic residue, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, and the respective remaining substituents of X ⁴ and X ⁵ each independently of one another represent H; CH2F; CHF2; CF3; an unsubstituted Ci-4-aliphatic residue, or X ² and X ⁴ together with the carbon atoms connecting them, form a C3-io-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an unsubstituted aliphatic residue, CH2F, CHF2, CF3, and an unsubstituted Ci-4-aliphatic residue, and the remaining substituent X ³ represents H; F; Cl; Br; I; OH; an unsubstituted Ci- 4-aliphatic residue, or an unsubstituted O — C1-4 aliphatic residue, and the remaining substituent X ⁵ represents H; CH2F; CHF2; CF3; an unsubstituted Ci-4-aliphatic residue. [00363] In further embodiments, X ² and X ³ independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH3)(C2Hs), C(CH3)2(C2Hs), OCH3 or OCH2CH3, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, X ⁴ and X ⁵ independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH ₃ )(C ₂ H ₅ ), C(CH ₃ )2(C ₂ H ₅ ), CH ₂ F; CHF ₂ ; CF ₃ ; or X ² and X ³ or X ⁴ and X ⁵ in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, methyl; ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituents of X ² and X ³ each independently of one another represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH3)(C2Hs), C(CH3)2(C2Hs), OCH3 or OCH2CH3, with the proviso that at least one of X ² and X ³ denotes H or is linked via a carbon atom, and the respective remaining substituents of X ⁴ and X ⁵ each independently of one another represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH3)(C2Hs), C(CH3)2(C2Hs), CH2F; CHF2; CF3; or X ² and X ⁴ together with the carbon atoms connecting them, form a C3-6- cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, methyl; ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituent of X ³ represents H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH3)(C2HS), C(CH3) ₂ (C ₂ H ₅ ), OCH3 or OCH2CH3, and the respective remaining substituent X ⁵ represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2 — CH(CH3)(C2Hs), C(CH3)2(C2Hs), CH ₂ F; CHF ₂ ; CF ₃ .

[00364] In further embodiments, X ¹ represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OX ⁶ , wherein X ⁶ represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, or tert.- butyl, X ² and X ³ in dependently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, or tert.-butyl, X ⁴ and X ⁵ independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, CH2F, CHF2, or CF3; or X ² and X ³ or X ⁴ and X ⁵ in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituents of X ² and X ³ in dependently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, or tert.-butyl, and the respective remaining substituents of X ⁴ and X ⁵ independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.- butyl, CH2F, CHF2, or CF3; or X ² and X ⁴ together with the carbon atoms connecting them, form a C3-6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and X ³ represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, or tert.-butyl, and X ⁵ represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.- butyl, CH ₂ F, CHF ₂ , or CF ₃ . [00365] In further embodiments, the Kv7 cannel activator is selected from the group consisting of: 2-Cyclopropyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-m orpholin-4-yl- pyridine-3 -carboxylic acid amide; 2-Cyclopropyl-N-[[(lS,2R)-2-hydroxy-cyclohexyl]- methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N- [[(lR,2S)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6-morpholin -4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6- morpholin-4-yl- pyridine-3 -carboxylic acid amide; N-(3-Hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl- 6-morpholin-4-yl-pyridine-3 -carboxylic acid amide; 2-Isopropyl-4-methyl-6-morpholin-4-yl- N-(4,4,4-trifluoro-3-hydroxy-butyl)-pyridine-3-carboxylic acid amide; and N-[[(lS,2R)-2- Hydroxy-cyclohexyl]-methyl]-2-isopropyl-4-methyl-6-morpholin -4-yl-pyridine-3-carboxylic acid amide; optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof.

Formula 25

[00366] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 25. Such compounds are described in US Patent No. 8,653,101 issued February 18, 2014 and corresponding to US Application No.

10/992,118 filed November 18, 2005; International Publication No. WO2012025236A1, published March 1, 2012 and corresponding to International Application No.

PCT/EP2011/004277 filed August 26, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 25, these references incorporated by reference herein control.

[00367] In an embodiment, the Kv7 channel activator is a compound according to formula 25. wherein, R ¹ represents a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents H; F; Cl; Br; I; CN; CF3; C(=O)H; NO2; OCF3; SCF3; a Cisaliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — C1-4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the Ci- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Cis-aliphatic residue, a S — Cis-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Cis-aliphatic residue, wherein the Cn 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-8- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; SCF ₃ ; S(=O) ₂ — OH; NO ₂ ; OCF ₃ ; a Ci- ₄ -aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — Cn 4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — C1-4- aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(Ci-4 aliphatic residue), a N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — Ci-4-aliphatic residue, a N(CI-4 aliphatic residue)-C(=O) — C1-4 aliphatic residue, or a N(CI-4 aliphatic residue)-S(=O)2 — C1-4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ⁷ represents a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, in which an “aliphatic group” and “aliphatic residue” can in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” can in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group” and an “aliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — Ci-

4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, a S(=O)2 — NH — Ci-4-aliphatic residue, CN, CF3, CHO, COOH, a Ci-4-aliphatic residue, a C(=O) — Ci-4-aliphatic residue, a C(=O) — O — Cisaliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH2, a C(=O) — NH(CI-4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue)2; in which “mono- or polysubstituted” with respect to a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Cis-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Cis-aliphatic residue, S(=0)20H, a S(=0)2 — C1-4- aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, a S(=O)2 — NH — Ci-4-aliphatic residue, CN, CF3, CHO, COOH, a Ci-4-aliphatic residue, a C(=O) — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH2, a C(=O) — NH(CI-4 aliphatic residue), and a

C(=0) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, aliphatic residue), an N(CI-4 aliphatic residue)2, an NH — C(=O) — C1-4 aliphatic residue, an NH — S(=O)2 — C1-4 aliphatic residue, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Cisaliphatic residue, a S(=O)2 — NH — Cis-aliphatic residue, CN, CF3, C(=O)H, C(=O)OH, a Ci-4-aliphatic residue, a C(=O) — Cis-aliphatic residue, a C(=O) — O — Cis-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=O) — NH2, a C(=O) — NH(C 1-4 aliphatic residue), and a C(=O) — N(Cn 4 aliphatic residue^; in the form of the free compounds, the racemate, the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio, or of an individual enantiomer or diastereomer, or in the form of the salts of physiologically acceptable acids or bases.

[00368] In further embodiments, R ¹ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Ci-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) —

OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH,

C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— C ₂ H ₅ , a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF ₃ , O— CH ₂ — OH, O— CH ₂ — O— CH ₃ , SH, SCF ₃ , a S— Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, C(=0) — CH3, C(=0) — C2H5, C(=0) — O — CH3 and C(=0) — O — C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(=0) — OH, and wherein the aryl or the heteroaryl residue may in each case be optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN and C(=0)— OH, R ² represents H; F; Cl; Br; I; CN; CF ₃ ; N0 ₂ ; OCF ₃ ; SCF ₃ ; a Ci- ₄ -aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; S(=O) ₂ — OH; NO ₂ ; a Ci- ₄ -aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — Cn 4 aliphatic residue, a C(=O) — N(CI- ₄ aliphatic residue) ₂ , a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O) ₂ — Ci-4-aliphatic residue, a NH(CI-4 aliphatic residue), a N(CI- ₄ aliphatic residue) ₂ , a NH — C(=O) — C1-4 aliphatic residue, and a NH — S(=O) ₂ — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and a O — Ci-4-aliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, R ⁷ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , an NH(Cn 4 aliphatic residue), an N(CI- ₄ aliphatic residue) ₂ , OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , an NH(CI-4 aliphatic residue), an N(CI- ₄ aliphatic residue) ₂ , OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, N0 ₂ , NH ₂ , an NH(CI-4 aliphatic residue), an N(CI- ₄ aliphatic residue) ₂ , OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00369] In further embodiments, R ² represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted aliphatic residue, a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a C1-4- aliphatic residue and a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue.

[00370] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF ₃ ; OCF ₃ ; SCF ₃ ; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; S(=O)2 — OH; NO2; a Ci-4-aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and a O — Ci-4-aliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group. [00371] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO2; CF3; CN; OCF3; SCF3; a (C=O) — C1-4 aliphatic residue, a C1-4 aliphatic residue, O — C1-4 aliphatic residue, a S — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and O— CH ₃ .

[00372] In further embodiments, at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is H.

[00373] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4 aliphatic residue or C(=O) — OH, or together denote =0, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH.

[00374] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, or 2, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, an O — C1-4 aliphatic residue or a C1-4 aliphatic residue, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Cisaliphatic residue, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cis-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, CF3 a C1-4- aliphatic residue and C(=O) — OH.

[00375] In further embodiments, R ⁷ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Cn 4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁷ denotes a

3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00376] In further embodiments, R ⁷ denotes a Ci-s-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-

4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue is bridged via a unsubstituted C1-8 aliphatic group.

[00377] In further embodiments, R ¹ represents the partial structure: wherein: m is 0, 1 or 2 and R ^8a and R ^8b each independently of one another represent H, F, a O — Ci-4 aliphatic residue or a Ci-4 aliphatic residue; R ^8c denotes a Ci-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — Ci-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or denotes a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or wherein m is 0, R ^8a and R ^8b each independently of one another represent H, F, a O — Cn 4 aliphatic residue or a C1-4 aliphatic residue; and R ^8c denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cisaliphatic residue, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ , C(=O)— O— C ₂ H ₅ and phenyl, wherein phenyl may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cis-aliphatic residue, C(=O) — CH3, C(=O) — C ₂ H>, C(=O) — O — CH3 and C(=O) — O — C ₂ Hs, R ² is selected from the group consisting of H; F; Cl; CF3; CH3; C ₂ HS, iso-propyl; cyclopropyl; and O — CH3; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently of one another selected from the group consisting of H; F; Cl; Br; CF3; CN; OCF3 and NO ₂ ;

R ⁷ denotes a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Cisaliphatic residue, a C(=O) — O — Cis-aliphatic residue, OCF3, SH, SCF3, a S — Cis-aliphatic residue, CF3, and a Cis-aliphatic residue, wherein the Cis-aliphatic residue in each case is unsubstituted.

[00378] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-(3,3-dimethyl-butyl)-2-methoxy-4-methyl-7-(trifluoromethyl )-quinoline-3- carboxylic acid amide; 2-ethoxy-4-methyl-N-(thiophene-2-yl-methyl)-7-(trifluorometh yl)- quinoline-3 -carboxylic acid amide; 2-ethoxy-N-[(4-fluorophenyl)-methyl]-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2- methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(4- fluorophenyl)-methyl]-2-methoxy-4-methyl-7-(trifluoromethyl) -quinoline-3-carboxylic acid amide; 2-ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluorome thyl)-quinoline-3- carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2-(2- methoxy-ethoxy)-4-methyl-7-(trifluoromethyl)-quinoline-3-car boxylic acid amide; N-[(3- fluorophenyl)-methyl]-2-(2-hydroxy-ethoxy)-4-methyl-7-(trifl uoromethyl)-quinoline-3- carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2-isopropoxy-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2- isopropoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxyl ic acid amide; 2-ethoxy-N-[(3- fluorophenyl)-methyl]-4-methoxy-7-(trifluoremethyl)-quinolin e-3-carboxylic acid amide; N- [(3-fluorophenyl)-methyl]-2,4-dimethoxy-7-(trifluoromethyl)- quinoline-3-carboxylic acid amide; 2-ethoxy-N-[(4-fluorophenyl)-methyl]-4-methoxy-7-(trifluorom ethyl)-quinoline-3- carboxylic acid amide; 2-ethoxy-6,7-difluoro-N-[(3-fluorophenyl)-methyl]-4-methoxy- quinoline-3 -carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2,4-dimethoxy-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; 6,7-difluoro-N-[(3-fluorophenyl)- methyl]-2,4-dimethoxy-quinoline-3-carboxylic acid amide; 7-fluoro-N-[(3-fluorophenyl)- methyl]-2-methoxy-4-methyl-quinoline-3-carboxylic acid amide; N-[(3-fluoro-4-methyl- phenyl)-methyl]-2-methoxy-4-methyl-7-(trifluoromethyl)-quino line-3-carboxylic acid amide; 2-ethoxy-N-[(3-fluoro-4-methyl-phenyl)-methyl]-4-methyl-7-(t rifluoromethyl)-quinoline-3- carboxylic acid amide; 2-methoxy-4-methyl-N-(m-tolyl-methyl)-7-(trifluoromethyl)- quinoline-3 -carboxylic acid amide; 2-ethoxy-4-methyl-N-(m-tolyl-methyl)-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(4-fluoro-3-methyl-phenyl)-methyl]- 2-methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxyli c acid amide; 2-ethoxy-N-[(4- fluoro-3-methyl-phenyl)-methyl]-4-methyl-7-(trifluoromethyl) -quinoline-3-carboxylic acid amide; 2-methoxy-4-methyl-N-(p-tolyl-methyl)-7-(trifluoromethyl)-qu inoline-3-carboxylic acid amide; 2-ethoxy-4-methyl-N-(p-tolyl-methyl)-7-(trifluoromethyl)-qui noline-3- carboxylic acid amide; 2-ethoxy-4-methyl-N-(4-methyl-pentyl)-7-(trifluoromethyl)- quinoline-3 -carboxylic acid amide; 2-methoxy-4-methyl-N-(4-methyl-pentyl)-7- (trifluoromethyl)-quinoline-3 -carboxylic acid amide; N-(4,4-dimethyl-pentyl)-2-methoxy-4- methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-(4,4-dimethyl-pentyl)-2- ethoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; 7-bromo-2-ethoxy- N-[(4-fluorophenyl)-methyl]-4-methyl-quinoline-3-carboxylic acid amide; 7-bromo-2- ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-quinoline-3-carb oxylic acid amide; 7-bromo- N-[(3-fluorophenyl)-methyl]-2-methoxy-4-methyl-quinoline-3-c arboxylic acid amide; 7- bromo-N-[(4-fluorophenyl)-methyl]-2-methoxy-4-methyl-quinoli ne-3 -carboxylic acid amide; 7-cyano-2-ethoxy-N-[(4-fluorophenyl)-methyl]-4-methyl-quinol ine-3-carboxylic acid amide; 7-cyano-2-ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-quinol ine-3-carboxylic acid amide; 7-cyano-N-[(3-fluorophenyl)-methyl]-2-methoxy-4-methyl-quino line-3-carboxylic acid amide; 7-cyano-N-[(4-fluorophenyl)-methyl]-2-methoxy-4-methyl-quino line-3-carboxylic acid amide; N-[(3-fluoro-2-methoxy-phenyl)-methyl]-2-methoxy-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluoro-5-methoxy-phenyl)- methyl]-2-methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-c arboxylic acid amide; N-[(5- fluoro-2-methoxy-phenyl)-methyl]-2-methoxy-4-methyl-7-(trifl uoromethyl)-quinoline-3- carboxylic acid amide; N-[(3-fluoro-2-hydroxy-phenyl)-methyl]-2-methoxy-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluoro-5-hydroxy-phenyl)- methyl]-2-methoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-c arboxylic acid amide; N-[(5- fluoro-2-hydroxy-phenyl)-methyl]-2-methoxy-4-methyl-7-(trifl uoromethyl)-quinoline-3- carboxylic acid amide; N-[(3-fluoro-4-hydroxy-phenyl)-methyl]-2-methoxy-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; 7-fluoro-N-[(4-fluorophenyl)-methyl]- 2-methoxy-4-methyl-quinoline-3-carboxylic acid amide: 5,7-difluoro-N-[(3-fluorophenyl)- methyl]-2-methoxy-4-methyl-quinoline-3-carboxylic acid amide; 6,7-difluoro-N-[(3- fluorophenyl)-methyl]-2-methoxy-4-methyl-quinoline-3-carboxy lic acid amide; 7,8-difluoro- N-[(3-fluorophenyl)-methyl]-2-methoxy-4-methyl-quinoline-3-c arboxylic acid amide; N-[(3- fluorophenyl)-methyl]-4-methyl-2-(2,2,2-trifluoro-ethoxy)-7- (trifluoromethyl)-quinoline-3- carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2-methoxy-4-(trifluoromethyl)- quinoline-3 -carboxylic acid amide; 2-ethoxy-N-[(3-fluorophenyl)-methyl]-4- (trifluoromethyl)-quinoline-3-carboxylic acid amide; and N-[(3-fluorophenyl)-methyl]-2- isopropoxy-4-(trifluoromethyl)-quinoline-3-carboxylic acid amide; respectively in the form of the free compounds; the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio or of an individual enantiomer or diastereomer; or in the form of the salts of physiologically acceptable acids or bases.

Formula 26

[00379] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 26. Such compounds are described in International Publication No. WO2012025236A1, published March 1, 2012 and corresponding to International Application No. PCT/EP2011/004277 filed August 26, 2011; US Patent No. 9,073,862 issued July 7, 2015 and corresponding to US Application No. 14/098,842 filed November 26, 2013; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 26, these references incorporated by reference herein control.

[00380] In an embodiment, the Kv7 channel activator is a compound according to formula 26:

Formula 26 wherein, R ¹ represents a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents H; F; Cl; Br; I; CN; CF3; C(=O)H; NO2; OCF3; SCF3; a Cisaliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — C1-4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the Ci- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Cis-aliphatic residue, a S — Cis-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Cis-aliphatic residue, wherein the Cn 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; SCF ₃ ; S(=O) ₂ — OH; NO ₂ ; OCF ₃ ; a Ci- ₄ -aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — Cn 4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — C1-4- aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(CI-4 aliphatic residue), a N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — Ci-4-aliphatic residue, a N(CI-4 aliphatic residue)-C(=O) — C1-4 aliphatic residue, or a N(CI-4 aliphatic residue)-S(=O)2 — C1-4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; a Cs-e-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ⁷ represents a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁷ represents an unsubstituted aliphatic residue, then R ⁷ does not represent methyl or ethyl, and on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, in which an “aliphatic group” and “aliphatic residue” can in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” can in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group” and an “aliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — Ci- 4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — C1-4- aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O) ₂ OH, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, a S(=O)2 — NH — Ci-4-aliphatic residue, CN, CF3, CHO, COOH, a Ci-4-aliphatic residue, a C(=O) — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH2, a C(=O) — NH(Ci- 4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=0)20H, a S(=0)2 — Ci-4-aliphatic residue, a S(=0)2 — O — Ci-4-aliphatic residue, a S(=0)2 — NH — Ci-4-aliphatic residue, CN, CF3, CHO, COOH, a Ci-4-aliphatic residue, a C(=0) — Ci-4-aliphatic residue, a C(=0) — O — Cisaliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0) — NH2, a C(=0) — NH(CI-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue)2; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, an NH — C(=0) — C1-4 aliphatic residue, an NH — S(=0)2 — C1-4 aliphatic residue, OH, OCF3, a O — Cis-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=0)20H, a S(=0)2 — Ci-4-aliphatic residue, a S(=0)2 — O — Ci-4-aliphatic residue, a S(=0)2 — NH — Cisaliphatic residue, CN, CF3, C(=0)H, C(=0)0H, a Cis-aliphatic residue, a C(=0) — C1-4- aliphatic residue, a C(=0) — O — Cis-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=0) — NH2, a C(=0) — NH(CI-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; in the form of the free compounds, the racemate, the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio, or of an individual enantiomer or diastereomer, or in the form of the salts of physiologically acceptable acids or bases.

[00381] In further embodiments, R ¹ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, c , y p , benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, 0CF3, O— CH ₂ — OH, O— CH ₂ — O— CH ₃ , SH, SCF ₃ , a S—C1-4 aliphatic residue, CF ₃ , CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O) — O — C2H5, and wherein the C ₃ -6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF ₃ , SH, SCF ₃ , a S — C1-4 aliphatic residue, CF ₃ , CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the aryl or the heteroaryl residue may in each case be optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF ₃ , SH, SCF ₃ , a S — C1-4 aliphatic residue, CF ₃ , CN and C(=0) — OH, R ² represents H; F; Cl; Br; I; CN; CF ₃ ; NO2; OCF ₃ ; SCF ₃ ; a Ci-4-aliphatic residue, a S — Cisaliphatic residue, a O — Cis-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C ₃ -6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF ₃ ; OCF ₃ ; SCF ₃ ; C(=0)H; C(=0)— OH;

C(=0) — NH2; S(=0)2 — OH; NO2; a Cis-aliphatic residue, a C(=0) — C1-4 aliphatic residue, a C(=0) — O — C1-4 aliphatic residue, a C(=0) — NH — C1-4 aliphatic residue, a C(=0) — N(Ci- 4 aliphatic residue^, a O — Cis-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, a NH(CI-4 aliphatic residue), aN(Ci- 4 aliphatic residue^, a NH — C(=0) — C1-4 aliphatic residue, and a NH — S(=0)2 — Cisaliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and a O — Cis-aliphatic residue; a C ₃ -6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, R ⁷ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, on the condition that if R ⁷ represents an unsubstituted aliphatic residue, then R ⁷ does not represent methyl or ethyl, and on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00382] In further embodiments, R ² represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a C1-4- aliphatic residue and a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a Ci-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue.

[00383] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF ₃ ; OCF ₃ ; SCF ₃ ; C(=0)H; C(=0)— OH; C(=0)— NH ₂ ; S(=0) ₂ — OH; N0 ₂ ; a Ci-4-aliphatic residue, a C(=0) — Ci-4 aliphatic residue, a C(=0) — O — Ci-4 aliphatic residue, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=0) ₂ — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and a O — Ci-4-aliphatic residue; a C ₃ -6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted Ci-4 aliphatic group.

[00384] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another are selected from the group consisting of H; F; Cl; Br; I; N0 ₂ ; CF ₃ ; CN; OCF ₃ ; SCF ₃ ; a (C=0) — Ci-4 aliphatic residue, a Ci-4 aliphatic residue, O — Ci-4 aliphatic residue, a S — Ci-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and o— CH ₃ .

[00385] In further embodiments, at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is H.

[00386] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4 aliphatic residue or C(=O) — OH, or together denote =0, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue)2, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF ₃ , CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH3 and C(=O) — O — C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cis aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH.

[00387] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, or 2, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, an O — C1-4 aliphatic residue or a C1-4 aliphatic residue, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Cisaliphatic residue, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cis-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, CF3 a C1-4- aliphatic residue and C(=O) — OH.

[00388] In further embodiments, R ⁷ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Cn

4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁷ represents an unsubstituted aliphatic residue, then R ⁷ does not represent methyl or ethyl, and on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00389] In further embodiments, R ⁷ denotes a Ci-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue is bridged via a unsubstituted C1-8 aliphatic group, on the condition that if R ⁷ represents an unsubstituted aliphatic residue, then R ⁷ does not represent methyl or ethyl.

[00390] In further embodiments, R ¹ represents the partial structure: wherein: m is 0, 1 or 2 and R ^8a and R ^8b each independently of one another represent H, F, a O — C1-4 aliphatic residue or a C1-4 aliphatic residue; R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or wherein m is 0, R ^8a and R ^8b each independently of one another represent H, F, a O — Ci- 4 aliphatic residue or a C1-4 aliphatic residue; and R ^8c denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cisaliphatic residue, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ , C(=O)— O— C ₂ H ₅ and phenyl, wherein phenyl may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cis-aliphatic residue, C(=O) — CH3, C(=O) — C ₂ H>, C(=O) — O — CH3 and C(=O) — O — C ₂ Hs, R ² is selected from the group consisting of H; F; Cl; CF3; CH3; C ₂ HS, iso-propyl; cyclopropyl; and O — CH3; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently of one another selected from the group consisting of H; F; Cl; Br; CF3; CN; OCF3 and NO ₂ ;

R ⁷ denotes a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Cisaliphatic residue, a C(=0) — O — Cis-aliphatic residue, OCF3, SH, SCF3, a S — Cis-aliphatic residue, CF3, and a Cis-aliphatic residue, wherein the Cis-aliphatic residue in each case is unsubstituted, and on the condition that if R ⁷ represents an unsubstituted aliphatic residue, then R ⁷ does not represent methyl or ethyl.

[00391] In further embodiments, the Kv7 channel activator may be selected from the group consisting of:

[00392] N-[(3-fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4-methyl-7- (trifluoromethyl)- quinoline-3 -carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2-(2-methoxy-ethoxy)-4- methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]- 2-(2-hydroxy-ethoxy)-4-methyl-7-(trifluoromethyl)-quinoline- 3-carboxylic acid amide; N- [(3-fluorophenyl)-methyl]-2-isopropoxy-4-methyl-7-(trifluoro methyl)-quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2-isopropoxy-4-methyl-7-(trifluo romethyl)- quinoline-3 -carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-4-methyl-2-(2,2,2-trifluoro- ethoxy)-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; and N-[(3-fluorophenyl)- methyl]-2-isopropoxy-4-(trifluoromethyl)-quinoline-3-carboxy lic acid amide; respectively in the form of the free compounds; the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio or of an individual enantiomer or diastereomer; or in the form of the salts of physiologically acceptable acids or bases.

Formula 27

[00393] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 27. Such compounds are described in International Publication No. WO2012025238A1, published March 1, 2012 and corresponding to International Application No. PCTZEP2011/004279 filed August 26, 2011; US Patent No. 8,445,512 issued May 21, 2013 and corresponding to US Application No. 13/218,556 filed August 26, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 27, these references incorporated by reference herein control.

[00394] In an embodiment, the Kv7 channel activator is a compound according to formula 27: Formula 27 wherein: R ¹ represents a Cnio-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents H; F; Cl; Br; I; CN; CF3; C(=O)H; NO2; OCF3; SCF3; a C1-4- aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — C1-4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the Ci- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, wherein the Cn 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-8- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(=O)H; C(=0)— OH; C(=O)— NH ₂ ; SCF ₃ ; S(=O) ₂ — OH; NO ₂ ; OCF ₃ ; a Cis-aliphatic residue, a C(=O) — Ci-4 aliphatic residue, a C(=O) — O — Ci- ₄ aliphatic residue, a C(=O) — NH — Ci- 4 aliphatic residue, a C(=O) — N(CI- ₄ aliphatic residue) ₂ , wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O) ₂ — C1-4- aliphatic residue, a S(=O) ₂ — O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(CI-4 aliphatic residue), a N(CI- ₄ aliphatic residue) ₂ , a NH — C(=O) — Ci- ₄ aliphatic residue, a NH — S(=O) ₂ — Ci-4-aliphatic residue, a N(CI- ₄ aliphatic residue)-C(=O) — C1-4 aliphatic residue, or a N(CI-4 aliphatic residue)-S(=O) ₂ — C1-4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; a C ₃ -6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- ₄ aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is H, R ⁷ represents a C ₂ -io-aliphatic residue, unsubstituted or mono- or polysubstituted; a C ₃ -io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the binding is carried out via a carbon atom of the 3 to 10 membered heterocycloaliphatic residue, in which an “aliphatic group” and “aliphatic residue” can in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” can in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group” and an “aliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue) ₂ , a NH — C(=O) — Ci- ₄ aliphatic residue, a NH — S(=O) ₂ — Ci- 4 aliphatic residue, =0, OH, OCF ₃ , a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF ₃ , a S — Ci-4-aliphatic residue, S(=O) ₂ OH, a S(=O) ₂ — Ci-4-aliphatic residue, a S(=O) ₂ — O — Ci-4-aliphatic residue, a S(=O) ₂ — NH — Ci-4-aliphatic residue, CN, CF ₃ , CHO, COOH, a Ci-4-aliphatic residue, a C(=O) — Ci-4-aliphatic residue, a C(=O) — O — Cisaliphatic residue, a C ₃ -6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH ₂ , a C(=O) — NH(CI-4 aliphatic residue), and a C(=O) — N(CI- ₄ aliphatic residue)2; in which “mono- or polysubstituted” with respect to a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=0)20H, a S(=0)2 — Cisaliphatic residue, a S(=0)2 — O — Cis-aliphatic residue, a S(=0)2 — NH — Cis-aliphatic residue, CN, CF3, CHO, COOH, a Cis-aliphatic residue, a C(=0) — Cis-aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0) — NH2, a C(=0) — NH(CI-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, aliphatic residue), an N(Ci-

4 aliphatic residue^, an NH — C(=0) — C1-4 aliphatic residue, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O) ₂ OH, a S(=0)2 — Ci-4-aliphatic residue, a S(=0)2 — O — Ci-4-aliphatic residue, a S(=0)2 — NH — Ci-4-aliphatic residue, CN, CF3, C(=0)H, C(=0)0H, a Ci-4-aliphatic residue, a C(=0) — Ci-4-aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=0) — NH2, a C(=0) — NH(CI-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; in the form of the free compounds, the racemate, the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio, or of an individual enantiomer or diastereomer, or in the form of the salts of physiologically acceptable acids or bases.

[00395] In further embodiments, R ¹ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— O ₂ H ₅ , a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of

F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, C(=O) — CH3, C(=O) — O2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Ci- 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the aryl or the heteroaryl residue may in each case be optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN and C(=0) — OH, R ² represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF ₃ ; OCF ₃ ; SCF ₃ ; C(=0)H; C(=0)— OH; C(=0)— NH ₂ ; S(=0) ₂ — OH; N0 ₂ ; a Ci- ₄ - aliphatic residue, a C(=0) — C1-4 aliphatic residue, a C(=0) — O — C1-4 aliphatic residue, a C(=0) — NH — C1-4 aliphatic residue, a C(=0) — N(CI-4 aliphatic residue^, a O — Cisaliphatic residue, a O — C(=0) — Cis-aliphatic residue, a S — Cis-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, a NH(CI-4 aliphatic residue), a N(CI-4 aliphatic residue^, a NH — C(=0) — C1-4 aliphatic residue, and a NH — S(=0)2 — Cis-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and a O — Ci- 4-aliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, on the condition that at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is H, R ⁷ denotes a C2-10- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Cisaliphatic residue, CF3, CN, a Cis-aliphatic residue and C(=0) — OH, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Cis-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00396] In further embodiments, R ² represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted aliphatic residue, a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a C1-4- aliphatic residue and a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted aliphatic residue, and wherein the Cs-e-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a Ci-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue.

[00397] In further embodiments, R ² is 1.

[00398] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF ₃ ; OCF ₃ ; SCF ₃ ; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; S(=O) ₂ — OH; NO ₂ ; a Ci-4-aliphatic residue, a C(=O) — Ci-4 aliphatic residue, a C(=O) — O — Ci-4 aliphatic residue, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O) ₂ — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and a O — Ci-4-aliphatic residue; a C ₃ -6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted Ci-4 aliphatic group, on the condition that at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is 1.

[00399] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO ₂ ; CF ₃ ; CN; OCF ₃ ; SCF ₃ ; a (C=O) — Ci-4 aliphatic residue, a Ci-4 aliphatic residue, O — Ci-4 aliphatic residue, a S — Ci-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and O — CH ₃ , on the condition that at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is 1. [00400] In further embodiments, R ¹ represents the partial structure:

[00401] Wherein, m denotes 0, 1, 2, 3 or 4, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4 aliphatic residue or C(=O) — OH, or together denote =0, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, or denotes a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— O ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— O2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF ₃ , CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— O ₂ H ₅ , C(=O)— O— CH3 and C(=O) — O — O2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH.

[00402] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, or 2, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, an O — C1-4 aliphatic residue or a C1-4 aliphatic residue, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Cisaliphatic residue, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cis-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — O2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — O2H5, C(=O) — O — CH3 and C(=O) — O — O2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, CF3 a C1-4- aliphatic residue and C(=O) — OH.

[00403] In further embodiments, R ⁷ denotes a C2-io-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Cn 4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00404] In further embodiments, R ⁷ denotes a C2-s-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a unsubstituted Cn 8 aliphatic group, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00405] In further embodiments, R ¹ represents the partial structure: wherein:_m is 0, 1 or 2 and R ^8a and R ^8b each independently of one another represent H, F, a O — Ci-4 aliphatic residue or a Ci-4 aliphatic residue; R ^8c denotes a Ci-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — Ci-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or denotes a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or wherein m is 0, R ^8a and R ^8b each independently of one another represent H, F, a O — Ci- 4 aliphatic residue or a C1-4 aliphatic residue; and R ^8c denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cisaliphatic residue, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ , C(=O)— O— C ₂ H ₅ and phenyl, wherein phenyl may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cis-aliphatic residue, C(=O) — CH3, C(=O) — C ₂ H>, C(=O) — O — CH3 and C(=O) — O — C ₂ Hs, R ² is selected from the group consisting of H; F; Cl; CF3; CH3; C ₂ HS, iso-propyl; cyclopropyl; and O — CH3; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently of one another selected from the group consisting of H; F; Cl; Br; CH3; CF3; CN; OCF3 and NO ₂ ; on the condition that at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is H, R ⁷ denotes ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert. -butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl or propenyl (— CH ₂ CH=CH ₂ , — CH=CH— CH ₃ , — C(=CH ₂ )— CH ₃ ), in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, O — CH3, CF3, and N(CH ₂ ) ₂ , or denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, piperidinyl tetrahydrofuranyl, or tetrahydropyranyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, an O — Ci-4-aliphatic residue, CF3, and a C1-4- aliphatic residue, wherein the Ci-4-aliphatic residue in each case is unsubstituted, and wherein cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, piperidinyl tetrahydrofuranyl, or tetrahydropyranyl may in each case be optionally bridged, via an unsubstituted C1-4 aliphatic group, on the condition that if R ⁷ denotes piperidinyl tetrahydrofuranyl, or tetrahydropyranyl, each of these residues is linked via a carbon atom.

[00406] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 4-methyl-2-propyl-N-(thiophene-2-yl-methyl)-7-(trifluorometh yl)-quinoline-3- carboxylic acid amide; N-(cycloheptyl-methyl)-4-methyl-2-propyl-7-(trifluoromethyl) - quinoline-3 -carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-4-methyl-2-propyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-4-methyl- 2-propyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; 2-ethyl-N-[(4-fluorophenyl)- methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; 2-ethyl-N-[(3- fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline -3-carboxylic acid amide; N- [(4-fluorophenyl)-methyl]-2-isopropyl-4-methyl-7-(trifluorom ethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2-isopropyl-4-methyl-7-(trifluor omethyl)- quinoline-3 -carboxylic acid amide; 2-cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; 2-cyclopropyl-N-[(3-fluorophenyl)- methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3- fluorophenyl)-methyl]-2-isopropyl-7-(trifluoromethyl)-quinol ine-3-carboxylic acid amide; N- [(4-fluorophenyl)-methyl]-2-isopropyl-7-(trifluoromethyl)-qu inoline-3-carboxylic acid amide; 2-tert-butyl-N-[(3-fluorophenyl)-methyl]-7-(trifluoromethyl) -quinoline-3-carboxylic acid amide; 2-tert-butyl-N-[(4-fluorophenyl)-methyl]-7-(trifluoromethyl) -quinoline-3- carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2-(methoxymethyl)-4-methyl-7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2- (methoxymethyl)-4-methyl-7-(trifluoromethyl)-quinoline-3-car boxylic acid amide; N-[(3- fluorophenyl)-methyl]-2-(hydroxymethyl)-4-methyl-7-(trifluor omethyl)-quinoline-3- carboxylic acid amide; 2-(2,2-dimethyl-propyl)-N-[(3-fluorophenyl)-methyl]-4-methyl -7- (trifluoromethyl)-quinoline-3-carboxylic acid amide; 2-(2,2-dimethyl-propyl)-N-[(4- fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline -3-carboxylic acid amide; 2- cyclopentyl-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluor omethyl)-quinoline-3- carboxylic acid amide; 2-cyclopentyl-N-[(4-fluorophenyl)-methyl]-4-methyl-7- (trifluoromethyl)-quinoline-3 -carboxylic acid amide; N-(4,4-dimethyl-pentyl)-4-methyl-2- propyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]- 4-methyl-2-[(E)-prop-l-enyl]-7-(trifluoromethyl)-quinoline-3 -carboxylic acid amide; N-[(3- fluorophenyl)-methyl]-4-methyl-2-(2-methyl-prop-l-enyl)-7-(t rifluoromethyl)-quinoline-3- carboxylic acid amide; 7-bromo-2-ethyl-N-[(3-fluorophenyl)-methyl]-4-methyl-quinoli ne-3- carboxylic acid amide; 7-bromo-2-ethyl-N-[(4-fluorophenyl)-methyl]-4-methyl-quinoli ne-3- carboxylic acid amide; 7-bromo-2-cyclopropyl-N-[(3-fluorophenyl)-methyl]-4-methyl- quinoline-3 -carboxylic acid amide; 7-bromo-2-cyclopropyl-N-[(4-fluorophenyl)-methyl]-4- methyl-quinoline-3 -carboxylic acid amide; 7-bromo-N-[(3-fluorophenyl)-methyl]-2- isopropyl-4-methyl-quinoline-3-carboxylic acid amide; 7-bromo-N-[(4-fluorophenyl)- methyl]-2-isopropyl-4-methyl-quinoline-3-carboxylic acid amide; 2-(dimethylaminomethyl)- N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-qui noline-3-carboxylic acid amide; 2-ethyl-N-[(4-fluoro-3-methyl-phenyl)-methyl]-4-methyl-7-(tr ifluoromethyl)- quinoline-3 -carboxylic acid amide; 7-cyano-2-ethyl-N-[(3-fluorophenyl)-methyl]-4-methyl- quinoline-3 -carboxylic acid amide; 2-ethyl-N-[(3-fluoro-4-methyl-phenyl)-methyl]-4-methyl- 7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; 7-cyano-2-ethyl-N-[(4-fluorophenyl)- methyl]-4-methyl-quinoline-3-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-4-methyl- 2-(2-methyl-propyl)-7-(trifluoromethyl)-quinoline-3-carboxyl ic acid amide; 7-cyano-2- cyclopropyl-N-[(3-fluorophenyl)-methyl]-4-methyl-quinoline-3 -carboxylic acid amide; 7- cyano-2-cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-qui noline-3-carboxylic acid amide; 7-cyano-N-[(3-fluorophenyl)-methyl]-2-isopropyl-4-methyl-qui noline-3-carboxylic acid amide; and 7-cyano-N-[(4-fluorophenyl)-methyl]-2-isopropyl-4-methyl-qui noline-3- carboxylic acid amide; respectively in the form of the free compounds; the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio or of an individual enantiomer or diastereomer; or in the form of the salts of physiologically acceptable acids or bases.

Formula 28

[00407] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 28. Such compounds are described in International Publication No. W02012028300A1, published March 8,2012 and corresponding to International Application No. PCT/EP2011/004369 filed August 31, 2011; US Patent No. 8,618,129 issued December 31, 2013 and corresponding to US Application No. 13/222,023 filed August 31, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 28, these references incorporated by reference herein control.

[00408] In an embodiment, the Kv7 channel activator is a compound according to formula 28: wherein, R ¹ represents a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue, unsubstituted or mono- or polysubstituted and optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents F; Cl; Br; I; CN; CF3; C(=O)H; NO2; OCF3; SCF3; a C1-4- aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — C1-4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the Ci- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, wherein the Cn 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; SCF ₃ ; S(=O) ₂ — OH; NO ₂ ; OCF ₃ ; a Ci- ₄ -aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — Cn 4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — C1-4- aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(CI-4 aliphatic residue), a N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — Ci-4-aliphatic residue, a N(CI-4 aliphatic residue)-C(=O) — C1-4 aliphatic residue, or a N(CI-4 aliphatic re si due) S (=0)2 — C1-4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ⁷ represents a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, in which an “aliphatic group” and “aliphatic residue” can in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” can in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group” and an “aliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, OH, =0, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=0)2 — Ci-4-aliphatic residue, a S(=0)2 — O — Ci-4-aliphatic residue, a S(=0)2 — NH — Cisaliphatic residue, CN, CF3, CHO, COOH, a Cis-aliphatic residue, a C(=0) — Cis-aliphatic residue, a C(=0) — O — Cis-aliphatic residue, a C3-6-cycloaliphatic residue, C(=0) — NH2, a C(=0) — NH(CI-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=0)2 — Cisaliphatic residue, a S(=0)2 — O — Cis-aliphatic residue, a S(=0)2 — NH — Cis-aliphatic residue, CN, CF3, CHO, COOH, a Cis-aliphatic residue, a C(=0) — Cis-aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0) — NH2, a C(=0) — NH(Ci-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, aliphatic residue), an N(Ci-

4 aliphatic residue^, an NH — C(=0) — C1-4 aliphatic residue, an NH — S(=0)2 — C1-4 aliphatic residue, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=0)2 — Ci-4-aliphatic residue, a S(=0)2 — O — Ci-4-aliphatic residue, a S(=0)2 — NH — Ci-4-aliphatic residue, CN, CF3, C(=0)H, C(=0)0H, a Ci-4-aliphatic residue, a C(=0) — Ci-4-aliphatic residue, a C(=0) — O — C1-4- aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=0) — NH2, a C(=0) — NH(C 1-4 aliphatic residue), and a C(=0) — N(CI-4 aliphatic residue^; in the form of the free compounds, the racemate, the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio, or of an individual enantiomer or diastereomer, or in the form of the salts of physiologically acceptable acids or bases.

[00409] In further embodiments, R ¹ denotes a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, and wherein the C3-io-cycloaliphatic residue may optionally be bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, C(=0) — CH3, C(=0) — C2H5, C(=0) — O — CH3 and C(=0) — O — C2H5, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the aryl or the heteroaryl residue may in each case be optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN and C(=0) — OH, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF ₃ ; OCF ₃ ; SCF ₃ ; C(=0)H; C(=0)— OH; C(=0)— NH ₂ ; S(=0) ₂ — OH; N0 ₂ ; a Ci-4-aliphatic residue, a C(=0) — C1-4 aliphatic residue, a C(=0) — O — C1-4 aliphatic residue, a C(=0) — NH — C1-4 aliphatic residue, a C(=0) — N(CI-4 aliphatic residue^, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, a NH(CI-4 aliphatic residue), a N(CI-4 aliphatic residue^, a NH — C(=0) — C1-4 aliphatic residue, and a NH — S(=0)2 — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and a O — Ci- 4-aliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, a Ci-4-aliphatic residue and a O — Cisaliphatic residue, and in each case optionally bridged via an unsubstituted Ci-4 aliphatic group, R ⁷ denotes a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Cis-aliphatic residue, CF3, CN, a Cis-aliphatic residue and C(=0) — OH, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, =0, OH, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [00410] In further embodiments, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a C1-4- aliphatic residue and a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue.

[00411] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF ₃ ; OCF ₃ ; SCF ₃ ; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; S(=O) ₂ — OH; NO2; a Ci-4-aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, and a O — Ci-4-aliphatic residue; a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group.

[00412] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO2; CF3; CN; OCF3; SCF3; a (C=O) — C1-4 aliphatic residue, a C1-4 aliphatic residue, O — C1-4 aliphatic residue, a S — C1-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and o— CH ₃ .

[00413] In further embodiments, at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is H. [00414] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, 2, 3 or 4, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, NO2, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4 aliphatic residue or C(=O) — OH, or together denote =0, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, =0, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes a C3-io-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Ci-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Ci-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Ci-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, C(=0) — CH3, C(=0) — C2H5, C(=0) — O — CH3 and C(= to

6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Cn 4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, and wherein the C3-

6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH.

[00415] In further embodiments, R ¹ represents the partial structure wherein, m denotes 0, 1, or 2, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, an O — C1-4 aliphatic residue or a C1-4 aliphatic residue, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a C1-4- aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, in each case may be unsubstituted or mono- or polysubstituted, preferably unsubstituted or mono- or disubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci- 4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, preferably with at least one substituent selected from the group consisting of F, Cl, CH3, O — CH3, CF3 and OCF3, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, CF3 a C1-4- aliphatic residue and C(=0) — OH.

[00416] In further embodiments, R ⁷ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, =0, OH, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — Ci- 4 aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00417] In further embodiments, R ⁷ denotes a Ci-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue in each case may be bridged via an unsubstituted C1-8 aliphatic group, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00418] In further embodiments, R ¹ represents the partial structure: wherein: m is 0, 1 or 2 and R ^8a and R ^8b each independently of one another represent H, F, a O — C1-4 aliphatic residue or a C1-4 aliphatic residue; R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or wherein m is 0, R ^8a and R ^8b each independently of one another represent H, F, a O — Ci-4 aliphatic residue or a C1-4 aliphatic residue; R ^8c denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cisaliphatic residue, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ , C(=O)— O— C ₂ H ₅ and phenyl, wherein phenyl may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cis-aliphatic residue, C(=O) — CH3, C(=O) — C ₂ H>, C(=O) — O — CH3 and C(=O) — O — C ₂ Hs, R ² is selected from the group consisting of F; Cl; CF3; CH3; C ₂ HS, iso-propyl; cyclopropyl; and O — CH3; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently of one another selected from the group consisting of H; F; Cl; CF3; CN; OCF3 and NO ₂ ; R ⁷ denotes a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, and an unsubstituted O — Ci-4-aliphatic residue.

[00419] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-(3-fluorobenzyl)-2,4-dimethyl-l-oxo-7-(trifluoromethyl)-l, 2- dihydroisoquinoline-3-carboxamide; N-(3-fluorobenzyl)-4-methyl-l-oxo-2-propyl-7- (trifluoromethyl)-l,2-dihydroisoquinoline-3-carboxamide; 2-ethyl-N-(3-fluorobenzyl)-4- methyl-l-oxo-7-(trifluoromethyl)-l,2-dihydroisoquinoline-3-c arboxamide; N-(3- fluorobenzyl)-2-isopropyl-4-methyl-l-oxo-7-(trifluoromethyl) -l,2 dihydroisoquinoline-3- carboxamide; andN-(3-fluorobenzyl)-2-(2-methoxyethyl)-4-methyl-l-oxo-7- (trifluoromethyl)-l,2-dihydroisoquinoline-3-carboxamide; respectively in the form of the free compounds; the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio or of an individual enantiomer or diastereomer; or in the form of the salts of physiologically acceptable acids or bases.

Formula 29

[00420] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 29. Such compounds are described in US Patent No. 8,653,102 issued February 18, 2014and corresponding to US Application No. 13/218,579 filed August 26, 2011; International Publication No. PCT/EP2011/004280, published March 1, 2012, and corresponding to International Application No. WO2012025239Alfiled August 25, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 29, these references incorporated by reference herein control.

[00421] In an embodiment, the Kv7 channel activator is a compound according to formula 29: Formula 29 wherein: X denotes O or S, R ¹ represents a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ² represents F; Cl; Br; I; CN; CF3; C(=O)H; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — C1-4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, wherein the Cn 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; SCF ₃ ; S(=O) ₂ — OH; NO ₂ ; OCF ₃ ; a Ci- ₄ -aliphatic residue, a C(=O) — C1-4 aliphatic residue, a C(=O) — O — C1-4 aliphatic residue, a C(=O) — NH — Cn 4 aliphatic residue, a C(=O) — N(CI-4 aliphatic residue^, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O)2 — C1-4- aliphatic residue, a S(=0)2 — O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(CI-4 aliphatic residue), a N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — Ci-4-aliphatic residue, a N(CI-4 aliphatic residue)-C(=O) — C1-4 aliphatic residue, or a N(CI-4 aliphatic residue)-S(=O)2 — C1-4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; a Cs-e-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R ⁷ represents a Ci-io-aliphatic residue, unsubstituted or mono- or polysubstituted; a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, in which an “aliphatic group” and “aliphatic residue” can in each case be branched or unbranched, saturated or unsaturated, in which a “cycloaliphatic residue” and a “heterocycloaliphatic residue” can in each case be saturated or unsaturated, in which “mono- or polysubstituted” with respect to an “aliphatic group” and an “aliphatic residue” relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Cisaliphatic residue, S(=O)2OH, a S(=O)2 — Cis-aliphatic residue, a S(=O)2 — O — Cis-aliphatic residue, a S(=O)2 — NH — Cis-aliphatic residue, CN, CF3, CHO, COOH, a Cis-aliphatic residue, a C(=O) — Cis-aliphatic residue, a C(=O) — O — Cis-aliphatic residue, a C3-6- cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH2, a C(=O) — NH(CI-4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to a “cycloaliphatic residue” and a “heterocycloaliphatic residue” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, a NH — C(=O) — C1-4 aliphatic residue, a NH — S(=O)2 — C1-4 aliphatic residue, =0, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=0)20H, a S(=0)2 — Cisaliphatic residue, a S(=0)2 — O — Cis-aliphatic residue, a S(=O)2 — NH — Cis-aliphatic residue, CN, CF3, CHO, COOH, a Cis-aliphatic residue, a C(=O) — Cis-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=O) — NH2, a C(=O) — NH(CI-4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue^; in which “mono- or polysubstituted” with respect to “aryl” and a “heteroaryl” relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Ci-

4 aliphatic residue^, an NH — C(=O) — C1-4 aliphatic residue, an NH — S(=O)2 — C1-4 aliphatic residue, OH, OCF3, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, SH, SCF3, a S — Ci-4-aliphatic residue, S(=O)2OH, a S(=O)2 — Ci-4-aliphatic residue, a S(=O)2 — O — Ci-4-aliphatic residue, a S(=O)2 — NH — Ci-4-aliphatic residue, CN, CF3, C(=O)H, C(=O)OH, a Ci-4-aliphatic residue, a C(=O) — Ci-4-aliphatic residue, a C(=O) — O — C1-4- aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(=O) — NH2, a C(=O) — NH(C 1-4 aliphatic residue), and a C(=O) — N(CI-4 aliphatic residue^; with the exception of the following compound: 1-ethyl- N-(4-methoxybenzyl)-4-methyl-2-oxo-l,2-dihydroquinoline-3 -carboxamide, in the form of the free compounds, the racemate, the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio, or of an individual enantiomer or diastereomer, or in the form of the salts of physiologically acceptable acids or bases.

[00422] In further embodiments, R ¹ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), OH, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn 8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Ci-

4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I,

NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — Ci-

4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O)— OH, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ and C(=O)— O— c residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, an O — C1-4 aliphatic residue, OCF3, O — CH2 — OH, O — CH2 — O — CH3, SH, SCFs, a S — Ci-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0) — OH, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, and wherein the C3- 6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(Cn 4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — Ci- 4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the aryl or the heteroaryl residue may in each case be optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN and C(=0) — OH, X represents O or S; R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a C3- 6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted and in each case optionally bridged via a Ci- 4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(=0)H; C(=0)— OH; C(=0)— NH ₂ ; S(=0) ₂ — OH; N0 ₂ ; a Ci- ₄ -aliphatic residue, a C(=0) — C1-4 aliphatic residue, a C(=0) — O — C1-4 aliphatic residue, a C(=0) — NH — Cn 4 aliphatic residue, a C(=0) — N(CI-4 aliphatic residue^, a O — Ci-4-aliphatic residue, a O — C(=0) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=0)2 — Ci-4-aliphatic residue, a NH(CI-4 aliphatic residue), a N(CI-4 aliphatic residue^, a NH — C(=0) — C1-4 aliphatic residue, and a NH — S(=0)2 — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and a O — Ci-4-aliphatic residue; a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, R ⁷ denotes a Ci- 10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), OH, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, a C(=0) — O — Ci-4-aliphatic residue and C(=0) — OH, wherein the Ci- 4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to

10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=O) — OH, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a Cn

8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(Ci- 4 aliphatic residue), OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=O) — OH, on the condition that if

R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00423] In further embodiments, R ² represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a O — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted aliphatic residue, a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a C1-4- aliphatic residue and a O — Ci-4-aliphatic residue, wherein the Ci -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and an unsubstituted aliphatic residue, and wherein the Cs-e-cycloaliphatic residue or the 3 to 6 membered heterocycloaliphatic residue may in each case be optionally bridged via a Ci-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an unsubstituted Ci-4-aliphatic residue and an unsubstituted O — Ci-4-aliphatic residue.

[00424] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another represent H; F; Cl; Br; I; CN; CF ₃ ; OCF ₃ ; SCF ₃ ; C(=O)H; C(=O)— OH; C(=O)— NH ₂ ; S(=O) ₂ — OH; NO ₂ ; a Ci-4-aliphatic residue, a C(=O) — Ci-4 aliphatic residue, a C(=O) — O — Ci-4 aliphatic residue, a O — Ci-4-aliphatic residue, a O — C(=O) — Ci-4-aliphatic residue, a S — Ci-4-aliphatic residue, a S(=O) ₂ — Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, and a O — Ci-4-aliphatic residue; a Cs-e- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, =0, OH, a Ci-4-aliphatic residue and a O — Ci-4-aliphatic residue, and in each case optionally bridged via an unsubstituted Ci-4 aliphatic group.

[00425] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each independently of one another are selected from the group consisting of H; F; Cl; Br; I; NO ₂ ; CF ₃ ; CN; OCF ₃ ; SCF ₃ ; a (C=O) — Ci-4 aliphatic residue, a Ci-4 aliphatic residue, O — Ci-4 aliphatic residue, a S — Ci-4 aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, and o— CH ₃ .

[00426] In further embodiments, at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is H.

[00427] In further embodiments, R ¹ represents the partial structure: wherein, m denotes 0, 1, 2, 3 or 4, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, NO ₂ , NH ₂ , a NH(Ci-4 aliphatic residue), OH, an O — Ci-4 aliphatic residue, OCF ₃ , SH, SCF ₃ , a S — Ci-4 aliphatic residue, CF ₃ , CN, a Ci-4 aliphatic residue or C(=O) — OH, R ^8c denotes a Ci-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO ₂ , NH ₂ , an NH(Ci- 4 aliphatic residue), OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue, C(=0) — OH, a C3-6 cycloaliphatic residue and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH ₃ and C(=0)— O— c residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue)2, OH, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF ₃ , CN, a Ci-4-aliphatic residue, C(=0)— OH, C(=0)— CH ₃ , C(=0)— C ₂ H ₅ , C(=0)— O— CH3 and C(=0) — O — C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(CI-4 aliphatic residue), an N(CI-4 aliphatic residue^, OH, =0, an O — Ci- 4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, a Ci-4-aliphatic residue and C(=0) — OH.

[00428] In further embodiments, R ¹ represents the partial structure: wherein: m denotes 0, 1, or 2, R ^8a and R ^8b each independently of one another represent H, F, Cl, Br, I, an O — C1-4 aliphatic residue or a C1-4 aliphatic residue, R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an O — C1-4 aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, CF3 and an unsubstituted O — Ci- 4-aliphatic residue, or denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, benzyl, phenyl, thienyl or pyridyl, wherein benzyl, phenyl, thienyl and pyridyl, may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Ci-4-aliphatic residue, C(=O) — CH3, C(=O) — C2H5, C(=O) — O — CH3 and C(=O) — O — C2H5, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — C1-4 aliphatic residue, OCF3, CF3 a C1-4- aliphatic residue and C(=0) — OH.

[00429] In further embodiments, R ⁷ denotes a Ci-10-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, an O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, COOH, CF3, CN, and a Ci-4-aliphatic residue wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, CN, a Ci-4-aliphatic residue, a C3-6 cycloaliphatic residue, and a 3 to 6 membered heterocycloaliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted O — Ci-4-aliphatic residue, and wherein the C3-6 cycloaliphatic residue and the 3 to 6 membered heterocycloaliphatic residue may in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, =0, an O — C1-4 aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, an O — Ci- 4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — C1-4 aliphatic residue, CF3, CN, and a Ci-4-aliphatic residue, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00430] In further embodiments, R ⁷ denotes a Ci-s-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci-4-aliphatic residue, COOH, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CF3 and an unsubstituted aliphatic residue, or denotes a Cs-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, =0, an O — Ci-4 aliphatic residue, OCF3, SCF3, a S — C1-4 aliphatic residue, a C(=O) — O — Ci-4-aliphatic residue, CF3, and a Ci-4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, OCF3, CF3 and an unsubstituted C1-4- aliphatic residue, and wherein the C3-io-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue in each case may be bridged via an unsubstituted C1-8 aliphatic group, on the condition that if R ⁷ denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom.

[00431] In further embodiments, R ¹ represents the partial structure: wherein: m is 0, 1 or 2 and R ^8a and R ^8b each independently of one another represent H, F, a O — C1-4 aliphatic residue or a C1-4 aliphatic residue; R ^8c denotes a C1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or denotes a C3-io-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, an unsubstituted O — C1-4 aliphatic residue, CF3, and an unsubstituted Ci-4-aliphatic residue, or wherein m is 0, R ^8a and R ^8b each independently of one another represent H, F, a O — Cn 4 aliphatic residue or a C1-4 aliphatic residue; and R ^8c denotes an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cisaliphatic residue, C(=O)— CH ₃ , C(=O)— C ₂ H ₅ , C(=O)— O— CH ₃ , C(=O)— O— C ₂ H ₅ and phenyl, wherein phenyl may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — C1-4 aliphatic residue, OCF3, CF3, CN, a Cis-aliphatic residue, C(=O) — CH3, C(=O) — C ₂ H>, C(=O) — O — CH3 and C(=O) — O — C2H5, X represents O or S; R ² is selected from the group consisting of F; Cl; Br; CF3; CH3; C2H5, iso-propyl; cyclopropyl; and O — CH3; R ³ , R ⁴ , R ⁵ and R ⁶ are each independently of one another selected from the group consisting of H; F; Cl; Br; CF3; CN; OCF3 and NO2; R ⁷ denotes a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, an O — Ci- 4-aliphatic residue, COOH, a C(=O) — O — Ci-4-aliphatic residue, OCF3, SH, SCF3, a S — Cisaliphatic residue, CF3, and a Cis-aliphatic residue, wherein the Cis-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, and an unsubstituted O — C 1.4-al iphatic residue, or denotes an unsubstituted C3-6-cycloaliphatic residue or an unsubstituted 3 to 6 membered heterocycloaliphatic residue, on the condition that if R ⁷ denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom.

[00432] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[(3-Fluorophenyl)-methyl]-l,4-dimethyl-2-oxo-7-(trifluorom ethyl)-lH- quinoline-3 -carboxylic acid amide; l-Butyl-N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-7- (trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l,4- dimethyl-2-thioxo-7-(trifluoromethyl)-lH-quinoline-3-carboxy lic acid amide; N-[(3- Fluorophenyl)-methyl]-l-(2-methoxy-ethyl)-4-methyl-2-oxo-7-( trifluoromethyl)-lH- quinoline-3 -carboxylic acid amide; l-Ethyl-N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-7- (trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-l,4- dimethyl-2-oxo-7-(trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(4- Fluorophenyl)-methyl]-l-(2-methoxy-ethyl)-4-methyl-2-oxo-7-( trifluoromethyl)-lH- quinoline-3 -carboxylic acid amide; l-Ethyl-N-[(4-fluorophenyl)-methyl]-4-methyl-2-oxo-7- (trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l,4- dimethyl-2-oxo-lH-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l-(2- methoxy-ethyl)-4-methyl-2-oxo-lH-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)- methyl]-4-methyl-2-oxo-l-propyl-7-(trifluoromethyl)-lH-quino line-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-l-(3-methyl-butyl)-2-ox o-7-(trifluoromethyl)-lH- quinoline-3 -carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-l-(4-methyl- pentyl)-2-oxo-7-(trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-l-(3-methoxy-propyl)-4-methyl-2-oxo-7- (trifluoromethyl)-lH- quinoline-3 -carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l-[2-(2-methoxy-ethoxy)- ethyl]-4-methyl-2-oxo-7-(trifluoromethyl)-lH-quinoline-3-car boxylic acid amide; 7-Bromo- N-[(3-fluorophenyl)-methyl]-l,4-dimethyl-2-oxo-lH-quinoline- 3-carboxylic acid amide; 7- Bromo-N-[(4-fluorophenyl)-methyl]-l,4-dimethyl-2-oxo-lH-quin oline-3-carboxylic acid amide; 7-Bromo-N-[(3-fluorophenyl)-methyl]-l-(2-methoxy-ethyl)-4-me thyl-2-oxo-lH- quinoline-3 -carboxylic acid amide; 7-Bromo-N-[(4-fluorophenyl)-methyl]-l-(2-methoxy- ethyl)-4-methyl-2-oxo-lH-quinoline-3-carboxylic acid amide; 7-Cyano-N-[(3-fluorophenyl)- methyl]-l,4-dimethyl-2-oxo-lH-quinoline-3-carboxylic acid amide; 7-Cyano-N-[(4- fluorophenyl)-methyl]-l,4-dimethyl-2-oxo-lH-quinoline-3-carb oxylic acid amide; 7-Cyano- N-[(3-fluorophenyl)-methyl]-l-(2-methoxy-ethyl)-4-methyl-2-o xo-lH-quinoline-3- carboxylic acid amide; 7-Cyano-N-[(4-fluorophenyl)-methyl]-l-(2-methoxy-ethyl)-4-me thyl- 2-oxo-lH-quinoline-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-l-(2-methoxy-ethyl)- 4-methyl-2-oxo-7-(trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-(4,4-Dimethyl- pentyl)-l,4-dimethyl-2-oxo-7-(trifluoromethyl)-lH-quinoline- 3-carboxylic acid amide; 2-[3- [(3-Fluorophenyl)-methyl-carbamoyl]-4-methyl-2-oxo-7-(triflu oromethyl)-lH-quinolin-l-yl]- acetic acid methyl ester; 3-[3-[(3-Fluorophenyl)-methyl-carbamoyl]-4-methyl-2-oxo-7- (trifluoromethyl)-lH-quinolin-l-yl]-propionic acid methyl ester; 2-[3-[(3-Fluorophenyl)- methyl-carbamoyl]-4-methyl-2-oxo-7-(trifluoromethyl)-lH-quin olin-l-yl]-acetic acid; 3-[3- [(3-Fluorophenyl)-methyl-carbamoyl]-4-methyl-2-oxo-7-(triflu oromethyl)-lH-quinolin-l-yl]- propionic acid; N-[(3-Fluorophenyl)-methyl]-l-[l-(methoxymethyl)-propyl]-4-m ethyl-2-oxo- 7-(trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l- [2-methoxy-l-(methoxymethyl)-ethyl]-4-methyl-2-oxo-7-(triflu oromethyl)-lH-quinoline-3- carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l-(2-methoxy-butyl)-4-methyl-2-o xo-7- (trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l,4- dimethyl-2-oxo-7-(trifhioromethyloxy)-lH-quinoline-3-carboxy lic acid amide; 7-Fluoro-N- [(3-fluorophenyl)-methyl]-l,4-dimethyl-2-oxo-lH-quinoline-3- carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-l -(2 -methoxy- l-methyl-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)- lH-quinoline-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-l,4-dimethyl-2-thioxo- 7-(trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; 7-Chloro-N-[(3-fluorophenyl)- methyl]-l,4-dimethyl-2-oxo-lH-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)- methyl]-l-(2-hydroxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethy l)-lH-quinoline-3-carboxylic acid amide; l-(2-Ethoxy-ethyl)-N-[(3-fluorophenyl)-methyl]-4-methyl-2-ox o-7- (trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l- isopropyl-4-methyl-2-oxo-7-(trifluoromethyl)-lH-quinoline-3- carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-4-methyl-2-oxo-l-pentyl-7-(trifluorome thyl)-lH-quinoline-3- carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l-methyl-2-oxo-4-(trifluoromethy l)-lH- quinoline-3 -carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-l-(2-methoxy-propyl)-4- methyl-2-oxo-7-(trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-4-methyl-2-oxo-l-tetrahydro-pyran-4-yl -7-(trifluoromethyl)-lH- quinoline-3 -carboxylic acid amide; and N-[(3-Fluorophenyl)-methyl]-4-methoxy-l-methyl-2- oxo-7-(trifluoromethyl)-lH-quinoline-3-carboxylic acid amide; respectively in the form of the free compounds; the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers in any mixing ratio or of an individual enantiomer or diastereomer; or in the form of the salts of physiologically acceptable acids or bases.

Formula 30

[00433] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 30. Such compounds are described in International Publication No. W02010075973A1, published July 8, 2010, and corresponding to International Application No. PCT/EP2009/009040 filed December 16, 2009; US Patent No. 8,367,700 issued February 5, 2013 and corresponding to US Application No. 12/635,800 filed December 11, 2009; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 30, these references incorporated by reference herein control.

[00434] In an embodiment, the Kv7 channel activator is a compound according to formula 30: wherein, R° stands for Cnio alkyl or C2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C1-8 alkyl-bridged C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or C1-8 alkyl-bridged aryl or heteroaryl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R ¹ stands for F; Cl; Br; CN; Cnio alkyl or C2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C1-8 alkyl-bridged C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; C1-8 alkyl-bridged heteroaryl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or C1-8 alkyl-bridged aryl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be unbranched, saturated or unsaturated, unsubstituted; R ² stands for H; F; Cl; Br; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; or R ¹ and R ² together with the carbon atom binding them as ring member form a C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, each optionally fused to (hetero)aryl, unsubstituted or mono- or polysubstituted; R ³ , R ⁴ , R ⁵ and R ⁶ each mutually independently denote H; F; Cl; Br; I; NO2; CF3; CN; R°; C(=O)H; C(=O)R°;

CO2H; C(=O)OR°; CONH2; C(=O)NHR°; C(=O)N(R°) ₂ ; OH; OR ⁰ ; — O— (C1-8 alkyl)-O— ; O— C(=O)— R°; O— C(=O)— O— R°; O— (C=O)— NH— R°; O— C(=O)— N(R°) ₂ ; O— S(=O) ₂ — R°; O— S(=O) ₂ OH; O— S(=O) ₂ OR°; O— S(=O) ₂ NH ₂ ; O— S(=O) ₂ NHR°; O— S(=O) ₂ N(R°) ₂ ; NH ₂ ; NH— R°; N(R ^O ) ₂ ; NH— C(=O)— R°; NH— C(=O)— O— R°; NH— C(=O)— NH ₂ ; NH— C(=O)— NH— R°; NH— C(=O)— N(R°) ₂ ; NR°— C(=O)— R°; NR°— C(=O)— O— R°; NR°— C(=O)— NH ₂ ; NR°— C(=O)— NH— R°; NR°— C(=O)— )— N(R ^O ) ₂ ; NH— S(=O) ₂ OH; NH— S(=O) ₂ R°; NH— S(=O) ₂ OR°; NH— S(=O) ₂ NH ₂ ; NH— S(=O) ₂ NHR°; NH— S(=O) ₂ N(R°) ₂ ; NR°— S(=O) ₂ OH; NR°— S(=O) ₂ R°; NR°— S(=O) ₂ OR°; NR°— S(=O) ₂ NH ₂ ; NR°— S(=O) ₂ NHR°; NR°— S(=O) ₂ N(R°) ₂ ; SH; SR°; S(=O)R°;

S(=O) ₂ R°; S(=O) ₂ OH; S(=O) ₂ OR°; S(=O) ₂ NH ₂ ; S(=O) ₂ NHR°; or S(=O) ₂ N(R) ₂ ; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ each mutually independently stand for H; F; Cl; Br; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; R ¹¹ stands for H; F; Cl; Br; CN; or R°; R ¹² stands for H; F; Cl; Br; CN; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; R ¹³ stands for H; F; Cl; Br; CN; C1-10 alkyl or C2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; Cns alkyl-bridged C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or C2-8 alkyl-bridged aryl or heteroaryl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R ¹⁴ stands for H; F; Cl; Br; CN; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; or R ¹¹ and R ¹³ together with the carbon atoms binding them as ring members form a C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, optionally fused to (hetero)aryl, unsubstituted or mono- or polysubstituted; or R ¹¹ and R ¹² ; or R ¹³ and R ¹⁴ , together with the carbon atoms binding them as ring members form a C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, each optionally fused to (hetero)aryl, unsubstituted or mono- or polysubstituted; R ¹⁵ stands for R°; wherein “alkyl-substituted”, “heteroalkyl-substituted”, “heterocyclyl-substituted” and “cycloalkyl-substituted” stand for the substitution of one or more hydrogen atoms, each mutually independently, with F; Cl; Br; I; CN; CF3; =0; =NH; =C(NH2)2; NO2; R°; C(=0)H; C(=0)R°; C0 ₂ H; C(=0)0R°; C0NH ₂ ; C(=0)NHR°; C(=0)N(R°) ₂ ; OH; OR ⁰ ; O— (Ci- ₈ alkyl)-O; O— C(=0)— R°; O— C(=0)— O— R°; O— (C=0)— NH— R°; O— C(=0)— N(R°) ₂ ; O— S(=0) ₂ — R°; O— S(=O) ₂ OH; O— S(=O) ₂ OR°; O— S(=O) ₂ NH ₂ ; O— S(=0) ₂ NHR°; O— S(=O) ₂ N(R°) ₂ ; NH ₂ ; NH— R°; N(R ^O ) ₂ ; NH— C(=0)— R°; NH— C(=0)— O— R°; NH— C(=0)— NH ₂ ; NH— C(=0)— NH— R°; NH— C(=0)— N(R°) ₂ ; NR°— C(=0)— R°; NR°— C(=0)— O— R°; NR°— C(=0)— NH ₂ ; NR°— C(=0)— NH— R°; NR°— C(=0)— N(R°) ₂ ; NH— S(=O) ₂ OH; NH— S(=O) ₂ R°; NH— S(=O) ₂ OR°; NH— S(=O) ₂ NH ₂ ; NH— S(=0) ₂ NHR°; NH— S(=O) ₂ N(R) ₂ ; NR°— S(=O) ₂ OH; NR°— S(=O) ₂ R°; NR°— S(=O) ₂ OR°; NR°— S(=O) ₂ NH ₂ ; NR°— S(=0) ₂ NHR°; NR°— S(=O) ₂ N(R°) ₂ ; SH; SR°; S(=O)R°; S(=O) ₂ R°; S(=O) ₂ OH; S(=O) ₂ OR°; S(=O) ₂ NH ₂ ; S(=0) ₂ NHR°; or S(=O) ₂ N(R) ₂ ; wherein “aryl -substituted” and “heteroaryl-substituted” stand for the substitution of one or more hydrogen atoms, each mutually independently, with F; Cl; Br; I; NO2; CF3; CN; R°; C(=0)H; C(=0)R°; C0 ₂ H; C(=0)0R°; C0NH ₂ ; C(=0)NHR°; C(=0)N(R°) ₂ ; OH; OR ⁰ ; O— (Ci- ₈ alkyl)-O; O— C(=0)— R°; O— C(=0)— O— R°; O— (C=0)— NH— R°; O— C(=0)— N(R°) ₂ ; O— S(=0) ₂ — R°; O— S(=O) ₂ OH; O— S(=O) ₂ OR°; O— S(=O) ₂ NH ₂ ; O— S(=0) ₂ NHR°; O— S(=O) ₂ N(R°) ₂ ; NH ₂ ; NH— R°; N(R ^O ) ₂ ; NH— C(=0)— R°; NH— C(=0)— O— R°; NH— C(=0)— NH ₂ ; NH— C(=0)— NH— R°; NH— C(=0)— N(R°) ₂ ; NR°— C(=0)— R°; NR°— C(=0)— O— R°; NR°— C(=O)— NH ₂ ; NR°— C(=O)— NH— R°; NR°— C(=0)— N(R°) ₂ ; NH— S(=O) ₂ OH; NH— S(=O) ₂ R°; NH— S(=O) ₂ OR°; NH— S(=O) ₂ NH ₂ ; NH— S(=O) ₂ NHR°; NH— S(=O) ₂ N(R°) ₂ ; NR°— S(=O) ₂ OH; NR°— S(=O) ₂ R°; NR°— S(=O) ₂ OR°; NR°— S(=O) ₂ NH ₂ ; NR°— S(=O) ₂ NHR°; NR°— S(=O) ₂ N(R°) ₂ ; SH; SR°; S(=O)R°; S(=O) ₂ R°; S(=O) ₂ OH; S(=O) ₂ OR°; S(=O) ₂ NH ₂ ; S(=O) ₂ NHR°; or S(=O) ₂ N(R) ₂ ; in the form of a free compound or salt of a physiologically compatible acid or base.

[00435] In further embodiments, R ¹ stands for Cnio alkyl or C ₂ -io heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3- 7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C1-8 alkyl-bridged C3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; C1-8 alkyl-bridged heteroaryl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or C1-8 alkyl-bridged aryl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be unbranched, saturated or unsaturated, unsubstituted; R ² stands for H; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.

[00436] In further embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ each mutually independently denote H; F; Cl; Br; I; NO ₂ ; CF ₃ ; CN; R°; C(=O)(R° or H); C(=O)O(R° or H); C(=O)N(R° or H) ₂ ; OH; OR ⁰ ; — O— (C1.8 alkyl)-O— ; O— (C1-8 alkyl)-O— C1-8 alkyl; OCF ₃ ; N(R° or H) ₂ ; N(R° or H)— C(=O)— R°; N(R° or H)— C(=O)— N(R° or H) ₂ ; SH; SCF ₃ ; SR°; S(=O) ₂ R°; S(=O) ₂ O(R° or H); S(=O) ₂ — N(R° or H) ₂ .

[00437] In further embodiments, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ mutually independently stand for H; or Cn 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.

[00438] In further embodiments, R ¹¹ stands for H; F; Cl; Br; CN; C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; phenyl or heteroaryl, each unsubstituted or mono- or polysubstituted; or C1-4 alkyl-bridged phenyl or heteroaryl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; R ¹³ stands for H; F; Cl; Br; CN; C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; phenyl or heteroaryl, each unsubstituted or mono- or polysubstituted; or C ₂ -4 alkyl-bridged phenyl or heteroaryl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; or R ¹¹ and R ¹³ together with the carbon atoms binding them as ring members form a C3- 7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, optionally fused to phenyl, unsubstituted or mono- or polysubstituted. [00439] In further embodiments, R ¹² and R ¹⁴ each mutually independently stand for H; or Ci- 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.

[00440] In further embodiments, R ¹⁵ stands for C3-10 alkyl or C2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3- 7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; C1-8 alkyl-bridged C3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or C1-8 alkyl-bridged aryl or heteroaryl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.

Formula 31

[00441] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 31. Such compounds are described in International Publication No. W02010075973A1, published July 8, 2010, and corresponding to International Application No. PCT/EP2009/009040 filed December 16, 2009; US Patent No. 8,367,700 issued February 5, 2013, and corresponding to US Application No. 12/635,800 filed December 11, 2009; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 31, these references incorporated by reference herein control.

[00442] In an embodiment, the Kv7 channel activator is a compound according to formula 31 : Formula 31 wherein, R ¹ stands for Ci-io alkyl or C2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl or thienyl, each unsubstituted or mono- or polysubstituted; Ci-8 alkyl-bridged C3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Ci-8 alkyl-bridged phenyl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted; or Ci-8 alkyl-bridged thienyl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; R ³ , R ⁴ , R ⁵ and R ⁶ each mutually independently denote H; F; Cl; Br; I; NO2; CF3; CN; R°; C(=O)(R° or H); C(=O)O(R° or H); C(=O)N(R° or H) ₂ ; OH; OR ⁰ ; O— (Ci-8 alkyl)-O; O— (Ci- ₈ alkyl)-O— C1-8 alkyl; N(R° or H) ₂ ; N(R° or H)— C(=O)— R°; N(R° or H)— C(=O)— N(R° or H) ₂ ; SH; SR°; S(=O) ₂ R°; S(=O) ₂ O(R° or H); or S(=O)2 — N(R° or H)2; R ⁷ , R ⁸ , R ⁹ , R ¹⁰ each mutually independently stand for H; or C1-4 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; R ¹¹ and R ¹³ each independently stand for H; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; or R ¹¹ and R ¹³ together with the carbon atoms binding them as ring members form a C3- 7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; R ¹⁵ stands for C3-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged C3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or Ci-8 alkyl- bridged aryl or heteroaryl, each unsubstituted or mono- or polysubstituted, wherein the alkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. [00443] In further embodiments, R ¹⁵ stands for C3-10 alkyl, saturated or unsaturated; branched or unbranched, unsubstituted or mono- or polysubstituted; or is selected from the following substructures: wherein: n=0, 1, 2, 3, 4, 5, 6, 7 or 8; m=0, 1, 2 or 3; ring X can contain one or two N atoms as ring member(s); ring Y contains at least 1 heteroatom selected from N, O or S and can contain up to 3 heteroatoms mutually independently selected from N, O or S; and/or can contain one or two double bonds; R ¹⁸ and R ¹⁹ mutually independently denote H; F; Cl; Br; I; NO ₂ ; CF ₃ ; CN; R°; C(=O)(R° or H); C(=O)O(R° or H); C(=O)N(R° or H) ₂ ; OH; OR ⁰ ; O— (C1-8 alkyl)-O; O— (Ci- ₈ alkyl)-O— Ci- ₈ alkyl; N(R° or H) ₂ ; N(R° or H)— C(=O)— R°; N(R° or H)— C(=O)— N(R° or H) ₂ ; SH; SR°; S(=O) ₂ R°; S(=O) ₂ O(R° or H); or S(=O) ₂ — N(R° or H) ₂ H; or R ¹⁸ and R ¹⁹ together with the carbon or nitrogen atoms binding them as ring members form an aryl or heteroaryl fused to the phenyl or heteroaryl ring, each unsubstituted or mono- or polysubstituted; or a C3-7 cycloalkyl or heterocyclyl fused to the phenyl or heteroaryl ring, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; R ²⁰ and R ²¹ mutually independently denote H or C1-10 alkyl, saturated or unsaturated; branched or unbranched, unsubstituted or mono- or polysubstituted; or C3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; or R ²⁰ and R ²¹ together with the carbon atoms or heteroatoms binding them as ring members form an aryl or heteroaryl fused to ring Y, each unsubstituted or mono- or polysubstituted; R ²² and R ²³ mutually independently denote H; or C1-10 alkyl, saturated or unsaturated; branched or unbranched, unsubstituted.

[00444] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 4-Oxo-4-(l-phenyl-3,4-dihydroisoquinolin-2(lH)-yl)-N-(3-

(trifluoromethyl)benzyl)butyric acid amide; 4-(l-Methyl-3,4-dihydro-lH-isoquinolin-2-yl)-4- oxo-N-[[3-(trifhioromethyl)phenyl]methyl]butyric acid amide; 4-Oxo-4-(l-thien-2-yl-3,4- dihydroisoquinolin-2(lH)-yl)-N-(3-(trifluoromethyl)benzyl)bu tyric acid amide; 4-Oxo-4-[l- (4-pyridyl)-3,4-dihydro-lH-isoquinolin-2-yl]-N-[[3-(trifluor omethyl)phenyl]methyl]butyric acid amide; 4-(7-Fluoro-l-phenyl-3,4-dihydroisoquinolin-2(lH)-yl)-4-oxo- N-(3- (trifluoromethyl)benzyl)butyric acid amide; 4-(5-Fluoro-l-phenyl-3,4-dihydro-lH- isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl ]butyric acid amide; 4-Oxo-4- (l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N-[[2-(trifluorom ethyl)phenyl]methyl]butyric acid amide; 4-Oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(4-Methyl-l-phenyl-3,4-dihydro-lH- isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl ]butyric acid amide; 4-(4,4- Dimethyl-l-phenyl-l,3-dihydroisoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(7-Methoxy-l-phenyl-3,4-dihydro-lH- isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl ]butyric acid amide; 4-(5- Methoxy-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxo-N-[[ 3- (trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(3-Methyl-l-phenyl-3,4-dihydro-lH- isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl ]butyric acid amide; N-(2- Chlorophenyl)-4-oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2 -yl)butyric acid amide; N- (2,l,3-Benzothiadiazol-4-yl)-4-oxo-4-(l-phenyl-3,4-dihydro-l H-isoquinolin-2-yl)butyric acid amide; N-(l-Methyl-6-indazolyl)-4-oxo-4-(l-phenyl-3,4-dihydro-lH-is oquinolin-2-yl)butyric acid amide; N-(2-Furylmethyl)-4-oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinol in-2-yl)butyric acid amide; N-Benzyl-4-oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)b utyric acid amide; 4-Oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2-pyri dylmethyl)butyric acid amide; N-[(4-Methoxyphenyl)methyl]-4-oxo-4-(l-phenyl-3,4-dihydro-lH -isoquinolin-2- yl)butyric acid amide; 4-Oxo-N-phenethyl-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2- yl)butyric acid amide; 4-Oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4- pyridylmethyl)butyric acid amide; 4-Oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N- (3-phenylpropyl)butyric acid amide; N-[2-(lH-Indol-3-yl)ethyl]-4-oxo-4-(l-phenyl-3,4- dihydro-lH-isoquinolin-2-yl)butyric acid amide; 4-(5,7-Dimethyl-l-phenyl-3,4-dihydro-lH- isoquinolin-2-yl)-N-(4-methoxyphenyl)-4-oxobutyric acid amide; N-(2-Chlorophenyl)-4- (5,7-dimethyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-ox obutyric acid amide; -(5,7- Dimethyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N-(l-meth yl-6-indazolyl)-4-oxobutyric acid amide; 4-(5,7-Dimethyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N- (2-furylmethyl)- 4-oxobutyric acid amide; N-Benzyl-4-(5,7-dimethyl-l-phenyl-3,4-dihydro-lH-isoquinolin -2- yl)-4-oxobutyric acid amide;4 -(5,7-Dimethyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4- oxo-N-(2-pyridylmethyl)butyric acid amide; 4-(5,7-Dimethyl-l-phenyl-3,4-dihydro-lH- isoquinolin-2-yl)-N-[(4-methoxyphenyl)methyl]-4-oxobutyric acid amide; 4-(5,7-Dimethyl- l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxo-N-phenethylb utyric acid amide; 4-(5,7- Dimethyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxo-N-( 3-phenylpropyl)butyric acid amide; N-(4-Methoxyphenyl)-4-(5-methyl-l-phenyl-3,4-dihydro-lH-isoq uinolin-2-yl)-4- oxobutyric acid amide; N-(2-Chlorophenyl)-4-(5-methyl-l-phenyl-3,4-dihydro-lH- isoquinolin-2-yl)-4-oxobutyric acid amide; N-(l-Methyl-6-indazolyl)-4-(5-methyl-l-phenyl-

3.4-dihydro-lH-isoquinolin-2-yl)-4-oxobutyric acid amide; N-(2-Furylmethyl)-4-(5-methyl- l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxobutyric acid amide; N-Benzyl-4-(5-methyl- l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxobutyric acid amide; 4-(5-Methyl-l-phenyl-

3.4-dihydro-lH-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl )butyric acid amide; N-[(4- Methoxyphenyl)methyl]-4-(5-methyl-l-phenyl-3,4-dihydro-lH-is oquinolin-2-yl)-4- oxobutyric acid amide; 4-(5-Methyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxo- N- phenethylbutyric acid amide; 4-(5-Methyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxo- N-(3-phenylpropyl)butyric acid amide; N-(4-Methoxyphenyl)-4-(7-methyl-l-phenyl-3,4- dihydro-lH-isoquinolin-2-yl)-4-oxobutyric acid amide; N-(2-Chlorophenyl)-4-(7-methyl-l- phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxobutyric acid amide; N-(l-Methyl-6- indazolyl)-4-(7-methyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2 -yl)-4-oxobutyric acid amide; N-(2-Furylmethyl)-4-(7-methyl-l-phenyl-3,4-dihydro-lH-isoqui nolin-2-yl)-4-oxobutyric acid amide; N-Benzyl-4-(7-methyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-y l)-4-oxobutyric acid amide; 4-(7 -Methyl- l-phenyl-3,4-dihy dro-lH-isoquinolin-2-yl)-4-oxo-N-(2- pyridylmethyl)butyric acid amide; N-[(4-Methoxyphenyl)methyl]-4-(7-methyl-l-phenyl-3,4- dihydro-lH-isoquinolin-2-yl)-4-oxobutyric acid amide; 4-(7-Methyl-l-phenyl-3,4-dihydro- lH-isoquinolin-2-yl)-4-oxo-N-phenethylbutyric acid amide; 4-(7-Methyl-l-phenyl-3,4- dihydro-lH-isoquinolin-2-yl)-4-oxo-N-(4-pyridylmethyl)butyri c acid amide; 4-Oxo-4-(l- phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2-thienylmethyl)b utyric acid amide; N-[(2- Chlorophenyl)methyl]-4-oxo-4-(l-phenyl-3,4-dihydro-lH-isoqui nolin-2-yl)butyric acid amide; N-[(2,4-Dichlorophenyl)methyl]-4-oxo-4-(l-phenyl-3,4-dihydro -lH-isoquinolin-2- yl)butyric acid amide; N-[(3,4-Dichlorophenyl)methyl]-4-oxo-4-(l-phenyl-3,4-dihydro -lH- isoquinolin-2-yl)butyric acid amide; 4-Oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N- (p-tolylmethyl)butyric acid amide; N-(l,3-Benzodioxol-5-ylmethyl)-4-oxo-4-(l-phenyl-3,4- dihydro-lH-isoquinolin-2-yl)butyric acid amide; N-[(3-Fluorophenyl)methyl]-4-oxo-4-(l- phenyl-3,4-dihydro-lH-isoquinolin-2-yl)butyric acid amide; N-[(2-Fluorophenyl)methyl]-4- oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)butyric acid amide; N-[(4- Fluorophenyl)methyl]-4-oxo-4-(l-phenyl-3,4-dihydro-lH-isoqui nolin-2-yl)butyric acid amide; N-[(2,5-Difluorophenyl)methyl]-4-oxo-4-(l-phenyl-3,4-dihydro -lH-isoquinolin-2- yl)butyric acid amide; N-(l-Naphthylmethyl)-4-oxo-4-(l-phenyl-3,4-dihydro-lH-isoqui nolin- 2-yl)butyric acid amide; 4-(7-Methyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxo- N- propylbutyric acid amide; 4-(5-Methyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxo- N- propylbutyric acid amide; 4-(5,7-Dimethyl-l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-4- oxo-N-propylbutyric acid amide; 4-Oxo-4-(l-phenyl-3,4-dihydro-lH-isoquinolin-2-yl)-N- propylbutyric acid amide; 4-Oxo-4-(l-(2-tolyl)-3,4-dihydro-lH-isoquinolin-2-yl)-N-[[3- (trifluoromethyl)-phenyl]methyl]butyric acid amide;4-Oxo-4-(l-(2-tolyl)-3,4-dihydro-lH- isoquinolin-2-yl)-N-[[4-(trifluoromethyl)-phenyl]methyl]buty ric acid amide; 4-Oxo-4-(l-(2- tolyl)-3,4-dihydro-lH-isoquinolin-2-yl)-N-[[2-(trifluorometh yl)-phenyl]methyl]butyric acid amide; 4-Oxo-4-(l-(2-tolyl)-6-methyl-3,4-dihydro-lH-isoquinolin-2-y l)-N-[[3- (trifluoromethyl)-phenyl]methyl]butyric acid amide; 4-(l-(2-Methyl-prop-2-yl)-3,4-dihydro- lH-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]met hyl]butyric acid amide; 4-(l- Cyclohexyl-3,4-dihydro-lH-isoquinolin-2-yl)-4-oxo-N-[[3-(tri fluoromethyl)- phenyl]methyl]butyric acid amide; and 4-Oxo-4-(l-(2-fluorophenyl)-3,4-dihydro-lH- isoquinolin-2-yl)-N-[[3-(trifluoromethyl)phenyl]methyl]butyr ic acid amide.

Formula 32

[00445] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 32. Such compounds are described in International Publication No. W02010037863A1, published April 8, 2010, and corresponding to International Application No. PCT/EP2009/062859 filed October 2, 2009; US Publication No. US20120238547A1, published September 20, 2012 and corresponding to US Application No. 13/394,345 filed September 2, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 32, these references incorporated by reference herein control.

[00446] In an embodiment, the Kv7 channel activator is a compound according to formula 32: Formula 32

.10 ! a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-lH-pyrrol- 1-yl, azetidinyl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo and trifluoromethyl;

R ³ represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one or more times with substituents selected from Ci-6-alkyl, Ci-6-alkoxy, halo and trifluoromethyl; R ⁴ represents Ci-6-alkyl; and R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form a heterocyclic ring selected from morpholinyl and 1,4-oxazepanyl.

[00447] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached is pyrrolidinyl which is optionally substituted one or more times with halo.

[00448] In further embodiments, R ³ represents furanyl which is optionally substituted with Ci-6-alkyl.

[00449] In further embodiments, R ⁴ represents Ci-6-alkyl.

[00450] In further embodiments, R ⁵ and R ⁶ , together with the nitrogen to which they are attached, represents morpholinyl.

[00451] In further embodiments, the compound is 3-Methyl-furan-2-carboxylic acid [2-((R)- 3 -fluoro-pyrrolidin- 1 -yl)-4-methyl-6-[ 1 ,4]oxazepan-4-yl-pyri din-3 -yl]-amide.

[00452] In further embodiments, the compound is 3-Methyl-furan-2-carboxylic acid [2-((R)- 3-fluoro-pyrrolidin-l-yl)-4-methyl-6-morpholin-4-yl-pyridin- 3-yl]-amide;

Formula 33

[00453] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 33. Such compounds are described in US Publication No. US20120232058A1, published September 13, 2012, and corresponding to US Application No. 13/394,468 filed September 2, 2010; International Publication No. WO201 1026891 Al, published March 10, 2011 and corresponding to International Application No. PCT/EP2010/062860 filed September 2, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 33, these references incorporated by reference herein control.

[00454] In an embodiment, the Kv7 channel activator is a compound according to formula 33:

Formula 33 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ represents Ci-6-alkyl; R ³ represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one or more times with substituents selected from Ci-6-alkyl, Ci -6-alkoxy, halo and trifluoromethyl; R ⁴ represents Ci-6-alkyl; and R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form a heterocyclic ring selected from morpholinyl and 1,4- oxazepanyl.

[00455] In further embodiments, R ¹ represents metyl or iso-propyl.

[00456] In further embodiments, R ³ represents furanyl which is optionally substituted with Ci-6-alkyl.

[00457] In further embodiments, R ⁴ represents Ci-6-alkyl.

[00458] In further embodiments, R ⁵ and R ⁶ , together with the nitrogen to which they are attached, represents 1,4-oxazepanyl.

[00459] In further embodiments, the compound is 3-Methyl-furan-2-carboxylic acid(2- isopropyl-4-methyl-6-[l,4]oxazepan-4-yl-pyridin-3-yl)-amide; or 3-Methyl-furan-2- carboxylic acid(2,4-dimethyl-6-[l,4]oxazepan-4-yl-pyridin-3-yl)-amide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof.

Formula 34

[00460] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 34. Such compounds are described in International Publication No. W02010122064A1, published October 28, 2010, and corresponding to International Application No. PCT/EP2010/055284 filed April 21, 2010; US Publication No. US20120115900A1, published May 10, 2012 and corresponding to US Application No. 13/265,273 filed April 21, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 34, these references incorporated by reference herein control.

[00461] In an embodiment, the Kv7 channel activator is a compound according to formula 34: Formula 34 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-lH-pyrrol- 1-yl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo, hydroxy, amino, Ci-6-alkyl, trifluoromethyl, Ci-6- alkoxy, hydroxy-Ci-6-alkyl and Ci-6-alkoxy-Ci-Ce-alkyl; L represents a linker selected from — CR'R"— , — CH ₂ — CR'R"— , — CR'R"-CH ₂ — , and — O— , wherein R' and R", independently of each other, represent hydrogen, Ci-6-alkyl or halo; n is 0 or 1; R ³ represents Ci-6-alkyl, phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or Cs-e-cycloalkyl, which phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl is optionally substituted one or more times with substituents selected from Ci-6-alkyl, C3-6-cycloalkyl, phenyl, Ci-6-alkoxy, halo and trifluoromethyl; R ⁴ represents hydrogen, halo or Ci-6-alkyl; and R ⁵ represents hydrogen or halo. [00462] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached is pyrrolidinyl or piperidinyl, which pyrrolidinyl and piperidinyl is optionally substituted one or more times with halo.

[00463] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halo.

[00464] In further embodiments, L represents — CH2 — .

[00465] In further embodiments, R ³ represents Ci-6-alkyl.

[00466] In further embodiments, R ³ represents phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or Cs-e-cycloalkyl, which phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl is optionally substituted one or more times with substituents selected from Ci-6-alkyl and halo.

[00467] In further embodiments, R ⁴ represents Ci-6-alkyl.

[00468] In further embodiments, R ⁵ represents hydrogen.

[00469] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N-[6-(7,8-dihydro-5H-[l,6]naphthyrid in-6-yl)-4- methyl-2-pyrrolidin-l-yl-pyridin-3-yl]-acetamide N-[6-(7,8-Dihydro-5H-[l,6]naphthyridin-6- yl)-4-methyl-2-pyrrolidin-l-yl-pyridin-3-yl]-3,3-dimethyl-bu tyramide; N-[6-(7,8-Dihydro- 5H-[l,6]naphthyridin-6-yl)-4-methyl-2-pyrrolidin-l-yl-pyridi n-3-yl]-3-fluoro-benzamide; N- [6-(7,8-dihydro-5H-l,6-naphthyridin-6-yl)-2-[(3R)-3-fluoropy rrolidin-l-yl]-4-methyl-3- pyridyl]-3-methyl-furan-2-carboxamide; 2-(3,5-difluorophenyl)-N-[6-(7,8-dihydro-5H-l,6- naphthyridin-6-yl)-2-[(3R)-3-fluoropyrrolidin-l-yl]-4-methyl -3-pyridyl]acetamide; N-[2- (4,4-difluoro-l-piperidyl)-6-(7,8-dihydro-5H-l,6-naphthyridi n-6-yl)-4-methyl-3-pyridyl]-3- methyl-furan-2-carboxamide; 2-(3,5-difluorophenyl)-N-[2-(4,4-difluoro-l-piperidyl)-6-(7, 8- dihydro-5H-l,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]acetami de; N-[2-(4,4-difluoro-l- piperidyl)-6-(7,8-dihydro-5H-l,6-naphthyridin-6-yl)-4-methyl -3-pyridyl]-l -methyl- imidazole-2-carboxamide; N-[2-(4,4-difluoro- 1 -piperidyl)-6-(7,8-dihydro-5H- 1,6- naphthyridin-6-yl)-4-methyl-3-pyridyl]-5-methyl-oxazole-4-ca rboxamide; N-[2-(4,4- difluoro-l-piperidyl)-6-(7,8-dihydro-5H-l,6-naphthyridin-6-y l)-4-methyl-3-pyridyl]-4- methyl-thiazole-5-carboxamide; N-[2-(4,4-difluoro-l-piperidyl)-6-(7,8-dihydro-5H-l,6- naphthyridin-6-yl)-4-methyl-3-pyridyl]-3-methyl-isoxazole-4- carboxamide; N-[2-(4,4- difluoro-l-piperidyl)-6-(7,8-dihydro-5H-l,6-naphthyridin-6-y l)-4-methyl-3-pyridyl]-4- methyl-oxazole-5-carboxamide; 2-cyclopropyl-N-[2-(4,4-difluoro-l-pipridyl)-6-(7,8-dihydro- 5H-l,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]acetamide; N-[2-(4,4-difluoro-l-piperidyl)-6- (7,8-dihydro-5H-l,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]-5 -ethyl-oxazole-4-carboxamide; N-[2-(4,4-difluoro-l-piperidyl)-6-(7,8-dihydro-5H-l,6-naphth yridin-6-yl)-4-methyl-3- pyridyl]-3-methyl-pyridine-2-carboxamide; N-[2-(4,4-difluoro-l-piperidyl)-6-(7,8-dihydro- 5H-l,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]-2,5-dimethyl-o xazole-4-carboxamide; N-[2- (4,4-difluoro-l-piperidyl)-6-(7,8-dihydro-5H-l,6-naphthyridi n-6-yl)-4-methyl-3-pyridyl]-5- phenyl-oxazole-4-carboxamide; 5-cyclopropyl-N-[2-(4,4-difluoro-l-piperidyl)-6-(7,8- dihydro-5H-l,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]oxazole -4-carb oxamide; N-[2-(4,4- difluoro-l-piperidyl)-6-(7,8-dihydro-5H-l,6-naphthyridin-6-y l)-4-methyl-3-pyridyl]-5- methyl-isothiazole-4-carboxamide; ethyl N-[2-(4,4-difluoro-l-piperidyl)-6-(7,8-dihydro-5H- l,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]carbamate; N-[6-(3-chloro-7,8-dihydro-5H-l,6- naphthyridin-6-yl)-2-[(3R)-3-fluoropyrrolidin-l-yl]-4,6-dime thyl-lH-pyridin-3-yl]-3,3- dimethyl-butanamide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof.

Formula 35

[00470] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 35. Such compounds are described in US Publication No. US20120059037A1, published March 8, 2012, and corresponding to US Application No. 13/256,893 filed March 11, 2010; International Publication No. W02010105960A1, published September 23, 2010 and corresponding to International Application No. PCT/EP2010/053072 filed March 11, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 35, these references incorporated by reference herein control.

[00471] In an embodiment, the Kv7 channel activator is a compound according to formula 35:

Formula 35 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , independently of each other, represent hydrogen, Ci-6-alkyl, hydroxy-Ci-6-alkyl or Ci-6-alkoxy-Ci-6-alkyl; or R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-lH-pyrrol-l-yl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, amino, Ci-6-alkyl, trifluoromethyl, Ci-6-alkoxy, hydroxy-Ci-6-alkyl and Ci- 6-alkoxy-Ci-6-alkyl; L represents a linker selected from — CR'R" — , — CH2 — CR'R" — and — CR'R" — CH2 — , wherein R' and R", independently of each other, represent hydrogen, C1-6- alkyl or halogen; n is 0, 1; R ³ represents Ci-6-alkyl, phenyl or furanyl, which phenyl and furanyl is optionally substituted one or more times with substituents selected from Ci-6-alkyl, Ci-6-alkoxy, halogen and trifluoromethyl; and R ⁴ represents hydrogen, halogen or Ci-6-alkyl. [00472] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen.

[00473] In further embodiments, L represents — CH2 — , and n is 1.

[00474] In further embodiments, R ³ represents phenyl, which phenyl is optionally substituted one or more times with halogen.

[00475] In further embodiments, R ³ represents Ci-6-alkyl.

[00476] In further embodiments, R ⁴ represents halogen.

[00477] In further embodiments, R ⁴ represents hydrogen.

[00478] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-{6-[(6-Chloro-pyridin-3-ylmethyl)-amino]-2-pyrrolidin-l-yl -pyridin-3-yl}- 2-(3 , 5 -difluoro-phenyl)-acetamide; 2-(3 , 5 -Difluoro-phenyl)-N- { 6-[(pyri din-3 -ylmethyl)- amino]-2-pyrrolidin-l-yl-pyridin-3-yl}-acetamide; N-{6-[(6-Chloro-pyridin-3-ylmethyl)- amino]-2-pyrrolidin-lyl-pyridin-3-yl}-3,3-dimethyl-butyramid e; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N- oxide thereof.

Formula 36

[00479] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 36. Such compounds are described in Patent Cooperation Treaty application No. EP2010/052257 published September 2, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 36, these references incorporated by reference herein control. [00480] In an embodiment, the Kv7 channel activator is a compound according to formula 36:

Formula 36 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , independently of each other, represent hydrogen, Ci-6-alkyl, hydroxy- C-r-6-alkyl or Ci-6-alkoxy-Ci-6-alkyl; or R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-l H-pyrrol-l-yl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, amino, Ci-6-alkyl, trifluoro- methyl, Ci-6-alkoxy, hydroxy-d-6-alkyl and d- 6-alkoxy- d-6-alkyl; L represents a linker selected from -CR'R"-, -CH2-CR ¹ R"- and -CR'R"- CH2-, wherein R' and R", independently of each other, represent hydrogen, d-6-alkyl or halogen; R ³ represents Ci-6-alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from Ci-6-alkyl, Ci-6-alkoxy, halogen and trifluoromethyl; and R ⁴ represents H or Ci-6-alkyl.

[00481] In further embodiments, R ¹ and R ² , independently of each other, represent Ci-6- alkyl.

[00482] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached, is morpholinyl.

[00483] In further embodiments, L represents -CH2-.

[00484] In further embodiments, R ³ represents phenyl, which phenyl is optionally substituted one or more times with halogen.

[00485] In further embodiments, R ⁴ represents methyl.

[00486] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N-{4-methyl-6-morpholin-4-yl-2-[(tet rahydro-pyran- 4- ylmethyl)-amino]-pyrimidin-5-yl } -acetamide; 2-(3 , 5-Difluoro-phenyl)-N- {4- dimethylamino-6-methyl-2-[(tetrahydro-pyran-4- ylmethyl)-amino]-pyrimidin-5-yl}- acetamide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically- acceptable addition salt thereof, or an /V-oxide thereof.

Formula 37

[00487] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 37. Such compounds are described in International Publication No. W02010094644A1, published August 26, 2010, and corresponding to International Application No. PCT/EP2010/051839 filed February 15, 2010; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 37, the reference incorporated by reference herein controls.

[00488] In an embodiment, the Kv7 channel activator is a compound according to formula

37:

Formula 37 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , independently of each other, represent Ci-6-alkyl; or R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-l H-pyrrol-1 -yl, piperidinyl and morpholinyl, which pyrrolidinyl and piperidinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, amino, Ci-6-alkyl, trifluoromethyl, Ci-6-alkoxy, hydroxy-d-6-alkyl and Ci-6-alkoxy-Ci-6-alkyl; L represents a linker selected from -CR’R"- and -O-CR'R"-, wherein R' and R", independently of each other, represent hydrogen, d-6-alkyl or halogen; n is 0 or 1 ; R ³ represents d-6-alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from d-6- alkyl, Ci-6-alkoxy, halogen and trifluorom ethyl; and R ⁴ represents Ci-6-alkyl.

[00489] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen. [00490] In further embodiments, R' and R", independently of each other, represents hydrogen or methyl.

[00491] In further embodiments, R ³ represents phenyl, which phenyl is optionally substituted one or more times with halogen.

[00492] In further embodiments, R ³ represents d-e-alkyl.

[00493] In further embodiments, R ⁴ represents methyl.

[00494] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 3,3-Dimethyl-N-(5-methyl-6-morpholin-4-yl-2-pyrrolidin-l-yl- pyridin-3-yl)- butyramide; 2-(3,5-Difluoro-phenyl)-N-(5-methyl-6-morpholin-4-yl-2-pyrro lidin-l-yl- pyri din-3 -yl)-acetamide; N-[2-((R)-3-Fluoro-pyrrolidin-l-yl)-5-methyl-6-morpholin-4-y l- pyridin-3-yl]-3,3-dimethylbutyramide; (S)-N-[2-((R)-3-Fluoro-pyrrolidin-l-yl)-5-methyl-6- morpholin-4-yl-pyridin-3-yl]-2-phenylpropionamide;[2-((R)-3- Fluoro-pyrrolidin-l-yl)-5- methyl-6-morpholin-4-yl-pyridin-3-yl]-carbamic acid ethyl ester; (S)-N-[2-((R)-3-Fluoro- pyrrolidin-l-yl)-5-methyl-6-morpholin-4-yl-pyridin-3-yl]-2-m ethyl-butyramide;or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an /V-oxide thereof.

Formula 38

[00495] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 38. Such compounds are described in International Publication No. WO2010094645 Al, published August 26, 2010, and corresponding to International Application No. PCT/EP2010/051840 filed February 15, 2010; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 38, the reference incorporated by reference herein controls.

[00496] In an embodiment, the Kv7 channel activator is a compound according to Formula 38: Formula 38 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , independently of each other, represent d-e-alkyl; or R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-l H-pyrrol-l-yl, piperidinyl, mor- pholinyl and 1 ,4-oxazepanyl, which pyrrolidinyl and piperidinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, amino, d-6-alkyl, trifluoromethyl, d-6-alkoxy, hydroxy-Ci-6-alkyl and Ci-6-alkoxy-Ci-6-alkyl; L represents a linker selected from -CR'R"- and -O-CR'R"-, wherein R' and R", independently of each other, represent hydrogen, Ci-6-alkyl or halogen; n is 0 or 1 ;

R ³ represents Ci-6-alkyl, phenyl or furanyl, which phenyl and furanyl is optionally substituted one or more times with substituents selected from d-6-alkyl, Ci-6- alkoxy, halogen and trifluoromethyl; and R ⁴ represents d-6-alkyl.

[00497] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen.

[00498] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached is 1 ,4-oxazepanyl.

[00499] In further embodiments, L is -CH2- and n is 1.

[00500] In further embodiments, n is 0.

[00501] In further embodiments, R ³ represents phenyl, which phenyl is optionally substituted one or more times with halogen.

[00502] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(3,4-Difluoro-phenyl)-N-[2-((R)-3-fluoro-pyrrolidin-l-yl)- 5-methyl-6- [1 ,4]oxazepan-4-yl-pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-/V-(5-methyl-2,6-bis-[l ,4]oxazepan-4-yl-pyridin-3-yl)- acetamide; 3-Fluoro-/V-(5-methyl-6-[l ,4]oxazepan-4-yl-2- pyrrolidin-l-yl-pyri din-3 -yl)- benzamide; 3-methyl-N-[5-methyl-6-(l ,4-oxazepan-4-yl)-2- pyrrolidin-l-yl-3-pyridyl]furan-2-carboxamide; 2-(3-fluorophenyl)-N-[2-[(3R)-3- fluoropyrrolidin-l-yl]-5-methyl-6-(l ,4-oxazepan-4- yl)-3-pyridyl]acetamide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically- acceptable addition salt thereof, or an /V-oxide thereof.

Formula 39

[00503] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 1. Such compounds are described in International Publication No. W02008142140A2, published November 27, 2008, and corresponding to International Application No. PCT/EP2008/056322 filed May 22, 2008; US Patent No. 8,178,544 published May 15, 2012 and corresponding to US Application No. 12/601,124 filed May 22, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 39, the reference incorporated by reference herein controls.

[00504] In an embodiment, the Kv7 channel activator is a compound according to Formula 39: a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ represents hydrogen, alkyl or halo; and R ² represents hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenyl-alkyl, amino, alkyl-carbonyl-amino, cyano or nitro; or R ¹ and R ² together with the carbon atom to which they are attached form a cycloalkyl (spiro) group; or R ¹ represents hydrogen; and R ² together with one of R ³ , R ⁴ and R ⁵ , attached in ortho-position on the aromatic ring, form a — (CH2) _n — bridge, wherein n is 1, 2 or 3; R ³ , R ⁴ and R ⁵ , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino, alkyl-sulfanyl, alkyl-sulfonyl, phenyl, phenoxy, benzoyl, cyano or nitro; or two of R ³ , R ⁴ and R ⁵ , together form a methylenedi oxy group; and the remaining of R ³ , R ⁴ and R ⁵ is as defined above; or two of R ³ , R ⁴ and R ⁵ , together with the phenyl ring to which they are attached, form a naphthyl group; and the remaining of R ³ , R ⁴ and R ⁵ is as defined above; or one of R ³ , R ⁴ and R ⁵ , attached in ortho-position on the aromatic ring, and together with R ² form a — (CH2) _n — bridge, wherein n is 1, 2 or 3; and the remaining of R ³ , R ⁴ and R ⁵ , are as defined above; R ⁶ and R ⁷ , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino, nitro, cyano or phenyl; and R' and R", independently of each other, represent alkyl, hydroxy-alkyl, amino-alkyl, cycloalkyl, phenyl-alkyl, phenyl-hydroxyalkyl, N-alkyl-amino-alkyl, N,N-dialkyl-amino-alkyl, alkoxy-alkyl, piperidinyl, N-alkyl- piperidinyl, furanyl-alkyl, pyridinyl-alkyl, pyrazolyl -alkyl, imidazolyl-alkyl, pyrimidinyl, pyrimidinyl substituted with one or two substituents selected from N-alkyl-amino, N,N- dialkyl-amino and phenyl; or R' and R", together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-lH-pyrrol-l-yl, thiazolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl and homomorpholinyl, which pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl and homomorpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of alkyl, alkoxy, alkoxy-alkyl, alkyl-carbonyl-amino, cycloalkyl- carbonyl-amino, hydroxy-alkyl, hydroxy, amino, N-alkyl-amino, N,N-dialkyl-amino, aminoalkyl, N-alkyl-amino-alkyl, N,N-dialkyl-amino-alkyl, carbamoyl-alkyl, N-alkyl-carbamoyl- alkyl, N,N-dialkyl-carbamoyl-alkyl, N-hydroxy-alkyl-carbamoyl, N,N-dialkyl-amino-alkyl- carbamoyl, alkoxy-carbonyl, cyano-alkyl, pyrrolidinyl, pyrrolidinyl-alkyl, piperidinyl, piperidinyl-carbonyl, hydroxy-piperidinyl, hydroxy-piperidinyl-alkyl, hydroxy-piperidinyl- carbonyl, N-alkyl-piperidinyl, piperidinyl-alkyl, N-alkyl-piperidinyl-alkyl, morpholino-alkyl, morpholino-alkyl-carbamoyl, morpholino-carbonyl-alkyl, triazolyl-alkyl, piperazinyl, piperazinyl-alkyl, piperazinyl-carbonyl, N-alkyl-piperazinyl, N-alkyl-piperazinyl-alkyl, N- alkyl-piperazinyl-carbonyl, pyridinyl, pyridinyl-alkyl, and pyridinyl substituted once or twice with alkyl, trifluoromethyl and/or cyano.

[00505] In further embodiments, R ¹ represents hydrogen or alkyl; and R ² represents hydrogen or alkyl.

[00506] In further embodiments, R ³ , R ⁴ and R ⁵ , independently of each other, represent hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, alkyl-sulfanyl, alkyl-sulfonyl, phenyl or phenoxy.

[00507] In further embodiments, R ⁶ and R ⁷ , independently of each other, represent hydrogen, halo, haloalkyl, hydroxy, alkoxy, or amino.

[00508] In further embodiments, R' and R", independently of each other, represent alkyl, hydroxy-alkyl, cycloalkyl, or phenyl-alkyl.

[00509] In further embodiments, R' and R", together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, thiazolidinyl, piperidinyl, piperazinyl, homopiperazinyl and morpholinyl, which piperazinyl is optionally substituted one or more times with alkyl.

[00510] In further embodiments, the Kv7 Channel activator is selected from the group consi sting of: 2-(3 , 5 -Difluoro-phenyl)-N -(4-oxo-2-pyrrolidin- 1 -yl-4H-quinazolin-3 -yl)- acetamide; 2-(3,5-Difluoro-phenyl)-N-(2-dimethylamino-4-oxo-4H-quinazol in-3-yl)- acetamide; 2-(4-Chloro-phenyl)-N-(2-diethylamino-4-oxo-4H-quinazolin-3- yl)-acetamide; 2- (3,5-Difluoro-phenyl)-N-[2-(ethyl-methyl-amino)-4-oxo-4H-qui nazolin-3-yl]-acetamide; 2- (3,5-Difluoro-phenyl)-N-(2-dimethylamino-4-oxo-7-trifluorome thyl-4H-quinazolin-3-yl)- propionamide; N-(2-Diethylamino-4-oxo-4H-quinazolin-3-yl)-2-(4-methanesulf onyl-phenyl)- acetamide; N-{2-[(2-Methoxy-ethyl)-methyl-amino]-4-oxo-4H-quinazolin-3- yl}-2-(4- trifluoromethyl-phenyl)-acetamide; 2-(4-Butoxy-phenyl)-N-{2-[(2-methoxy-ethyl)-methyl- amino]-4-oxo-4H-quinazolin-3-yl}-acetamide; N-[2-(Benzyl-methyl-amino)-4-oxo-4H- quinazolin-3-yl]-2-(4-methanesulfonyl-phenyl)-acetamide; 2-(4-Butoxy-phenyl)-N-(4-oxo-2- pyrrolidin-l-yl-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-(4-oxo-2- thiazolidin-3-yl-4H-quinazolin-3-yl)-acetamide; N-(2-Diethylamino-4-oxo-4H-quinazolin-3- yl)-2-(3,5-difluoro-phenyl)-acetamide; 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-oxo-2- thiazolidin-3-yl-4H-quinazolin-3-yl)-acetamide; 2-Benzo[l,3]dioxol-5-yl-N-(2-diethylamino- 4-oxo-4H-quinazolin-3-yl)-acetamide; N-(2-Diethylamino-4-oxo-4H-quinazolin-3-yl)-2- phenyl-acetamide; or N-[2-(Ethyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-2-phenyl - acetamide; or a stereoisomer or a mixture of its stereoisomers, a pharmaceutically-acceptable addition salt thereof.

[00511] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(3-Fluoro-4-trifluoromethyl-phenyl)-N-(4-oxo-2-pyrrolidin- l-yl-4H- quinazolin-3-yl)-acetamide; 2-(3,5-Bis-trifluoromethyl-phenyl)-N-{2-[(2-methoxy-ethyl)- methyl-amino]-4-oxo-4H-quinazolin-3-yl}-acetamide; N-[2-(Benzyl-methyl-amino)-4-oxo- 4H-quinazolin-3-yl]-2-(3,4-difluoro-phenyl)-acetamide; 2-(3,5-Difhioro-phenyl)-N-(2- morpholin-4-yl-4-oxo-4H-quinazolin-3-yl)-acetamide; 2-(4-Chloro-phenyl)-N-{7-fluoro-2- [(2-methoxy-ethyl)-methyl-amino]-4-oxo-4H-quinazolin-3-yl} -acetamide; 2-(4-Chloro- phenyl)-N-(2-morpholin-4-yl-4-oxo-4H-quinazolin-3-yl)-acetam ide; 2-(3,5-Difluoro-phenyl)- N-{7-fluoro-2-[(2-methoxy-ethyl)-methyl-amino]-4-oxo-4H-quin azolin-3-yl}-acetamide; 2- (4-Chloro-phenyl)-N-(2-dimethylamino-4-oxo-4H-quinazolin-3-y l)-acetamide; N-(2- Diethylamino-6-fluoro-4-oxo-4H-quinazolin-3-yl)-2-(3,5-diflu oro-phenyl)-acetamide; 2-(4- Chloro-phenyl)-N-(2-diethylamino-6-fluoro-4-oxo-4H-quinazoli n-3-yl)-acetamide; 2-(3,5- Difluoro-phenyl)-N-[2-(4-methyl-piperazin-l-yl)-4oxo-4H-quin azolin-3-yl]-acetamide; N-(2- Diethylamino-6-fluoro-4-oxo-4H-quinazolin-3-yl)-2-(3-fluoro- 5-trifluoromethyl-phenyl)- acetamide; N-[2-(Benzyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-2-(3,5- difluoro-phenyl)- acetamide; 2-(3,5-Difluoro-phenyl)-N-{2-[(2-methoxy-ethyl)-methyl-amino ]-4-oxo-4H- quinazolin-3-yl} -acetamide; 2-(3-Fluoro-5-trifluoromethyl-phenyl)-N-(4-oxo-2-pyrrolidin- l- yl-7-trifluoromethyl-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-(4-oxo-2- pyrrolidin-l-yl-7-trifluoromethyl-4H-quinazolin-3-yl)-acetam ide; 2-(3-Fluoro-5- trifluoromethyl-phenyl)-N-{2-[(2-methoxy-ethyl)-methyl-amino ]-4-oxo-7-trifluoromethyl- 4H-quinazolin-3 -yl } -acetamide; 2-(3 , 5 -Difluoro-phenyl)-N- { 2-[(2-methoxy-ethyl)-methyl- amino]-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl}-acetamide ; N-(6-Butoxy-2-morpholin- 4-yl-4-oxo-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-aceta mide; N-(5-Chloro-4-oxo-2- pyrrolidin-l-yl-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)- acetamide; N-(5-Chloro-2- diethylamino-4-oxo-4H-quinazolin-3-yl)-2-(3,5-difluoro-pheny l)-acetamide; N-(2- Diethylamino-7-fluoro-4-oxo-4H-quinazolin-3-yl)-2-(3,5-diflu oro-phenyl)-acetamide; N-(2- Diethylamino-5-fluoro-4-oxo-4H-quinazolin-3-yl)-2-(3,5-diflu oro-phenyl)-acetamide; N-(2- Diethylamino-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-2-( 3,5-difluoro-phenyl)- acetamide; N-(7-Chloro-2-diethylamino-4-oxo-4H-quinazolin-3-yl)-2-(3,5- difluoro-phenyl)- acetamide; N-(7-Chloro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-2-(3 ,5-difluoro- phenyl)-acetamide; N-(6-Chloro-2-diethylamino-7-fluoro-4-oxo-4H-quinazolin-3yl) -2-(3,5- difluoro-phenyl)-acetamide; N-(2-Diethylamino-5,7-difluoro-4-oxo-4H-quinazolin-3-yl)-2- (3,5-difluoro-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-(7-fluoro-4-oxo-2-pyrrolidin-l- yl-4H-quinazolin-3-yl)-acetamide; N-(6-Chloro-7-fluoro-4-oxo-2-pyrrolidin-l-yl-4H- quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(5,7-Difluoro-4-oxo-2-pyrrolidin-l- yl-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(5,7-Dichloro-2-diethylamino- 4-oxo-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(2-Diethylamino-6,7- difluoro-4-oxo-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-a cetamide; N-(6,7-Difluoro-4- oxo-2-pyrrolidin- 1 -yl-4H-quinazolin-3 -yl)-2-(3 , 5-difluoro-phenyl)-acetamide; 2-(3 -Fluoro-4- trifluoromethyl-phenyl)-N-(2-morpholin-4-yl-4-oxo-4H-quinazo lin-3-yl)-acetamide; N-(2- Dimethylamino-4-oxo-4H-quinazolin-3-yl)-2-(3-fluoro-4-triflu oromethyl-phenyl)-acetamide; N-(6-Chloro-2-diethylamino-4-oxo-4H-quinazolin-3-yl)-2-(3,5- difluoro-phenyl)-acetamide; N-(2-Dimethylamino-6-fluoro-4-oxo-4H-quinazolin-3-yl)-2-(3-f luoro-4-trifluoromethyl- phenyl)-acetamide; N-(6-Fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-2-(3 -fluoro-4- trifluoromethyl-phenyl)-acetamide; 2-(4-Chloro-3-fluoro-phenyl)-N-(6-fluoro-4-oxo-2- pyrrolidin-l-yl-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-(6-fluoro-4-oxo- 2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-acetamide; 2-(4-Chl oro-3 -fluoro-phenyl)-N-(2- dimethylamino-6-fluoro-4-oxo-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N- (2-dimethylamino-6-fluoro-4-oxo-4H-quinazolin-3-yl)-acetamid e; N-(5,7-Dichloro-4-oxo-2- pyrrolidin- 1 -yl-4H-quinazolin-3 -yl)-2-(3 , 5 -difluoro-phenyl)-acetamide; 2-(3 ,5 -Difluoro- phenyl)-N-(2-dimethylamino-5-fluoro-4-oxo-4H-quinazolin-3-yl )-acetamide; 2-(3,5- Difluoro-phenyl)-N-(2-dimethylamino-7-fluoro-4-oxo-4H-quinaz olin-3-yl)-acetamide; N-(2- Dimethylamino-5-fluoro-4-oxo-4H-quinazolin-3-yl)-2-(3-fluoro -5-trifluoromethyl-phenyl)- acetamide; N-(2-Dimethylamino-7-fluoro-4-oxo-4H-quinazolin-3-yl)-2-(3-f luoro-4- trifluoromethyl-phenyl)-acetamide; 2-(4-Chloro-phenyl)-N-(2-diethylamino-5,7-difluoro-4- oxo-4-quinazolin-3-yl)-acetamide; 2-(4-Chloro-phenyl)-N-(7-fluoro-4-oxo-2-pyrrolidin-lyl- 4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[5-fluoro-2-(isopropyl-methyl- amino)-4-oxo-4H-quinazolin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-(ethyl-methyl- amino)-5-fluoro-4-oxo-4H-quinazolin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-[7-fluoro- 2-(isopropyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-acetami de; 2-(3,5-Difluoro-phenyl)- N-[2-(ethyl-methyl-amino)-7-fluoro-4-oxo-4H-quinazolin-3-yl] -acetamide; 2-(4-Chloro- phenyl)-N-(7-fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3- yl)-propionamide; 2-(4- Chloro-phenyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl )-propionamide; N-(2- Diethylamino-8-fluoro-4-oxo-4H-quinazolin-3 -yl)-2-(3 , 5-difluoro-phenyl)-acetamide; 2-(3 , 5- Difluoro-phenyl)-N-(8-fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quin azolin-3-yl)-acetamide; 2- Naphthalen-2-yl-N-(4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-y l)-acetamide; N-(5,7- Difluoro-4-oxo-2-pyrrolidin- 1 -yl-4H-quinazolin-3 -yl)-2-(3 ,4-difluoro-phenyl)-acetamide; 2- (3,4-Difluoro-phenyl)-N-[2-(ethyl-methyl-amino)-7-fluoro-4-o xo-4H-quinazolin-3-yl]- acetamide; 2-(4-Chloro-phenyl)-N-[2-(ethyl-methyl-amino)-7-fluoro-4-oxo -4H-quinazolin-3- yl]-acetamide; 2-Naphthalen- 1 -yl-N-(4-oxo-2-pyrrolidin- 1 -yl-4H-quinazolin-3 -yl)- acetamide; 2-(4-Chloro-phenyl)-N-(5,7-difluoro-4-oxo-2-pyrrolidin-l-yl- 4H-quinazolin-3- yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-(ethyl-methyl-amino)-5,7-difluo ro-4-oxo-4H- quinazolin-3-yl]-acetamide; N-[5,7-Difluoro-2-(isopropyl-methyl-amino)-4-oxo-4H- quinazolin-3-yl]-2-(3,4-difluoro-phenyl)-acetamide; N-[5,7-Difluoro-2-(isopropyl-methyl- amino)-4-oxo-4H-quinazolin-3-yl]-2-(3,5-difluoro-phenyl)-ace tamide; N-[2-(Ethyl-methyl- amino)-7-fluoro-4-oxo-4H-quinazolin-3-yl]-2-(4-methylsulfany l-phenyl)-acetamide; 2-(4- Isobutyl-phenyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3- yl)-propionamide; N-[2- (Ethyl-methyl-amino)-7-fluoro-4-oxo-4H-quinazolin-3-yl]-2-(4 -methoxy-phenyl)-acetamide; N-(7-Fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-2-(4 -phenoxy-phenyl)-acetamide; 2-Biphenyl-4-yl-N-(7-fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quina zolin-3-yl)-acetamide; 2-(4- Chloro-phenyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl )-acetamide; 2-(3,4-Difluoro- phenyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-aceta mide; N-[2-(Ethyl-methyl- amino)-7-fluoro-4-oxo-4H-quinazolin-3-yl]-2-(4-isopropyl-phe nyl)-acetamide; 2-(3,5- Difluoro-phenyl)-N-[2-(isopropyl-methyl-amino)-4-oxo-4-quina zolin-3-yl]-acetamide; 2- (3,4-Difluoro-phenyl)-N-[2-(isopropyl-methyl-amino)-4-oxo-4H -quinazolin-3-yl]-acetamide; 2-(3,4-Difluoro-phenyl)-N-(7-fluoro-4-oxo-2-pyrrolidin-l-yl- 4H-quinazolin-3-yl)-acetamide; 2-(3,4-Difluoro-phenyl)-N-(8-fluoro-4-oxo-2-pyrrolidin-l-yl- 4H-quinazolin-3-yl)-acetamide; 2-(3,4-Difluoro-phenyl)-N-[2-(isobutyl-methyl-amino)-4-oxo-4 H-quinazolin-3-yl]- acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-(isobutyl-methyl-amino)-4-oxo-4 H-quinazolin-3- yl]-acetamide; 2-(3,4-Difluoro-phenyl)-N-[7-fluoro-2-(isopropyl-methyl-amin o)-4-oxo-4H- quinazolin-3-yl]-acetamide; N-(7-Chloro-6-fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3 - yl)-2-(3,5-difluoro-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-(2-diisopropylamino-4- oxo-4H-quinazolin-3-yl)-acetamide; N-[2-(Cyclopentyl-methyl-amino)-4-oxo-4H- quinazolin-3-yl]-2-(3,5-difluoro-phenyl)-acetamide; N-[2-(Cyclopentyl-methyl-amino)-4- oxo-4H-quinazolin-3-yl]-2-(3,4-difluoro-phenyl)-acetamide; 2-(3,4-Difluoro-phenyl)-N-(2- diisopropylamino-4-oxo-4H-quinazolin-3-yl)-acetamide; 2-(3,4-Difluoro-phenyl)-N-(4-oxo- 2-piperidin-l-yl-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-(4-oxo-2- piperidin-l-yl-4H-quinazolin-3-yl)-acetamide; N-(8-Chloro-4-oxo-2-pyrrolidin-l-yl-4H- quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(2-Diethylamino-6-hydroxy-4-oxo- 4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(6,8-Dichloro-2-diethylamino-4- oxo-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(6-Amino-2-diethylamino-4- oxo-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(7-Amino-2-diethylamino-4- oxo-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(7-Amino-4-oxo-2- pyrrolidin-l-yl-4H-quinazolin-3-yl)-2-(3,5-difluoro-phenyl)- acetamide; or a stereoisomer or a mixture of its stereoisomers, a pharmaceutically-acceptable addition salt thereof.

[00512] In further embodiments, 2-(3,5-difluorophenyl)-N-(2-dimethylamino-4-oxo-7- trifhioromethyl-4H-quinazolin-3-yl )-propionamide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof.

Formula 40

[00513] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 40. Such compounds are described in International Publication No. W02010060955A1, published June 3, 2010 and corresponding to International Application No. PCT/EP2009/065890 filed November 26, 2009; US Publication No. US20110312962A1, published December 22, 2011 and corresponding to US Application No. 13/131,218 filed November 26, 2009; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 40, these references incorporated by reference herein control.

[00514] In an embodiment, the Kv7 channel activator is a compound according to Formula 40: Formula 40 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein Y represents — (CH2) _n — , — (CH2) _n — O — or — (CH2) _n — S — wherein n is 0 or 1; R ¹ represents Ci-6-alkyl, benzo[l,3]dioxolyl, phenyl or pyridyl, which phenyl and pyridyl are optionally substituted one or more times with substituents selected from the group consisting of Ci-6-alkyl, halogen, trifluoromethyl, hydroxy, Ci-6-alkoxy and trifluoromethoxy; R ² and R ³ , independently of each other, represent hydrogen or Ci-6-alkyl; and R ⁴ and R ⁵ , independently of each other, represent hydrogen, Ci-6- alkyl, halogen, trifluoromethyl, hydroxy, Ci-6-alkoxy or trifluoromethoxy.

[00515] In further embodiments, Y represents — (CH2) _n — , wherein n is 0 or 1; R ¹ represents Ci-6-alkyl, benzo[l,3]dioxolyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of Ci-6-alkyl, halogen, trifluoromethyl, hydroxy, Ci-6-alkoxy and trifluoromethoxy; R ² and R ³ , independently of each other, represent hydrogen or Ci-6-alkyl; and R ⁴ and R ⁵ , independently of each other, represent hydrogen, Ci-6-alkyl, halogen, trifluoromethyl, hydroxy, Ci-6-alkoxy or trifluoromethoxy. [00516] In further embodiments, n is 1.

[00517] In further embodiments, R ¹ represents phenyl optionally substituted one or more times with substituents selected from the group consisting of Ci-6-alkyl, halogen, trifluorom ethyl and Ci-6-alkoxy.

[00518] In further embodiments, R ² and R ³ represent hydrogen. [00519] In further embodiments, R ² and R ³ represent Ci-6-alkyl.

[00520] In further embodiments, R ⁴ and R ⁵ , independently of each other, represent hydrogen or halogen.

[00521] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N-[6-(4-fluoro-benzylamino)-2-morpho lin-4-yl- pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-{6-[l-(4-fluoro-phenyl)-l-methyl- ethylamino]-2-morpholin-4-yl-pyridin-3-yl}-acetamide; N-[6-(4-Fluoro-benzylamino)-2- morpholin-4-yl-pyridin-3-yl]-2-methyl-benzamide; 2-Benzo[l,3]dioxol-5-yl-N-[6-(4-fluoro- benzylamino)-2-morpholin-4-yl-pyridin-3-yl]-acetamide; N-[6-(4-Fluoro-benzylamino)-2- morpholin-4-yl-pyridin-3-yl]-2-(4-methoxy-phenyl)-acetamide; N-[6-(4-Fluoro- benzylamino)-2-morpholin-4-yl-pyridin-3-yl]-2-(3-methoxy-phe nyl)-acetamide; 2-(2,4- Dichloro-phenyl)-N-[6-(4-fluoro-benzylamino)-2-morpholin-4-y l-pyridin-3-yl]-acetamide; N-[6-(4-Fluoro-benzylamino)-2-morpholin-4-yl-pyridin-3-yl]-2 -(3-trifluoromethyl-phenyl)- acetamide; N-[6-(4-Fluoro-benzylamino)-2-morpholin-4-yl-pyridin-3-yl]-2 -(2 -fluoro- phenyl)-acetamide; N-[6-(4-Fluoro-benzylamino)-2-morpholin-4-yl-pyridin-3-yl]-2 -(3- fluoro-phenyl)-acetamide; or 2-(4-Chloro-phenyl)-N-[6-(4-fluoro-benzylamino)-2- morpholin-4-yl-pyridin-3-yl]-acetamide, N-[6-[(4-Fluorophenyl)-methylamino]-2- morpholino-3-pyridyl]-2-(4-fluorophenyl)-sulfanyl-acetamide; 2-(3-fluorophenoxy)-N-[6- [(4-fluorophenyl)-methyl amino]-2-morpholino-3-pyridyl]acetamide; 2-(6-chl oro-3 -pyridyl)- N-[6-[(4-fluorophenyl)-methylamino]-2-morpholino-3-pyridyl]a cetamide; 2-fluoro-N-[6-[(4- fluorophenyl)-methylamino]-2-morpholino-3-pyridyl]pyridine-3 -carboxamide; a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof.

Formula 41

[00522] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 41. Such compounds are described in US Publication No. US20110269783A1, published November 3, 2011, and corresponding to US Application No. 13/128,015 filed November 6, 2009; International Publication No. W02010051819A1, published May 14, 2010, and corresponding to International Application No. PCT/DK2009/050293 filed November 6, 2009; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 41, these references incorporated by reference herein control. [00523] In an embodiment, the Kv7 channel activator is a compound according to Formula

41 :

Formula 41 , lly acceptable addition salt thereof, or an N-oxide thereof, wherein L represents a linker selected from wherein R' and R", independently of each other, represent hydrogen, Ci-6-alkyl or halogen; R ¹ and R ² , independently of each other, represent Ci-6-alkyl, hydroxy-Ci-6-alkyl-, Ci-6-alkoxy-Ci-6-alkyl- , phenyl, phenyl-Ci-6-alkyl-, which phenyl is optionally substituted with one or two times with a substituent selected from the group consisting of Ci-6-alkoxy, halogen and cyano; or R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-lH-pyrrol-l-yl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, amino, Ci-6-alkyl, trifluoromethyl, Ci-6-alkoxy, hydroxy-Ci-6-alkyl- and Ci-6-alkoxy-Ci-6-alkyl-; R ³ , R ⁴ and R ⁵ , independently of each other, represent hydrogen, Ci-6- alkyl, halogen, trihalomethyl, hydroxy, Ci-6-alkoxy, trifluoromethoxy, amino, cyano or nitro; and R ⁶ and R ⁷ , independently of each other, represent hydrogen, Ci-6-alkyl, halogen, trihalomethyl, hydroxy, Ci-6-alkoxy, trifluoromethoxy, amino, nitro, cyano or phenyl. [00524] In further embodiments, R ¹ and R ² , independently of each other, represent Ci-6- alkyl, alkoxy-Ci-6-alkyl- or phenyl-Ci-6-alkyl-.

[00525] In further embodiments, R ¹ and R ² , together with the nitrogen to which they are attached, form a pyrrolidinyl ring.

[00526] In further embodiments, R ³ , R ⁴ and R ⁵ , independently of each other, represent hydrogen, Ci-6-alkyl or halogen.

[00527] In further embodiments, R ⁶ and R ⁷ , independently of each other, represent hydrogen or halogen.

[00528] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-(7-Fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-3-(3 -fluoro-phenyl)- propionamide; 3-(3-Fluoro-phenyl)-N-{2-[(2-methoxy-ethyl)-methyl-amino]-4- oxo-4H- quinazolin-3-yl} -propionamide; N-[2-(Benzyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-3- (3-fluoro-phenyl)-propionamide; N-[2-(Benzyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-3- (3,5-difluoro-phenyl)-propionamide; 3-(3-Fluoro-phenyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H- quinazolin-3 -yl)-propionamide; N-(4-Oxo-2-pyrrolidin- 1 -yl-4H-quinazolin-3 -y l)-3 -phenylpropionamide; N-(2-Dimethylamino-7-fluoro-4-oxo-4H-quinazolin-3-yl)-3-(3-f luoro- phenyl)-propionamide; N-(4-Oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-2-phenylsulfa nyl- acetamide; N-(4-Oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-2-phenoxy-ace tamide; N-(5- Fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-3-(3-fluo ro-phenyl)-propionamide; 2-(4- Fluoro-phenylsulfanyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H-quinazo lin-3-yl)-acetamide; N-(5,7- Difluoro-4-oxo-2-pynolidin- 1 -yl-4H-quinazolin-3 -y l)-3 -(3 -fluoro-phenyl)-propionamide; 2- (4-tert-Butyl-phenylsulfanyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H- quinazolin-3-yl)-acetamide; N- [5,7-Difluoro-2-(isopropyl-methyl-amino)-4-oxo-4H-quinazolin -3-yl]-3-(3-fluoro-phenyl)- propionamide; N-(5,7-Difluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)- 3-(3,5-difluoro- phenyl)-propionamide; (S)-N-(5,7-Difluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3- yl)-3- phenyl-butyramide; 3-(4-Chloro-phenyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H-quinazolin -3-yl)- butyramide; 3-(3-Fluoro-phenyl)-N-(4-oxo-2-pyrrolidin-l-yl-4H-quinazolin -3-yl)- butyramide; cis-2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid(2-dimethylamino-7- fluoro-4-oxo-4H-quinazolin-3-yl)-amide; cis-2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid[5,7-difluoro-2-(isopropyl-methyl-amino)-4-oxo-4H-quinaz olin-3-yl]-amide; cis-2-(4- Chloro-phenyl)-cyclopropanecarboxylic acid(5,7-difluoro-4-oxo-2-pyrrolidin-l-yl-4H- quinazolin-3-yl)-amide; cis-2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid[2-(ethyl- methyl-amino)-7-fluoro-4-oxo-4H-quinazolin-3-yl]-amide; cis-2-(4-Chloro-phenyl)- cyclopropanecarboxylic acid[7-fluoro-2-(isopropyl-methyl-amino)-4-oxo-4H-quinazolin -3- yl]-amide; cis-2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid[2-(ethyl-methyl-amino)-5,7- difluoro-4-oxo-4H-quinazolin-3-yl]-amide; cis-2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid(8-fluoro-4-oxo-2-pyrrolidin-l-yl-4H-quinazolin-3-yl)-am ide; or a stereoisomer or a mixture of its stereoisomers, a pharmaceutically acceptable addition salt thereof, or an N- oxide thereof.

[00529] In further embodiments, the compound is of formula: wherein: X represents — CR'R" — , — S — , or — O — , wherein R' and R", independently of each other, represent hydrogen, Ci-6-alkyl or halogen, and R', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.

[00530] In further embodiments, the compound is of formula: wherein: R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.

Formula 42

[00531] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in International Publication No. WO201 1026890A1, published March 10, 2011, and corresponding to International Application No. PCT/EP2010/062859 filed September 2, 2010; US Publication No.

US20120238547A1, published September 20, 2012, and corresponding to US Application No. 13/394,345 filed September 2, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 42, these references incorporated by reference herein control.

[00532] In an embodiment, the Kv7 channel activator is a compound according to Formula 42: Formula 42 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-lH-pyrrol- 1-yl, azetidinyl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo and trifluoromethyl;

R ³ represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one or more times with substituents selected from Ci-6-alkyl, Ci-6-alkoxy, halo and trifluoromethyl; R ⁴ represents Ci-6-alkyl; and R ⁵ and R ⁶ , together with the nitrogen to which they are attached, form a heterocyclic ring selected from morpholinyl and 1,4-oxazepanyl.

[00533] In further embodiments, R ¹ and R ² together with the nitrogen to which they are attached is pyrrolidinyl which is optionally substituted one or more times with halo.

[00534] In further embodiments, R ³ represents furanyl which is optionally substituted with Ci-6-alkyl.

[00535] In further embodiments, R ⁴ represents Ci-6-alkyl.

[00536] In further embodiments, R ⁵ and R ⁶ , together with the nitrogen to which they are attached, represents morpholinyl.

[00537] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 3-Methyl-furan-2-carboxylic acid [2-((R)-3-fluoro-pyrrolidin-l-yl)-4-methyl-6- [l,4]oxazepan-4-yl-pyri din-3 -yl]-amide; 3-Methyl-furan-2-carboxylic acid [2-((R)-3-fluoro- pyrrolidin-l-yl)-4-methyl-6-morpholin-4-yl-pyri din-3 -yl]-amide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N- oxide thereof. Formula 43

[00538] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 43. Such compounds are described in International Publication No. W02010026104A1, published March 11, 2010, and corresponding to International Application No. PCT/EP2009/061125 filed August 28, 2009; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 43, the reference incorporated by reference herein controls.

[00539] In an embodiment, the Kv7 channel activator is a compound according to Formula 43: Formula 43 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , independently of each other, represent Ci-6-alkyl, hydroxy-d-e-alkyl or Ci-6- alkoxy-Ci-6-alkyl; or R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5- dihydro-1 H-pyrrol-1 -yl, azetidinyl, thiazolidinyl, piperidinyl, piperazinyl and morpholinyl, which pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo, hydroxy, amino, Ci-6-alkyl, trifluoromethyl, Ci-6-alkoxy, hydroxy-Ci-6-alkyl and Ci-6-alkoxy- Ci-6-alkyl; R ³ represents Ci-6-alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from Ci-6-alkyl, Ci-6-alkoxy, halo and trifluoromethyl; and L represents a linker selected from -CR’R"-, -CH2-CR ¹ R"- and -CR ¹ R ^1A CH2-, wherein R ¹ and R", independently of each other, represent hydrogen, Ci-6-alkyl or halo.

[00540] In further embodiments, R ¹ and R ² , independently of each other, represent Ci-6- alkyl.

[00541] In further embodiments, R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl is optionally substituted one or more times with a substituent selected from the group consisting of halo, d- e-alkyl and trifluoromethyl.

[00542] In further embodiments, R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring which is pyrrolidinyl optionally substituted one or more times with a substituent selected from the group consisting of halo, d-e-alkyl and tri fluoromethyl.

[00543] In further embodiments, R ¹ and R ² , together with the nitrogen to which they are attached, form a heterocyclic ring which is piperidinyl optionally substituted one or more times with a substituent selected from the group consisting of halo, d-e-alkyl and tri fluorom ethyl.

[00544] In further embodiments, R ³ represents te/t-butyl.

[00545] In further embodiments, R ³ represents phenyl, which is optionally substituted one or more times with substituents selected from Ci-6-alkyl, Ci-6-alkoxy, halo and trifluoromethyl. [00546] In further embodiments, L represents -CH2-.

[00547] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluorophenyl)-N-{2-pyrrolidin-l-yl-6-[(tetrahydro-p yran-4-ylmethyl)- amino]- pyri din-3 -yll-acetamide; 3,3-Dimethyl-N-{2-pyrrolidin-l-yl-6-[(tetrahydro-pyran-4- ylmethyl)-amino]-pyridin-3-yllbutyramide; 2-(3,5-Difluoro-phenyl)-N-{2-morpholin-4-yl-6- [(tetrahydro-pyran-4-ylmethyl)-amino]- pyri din-3 -yll-acetamide; 2-(3,5-Difluoro-phenyl)-N- {2-dimethylamino-6-[(tetrahydro-pyran-4-ylmethyl)-amino]- pyri din-3 -yll-acetamide; N-{2- Dimethylamino-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-pyridi n-3-yll-3,3-dimethyl- butyramide; 2-(3,5-Difluoro-phenyl)-N-{2-((S)-3-fluoro-pyrrolidin-l-yl)- 6-[(tetrahydro- pyran-4-ylmethyl)-amino]-pyri din-3 -yll-acetamide; N- {2-((S)-3 -Fluoro-pyrrolidin- 1 -yl)-6- [(tetrahydro-pyran-4-ylmethyl)-amino]-pyridin-3-yll-3,3-dime thyl-butyramide; 2-(3,5- Difluoro-phenyl)-N-{2-(3,3-dimethyl-pyrrolidin-l-yl)-6-[(tet rahydro-pyran-4-ylmethyl)- amino]-pyridin-3-yll-acetamide; N-{2-(3,3-Dimethyl-pyrrolidin-l-yl)-6-[(tetrahydro-pyran-4- ylmethyl)-amino]-pyridin-3-yll-3,3-dimethyl-butyramide; N-{2-((R)-3-Fluoro-pyrrolidin-l- yl)-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-pyridin-3-yll-3, 3-dimethyl-butyramide; 2-(3,5- Difluoro-phenyl)-N-{2-((R)-3-fluoro-pyrrolidin-l-yl)-6-[(tet rahydro-pyran-4-ylmethyl)- amino]-pyridin-3-yll-acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-[(tetrahydro-pyran-4- ylmethyl)-amino]-2-((S)-2-trifluoromethyl-pyrrolidin- l-yl)-pyri din-3 -yl]-acetamide; 3,3- Dimethyl-N-[6-[(tetrahydro-pyran-4-ylmethyl)-amino]-2-((S)-2 -trifluoromethylpyrrolidin-l- yl)-pyridin-3-yl]-butyramide; or a pharmaceutically-acceptable addition salt thereof. Formula 44

[00548] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 44. Such compounds are described in International Publication No. W02010105960A1, published September 23, 2010, and corresponding to International Application No. PCT/EP2010/053072 filed March 11, 2010; US Publication No. US20110003865A1, published January 6, 2011, and corresponding to US Application No. 12/747,394 filed December 10, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 44, these references incorporated by reference herein control.

[00549] In an embodiment, the Kv7 channel activator is a compound according to Formula 44:

Formula 44 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluorom ethyl; R ² represents hydrogen; R ³ represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl; and L represents a linker selected from — CR'R" — , — QU — CR'R" — , — CR'R" — QU — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen, alkyl or halo.

[00550] In further embodiments, R ¹ represents alkyl.

[00551] In further embodiments, R ¹ represents phenyl optionally substituted one or more times with substituents selected from alkyl and halo.

[00552] In further embodiments, R ³ represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl. [00553] In further embodiments, R ³ represents alkyl.

[00554] In further embodiments, L represents a linker selected from — CR'R" — , — CH2 — CR'R" — , — CR'R" — CH2 — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen or alkyl.

[00555] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-[2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-( 3,5-difluoro- phenyl)-acetamide; N-[2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-( 3,4- difluoro-phenyl)-acetamide; N-[2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2- (3-fluoro-4-trifluoromethyl-phenyl)-acetamide; (S) — N-[2-Diethylamino-6-(4-fluoro- benzylamino)-pyridin-3-yl]-2-phenyl-propionamide; N-[2-Diethylamino-6-(4-fluoro- benzylamino)-pyridin-3-yl]-3-(3-fluoro-phenyl)-propionamide; (R) — N-[2-Diethylamino-6- (4-fluoro-benzylamino)-pyridin-3-yl]-3-phenyl-butyramide; trans-2 -Phenyl- cyclopropanecarboxylic acid [2-diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-amide ; N-[2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-( 3-fluoro-phenyl)-acetamide; N-[2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-3,3 -dimethyl-butyramide; N-[2- Diethylamino-6-(2,4,6-trimethyl-benzylamino)-pyridin-3-yl]-2 -(3,5-difluoro-phenyl)- acetamide; N-(2-Diethylamino-6-isobutylamino-pyridin-3-yl)-2-(3,5-diflu oro-phenyl)- acetamide; N-[2-Diethylamino dimethyl-benzylamino)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)- acetamide; N-[2-Diethylamino-6-(2,2-dimethyl-propylamino)-pyridin-3-yl] -2-(3,5-difluoro- phenyl)-acetamide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically- acceptable addition salt thereof, or an N-oxide thereof.

Formula 45

[00556] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 45. Such compounds are described in US Publication No. US20110039896A1, published February 17, 2011, and corresponding to US Application No. 12/747,346 filed December 10, 2008; International Publication No. W02009074593A1, published June 18, 2009, and corresponding to International Application No. PCT/EP2008/067164 filed December 10, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 45, these references incorporated by reference herein control.

[00557] In an embodiment, the Kv7 channel activator is a compound according to Formula 45: Formula 45 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ represents alkyl, phenyl, benzo[l,3]dioxolyl or benzofl, 4]dioxinyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, trifluoromethyl, alkoxy, cyano and difluoromethoxy; R ² represents hydrogen; R ³ represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl; and L represents a linker selected from — CR'R" — , — CH2 — CR'R" — , — CR'R" — CH2 — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen, alkyl or halo.

[00558] In further embodiments, R ¹ represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R ² represents hydrogen; R ³ represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; and L represents a linker selected from — CR'R" — , — CH2 — CR'R" — , — CR'R" — CH2 — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen, alkyl or halo.

[00559] In further embodiments, R ¹ represents alkyl.

[00560] In further embodiments, R ¹ represents phenyl, benzo[l,3]dioxolyl or benzofl, 4]dioxinyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, trifluoromethyl, alkoxy, cyano and difluoromethoxy. [00561] In further embodiments, R ³ represents alkyl.

[00562] In further embodiments, R ³ represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.

[00563] In further embodiments, L represents a linker selected from — CR'R" — , — CH2 — CR'R" — , — CR'R" — CH2 — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen or alkyl.

[00564] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-[6-(4-Fluoro-benzylamino)-2-pyrrolidin-l-yl-pyridin-3-yl]- 2-(3-fluoro-4- trifluoromethyl-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(4-fluoro-benzylamino)-2- pyrrolidin-l-yl-pyridin-3-yl]-acetamide; 2-(3,4-Difluoro-phenyl)-N-[6-(4-fluoro- benzylamino)-2-pyrrolidin-l-yl-pyridin-3-yl]-acetamide; (S)-N-[6-(4-Fluoro-benzylamino)-

2-pyrrolidin-l-yl-pyri din-3 -yl]-2-phenyl-propionamide; N-[6-(4-Fluoro-benzylamino)-2- pyrrolidin-l-yl-pyridin-3-yl]-3-(3-fluoro-phenyl)-propionami de; (R)-N-[6-(4-Fluoro- benzylamino)-2-pyrrolidin-l-yl-pyridin-3-yl]-3-phenyl-butyra mide; (R)-2 -Phenyl- cyclopropanecarboxylic acid [6-(4-fluoro-benzylamino)-2-pyrrolidin-l-yl-pyridin-3-yl]- amide; N-[6-(4-Fluoro-benzylamino)-2-pyrrolidin-l-yl-pyridin-3-yl]- 2-(3-fluoro-phenyl)- acetamide; N-[6-(4-Fluoro-benzylamino)-2-pyrrolidin-l-yl-pyri din-3 -yl]-3, 3 -dimethyl- butyramide; 2-(3,5-Difluoro-phenyl)-N-(6-isobutylamino-2-pyrrolidin-l-yl -pyridin-3-yl)- acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(5-fluoro-2-methyl-benzylamino) -2-pyrrolidin-l-yl- pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(2,6-dimethyl-benzylamino)-2- pyrrolidin-l-yl-pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-pyrrolidin-l-yl-6-(4- trifluoromethyl-benzylamino)-pyridin-3-yl]-acetamide; N-{6-[(Benzo[l,3]dioxol-5- ylmethyl)-amino]-2-pyrrolidin-l-yl-pyridin-3-yl}-3,3-dimethy l-butyramide; N-[6-(3,4- Difluoro-benzylamino)-2-pyrrolidin-l-yl-pyridin-3-yl]-2-(3,5 -difluoro-phenyl)-acetamide; N- {6-[(Benzo[l,3]dioxol-5-ylmethyl)-amino]-2-pyrrolidin-l-yl-p yridin-3-yl}-2-(3,5-difluoro- phenyl)-acetamide; N-[6-(4-Cyano-benzylamino)-2-pyrrolidin-l-yl-pyridin-3-yl]-2 -(3,5- difluoro-phenyl)-acetamide; N-[6-(3,4-Difluoro-benzylamino)-2-pyrrolidin-l-yl-pyri din-3 - yl]-3,3-dimethyl-butyramide; 2-(3,5-Difluoro-phenyl)-N-[6-(4-methoxy-benzylamino)-2- pyrrolidin-l-yl-pyridin-3-yl]-acetamide; N-[6-(4-Difluoromethoxy-benzylamino)-2- pyrrolidin-l-yl-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-acetam ide; N-[6-(4-Difluoromethoxy- benzylamino)-2-pyrrolidin-l-yl-pyridin-3-yl]-3,3-dimethyl-bu tyramide; 2-(3,5-Difluoro- phenyl)-N-{6-[(2,3-dihydro-benzo[l,4]dioxin-6-ylmethyl)-amin o]-2-pyrrolidin-l-yl-pyridin-

3 -yl} -acetamide; N-{6-[(2,3-Dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-2-pyr rolidin-l- yl-pyridin-3-yl}-3,3-dimethyl-butyramide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof.

Formula 46

[00565] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 46. Such compounds are described in International Publication No. W02009074591A1, published June 18, 2009, and corresponding to International Application No. PCT/EP2008/067161 filed December 10, 2008; US Publication No. US20110003866A1, published December 10, 2008, and corresponding to US Application No. 12/747,414 filed December 10, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 46, these references incorporated by reference herein control.

[00566] In an embodiment, the Kv7 channel activator is a compound according to Formula 46:

Formula 46 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R ² represents hydrogen; R ³ represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl; and L represents a linker selected from — CR'R" — , — CR'R" — CH2 — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen, alkyl or halo.

[00567] In further embodiments, R ¹ represents alkyl.

[00568] In further embodiments, R ¹ represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl.

[00569] In further embodiments, R ³ represents alkyl.

[00570] In further embodiments, R ³ represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.

[00571] In further embodiments, L represents a linker selected from — CR'R" — , — CR'R" — CH2 — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen, alkyl or halo.

[00572] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2- (3,4-difluoro- phenyl)-acetamide; N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2- (3,5- difluoro-phenyl)-acetamide; N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2- (3-fluoro-4-trifluoromethyl-phenyl)-acetamide; (S) — N-[2-Dimethylamino-6-(4-fluoro- benzylamino)-pyridin-3-yl]-2-phenyl-propionamide; N-[2-Dimethylamino-6-(4-fluoro- benzylamino)-pyridin-3-yl]-3-(3-fluoro-phenyl)-propionamide; trans-2-Phenyl- cyclopropanecarboxylic acid[2-dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]- amide; N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2- (3-fluoro-phenyl)- acetamide; N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-3, 3-dimethyl- butyramide; 2-(3,5-Difluoro-phenyl)-N-[2-dimethylamino-6-(2,4,6-trimethy l-benzylamino)- pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-dimethylamino-6-(2,6-dimethyl- benzylamino)-pyridin-3-yl]-acetamide; N-[2-Dimethylamino-6-(5-fluoro-2-methyl- benzylamino)-pyridin-3-yl]-3,3-dimethyl-butyramide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof.

Formula 47

[00573] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 47. Such compounds are described in US Publication No. US20110003867A1, published January 6, 2011, and corresponding to US Application No. 12/747,422 filed December 10, 2008; International Publication No. W02009074594A1, published June 18, 2009, and corresponding to International Application No. PCT/EP2008/067165 filed December 10, 2008; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 47, these references incorporated by reference herein control.

[00574] In an embodiment, the Kv7 channel activator is a compound according to Formula 47: Formula 47 a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluorom ethyl; R ² represents hydrogen; R ³ represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl; and L represents a linker selected from — CR'R" — , — QU — CR'R" — , — CR'R" — CH2 — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen, alkyl or halo.

[00575] In further embodiments, R ¹ represents alkyl.

[00576] In further embodiments, R ¹ represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo and trifluorom ethyl.

[00577] In further embodiments, R ³ represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.

[00578] In further embodiments, R ³ represents alkyl.

[00579] In further embodiments, L represents a linker selected from — CR'R" — , — CH2 — CR'R" — , — CR'R" — CH2 — and cycloalkyl, wherein R' and R", independently of each other, represent hydrogen, alkyl or halo.

[00580] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-[2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2- (3,5-difluoro- phenyl)-acetamide; N-[2-Ethylmethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl] -2-(3,4- difluoro-phenyl)-acetamide; N-[2-Ethylmethylamino-6-(4-fluoro-benzylamino)-pyridin-3- yl]-2-(3-fluoro-4-trifluoromethyl-phenyl)-acetamide; N-[2-Ethylmethylamino-6-(4-fluoro- benzylamino)-pyridin-3-yl]-3-(3-fluoro-phenyl)-propionamide; (R) — N-[2-(Ethyl-methyl- amino)-6-(4-fluoro-benzylamino)-pyridin-3-yl]-3-phenyl-butyr amide; trans-2 -Phenyl- cyclopropanecarboxylic acid [2-Ethylmethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]- amide; N-[2-Ethylmethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl] -2-(3-fluoro-phenyl)- acetamide; N-[2-Ethylmethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl] -3,3-dimethyl- butyramide; pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(2,2-dimethyl- propylamino)-2-(ethyl-methyl-amino)-pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N- [2-(ethyl-methyl-amino)-6-isobutylamino-pyridin-3-yl]-acetam ide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N- oxide thereof.

Formula 48

[00581] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 48. Such compounds are described in International Publication No. W02007104717A1, published September 20, 2007, and corresponding to International Application No. PCT/EP2007/052239 filed March 9, 2007; US Publication No. US20090036473A1, published February 5, 2009, and corresponding to US Application No. 12/278,091 filed March 9, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 48, these references incorporated by reference herein control.

[00582] In an embodiment, the Kv7 channel activator is a compound according to Formula

48: including any of its stereoisomers, or any mixture of its stereoisomers, or a pharmaceutically- acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ and R ² , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, baloalkoxy, amino, alkyl-carbonyl-amino, alkyl-sulfonyl, cyano or nitro; R ³ represents alkyl, cycloalkyl or alkoxy; and R ⁴ and R ⁵ , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino, nitro or cyano.

[00583] In further embodiments, R ¹ and R ² , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl- carbonyl-amino, alkyl-sulfonyl, cyano or nitro.

[00584] In further embodiments, R ³ represents alkyl, cycloalkyl or alkoxy.

[00585] In further embodiments, R ⁴ and R ⁵ , independently of each other, represent hydrogen, alkyd, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl- carbonyl-amino, nitro or cyano.

[00586] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H- quinazolin-3-yl)-amide; 2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4- oxo-4H-quinazolin-3-yl)-amide; 2-(3-Fluoro-4-methyl-phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)- amide; 2-Phenyl-cyclopropanecarboxylic acid (2- isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; 2-( ⁴ -Fluoro-phenyl)- cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; 2-p-Tolyl- cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; 2-(3-Fluoro- phenyl)-cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; or 2-p- Tolyl-cyclopropanecarboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; or a pharmaceutically-acceptable addition salt thereof. Formula 49

[00587] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 49. Such compounds are described in International Publication No. W02007057447A1, published May 24, 2007, and corresponding to International Application No. PCT/EP2006/068627 filed November 17, 2006; US Publication No. US20090291973A1, published November 26, 2009, and corresponding to US Application No. 12/085,188 filed November 17, 2006; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 49, these references incorporated by reference herein control.

[00588] In an embodiment, the Kv7 channel activator is a compound according to Formula 49:

Formula 49 including any of its stereoenantiomers or any mixture of its stereoenantiomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R ¹ represents hydrogen or alkyl; and R ² represents alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenylalkyl, amino, alkyl-carbonyl-amino, cyano or nitro; or R ¹ and R ² together with the carbon atom to which they are attached form a cycloalkyl group; or R ¹ represents hydrogen; and R ² together with R ³ attached in ortho-position on the aromatic ring form a — (CH2) _n — bridge, wherein n is 1, 2 or 3; R ³ and R ⁴ , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino, alkyl-sulfonyl, phenyl, benzoyl, cyano or nitro; or R ³ and R ⁴ together form a methylenedi oxy group; or R ³ attached in ortho-position on the aromatic ring and together with R ² form a — (CH2) _n — bridge, wherein n is 1, 2 or 3; and R ⁴ is as defined above; R ⁵ represents alkyl, cycloalkyl, alkoxy, alkylthio or phenyl; and R ⁶ and R ⁷ , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino(acetamido), nitro, cyano or phenyl; provided, however, that if R ¹ is hydrogen, R ² is methyl, R ³ and R ⁴ represent hydrogen, R ⁵ is isopropyl, and R ⁶ and R ⁷ represent hydrogen, then the compound it is not a quinazoline derivative racemate but the R- or S-enantiomer of the quinazoline derivative.

[00589] In further embodiments, R ¹ represents hydrogen or alkyl.

[00590] In further embodiments, R ² represents alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenylalkyl, amino, alkyl-carbonyl-amino, cyano or nitro.

[00591] In further embodiments, R ¹ represents hydrogen or methyl; and R ² represents methyl, ethyl, isopropyl, cyclohexyl, fluoro or benzyl.

[00592] In further embodiments, R ¹ and R ² together with the carbon atom to which they are attached form a cycloalkyl group.

[00593] In further embodiments, R ¹ represents hydrogen; and R ² together with R ³ attached in ortho-position on the aromatic ring form a — (CH2) _n — bridge, wherein n is 1, 2 or 3.

[00594] In further embodiments, R ³ and R ⁴ , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl- carbonyl-amino, alkyl-sulfonyl, phenyl, benzoyl, cyano or nitro; or R ³ and R ⁴ together form a methylenedioxy group.

[00595] In further embodiments, R ³ attached in ortho-position on the aromatic ring and together with R ² form a — (CH2) _n — bridge, wherein n is 1, 2 or 3; and R ⁴ is as defined in claim 7.

[00596] In further embodiments, R ⁵ represents alkyl, cycloalkyl, alkoxy, alkylthio or phenyl. [00597] In further embodiments, R ⁶ and R ⁷ , independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl- carbonyl-amino(acetamido), nitro, cyano or phenyl.

[00598] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-3-methyl-2-phenyl-b utyramide; 2- (4-Chloro-phenyl)-N-(2-isopropylsulfanyl-4-oxo-4H-quinazolin -3-yl)-butyramide; 2-(3,5- Difluoro-phenyl)-N-(2-isopropylsulfanyl-4-oxo-7-trifluoromet hyl-4H-quinazolin-3-yl)- propionamide; N-(2-Ethyl-7-fluoro-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propi onamide; (S)- N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionami de; N-(2-Isopropyl-4-oxo- 4H-quinazolin-3-yl)-2,3-diphenyl-propionamide; Bicyclo[4.2.0]octa-l,3,5-triene-7- carboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; N-(2-Isopropyl-4-oxo-4H- quinazolin-3-yl)-2-p-tolyl-propionamide; 2-Cyclohexyl-N-(2-isopropyl-4-oxo-4H- quinazolin-3-yl)-2-phenyl-acetamide; 2-(3-Benzoyl-phenyl)-N-(2-isopropyl-4-oxo-4H- quinazolin-3-yl)-propionamide; 1 -Phenyl-cyclopropanecarboxylic acid (2-isopropyl-4-oxo- 4H-quinazolin-3-yl)-amide; 2-(3,4-Dimethoxy-phenyl)-N-(2-isopropyl-4-oxo-4H-quinazolin-

3-yl)-propionamide; (R)-N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propio namide; N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-isobutyram ide; 2-(4-Chloro-phenyl)-N- (2-isopropyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-pro pionamide; N-(2-Isopropyl-4- oxo-4H-quinazolin-3-yl)-2-(4-trifluoromethyl-phenyl)-propion amide; 2-(3,4-Dichloro- phenyl)-N-(2-isopropyl-4-oxo-7-trifluoromethyl-4H-quinazolin -3-yl)-propionamide; 2-(3- Fluoro-phenyl)-N-(2-isopropyl-4-oxo-4H-quinazolin-3-yl)-prop ionamide; 2-(4-Chloro- phenyl)-N-(2-isopropyl-4-oxo-4H-quinazolin-3-yl)-propionamid e; N-(2-Isopropyl-4-oxo-7- trifluoromethyl-4H-quinazolin-3-yl)-2-(4-trifluoromethyl-phe nyl)-propionamide; N-(2- Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-(4-methoxy-phenyl)-pro pionamide; N-(2-Isopropyl-

4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-2-(4-methoxy- phenyl)-propionamide; 2-(3,4- Dichloro-phenyl)-N-(2-isopropyl-4-oxo-4H-quinazolin-3-yl)-pr opionamide; 2-(3-Fluoro-4- methyl-phenyl)-N-(2-isopropyl-4-oxo-7-trifluoromethyl-4H-qui nazolin-3-yl)-propionamide; 2-(3-Fluoro-4-methyl-phenyl)-N-(2-isopropyl-4-oxo-4H-quinazo lin-3-yl)-propionamide; 2- (4-Isobutyl-phenyl)-N-(2-isopropyl-4-oxo-4H-quinazolin-3-yl) -propionamide; N-(7-Chloro- 2-isopropyl-4-oxo-4H-quinazolin-3-yl)-2-(3-fluoro-phenyl)-pr opionamide; N-(6-Chloro-2- isopropyl-4-oxo-4H-quinazolin-3-yl)-2-(3-fluoro-phenyl)-prop ionamide; 2-(4-Fluoro- phenyl)-N-(2-isopropyl-4-oxo-4H-quinazolin-3-yl)-propionamid e; N-(5-Chloro-2-isopropyl- 4-oxo-4H-quinazolin-3-yl)-2-(3-fluoro-phenyl)-propionamide; N-(8-Chloro-2-isopropyl-4- oxo-4H-quinazolin-3-yl)-2-(3-fluoro-phenyl)-propionamide; N-(8-Cyano-2-isopropyl-4-oxo- 4H-quinazolin-3-yl)-2-(3-fluoro-phenyl)-propionamide; 7-Methyl-bicyclo[4.2.0]octa- l(6),2,4-triene-7-carboxylic acid (2-isopropyl-4-oxo-4H-quinazolin-3-yl)-amide; N-(2- Isopropylsulfanyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propion amide; 2-(4-Chloro-phenyl)- N-(2-isopropylsulfanyl-4-oxo-4H-quinazolin-3-yl)-propionamid e; 2-(4-Chloro-phenyl)-N-(2- ethoxy-4-oxo-4H-quinazolin-3-yl)-propionamide; 2-(3,5-Difluoro-phenyl)-N-(2- methylsulfanyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-p ropionamide; 2-Fluoro-N-(2- isopropyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionamide; (S)-2-Fluoro-N-(2-isopropyl- 4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionamide; (R)-2-Fluoro-N-(2-isopropyl-4-oxo-4H- quinazolin-3-yl)-2-phenyl-propionamide; (S)-2-Fluoro-N-(2-isopropyl-4-oxo-7- trifluoromethyl-4H-quinazolin-3-yl)-2-phenyl-propionamide; or (R)-2-Fluoro-N-(2- isopropyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-2-phen yl-propionamide; or an N- oxide thereof, any of its stereoenantiomers or any mixture of its stereoenantiomers, or a pharmaceutically-acceptable addition salt thereof. Formula 50

[00599] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 50. Such compounds are described in US Patent No. 7,741,352, issued June 22, 2010, and corresponding to US Application No. 10/546,533 filed March 11, 2004; International Publication No. W02004080377A2, published September 23, 2004, and corresponding to International Application No.

PCT/EP2004/050290 filed March 11, 2004; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 50, these references incorporated by reference herein control.

[00600] In an embodiment, the Kv7 channel activator is a compound according to Formula 50:

Formula 50 any of its enantiomers or any mixture of its enantiomers, or a prodrug, or a pharmaceutically - acceptable addition salt thereof, wherein R ¹ represents — CN; R ² represents halo, haloalkyl, hydroxyl or alkoxy; X represents, NR" or NR"CH2 (read in the stated direction); wherein R" represents hydrogen; R ⁴ represents aryl-alkyl, which is substituted one or more times with substituents selected from the group consisting of halo, or methylenedioxy; or R ⁴ represents a group of formula -Z'-L"-Z"; wherein Z' and Z", independently of one another, represent an aryl group, which aryl may be optionally substituted one or more times with halo; and L" represents a single (covalent) bond, or a linker selected from O or OCH2, with the proviso that when X represents NR", then R ⁴ represents aryl-alkyl and when X represents NR"CH2, then R ⁴ represents a group of formula -Z'-L"-Z".

[00601] In further embodiments, R ⁴ represents benzyl which is substituted one or two times with halo or one time with methylenedioxy.

[00602] In further embodiments, R ⁴ represents 4-fluoro-benzyl, 3,4-dichloro-benzyl or benzo[l,3]dioxol-5-ylmethyl.

[00603] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 4-(4-Fluoro-benzylamino)-2-hydroxy-benzonitrile 4-(3,4-Dichloro- benzylamino)-2-hydroxy -benzonitrile or 4-[(Benzo[l,3]dioxol-5-ylmethyl)-amino]-2- hydroxy -benzonitrile; or a pharmaceutically-acceptable addition salt thereof.

[00604] In further embodiments, R ⁴ represents a group of formula -Z'-L"-Z"; wherein Z' represents phenyl, or phen-4-yl; which phenyl may optionally be substituted one or two times with halo; and Z" represent phenyl; which may optionally be substituted one or two times with halo; and L" represents a single (covalent) bond, or a linker selected from alkyl, O, or OCH ₂ .

[00605] In further embodiments, R ⁴ represents 3 -phenoxy-phenyl, 3 -benzyloxy-phenyl, or biphenyl-4-yl.

[00606] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-Hydroxy-4-(3-phenoxy-benzylamino)-benzonitrile; 4-(3-Benzyloxy- benzylamino)-2-hydroxy -benzonitrile; or 4-[(Biphenyl-4-ylmethyl)-amino]-2-hydroxy- benzonitrile; or a pharmaceutically-acceptable addition salt thereof.

Formula 51

[00607] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 51. Such compounds are described in US Patent No. 7,741,352, issued June 22, 2010, and corresponding to US Application No. 10/546,533 filed March 11, 2004; International Publication No. W02004080377A2, published September 23, 2004 and corresponding to International Application No. PCT/EP2004/050290 filed March 11, 2004; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 51, these references incorporated by reference herein control.

[00608] In an embodiment, the Kv7 channel activator is a compound according to Formula 51 :

Formula 51 wherein, R represents hydrogen, halogen or hydroxy. R ¹ , R ² , R ³ and R ⁴ independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p- trihalogenmethyl-phenyl, or R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ are joined together to form a benzo fused ring, R ⁵ represents hydrogen or alkyl, and R ⁶ represents halogen or trihalogenmethyl, or a pharmaceutically-acceptable addition salt thereof.

[00609] In further embodiments, R represents hydrogen, halogen or hydroxy, R ¹ , R ² , R ³ and R ⁴ independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, and when R ¹ and R ⁴ are hydrogen, then R ² or R ³ is phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl; or R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ are joined together to form a benzo fused ring, R ⁵ represents hydrogen or alkyl, and R ⁶ represents halogen or trihalogenmethyl.

[00610] In further embodiments, R ¹ , R ³ and R ⁴ represent hydrogen, and R ² represents halogen, trihalogenmethyl or phenyl.

[00611] In further embodiments, R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ are j oined together to form a benzo fused ring.

[00612] In further embodiments, R ⁵ is hydrogen or methyl.

[00613] In further embodiments, R ⁶ is chlorine.

[00614] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: (+)-3-(5-chloro-2-methoxyphenyl)-l,3-dihydro-6-(trifluoromet hyl)-2H-indol-2- one; (-)-3-(5-chloro-2-methoxyphenyl)-l,3-dihydro-6-(trifluoromet hyl)-2H-indol -2-one; (±)- 3-(5-chloro-2-methoxyphenyl)-l,3-dihydro-6(4-methylphenyl)-2 H-indol-2-one; (±)-3-(5- chloro-2-hydroxyphenyl)-l,3-dihydro-2H-indol-one; (±)-3-(5-chloro-2-hydroxyphenyl)-4,6- dichloro-l,3-dihydro-2H-indol-one; (±)-3-(5-chloro-2-hydroxyphenyl)-l,3-dihydro-6-phenyl- 2H-indol-one; (±)-3-(5-chloro-2-hydroxyphenyl)-l,3-dihydro-6-iodo-2H-indo l-one; (±)-3-(5- chloro-2-hydroxyphenyl)-l,3-dihydro-6-trifluoromethyl)-2H-in dol-2-one; (±)-3-(5-chloro-2- hydroxyphenyl)-l,3-dihydro-6-[4-(trifluoromethyl)-phenyl]-2H -indol-2-one; (±)-3-(5-chloro-

2-hydroxyphenyl)-l,3-dihydro-2H-benz[e]indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-

1.3-dihydro-2H-benz[f]indol -2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-l,3-dihydro-2H- benx[g]indol -2-one; (±)-3-(5-chloro-2-methoxyphenyl)-l,3-dihydro-3-hydroxy-6- (trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-l,3-dihydro-3-hydroxy- 4-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-l,3-dihydro-3- hydroxy-6-(trifluoromethyl)-2H-indol-2-one; (-)-3-(5-chloro-2-methoxyphenyl)-l,3-dihydro- hydroxy-6-(trifluoromethyl)-2H-indol— 2-one; (±)-3-(5-chloro-2-methoxyphenyl)-l,3- dihydro-3-hydroxy-7-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-

1.3-dihydro-3-hydroxy-5-bromo-2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-l,3- dihydro-3-hydroxy-6-iodo-2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-4,6-dichloro- 1 , 3 -dihydro-3 -hy droxy-2H-indol-2-one; (±)-3 -(5 -chloro-2-methoxyphenyl)- 1 ,3 -dihydro-3 - hydroxy-2H-benz[f]indol -2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-l,3-dihydro-3-hydroxy- 4,6-bis-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-l,3-dihydro-3- hydroxy-4-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-l,3-dihydro-

3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one; (+)-3-(5-chloro-2-hydroxyphenyl)-l,3- dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one; (-)-3-(5-chloro-2-hydroxyphenyl)-

1.3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2- hydroxyphenyl)-l,3-dihydro-3-hydroxy-7-(trifluoromethyl)-2H- indol-2-one; (±)-3-(5-chloro-

2-hydroxyphenyl)-4,6-di chi oro-1, 3 -dihydro-3 -hydroxy-2H-indol-2-one; (±)-3-(5-chloro-2- hydroxyphenyl)-l,3-dihydro-3-hydroxy-5-bromo-2H-indol-2-one; (±)-3-(5-chloro-2- hy droxyphenyl)- 1 , 3 -dihydro-3 -hy droxy-6-iodo-2H-indol-2-one; (±)- 1 ,3 -dihydro-3 -hy droxy-

3-[2-hydroxy-5-(trifluoromethyl)-phenyl]-6-(trifluorometh yl)-2H-indol -2-one; (±)-3-(5- chloro-2-hydroxyphenyl)-l,3-dihydro-3-hydroxy-2H-benz[g]indo l-2-one; (±)-3-(5-chloro-2- hydroxyphenyl)-l,3-dihydro-3-hydroxy-2H-benz[f]indol -2-one; (±)-3-(5-chl oro-2 - hydroxyphenyl)-l,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-i ndol-2-one; (3S)-(+)-(5- chloro-2-m ethoxyphenyl)- 1, 3 -dihydro-3 -fluoro-6-(trifluoromethyl)-2H-indol-2-one; (3R)- (-)-(5-chloro-2-methoxyphenyl)-l,3-dihydro-3-fluoro-6-(trifl uoromethyl)-2H-indol2-one; (±)-3-(5-chloro-2-methoxyphenyl)-l,3-dihydro-3-fluoro-7-(tr ifluoromethyl)2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-l,3-dihydro-3-fluoro-6-phe nyl-2H-indol-2-one; (±)-3-(5- chloro-2-m ethoxyphenyl)- 1 ,3 -dihydro-3 -fluoro-6-iodo-2H-indol-2-one; (±)-3 -(5-chloro-2- methoxyphenyl)-l,3-dihydro-3-fluoro-5-methyl-2H-indol-2-one; (±)-3-(5-chloro-2- methoxyphenyl)-l,3-dihydro-3-fluoro-5-bromo-2H-indol-2-one; (±)-3-(5-chloro-2- methoxyphenyl)-l,3-dihydro-3-fluoro-4,6-bis-(trifluoromethyl )-2H-indol -2-one; or (±)-3-(5- chloro-2-methoxyphenyl)-l,3-dihydro-3-fluoro-7-(trifluoromet hyl)-2H-indol-2-one; or a pharmaceutically-acceptable addition salt thereof.

[00615] In further embodiments, R represents hydrogen, halogen or hydroxy, R ¹ , R ² , R ³ and R ⁴ independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, or R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ are joined together to form a bezo fused ring, R ⁵ represents hydrogen or alkyl, and R ⁶ represents halogen or trihalogenmethyl, or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent.

Formula 52

[00616] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 52. Such compounds are described in International Publication No. CN114380731 A, published April 22, 2022, and corresponding to International Application No. CN202210226122.7A filed March 9, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 52, this reference incorporated by reference herein controls.

[00617] In an embodiment, the Kv7 channel activator is a compound according to Formula 52:

Formula 52 wherein, Ri is selected from H, halogen, substituted or unsubstituted phenyl, or a substituted or unsubstituted phenylalkyl group, the substituents of said phenyl and phenylalkyl groups each being independently selected from halogen or haloalkyl; X is selected from S or C; R2 is optionally selected from H, alkyl, alkenyl or alkynyl; R3 and R4 each independently selected from H or alkyl; y is selected from O or S; R5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkoxy or furyl, the substituent of the alkyl is selected from alkoxy, dialkylamino or alkoxycarbonyl, and the substituent of the cycloalkyl is selected from halogen. [00618] In further embodiments, R2 is selected from H, Ci-CsAlkyl radical, Ci-CsAlkenyl or Ci-CsAlkynyl.

[00619] In further embodiments, R 3 and R4 are each independently selected from H or Ci- CeAn alkyl group.

[00620] In further embodiments, R5 is selected from substituted or unsubstituted Ci- CeAlkyl, substituted or unsubstituted O-CeCycloalkyl radical, Ci-CeAlkoxy or furyl, the substituents of the alkyl or the alkoxy being selected from Ci-CeAlkoxy, di (C)i-C4Alkyl) amino or Ci-CeAlkoxycarbonyl, the substituents of cycloalkyl being selected from halogen. [00621] In further embodiments, the formula is one of formulas II - IV: wherein, n is more than or equal to 0;Rnand R12 each independently selected from H, halogen or halomethyl; R2 is selected from H, Ci-CsAlkyl radical, C2-C3Alkenyl or C2-C3An alkynyl group; Rsand R4 are independently selected from H or Ci-Ce alkyl group; y is selected from O or S; R5 is selected from substituted or unsubstituted Ci-CeAlkyl, substituted or unsubstituted C3-CeCycloalkyl radical, Ci-CeAlkoxy or furyl, the substituents of the alkyl being selected from Ci-CeAlkoxy, di (C)i-C4Alkyl) amino or Ci-CeAlkoxycarbonyl, the substituents of cycloalkyl being selected from halogen.

[00622] In further embodiments, n is 0 to 3, R n is selected from H, F or trifluoromethyl, and R12 is selected from H, F, Cl or methyl.

[00623] In further embodiments, R3 is one of H or methyl, and R4 is other of H or methyl. [00624] In further embodiments, R5 is selected from methyl, ethyl, isopropyl, isobutyl, neopentyl, cyclobutyl, ethoxy, isopropoxy, tert-butoxy or tetrahydrofuranyl.

Formula 53

[00625] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 53. Such compounds are described in International Publication No. W02021260090A1, published December 30, 2021, and corresponding to International Application No. PCT/EP2021/067288 filed June 24, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 53, this reference incorporated by reference herein controls.

[00626] In an embodiment, the Kv7 channel activator is a compound according to Formula 53:

Formula 53 wherein, X ¹ represents nitrogen or CR ^X1 ; wherein R ^X1 represents hydrogen, halogen, (Ci- 4)alkyl, or (Ci-4)alkoxy; X ² represents nitrogen or CR ^X2 ; wherein R ^X2 represents hydrogen, halogen, (Ci-4)alkyl, or (Ci-4)alkoxy; X ³ represents nitrogen or CR ^X3 ; wherein R ^X3 represents hydrogen, halogen, (Ci-4)alkyl, (Ci- 4)alkoxy, or hydroxy; R ¹ represents hydrogen or methyl; R ^X4 represents hydrogen, halogen, or (Ci-4)alkyl; • R ^2A represents hydrogen; (Ci-4)alkyl; (C2- 4)alkenyl; (C2-4)alkynyl; (C3-e)cycloalkyl; (Ci- 4)fluoroalkyl; (Ci-4)hydroxyalkyl; (Ci-4)alkoxy- (Ci-2)alkyl; (Ci-2)alkoxy-(Ci-2)alkoxy-(Ci- 2)alkyl; (Ci-2)alkyl-S-(Ci-2)alkyl; (Ci-2)alkyl- (SO2)-(Ci-2)alkyl; cyano; (Ci-2)cy anoalkyl; H2N- C(O)-(Ci-2)alkyl; (R ^N1 )2N-(Ci-2)alkyl or (R ^N1 )2N-C(0)-, wherein R ^N1 independently represents hydrogen or (Ci-2)alkyl; or a 5- membered heteroaryl group containing one to four nitrogen atoms, wherein said 5-membered heteroaryl group is independently unsubstituted or mono-substituted with (Ci-4)alkyl; and R ^2B represents hydrogen or methyl; or • R ^2A and R ^2B form, together with the carbon atom to which they are attached, a ring of 3- to 6 members, wherein the members needed to complete said ring are each independently selected from -CH2- and -O- and wherein said ring does not contain more than one -O- member; L represents a direct bond, cycloprop- 1,1 -diyl, -CHR ^L - O-*, -O-CH2-*, -CH2-NH-*, -CH2- N(CHs)-*, -O-, or -(SO2)-; wherein R ^L represents hydrogen, (Ci-4)alkyl, CH3-O-CH2-, or (CH3)2NCH2-; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; R ³ represents hydrogen or fluoro; • R ⁴ represents hydrogen or (Ci-4)alkyl; R ⁵ represents hydrogen, fluoro, or hydroxy; and R ⁶ represents fluoro or (Ci)fluoroalkyl; or • R ⁴ and R ⁵ together represent a bridge selected from -CH2- and -CH2CH2-; and R ⁶ represents hydrogen, fluoro, (Ci)fluoroalkyl, or (Ci- 4)alkyl; or a salt thereof.

[00627] In further embodiments, X ¹ represents CR ^X1 ; wherein R ^X1 represents hydrogen or halogen; X ² represents nitrogen or CH; X ³ represents nitrogen or CH; R ¹ represents hydrogen; R ^X4 represents hydrogen, halogen, or (Ci-4)alkyl; R ^2A represents hydrogen; (Cn 4)alkyl; (Ci-4)fluoroalkyl; (Ci-4)hydroxyalkyl; or (Ci-4)alkoxy-(Ci- 2)alkyl; R ^2B represents hydrogen; L represents a direct bond, -CH2-O-*, or-O-; wherein the asterisk indicates the bond which is linked to the aromatic carbon atom; R ³ represents hydrogen or fluoro; • R ⁴ represents hydrogen or (Ci-4)alkyl; R ⁵ represents hydrogen, fluoro, or hydroxy; and R ⁶ represents fluoro or (Ci)fluoroalkyl; or • R ⁴ and R ⁵ together represent a bridge selected from -CH2- and -CH2CH2-; and R ⁶ represents hydrogen, fluoro, (Ci)fluoroalkyl, or (Ci- 4)alkyl; or a salt thereof (meaning a salt of the compound of Formula 53).

[00628] In further embodiments, R ^2A represents hydrogen, (Ci-4)alkyl, (Ci-4)fluoroalkyl, (Cn 4)hydroxyalkyl, or methoxy methyl; and R ^2B represents hydrogen; or a salt thereof.

[00629] In further embodiments, L represents a direct bond; or a salt thereof.

[00630] In further embodiments, R ³ represents fluoro; or a salt thereof.

[00631] In further embodiments, R ^X4 represents hydrogen; or a salt thereof.

[00632] In further embodiments, each of X ¹ , X ² , and X ³ represents CH; or a salt thereof.

[00633] In further embodiments, the fragment represents:

; wherein R ^X4 represents hydrogen or halogen; R ³ represents hydrogen or fluoro; and L represents a direct bond, -CH2-O-*, or-O-; wherein the asterisk indicates the bond which is linked to the aromatic carbon atom; or • ; wherein X ³ represents nitrogen or CH;

R ^X4 represents hydrogen or (Ci-4)alkyl; R ³ represents hydrogen or fluoro; and L represents - CH2-O-*, or-O-; wherein the asterisk indicates the bond which is linked to the aromatic carbon atom; or a salt thereof.

[00634] In further embodiments, R ⁴ represents hydrogen; R ⁵ represents hydrogen or fluoro; and R ⁶ represents fluoro, difluorom ethyl or trifluorom ethyl; or a salt thereof.

[00635] In further embodiments, R ⁴ and R ⁵ together represent a -CH2- bridge; and R ⁶ represents hydrogen, fluoro, difluoromethyl, or trifluoromethyl; or a salt thereof.

[00636] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: l-(3,3-Difluoro-cyclobutyl)-3-(3-trifluoromethyl-benzyl)-ure a; 1- Bicyclof 1.1.1 ]pent- 1 -yl-3 -[ 1 -(3 -trifluoromethyl-phenyl)-ethyl]-urea; 1 -(3 -Difluorom ethyl- cyclobutyl)-3 -[ 1 -(3 -trifluoromethyl-phenyl)-ethyl]-urea; 1 -(3 -Fluoro-bicyclof 1.1.1 ]pent- 1 - yl)-3 -[ 1 -(3 -trifluoromethyl-phenyl)-ethyl]-urea; 1 -(3 -Difluoromethyl-bicyclof 1.1.1 ]pent- 1 - yl)-3-[l-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1 -Bicyclof 1.1.1 ]pent-l -yl-3 -[1 -(3- trifluoromethoxy-phenyl)-ethyl]-urea; l-(3-Difluoromethyl-cyclobutyl)-3-[l-(3- trifluoromethoxy-phenyl)-ethyl]-urea; 1 -(3 -Fluoro-bicyclof 1.1.1 ]pent- 1 -yl)-3 -[ 1 -(3 - trifluoromethoxy-phenyl)-ethyl]-urea; l-[2,2-Difluoro-l-(3-trifluoromethyl-phenyl)-ethyl]-3- (3 -hydroxy-3 -trifluorom ethyl-cy cl obutyl)-urea; l-(3,3-Difluoro-l-methyl-cyclobutyl)-3-[2,2- difluoro-l-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1 -Bicyclofl .1. l]pent-l-yl-3-[l-(3- difluoromethoxy-phenyl)-ethyl]-urea; 1 -(3 -Difluoromethyl-bicyclof 1.1. l]pent-l-yl)-3-[2- hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1 -(3 -Difluoromethyl-bicyclof 1.1. l]pent-l- yl)-3-[2,2-difluoro-l-(3-trifluoromethyl-phenyl)-ethyl]-urea ; 1 -(3 -Difluoromethyl- bicyclof 1.1.1 ]pent- 1 -yl)-3 -[2-m ethoxy- 1 -(3 -trifluoromethyl-phenyl)-ethyl]-urea; 1 -(3 - Difluoromethyl-bicyclof 1.1. l]pent-l-yl)-3-(2-fluoro-3-trifluoromethyl-benzyl)-urea; l-(3- Difluoromethyl-bicyclofl .1. l]pent-l-yl)-3-(3-fluoro-5-trifluoromethyl-benzyl)-urea; l-(3- Fluoro-bicyclo[l. l.l]pent-l-yl)-3-[3-(2,2,2-trifluoro-ethoxy)-benzyl]-urea; l-(3- Difluoromethyl-cyclobutyl)-3-[3-(2,2,2-trifluoro-ethoxy)-ben zyl]-urea; l-[3-(2,2,2-Trifluoro- ethoxy)-benzyl]-3-(3-trifluoromethyl-bicyclo[l .1. l]pent-l-yl)-urea; 1 -(3 -Difluorom ethoxybenzyl)^ -(3 -fluoro-bicyclof 1.1.1 ]pent- 1 -yl)-urea; 1 -(3 -Difluorom ethoxy -benzyl)-3 -(3 - difluoromethyl-cyclobutyl)-urea; 1 -(3 -Difluorom ethoxy -benzyl)-3 -(3 -trifluorom ethylbicyclofl .1. l]pent-l-yl)-urea; 1 -(3 -Trifluorom ethoxy -benzyl)-3 -(3 -trifluorom ethylbicyclofl .1.1 ]pent- 1 -yl)-urea; 1 -(3 -Fluoro-bicyclof 1.1.1 ]pent- 1 -y l)-3 -(3 -trifluoromethoxy - benzyl)-urea; 1 -(3 -Difluorom ethyl-cyclobutyl)-3 -(3 -trifluorom ethoxy -benzyl)-urea; 1- Bicyclofl .1. l]pent-l -yl-3 -(3 -trifluorom ethoxy -benzyl)-urea; 1 -(3 -Difluorom ethyl-benzyl)-3- (3 -difluorom ethyl-cy cl obutyl)-urea; 1 -(3 -Difluorom ethyl-benzyl)-3 -(3 -trifluorom ethylbicyclofl .1. l]pent-l-yl)-urea; 1 -(3 -Difluorom ethyl-cy cl obutyl)-3 -(2 -trifluorom ethoxy - pyridin-4-ylmethyl)-urea; l-(2-Trifluoromethoxy-pyridin-4-ylmethyl)-3 -(3 -trifluorom ethylbicyclofl .1.1 ]pent- 1 -yl)-urea; 1 -(3 -Difluorom ethyl-cy cl obutyl)-3 - {2-m ethoxy- 1 - [2-(2,2, 2- trifluoro-ethoxy)-pyridin-4-yl]-ethyl}-urea; l-{2-Methoxy-l-[2-(2,2,2-trifluoro-ethoxy)- pyridin-4-yl]-ethyl}-3-(3-trifluoromethyl-cyclobutyl)-urea; l-[l-(2-Difluoromethoxy-pyridin- 4-yl)-ethyl]-3-(3-difluoromethyl-cyclobutyl)-urea; l-{ l-[2-Methyl-6-(2,2,2-trifluoro-ethoxy)- pyrimidin-4-yl]-ethyl}-3-(3-trifluoromethyl-bicyclo[l.l. l]pent-l-yl)-urea; 1-

Bicyclof 1.1.1 ]pent- 1 -yl-3 -(3 -trifluorom ethyl-benzyl)-urea; 1 -(3 -Fluoro-bicyclof 1.1.1 ]pent- 1 - yl)-3 -(3 -trifluorom ethyl-benzyl)-urea; 1 -(3 -Trifluorom ethyl-benzyl)-3 -(3 -trifluoromethyl- bicy clo[ 1.1. l]pent-l-yl)-urea; I -(3 -Difluoromethyl -cyclobutyl )-3 -(3 -trifl uoromethyl -benzyl )- urea; l-(3-Methyl-bicyclo[l.l.l]pent-l-yl)-3-(3-trifluoromethyl-be nzyl)-urea; l-(3- Fluoromethyl-bicyclofl .1. l]pent-l-yl)-3-(3-trifluoromethyl-benzyl)-urea; l-(3- Trifluoromethyl-benzyl)-3-(3-trifluoromethyl-cyclobutyl)-ure a; 1 -(3 -Hydroxy-3 - trifluoromethyl-cyclobutyl)-3-(3-trifluoromethyl-benzyl)-ure a; 1 -Bicyclofl .1. l]pent-l-yl-3- [2-(2,2,2-trifluoro-ethoxy)-pyridin-4-ylmethyl]-urea; 1 -(3 -Fluoro-bicyclofl .1. l]pent-l-yl)-3- [2-(2,2,2-trifluoro-ethoxy)-pyridin-4-ylmethyl]-urea; l-[2-(2,2,2-Trifluoro-ethoxy)-pyridin-4- ylmethyl]-3-(3-trifluoromethyl-bicyclo[l .1. l]pent-l-yl)-urea; 1 -(3 -Difluorom ethyl- cyclobutyl)-3-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-ylmethyl ]-urea; 1 -(3 -Difluorom ethylbicyclofl.1.1 ]pent-l-yl)-3 -(3 -trifluoromethyl-benzyl)-urea; l-Bicyclo[2.1.1]hex-l-yl-3-(3- trifluoromethyl-benzyl)-urea; l-(3,3-Difluoro-l-methyl-cyclobutyl)-3-(3-trifluoromethyl- benzyl)-urea; l-(3-(trifluoromethyl)benzyl)-3-((ls,3s)-3-(trifluoromethyl) cyclobutyl)urea; 1- (3 -(trifluoromethyl)benzyl)-3 -((1 r,3 r)-3 -(trifluoromethyl)cy clobutyl)urea; 1 -(( 1 s, 3 s)-3 - (difluorom ethyl)cy cl obutyl)-3 -(3 -(trifluoromethyl)benzyl)urea; l-((lr,3r)-3- (difluoromethyl)cyclobutyl)-3-(3-(trifluoromethyl)benzyl)ure a; l-{(S)-l-[2-Methyl-6-(2,2,2- trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-3-(3-trifluoromethy l-bicyclo[l .1. l]pent-l-yl)- urea; l-((lr,3r)-3-(difluoromethyl)cyclobutyl)-3-((2-(2,2,2-triflu oroethoxy)pyridin-4- yl)methyl)urea; l-((ls,3s)-3-(difluoromethyl)cyclobutyl)-3-((2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)urea; l-((ls,3R)-3-(difluoromethyl)cyclobutyl)-3-((S)-l- (3-(trifluoromethoxy)phenyl)ethyl)urea; and l-((lr,3S)-3 -(difluorom ethyl)cyclobutyl)-3-((S)- 1 -(3 -(trifluorom ethoxy )phenyl)ethyl)urea; or a salt thereof.

Formula 54

[00637] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 54. Such compounds are described in International Publication No. WO2021219594A1, published November 4, 2021 and corresponding to International Application No. PCT/EP2021/060918 filed April 27, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 54, this reference incorporated by reference herein controls.

[00638] In an embodiment, the Kv7 channel activator is a compound according to Formula 54: Formula 54 wherein, X ¹ represents nitrogen or CR ^xl ; wherein R ^X1 represents hydrogen, halogen, (Ci- 4)alkyl, or (Ci- 4)alkoxy;X ² represents nitrogen or CR ^X2 ; wherein R ^X2 represents hydrogen, halogen, (Ci-4)alkyl, or (Ci- 4)alkoxy; X ³ represents nitrogen or CR ^X3 ; wherein R ^X3 represents hydrogen, halogen, (Ci-4)alkyl, (Ci- 4)alkoxy, or hydroxy;* R ¹ represents hydrogen, or methyl; or* R ¹ and R ^X1 together represent a -CH2CH2- bridge; Y represents -C(R ^Y1 )(R ^Y2 )-, or *-CH2-C(R ^Y3 )(R ^Y4 )-, wherein the asterisk indicates the bond which is linked to the cyclobutyl ring;R ^Y1 represents hydrogen, or fluoro;R ^Y2 represents hydrogen or fluoro;R ^Y3 represents hydrogen, fluoro or iodo;R ^Y4 represents hydrogen or fluoro; R ^2A represents hydrogen; (Ci- 4)alkyl; (C2-4)alkenyl; (C2-4)alkynyl; (C3-e)cycloalkyl; (Ci- 4)fluoroalkyl; (Ci-4)hydroxy alkyl; (Ci-4)alkoxy-(Ci-2)alkyl; (Ci-2)alkoxy-(Ci-2)alkoxy-(Ci- 2)alkyl; (Ci-2)alkyl-S-(Ci-2)alkyl; (Cn 2)alkyl-(SO2)-(Ci-2)alkyl; cyano; (Ci-2)cy anoalkyl; H2N- C(O)-(Ci-2)alkyl; (R ^N1 )2N-(CI- 2)alkyl or (R ^N1 )2N-C(0)-, wherein R ^N1 independently represents hydrogen or (Ci-2)alkyl; or a 5-membered heteroaryl group containing one to four nitrogen atoms, wherein said 5- membered heteroaryl group is independently unsubstituted or mono-substituted with(Ci- 4)alkyl; and R ^2B represents hydrogen, or methyl; or R ^2A and R ^2B form, together with the carbon atom to which they are attached, a ring of 3- to 6 members, wherein the members needed to complete said ring are each independently selected from -CH2- and -O- and wherein said ring does not contain more than one -O- member; or R ^2A and R ^X3 together represent a -CH2-O-* bridge, wherein the asterisk indicates the bond which is linked to the aromatic carbon atom, andR ^2B represents hydrogen;R ³ represents -SFs; (Ci-2)alkyi-S(O)2-; or a fragmen wherein R ³¹ represents hydrogen, or fluoro; and L represents a direct bond, cycloprop- 1 ,1-diyl, -CHR ^L -O-*, -O-CH2-*, -CH2-NH-*, - CH ₂ -N(CH ₃ )-*, -O-, or - (SO2)-; wherein R ^L represents hydrogen, (Ci- )alkyl, CH3-O-CH2-, or (CH ₃ )2NCH2-; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; orR ³ and R ^X1 together represent a -O-CF2-O- bridge; orR ³ and R ^X2 together represent a -O-CF2-O- bridge; and R ⁴ represents hydrogen, halogen, or (Ci-4)alkyl; or a salt thereof.

[00639] In further embodiments, R ¹ represents hydrogen; or a salt thereof (meaning a salt of compound of Formula 54).

[00640] In further embodiments, R ^Y1 , R ^Y2 , R ^Y3 and R ^Y4 all represent hydrogen; or a salt thereof.

[00641] In further embodiments, R ^2A represents hydrogen, (Ci-4)alkyl, (C3-e)cycloalkyl, (Ci-

4)fluoroalkyl, (Ci-4)hydroxyalkyl, (Ci-4)alkoxy-(Ci-2)alkyl, (Ci-2)alkyl-S-(Ci-2)alkyl, (Ci- 2)alkyl-(SO2)-(Ci-2)alkyl, cyano, (Ci- 2)cyanoalkyl, H2N-C(O)-(Ci-2)alkyl, (R ^N1 )2N-(CI- 2)alkyl, or (R ^N1 )2N-C(O)-, wherein R ^N1 independently represents hydrogen or (Ci-2)alkyl; and R ^2B represents hydrogen; or R ^2A and R ^2B form, together with the carbon atom to which they are attached, a ring of 3- to 6 members selected from cycloprop-1 ,1-diyl, cyclobut-1 ,1-diyl, oxetane-3,3-diyl and tetrahydropyran-4,4-diyl; or a salt thereof.

[00642] In further embodiments, R ^2A represents hydrogen, methyl, or hydroxymethyl; and

R ^2B represents hydrogen; or a salt thereof.

[00643] In further embodiments, R ³ represents a fragment whereinR ³¹ represents hydrogen, or fluoro; and L represents a direct bond, -CHR ^L -O-*, -O- or -O-; wherein R ^L represents hydrogen, methyl, CH3-O-

CH2-, or (CH3)2NCH2-; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; or a salt thereof.

[00644] In further embodiments, R ⁴ represents hydrogen; or a salt thereof.

Y Y

[00645] In further embodiments, the fragment R ⁴ represents: wherein X ³ represents nitrogen and X ¹ represents CR ^X1 ; X ¹ represents nitrogen and X ³ represents CR ^X3 ; or X ¹ represents CR ^X1 and X ³ represents CR ^X3 ; or a salt thereof. [00646] In further embodiments, the fragment I represents wherein R ^X1 represents hydrogen, fluoro, chloro, methyl, or methoxy; R ^X2 represents hydrogen; R ^X3 represents hydrogen, fluoro, or chloro; R ⁴ represents hydrogen, fluoro, chloro, or methyl; R ³¹ represents hydrogen, or fluoro; and L represents a direct bond, -CHR ^L -O-*, - CH2-NH-*, -CH2-N(CH3)-*, -O-, or ; wherein R ^L represents hydrogen, or methyl; wherein the

F^ , L X ¹ -

F-q p H

^F N <^,X ³ R asterisks indicate the bond which is linked to the aromatic carbon atom; or ⁴ wherein X ³ represents nitrogen and X ¹ represents CR ^X1 ; X ¹ represents nitrogen and

X ³ represents CR ^X3 ; or X ¹ represents CR ^X1 and X ³ represents CR ^X3 ; wherein R ^X1 represents hydrogen, or methoxy; R ^X3 represents hydrogen; R ⁴ represents hydrogen, or methyl; and L represents -CHR ^L -O-*, -CH2-NH-*, or -CH2-N(CH3)-*; wherein R ^L represents hydrogen, methyl, CH3-O-CH2-, or (CH3)2NCH2-; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; or a salt thereof.

[00647] In further embodiments, X ¹ represents CR ^X1 ; wherein R ^X1 represents hydrogen;

X ² represents nitrogen or CR ^X2 ; wherein R ^X2 represents hydrogen; X ³ represents nitrogen or CR ^X3 ; wherein R ^X3 represents hydrogen; R ¹ represents hydrogen; Y represents -CH2-, or - CH2-CH2-; R ^2A represents hydrogen, or hydroxymethyl ;R ^2B represents hydrogen;

R ³ represents trifluoromethyl or 2,2,2-trifluoroethoxy; and R ⁴ represents hydrogen; or a salt thereof.

[00648] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: l-Spiro[3.3]hept-2-yl-3-(3-trifluoromethyl-benzyl)-urea;l-Sp iro[2.3]hex-5-yl-

3-(3-trifluoromethyl-benzyl)-urea;l -(1 , 1 -Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; l-((3r,5r)-l,l-Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; l-((3s,5s)-l , 1 -Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; l-(6,6-Difluoro-spiro[3.3]hept-2-yl)-3-(3-trifluoromethyl- benzyl)-urea;l-[l-(3-Difluoromethoxy-phenyl)-cyclopropyl]-3- spiro[3.3]hept-2-yl-urea;l-(2- Fluoro-3 -trifluorom ethoxy -benzyl)-3 -spiro[3.3 ]hept-2-yl-urea; 1 - [2-Methoxy- 1-(3- trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;l- [l-(2-Difluoromethoxy-pyridin-

4-yl)-2-methoxy-ethyl]-3-spiro[3.3]hept-2-yl-urea;l-Spiro [3.3]hept-2-yl-3-(5- tri fluoromethoxy-2, 3 -di hydro-benzofuran-3-yl)-urea;l-(2-Fluoro-3 -tri fluoromethyl -benzyl)- 3-spiro[3.3]hept-2-yl-urea;l-(3-Difluoromethoxy-benzyl)-3-sp iro[3.3]hept-2-yl-urea;l- Spiro[3.3]hept-2-yl-3-[3-(2,2,2-trifluoro-ethoxy)-benzyl]-ur ea;l-(3-Difluoromethyl-benzyl)- 3-spiro[3.3]hept-2-yl-urea;l-(2-Fluoro-5-trifluoromethyl-ben zyl)-3-spiro[3.3]hept-2-yl- urea; 1 -(4-Fluoro-3 -trifluoromethyl-benzyl)-3 -spiro[3.3 ]hept-2-yl-urea; 1 -(3 -Fluoro-5- trifluoromethyl-benzyl)-3-spiro[3.3]hept-2-yl-urea;l-[l-(2-B romo-5-trifluoromethyl-phenyl)- ethyl]-3-spiro[3.3]hept-2-yl-urea;l-[l-(2-Methoxy-5-trifluor omethyl-phenyl)-ethyl]-3- spiro[3.3]hept-2-yl-urea;l-[l-(2-Methoxy-3-trifluoromethyl-p henyl)-ethyl]-3-spiro[3.3]hept-

2-yl-urea;l-(2-Methoxy-3-trifluoromethyl-benzyl)-3-spiro[ 3.3]hept-2-yl-urea;l- Spiro[3.3]hept-2-yl-3-[l-(3-trifluoromethyl-phenyl)-ethyl]-u rea;l-[Cyclopropyl-(3- trifluoromethyl-phenyl)-methyl]-3-spiro[3.3]hept-2-yl-urea;l -[Cyclopropyl-(3- difluoromethoxy-phenyl)-methyl]-3-spiro[3.3]hept-2-yl-urea;l -{l-[4-Methyl-3-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea; l-{l-[4-Chloro-3-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;l-{l-[4-Me thoxy-3-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;l-{l-[2-Me thyl-3-(2,2,2-trifluoro-ethoxy)- phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;l-{l-[2-Chloro-3-( 2,2,2-trifluoro-ethoxy)-phenyl]- ethyl}-3-spiro[3.3]hept-2-yl-urea;l-{l-[2-Methoxy-3-(2,2,2-t rifluoro-ethoxy)-phenyl]-ethyl}-

3-spiro[3.3]hept-2-yl-urea;l-{l-[3-Methyl-5-(2,2,2-triflu oro-ethoxy)-phenyl]-ethyl}-3- spiro[3.3]hept-2-yl-urea;l-{l-[3-Chloro-5-(2,2,2-trifluoro-e thoxy)-phenyl]-ethyl}-3- spiro[3.3]hept-2-yl-urea;l-(l-(3-(pentafluoro-16-sulfaneyl)p henyl)ethyl)-3-(spiro[3.3]heptan- 2-yl)urea;l-(3-(pentafluoro-16-sulfaneyl)benzyl)-3-(spiro[3. 3]heptan-2-yl)urea;l-[l-(3- Methanesulfonyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea; l-Spiro[3.3]hept-2-yl-3-[3-(l- trifluoromethyl-cyclopropyl)-benzyl]-urea;l-(2-Hydroxy-5-tri fluoromethyl-benzyl)-3- spiro[3.3]hept-2-yl-urea;l-{l-[2-Chloro-5-(2,2,2-trifluoro-e thoxy)-phenyl]-ethyl}-3- spiro[3.3]hept-2-yl-urea;l-{l-[2-Methoxy-5-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-3- spiro[3.3]hept-2-yl-urea;l-Spiro[3.3]hept-2-yl-3-(3-trifluor omethoxy-benzyl)-urea;l- Spiro[3.3]hept-2-yl-3-(3-trifluoromethanesulfonyl-benzyl)-ur ea;l-Spiro[3.3]hept-2-yl-3-(3- trifluoromethoxymethyl-benzyl)-urea;l-Spiro[3.3]hept-2-yl-3- [3-(3-trifluoromethyl-phenyl)- oxetan-3-yl]-urea;l-[2-Hydroxy-2-methyl-l-(3-trifluoromethyl -phenyl)-propyl]-3- spiro[3.3]hept-2-yl-urea;l-(2,2-Difluoro-benzo[l,3]dioxol-4- ylmethyl)-3-spiro[3.3]hept-2-yl- urea;l-[l-(2,2-Difluoro-benzo[l,3]dioxol-4-yl)-ethyl]-3-spir o[3.3]hept-2-yl-urea;l-{2- Dimethylamino-l-[6-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-et hyl}-3-spiro[3.3]hept-2-yl- urea;l-Spiro[3.3]hept-2-yl-3-{4-[2-(2,2,2-trifluoro-ethoxy)- pyridin-4-yl]-tetrahydro-pyran-4- yl } -urea; 1 - { 2-Methoxy- 1 - [2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl] -ethyl } - 1 -methyl-3 - spiro[3.3]hept-2-yl-urea;l-[l-(2-Difluoromethoxy-pyridin-4-y l)-cyclobutyl]-3-spiro[3.3]hept- 2-yl-urea;l-[l-(2-Difluoromethoxy-pyridin-4-yl)-l -methyl-ethyl]-3-spiro[3.3]hept-2-yl-urea; 5-(2,2,2-Trifluoro-ethoxy)-3,4-dihydro-lH-[2,6]naphthyridine -2-carboxylic acid spiro[3.3]hept-2-ylamide; l-Methoxymethyl-5-(2,2,2-trifluoro-ethoxy)-3,4-dihydro-l H- isoquinoline-2-carboxylic acid spiro[3.3]hept-2- ylamide;l-[Cyano-(3-trifluoromethyl- phenyl)-methyl]-3-spiro[3.3]hept-2-yl-urea;l-Spiro[3.3]hept- 2-yl-3-[(l H-[l ,2,4]triazol-3- yl)-(3-trifluoromethyl-phenyl)-methyl]-urea;l-[2,2-Difluoro- l-(3-trifluoromethyl-phenyl)- ethy 1] -3 -spiro[3.3 ]hept-2-yl-urea; 1 -Spiro[3.3 ]hept-2-yl-3 -[2,2,2-trifluoro- 1 -(3 - trifluoromethyl-phenyl)-ethyl]-urea;l-Spiro[3.3]hept-2-yl-3- [6-(2,2,2-trifluoro-ethoxy)- pyrimidin-4-ylmethyl]-urea;l-[2-Methyl-6-(2,2,2-trifluoro-et hoxy)-pyrimidin-4-ylmethyl]-3- spiro[3.3]hept-2-yl-urea;l-Spiro[3.3]hept-2-yl-3-{l-[6-(2,2, 2-trifluoro-ethoxy)-pyrimidin-4- yl]-ethyl}-urea;2-(3-Spiro[3.3]hept-2-yl-ureido)-2-(3-triflu oromethyl-phenyl)-acetamide; N- Methyl-2-(3-spiro[3.3]hept-2-yl-ureido)-2-(3-trifluoromethyl -phenyl)-acetamide; l-[2- Methanesulfonyl-l-(3-trifluoromethoxy-phenyl)-ethyl]-3-spiro [3.3]hept-2-yl-urea; l-[l-(2,2- Difluoro-benzo[l,3]dioxol-5-yl)-ethyl]-3-spiro[3.3]hept-2-yl -urea; l-[2-Cyano-l-(3- trifluoromethoxy-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea; l-[2-Cyano-l-(3-trifluoromethyl- phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;l-{l-[2-Methyl-6-( 2,2,2-trifluoro-ethoxy)- pyrimidin-4-yl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;l-[2-Metha nesulfonyl-l-(3- trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;l- Spiro[3.3]hept-2-yl-3-[2-(2,2,2- trifluoro-ethoxy)-pyrimidin-4-ylmethyl]-urea;l-[2-(2-Methoxy -ethoxy)-l-(3-trifluoromethyl- phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;l-[2-lsopropoxy-l- (3-trifluoromethyl-phenyl)- ethyl]-3-spiro[3.3]hept-2-yl-urea;l-[3-Ethoxy-l-(3-trifluoro methyl-phenyl)-propyl]-3- spiro[3.3 ]hept-2-yl-urea; 1 - [3 -Hydroxy- 1 -(3 -trifluoromethyl-phenyl)-propyl] -3 - spiro[3.3 ]hept-2-yl-urea; 1 -[3 -Methylsulfanyl- 1 -(3 -trifluoromethyl-phenyl)-propyl]-3 - spiro[3.3]hept-2-yl-urea;l-[2-Hydroxy-l-(3-trifluoromethyl-p henyl)-ethyl]-3-spiro[3.3]hept- 2-yl-urea;l-{3-Ethoxy-l -[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-propyl)-3-spiro[3 .3]hept- 2-yl-urea;l-{2-Methoxy-l-[6-(2,2,2-trifluoro-ethoxy)-pyrimid in-4-yl]-ethyl}-3- spiro[3.3 ]hept-2-yl-urea;4-(3 -Spiro[3.3 ]hept-2-yl-ureido)-4-(3 -trifluoromethyl-phenyl)- butyramide;l-Spiro[3.3]hept-2-yl-3-[l -(3-trifluoromethyl-phenyl)-but-3-enyl]-urea;l-[3- Methanesulfonyl-l-(3-trifluoromethyl-phenyl)-propyl]-3-spiro [3.3]hept-2-yl-urea;l-{2- Hydroxy-l-[2-methyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-y l]-ethyl}-3-spiro[3.3]hept-2- yl-urea;l-{2-Hydroxy-l-[6-(2,2,2-trifluoro-ethoxy)-pyrimidin -4-yl]-ethyl}-3-spiro[3.3]hept- 2-yl-urea;l-[3,3-Difluoro-l-(3-trifluoromethyl-phenyl)-propy l]-3-spiro[3.3]hept-2-yl-urea;l- {3-Hydroxy-l-[6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl]-pro pyl}-3-spiro[3.3]hept-2-yl- urea;l-[l-(3-Methanesulfonyl-phenyl)-2-methoxy-ethyl]-3-spir o[3.3]hept-2-yl-urea;l-{2- Hydroxy-l-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro [3.3]hept-2-yl-urea;l-{3- Hydroxy-l-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-propyl)-3-spir o[3.3]hept-2-yl-urea;l-[Cyano- (3-trifluoromethyl-phenyl)-methyl]-3-spiro[3.3]hept-2-yl-ure a;l-Spiro[3.3]hept-2-yl-3-{l-[3- (2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-urea;l-{2-Methoxy-l- [3-(2,2,2-trifluoro-ethoxy)- phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;l-{2-Methoxy-l-[2- (2,2,2-trifluoro-ethoxy)- pyridin-4-yl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;l-Spiro[3.3] hept-2-yl-3-{l-[2-(2,2,2- trifhioro-ethoxy)-pyridin-4-yl]-ethyl}-urea;l-{2-Dimethylami no-l-[2-(2, 2, 2-tri fluoro- ethoxy)-pyridin-4-yl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;l-{l -[3-Fluoro-5-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;l-Spiro[3. 3]hept-2-yl-3-(2- trifluoromethoxy-pyridin-4-ylmethyl)-urea;l-Spiro[3.3]hept-2 -yl-3-[ 1 -(2-tri fluoromethoxy- pyridin-4-yl)-ethyl]-urea; l-{l-[2-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3- spiro[3.3]hept-2-yl-urea;l-{l-[2-Huoro-5-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-3- spiro[3.3]hept-2-yl-urea; l-[l-(2 -Difluoromethoxy -pyridin-4-yl)-ethyl]-3-spiro[3.3]hept-2-yl- urea; 1 -(Spiro[3.3 ]heptan-2-yl)-3 -( 1 -(2-((l , 1 , 1 -trifluoropropan-2-yl)oxy)pyridin-4- yl)ethyl)urea; 1 -(Spiro[3.3 ]heptan-2-yl)-3 -( 1 -(3 -(( 1 , 1 , 1 -trifluoropropan-2- yl)oxy)phenyl)ethyl)urea;l-Spiro[3.3]hept-2-yl-3-[2-(2,2,2-t rifluoro-ethoxy)-pyridin-4- ylmethyl]-urea;l-Spiro[3.3]hept-2-yl-3-[6-(2, 2, 2-tri fluoro- l-methoxymethyl-ethoxy)-pyridin-

2-ylmethyl]-urea;l-[6-(l-Dimethylaminomethyl-2, 2, 2-tri fluoro-ethoxy)-pyri din-2 -ylmethyl]-

3-spiro[33]hept-2-yl-urea;l-[2-(l-Dimethylaminomethyl-2, 2, 2-tri fluoro-ethoxy)-pyri din-4- ylmethyl]-3-spiro[3.3]hept-2-yl-urea;l-Spiro[3.3]hept-2-yl-3 -[2-(2,2,2-trifluoro-l- methoxymethyl-ethoxy)-pyridin-4-ylmethyl]-urea;l-[5-Methyl-6 -(2, 2, 2-tri fluoro-ethoxy)- pyridin-2-ylmethyl]-3-spiro[3.3]hept-2-yl-urea;l-[4-Methyl-3 -(2, 2, 2-tri fluoro-ethoxy)- benzyl]-3-spiro[3.3]hept-2-yl-urea;l-[3-Huoro-5-(2,2,2-trifl uoro-l-methyl-ethoxy)-benzyl]- 3-spiro[3.3]hept-2-yl-urea;l-Spiro[3.3]hept-2-yl-3-{l-[3-(2, 2,2-trifluoro-l-methyl-ethoxy)- phenyl]-cyclopropyl}-urea;l-Spiro[3.3]hept-2-yl-3-[4-(2,2,2- trifluoro-ethoxy)-pyrimidin-2- ylmethyl]-urea;l-{l-[4-Huoro-3-(2,2,2-trifluoro-ethoxy)-phen yl]-ethyl}-3-spiro[3.3]hept-2- yl-urea;l-[4-Huoro-3-(2,2,2-trifluoro-ethoxy)-benzyl]-3-spir o[3.3]hept-2-yl-urea;l-{2- [Methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-4-ylmethyl}-3 -spiro[3.3]hept-2-yl-urea;l- Spiro[3.3]hept-2-yl-3-[2-(2,2,2-trifluoro-ethylamino)-pyridi n-4-ylmethyl]-urea;l- Spiro[3.3]hept-2-yl-3-[4-(2,2,2-trifluoro-l-methyl-ethoxy)-p yridin-2-ylmethyl]-urea;l- Spiro[3.3]hept-2-yl-3-[2-(2,2,2-trifluoro-l-methyl-ethoxy)-p yrimidin-4-ylmethyl]-urea;l- Spiro[3.3]hept-2-yl-3-[l-(3-trifluoromethoxy-phenyl)-ethyl]- urea;l-Spiro[2.3]hex-5-yl-3-[6- (2,2,2-trifluoro- 1 -methyl-ethoxy)-pyrimidin-4-ylmethyl]-urea; 1 -[ 1 -(2,2-Difluoro-benzof 1 ,3]dioxol-4-yl)-ethyl]-3-spiro[2.3]hex-5-yl-urea; l-{2-Hydroxy-l-[6-(2,2,2-trifluoro-ethoxy)- pyrimidin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;l-{2-Hydrox y-l -[2-methyl-6-(2,2,2- trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-3-spiro[2.3]hex-5-y l-urea;l-[l-(3-Difluoromethoxy- phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;l-(2-Methoxy-5-trif luoromethyl-benzyl)-3- spiro[2.3]hex-5-yl-urea;l-Spiro[2.3]hex-5-yl-3-[4-(2,2,2-tri fluoro-ethoxy)-pyrimidin-2- ylmethyl]-urea;l-(l-(3-(pentafluoro-16-sulfaneyl)phenyl)ethy l)-3-(spiro[2.3]hexan-5- yl)urea; l-(2-Methoxy-3-trifluoromethyl-benzyl)-3-spiro[2.3]hex-5-yl- urea; l-{l-[2-Huoro-5- (2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[2.3]hex-5-yl -urea;l-(3-(pentafluoro-16- sulfaneyl)benzyl)-3-(spiro[2.3]hexan-5-yl)urea;l-{l-[2-Huoro -3-(2,2,2-trifluoro-ethoxy)- phenyl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;l-{l-[3-Huoro-5-(2, 2,2-trifluoro-ethoxy)-phenyl]- ethyl}-3-spiro[2.3]hex-5-yl-urea;l-[l-(2-Methoxy-3-trifluoro methyl-phenyl)-ethyl]-3- spiro[2.3]hex-5-yl-urea;l-(2-Huoro-3-trifluoromethoxy-benzyl )-3-spiro[2.3]hex-5-yl-urea;l- Spiro[2.3]hex-5-yl-3-{l-[3-(2,2,2-trifluoro-l-methyl-ethoxy) -phenyl]-cyclopropyl}-urea;l- [l-(3-Difluoromethoxy-phenyl)-cyclopropyl]-3-spiro[2.3]hex-5 -yl-urea;l-[l-(2-Methoxy-5- trifluoromethyl-phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;l-[ 3-Hydroxy-l-(3- trifluoromethoxy-phenyl)-propyl]-3-spiro[2.3]hex-5-yl-urea;l -[l-(2-Difluoromethoxy- pyridin-4-yl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;l-Spiro[2.3]h ex-5-yl-3-[l-(3-trifluoromethyl- phenyl)-ethyl]-urea;l-Spiro[2.3]hex-5-yl-3-[l-(3-trifluorome thoxy-phenyl)-ethyl]-urea;l-(3- Huoro-5-trifluoromethyl-benzyl)-3-spiro[2.3]hex-5-yl-urea;l- [2-Hydroxy-l-(3- trifluoromethyl-phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;l-S piro[2.3]hex-5-yl-3-{l-[6-(2,2,2- trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-urea;l-{l -[2 -Methyl-6-(2, 2, 2-tri fluoro-ethoxy)- pyrimidin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;l-[2,2-Difl uoro-l -(3-trifluoromethyl- phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;l-[2-Methoxy-l-(3-t rifluoromethyl-phenyl)-ethyl]- 3-spiro[2.3]hex-5-yl-urea;l-(4-Huoro-3-trifluoromethyl-benzy l)-3-spiro[2.3]hex-5-yl-urea;l- (2 -Huoro-3-trifluoromethyl-benzyl)-3-spiro[2.3]hex-5-yl-urea;l -(2-Chloro-3-tri fluoromethyl- benzyl)-3-spiro[2.3]hex-5-yl-urea;l-(2-Huoro-5-trifluorometh yl-benzyl)-3-spiro[2.3]hex-5- yl-urea;l-{l-[5-Methoxy-6-(2,2,2-trifluoro-ethoxy)-pyrimidin -4-yl]-ethyl}-3-spiro[2.3]hex- 5-yl-urea;l-Spiro[2.3]hex-5-yl-3-(2-trifluoromethoxy-pyridin -4-ylmethyl)-urea;l-{2- Methoxy-l-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-ethyl}-3 -spiro[2.3]hex-5-yl-urea;l-(3- Difluoromethoxy-benzyl)-3-spiro[2.3]hex-5-yl-urea;l -Spiro [2.3] h ex-5-y I -3-(3- trifhioromethoxy -benzyl )-urea; l-Spiro[2.3]hex-5-yl-3-[3-(2,2,2-trifluoro-ethoxy)-benzyl]- urea; l-(3-Difluoromethyl-benzyl)-3-spiro[2.3]hex-5-yl-urea; l-Spiro[2.3]hex-5-yl-3-[2- (2,2,2-trifluoro-ethoxy)-pyridin-4-ylmethyl]-urea; l-(6,6-Difluoro-spiro[3.3]hept-2-yl)-3-[2- (2,2,2-trifluoro-ethoxy)-pyridin-4-ylmethyl]-urea;l-(6,6-Dif luoro-spiro[3.3]hept-2-yl)-3-[l- (3-trifluoromethyl-phenyl)-ethyl]-urea;l-Spiro[3.3]hept-2-yl -3-[(l H-[l ,2,3]triazol-4-yl)-(3- trifluoromethyl-phenyl)-methyl]-urea;l-[(l -Methyl- 1 H-tetrazol-5-yl)-(3-trifluoromethyl- phenyl)-methyl]-3-spiro[3.3]hept-2-yl-urea;l-[(2-Methyl-2H-t etrazol-5-yl)-(3- trifluoromethyl-phenyl)-methyl]-3-spiro[3.3]hept-2-yl-urea;l -[(3-Methyl-3H-[l,2,3]triazol-4- yl)-(3-trifluoromethyl-phenyl)-methyl]-3-spiro[3.3]hept-2-yl -urea;l-[l-(2-Difluoromethoxy- pyridin-4-yl)-ethyl]-3-(6-iodo-spiro[3.3]hept-2-yl)-urea;l-[ (R)-l-(2-Difluoromethoxy- pyridin-4-yl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;l-[(S)-l-(2- Difluoromethoxy-pyridin-4-yl)- ethyl]-3-spiro[3.3]hept-2-yl-urea;l-Spiro[3.3]hept-2-yl-3-{l -[3-((R)-2,2,2-trifluoro-l-methyl- ethoxy)-phenyl]-cyclopropyl } -urea; 1 -Spiro[3.3 ]hept-2-yl-3 - { 1 -[3 -((S)-2,2,2-trifluoro- 1 - methyl-ethoxy)-phenyl]-cyclopropyl}-urea;l-Spiro[3.3]hept-2- yl-3-[2-((R)-2,2,2-trifluoro-l- methoxymethyl-ethoxy)-pyridin-4-ylmethyl]-urea;l-Spiro[3.3]h ept-2-yl-3-[2-((S)-2,2,2- trifluoro- 1 -methoxymethyl-ethoxy)-pyridin-4-ylmethyl]-urea; 1 - [( S)- 1 -(3 -Difluoromethoxy- phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;l-[(R)-l-(3-Difluo romethoxy-phenyl)-ethyl]-3- spiro[3.3]hept-2-yl-urea;l-Spiro[3.3]hept-2-yl-3-[(S)-l-(3-t rifluoromethyl-phenyl)-ethyl]- urea;l-Spiro[3.3]hept-2-yl-3-{(S)-l-[3-(2,2,2-trifluoro-etho xy)-phenyl]-ethyl}-urea;l-{(S)-l- [4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[ 3.3]hept-2-yl-urea;l- Spiro[3.3]hept-2-yl-3-[(R)-2,2,2-trifluoro-l-(3-trifluoromet hyl-phenyl)-ethyl]-urea;l- Spiro[3.3]hept-2-yl-3-[(R)-(lH-[l,2,4]triazol-3-yl)-(3-trifl uoromethyl-phenyl)-methyl]- urea;l-Spiro[3.3]hept-2-yl-3-[2-((R)-2,2,2-trifluoro-l-methy l-ethoxy)-pyrimidin-4-ylmethyl]- urea;l-Spiro[3.3]hept-2-yl-3-[2-((S)-2,2,2-trifluoro-l-methy l-ethoxy)-pyrimidin-4-ylmethyl]- urea;l-Spiro[3.3]hept-2-yl-3-{(S)-l-[6-(2,2,2-trifluoro-etho xy)-pyrimidin-4-yl]-ethyl}- urea; 1 - Spiro[3.3 ]hept-2-yl-3 - { (R)- 1 - [6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl] -ethyl } - urea;l-[(R)-2-Hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-3- spiro[3.3]hept-2-yl-urea;l-[(S)- 2 -Hydroxy-l-(3-trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hep t-2-yl-urea;l-[(R)-2 -Hydroxy- l-(3-trifluoromethyl-phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-ure a;l-[(R)-l-(2-Difluoromethoxy- pyridin-4-yl)-2-methoxy-ethyl]-3-spiro[3.3]hept-2-yl-urea;l- {(R)-2-Methoxy-l-[2-(2,2,2- trifluoro-ethoxy)-pyridin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl- urea;l-[(S)-l-(2- Difluoromethoxy-pyridin-4-yl)-ethyl]-3-spiro[2.3]hex-5-yl-ur ea; or l-[(S)-l-(2-Bromo-5- trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea; or a salt thereof.

Formula 55

[00649] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds of Formula 55. Such compounds are described in International Publication No. WO2020157126A1, published August 6, 2020, and corresponding to International Application No. PCT/EP2020/052156 filed January 29, 2020; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 55, this reference incorporated by reference herein controls.

[00650] In an embodiment, the Kv7 channel activator is a compound according to Formula 55:

Formula 55 or a tautomer, salt, solvate, stereoisomer or isotope thereof, wherein: Y is selected from: Cl- C10 alkylamino, Cl -CIO alkyl, Cl -CIO alkoxy, C3-C8 cycloalkyl, Cl- CIO alkylcarbonyl, Cl -CIO alkylaminocarbonyl, Cl -CIO alkylthio, aryl, heterocycle, Cl -CIO carbonyl, Cl -CIO amide and Cl -CIO carboxyl and it is optionally mono-substituted or bi- substituted with a first substituent independently selected from: hydroxyl, amino, thiol, carboxylic acid, amide, carbonyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkyloxy, C1-C6 alkylthio, C2-C8 alkenyl, C5-C7 cycloalkenyl, C2-C8 alkynyl and C5-C10 aryl, any of said first substituents being optionally substituted by one or more second substituents independently selected from: hydroxyl, amino, thiol, carboxylic acid, amide, carbonyl, halogen, C1-C6 alkyl, C3- C6 cycloalkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkyloxy, C1-C6 alkylthio, C2-C8 alkenyl, C5-C7 cycloalkenyl, C2- C8 alkynyl and C5-C10 aryl; b is an integer comprised between 1 and 3;or Y is NH or O and b is 1;R.2 is selected from: an aromatic ring, a cycloalkyl, a heterocycle, a linear or branched saturated alkyl and a linear or branched unsaturated alkyl, any of which optionally bearing in one or more positions at least one substituent independently selected from the group consisting of: OH, NO2, CN, halogen, NH2, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylaminocarbonyl, acetamidyl, C1-C6 alkyloxy, C1-C6 alkylthio, C2-C8 alkenyl, C5-C7 cycloalkenyl, C2-C8 alkynyl, C5-C10 aryl, thiol and thiol ether; Ri, R3, R4 and R5 are each independently selected from the group consisting of: H, N ³ /4, OH, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkyloxy, C1-C6 alkylthio, C2-C8 alkenyl, C5-C7 cycloalkenyl, heterocycle, C2-C8 alkynyl and C5-C10 aryl, any of which being optionally substituted by one or more substituents independently selected from: hydroxyl, amine, thiol, carboxyl, carboxylic acid, and halogen; Q is selected from the group consisting of: C=0, SO2, SO, S02NH, CONH, CSNH, C=NH, CNHNH, and C=S; when Q is C=0 or C=S, R ₆ is selected from: linear or branched C3-C30 alkyl, linear or branched C5-C30 arylalkyl, C3-C8 cycloalkyl, linear or branched C2-C4 alkyl substituted by C3-C8 cycloalkyl, linear or branched C3-C10 cycloalkylamino, linear or branched Cl -CIO alkylamino, linear or branched C2-C10 alkenylamino, linear or branched C2-C10 alkynylamino, C5-C10 aryl, linear or branched C7-C15 arylalkylamino, linear or branched C7-C15 arylalkenylamino, linear or branched C7-C15 arylalkynylamino, C2-C30 alkenyl, C2-C30 alkynyl and C1-C30 alkoxyl, any of which being optionally substituted with one or more substituents independently selected from: linear or branched alkyl group, halogen, hydroxyl group, amine group, alkylamine, dialkylamine, thiol, thioether and cycloalkyl; when Q is SO2, SO, S02NH, CONH, CSNH, C=NH, or CNHNH, R ₆ is selected from: linear or branched C1-C30 alkyl, C3-C8 cycloalkyl, linear or branched C1-C30 alkylcarbonyl, linear or branched Cl- C30 alkoxycarbonyl, linear or branched C1-C30 alkylamino, linear or branched Cl- C30 alkylaminocarbonyl, linear or branched C1-C30 alkyloxy, linear or branched C1-C30 alkylthio, linear or branched C2-C30 alkenyl, C5-C8 cycloalkenyl, linear or branched C2- C30 alkynyl, heterocycle and aryl, any of which being optionally substituted with one or more substituents independently selected from: halogen, C1-C6 alkyl, oxo and C3-C7 cycloalkyl.

[00651] In further embodiments, b is 1.

[00652] In further embodiments, Q is C=0 or SO2.

[00653] In further embodiments, Y is Cl -CIO alkylamino, Cl -CIO alkyl or Cl -CIO alkoxy. [00654] In further embodiments, R2 is an aromatic ring optionally substituted with one or more substituents independently selected from the group consisting of: OH, NO2, halogen, NH2, C1-C3 haloalkyl, acetamidyl, C1-C6 alkyloxy, C1-C3 haloalkoxy, and C1-C6 alkylcarbonyl.

[00655] In further embodiments, Ri, R3, R4 and R5 are each independently: H, C1-C6 alkyl, C3- C6 cycloalkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2 , azepane, pirrolidine, piperidine, aziridine or halogen.

[00656] In further embodiments, when Q is C=0 or C=S, Rs is selected from: linear or branched C3-C30 alkyl, linear or branched C5-C30 arylalkyl, C3-C8 cycloalkyl, linear or branched C2-C4 alkyl substituted by C3-C8 cycloalkyl, linear or branched C1-C10 alkylamino, linear or branched C7-C15 arylalkylamino, C2- C30 alkenyl, C2-C30 alkynyl and C1-C30 alkoxyl, any of which being optionally substituted with one or more substituents independently selected from: halogen and cycloalkyl; and where Q is SO2, SO, SO2NH, CONH, CSNH, C=NH, or CNHNH, Re is C3-C8 cycloalkyl or aryl and is optionally substituted with one or more C1-C6 alkyl.

[00657] In further embodiments, the Kv7 Channel activator is selected from the group consisting of those listed in the following table

B > | Off PSP

Formula 56

[00658] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 56. Such compounds are described in International Publication No. W02020016297A1, published January 23, 2020, and corresponding to International Application No. PCTZEP2019/069240 filed July 17, 2019; Patent Cooperation Treaty application No. PCTZEP2019/069240 published January 23, 2020, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 56, this reference incorporated by reference herein controls.

[00659] In an embodiment, the Kv7 channel activator is a compound according to Formula unbranched Cl to C5 alkyl group and - NRi _a Rib group, where Ri _a and Rib are selected independently of one another from hydrogen atom and branched or unbranched Cl to C5 alkyl group or with one another and with the nitrogen atom the NRi _a Rib group form a C3 to C9 heterocycloalkyl group, the C3 to C9 heterocycloalkyl group each having at least one substituent selected from the hydrogen atom and Cl to C3 alkyl group and optionally in addition to the nitrogen atom of the NRi _a Rib - Group has at least one further heteroatom in the cycle; R 2 is selected from the group consisting of branched or unbranched Cl to CIO alkyl group, C3 to CIO cycloalkyl group, C3 to CIO heterocycloalkyl group, at least one hetero atom being selected from nitrogen and oxygen atom, C6 to C12 aryl group; and C5 to Cl 1 heteroaryl group, the Cl to CIO alkyl group, C3 to CIO cycloalkyl group, C3 to CIO heterocycloalkyl group, C6 to C12 aryl group, or C5 to Cl 1 heteroaryl group in each case at least one further Substituents R 2 _a , wherein R 2 _a is selected from the group consisting of hydrogen atom, halogen atom, branched or unbranched Cl to C3 alkyl group, branched or unbranched (per) halogenated Cl to C3 alkyl group and branched or unbranched Cl to C3 Alkoxy group, and wherein the C3 to CIO cycloalkyl group, C3 to CIO heterocycloalkyl group, C6 to C12 aryl group or C5 to Cl 1 heteroaryl group comprises one or more ring systems which are condensed or separated; R 3 is selected from the group consisting of branched or unbranched Cl to CIO alkoxy group; branched or unbranched Cl -CIO alkyl group and - (CH2 ) p -C6 to C12 aryl group, which has at least one substituent selected from hydrogen atom, halogen atom and Cl to C3 alkoxy group and wherein the C6 to C12 aryl group has one or comprises several ring systems which are condensed or separated; R 4 is selected from hydrogen, halogen atom and branched or unbranched Cl -C5 alkyl group; X is a nitrogen atom or a -CH group; n is zero or an integer ranging from 1 to 3; m is zero or an integer ranging from 1 to 5; and p is zero or an integer ranging from 1 to 5.

[00660] In further embodiments, n is zero and / or m is 1 and / or X is a nitrogen atom. [00661] In further embodiments, Ri is selected from the group consisting of branched or unbranched Cl - to C3 -alkyl group and - NRi _a Rib group, wherein Ri _a and Rib are independently selected from hydrogen atom and branched or unbranched Cl- to C3-alkyl group or with one another and form a C4 to C6 heterocycloalkyl group with the nitrogen atom of the NRi _a Rib group, the C4 to C6 heterocycloalkyl group each having at least one substituent selected from the hydrogen atom and Cl to C3 alkyl group and optionally in addition to the nitrogen atom of the NRi _a Rib group has at least one further oxygen atom in the cycle; and or R 2 is selected from the group consisting of mono- or difluorophenyl group; CF 3 phenyl group; F 5 S-phenyl group; C4 to C8 cycloalkyl group; branched or unbranched Cl to C5 alkyl group; Biphenyl group; Pyridine group; Piperidine group; Tetrahydropyran group; Dioxolane group and phenyl group, the phenyl group having at least one substituent R 2a selected from hydrogen atom and methoxy group; and or R 3 is selected from the group consisting of ethoxy group, propyl group, tert-butyl group, - (CH 2 ) p -phenyl group, which has at least one substituent selected from hydrogen atom, halogen atom and methoxy group and where p is zero or is 1 or 2; and or R 4 is a hydrogen atom , a bromine atom or a methyl group.

[00662] In further embodiments, the Kv7 channel activator is selected from the group consisting of:

Formulas 57 - 139

[00663] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds of formulas 57 - 139. Such compounds are described in International Publication No. WO2018204765 Al, published November 8, 2018, and corresponding to International Application No. PCT/US2018/031057 filed May 4, 2018; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of any of Formulas 57 - 139, this reference incorporated by reference herein controls.

[00664] In an embodiment, the Kv7 channel activator is a compound according to any one of formulas 57 - 139:

wherein (for any of compounds 57 - 139), each and any of R' R ² andR ³ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SCi-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, Ci-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, C02C1-6 saturated, unsaturated alkyl, or aryl, CONH2, C02NHC1-6 saturated, unsaturated alkyl or aryl, C02N(CI-6 saturated, unsaturated alkyl or aryl)2, NHCI-6 saturated, unsaturated alkyl, or cycloalkyl, N(CI-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-varyl or heteroaryl; and wherein each X = independently C, CH, CH2, S, SO, SO2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O, and wherein each n, where present, is independently = 0-6.

Formula 140

[00665] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 140. Such compounds are described in International Publication No. WO2016077724A1, published May 19, 2016, and corresponding to International Application No. PCT/US2015/060627 filed November 13, 2015; US Patent No. 10,526,280, issued January 7, 2020 and corresponding to US Application No. US10526280B2 filed November 11, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 140, this reference incorporated by reference herein controls.

[00666] In an embodiment, the Kv7 channel activator is a compound according to Formula 140:

Formula 140 wherein, R ¹ is H or optionally-substituted alkyl;R ² is optionally-substituted alkyl;R ³ and R ⁴ are each independently H or optionally-substituted alkyl;R ⁵ is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl;R ⁶ and R ⁷ are each independently H, deuterium, optionally- substituted alkyl, or R ⁶ and R ⁷ together form a carbocycle;R ⁸ is optionally-substituted thiazolyl, optionally-substituted thiophenyl, or substituted phenyl, provided that if R ⁸ is 4- halophenyl, then R ² is substituted alkyl or branched alkyl or at least one of R ⁶ or R ⁷ is not H; andR ³⁰ , R ³¹ and R ³² are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy.

[00667] In further embodiments, R ¹ is H.

[00668] In further embodiments, R ² is Ci-Ce alkyl.

[00669] In further embodiments, R ² is carbocyclic-substituted alkyl or heterocyclic- sub stituted alkyl.

[00670] In further embodiments, R ³ and R ⁴ are each H.

[00671] In further embodiments, R ⁵ is H.

[00672] In further embodiments, R ⁶ and R ⁷ are both H; R ⁶ and R ⁷ are both deuterium; R ⁶ and R ⁷ together form a cycloalkyl; or at least one of R ⁶ or R ⁷ is a substituted alkyl. each independently H, halogen, optionally-substituted sulfanyl, or optionally-substituted alkyl.

[00674] In further embodiments, R ^s i s:> wherein at least one of R ⁹ or R ¹⁰ is halogen.

[00675] In further embodiments, R ⁸ is: wherein at least one of R ¹⁹ or R ²⁰ is halogen.

[00676] In further embodiments, R ⁸ is wherein at least one of R ¹⁴ -R ¹⁸ is substituted sulfanyl or haloalkyl; or wherein R ¹⁶ is F.

[00677] In further embodiments, at least one of R ¹⁴ -R ¹⁸ is — SF> or CF3. [00678] In further embodiments, wherein at least one of R ⁿ -R ¹³ or R ²³ -R ²⁵ is substituted sulfanyl.

[00679] In further embodiments, R ⁸ is: wherein at least one of R ¹⁴ -R ¹⁸ is halo-substituted sulfanyl, haloalkyl or halogen. [00680] In further embodiments, at least one of R ¹⁴ -R ¹⁸ is — SF5 or — CF3. [00681] In further embodiments, R ¹⁵ , R ¹⁶ , or R ¹⁷ is — SF5 or — CF3. [00682] In further embodiments, R ³² is — F, and R ³⁰ and R ³¹ are each H. [00683] In further embodiments, the Kv7 Channel activator is selected from the group consisting of:

[00684] In further embodiments, the compound is according to formula 141 wherein: R ¹ is H or optionally-substituted alkyl; R ² is substituted alkyl having one or more hydrogen atoms substituted with a substituent selected from halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl; R ³ and R ⁴ are each independently H or optionally-substituted alkyl; R ⁵ is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R ⁶ and R ⁷ are each independently H, deuterium, optionally-substituted alkyl, or R ⁶ and R ⁷ together form a carbocycle; R ⁸ is optionally-substituted thiazolyl, optionally-substituted thiophenyl, or substituted phenyl; andR ³⁰ , R ³¹ and R ³² are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy.

[00685] In further embodiments, the compound is according to formula 141 wherein: R ¹ is H or optionally-substituted alkyl; R ² is optionally-substituted alkyl; R ³ and R ⁴ are each independently H or optionally-substituted alkyl; R ⁵ is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R ⁶ and R ⁷ are each independently H, deuterium, optionally-substituted alkyl, or R ⁶ and R ⁷ together form a carbocycle, provided at least one R ⁶ or R ⁷ is not H; R ⁸ is optionally-substituted thiazolyl, optionally-substituted thiophenyl, or substituted phenyl, provided that if R ⁸ is 4-halophenyl, then R ² is substituted alkyl or branched alkyl or at least one of R ⁶ or R ⁷ is not H; andR ³⁰ , R ³¹ and R ³² are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy.

[00686] In further embodiments, the compound is according to formula 141 wherein: R ¹ is H or optionally-substituted alkyl;R ² is optionally-substituted alkyl;R ³ and R ⁴ are each independently H or optionally-substituted alkyl;R ⁵ is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl;R ⁶ and R ⁷ are each independently H, deuterium, optionally-substituted alkyl, or R ⁶ and R ⁷ together form wherein at least one of R ¹⁴ -

R ¹⁸ is substituted sulfanyl or haloalkyl; andR ³ and R ³¹ are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy; andR ³² is deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy.

[00687] In further embodiments, R ³² is halogen.

[00688] In further embodiments, R ³² is — F.

[00689] In further embodiments, at least one of R ¹⁴ -R ¹⁸ is halo- substituted sulfanyl.

[00690] In further embodiments, at least one of R ¹⁴ -R ¹⁸ is haloalkyl.

[00691] In further embodiments, at least one of R ¹⁴ -R ¹⁸ is — SF5.

[00692] In further embodiments, at least one of R ¹⁴ -R ¹⁸ is — CF3.

[00693] In further embodiments, R ¹⁶ is — SF5.

[00694] In further embodiments, R ¹⁶ is — CF3.

[00695] In further embodiments, R ² is alkyl.

[00696] In further embodiments, R ² is Ci-Ce alkyl.

[00697] In further embodiments, R ² is ethyl. [00698] In further embodiments, R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each H.

[00699] In further embodiments, R ³² is — F and R ¹⁶ is — CF3.

[00700] In further embodiments, R ² is alkyl.

[00701] In further embodiments, R ³ and R ³¹ are each H.

[00702] In further embodiments, R ¹⁵ , R ¹⁶ , or R ¹⁷ is — SF5 or — CF3.

[00703] In further embodiments, R ¹ , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each H; R ² is alkyl; and R ³² is — F.

Formula 141

[00704] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 141. Such compounds are described in International Publication No. WO2016077724A1, published May 19, 2016, and corresponding to International Application No. PCT/US2015/060627 filed November 13, 2015; US Patent No. 10,526,280, issued January 7, 2020, and corresponding to US Application No. US10526280B2 filed November 11, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 141, these references incorporated by reference herein control.

[00705] In an embodiment, the Kv7 channel activator is a compound according to Formula 141 :

Formula 141 wherein, R ¹ is H or optionally-substituted alkyl; R ² is optionally-substituted alkyl; R ³ and R ⁴ are each independently H or optionally-substituted alkyl; R ⁵ is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R ⁶ and R ⁷ are each independently H, deuterium, optionally- substituted alkyl, or R ⁶ and R ⁷ together form a carbocycle; andR ⁸ is optionally-substituted thiazolyl.

[00706] In further embodiments, the compound is according to formula 142 wherein: R ¹ is H or optionally-substituted alkyl; R ² is optionally-substituted alkyl; R ³ and R ⁴ are each independently H or optionally-substituted alkyl; R ⁵ is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R ⁶ and R ⁷ are each independently H, deuterium, optionally-substituted alkyl, or R ⁶ and R ⁷ together form a carbocycle; and R ⁸ is substituted thiophenyl, wherein at least one substituent on the thiophenyl is halo- substituted sulfanyl.

Formula 142

[00707] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 142. Such compounds are described in US Patent No. 10,077,245, issued September 18, 2018, and corresponding to US Application No. 15/306,971 filed April 22, 2015; US Patent No. 10,316,008, issued June 11, 2019 and corresponding to US Application No. 15/870,276 filed January 12, 2018; international Publication No. WO2015165352A1, published November 5, 2015 and corresponding to International Application No. PCT/CN2015/077216 filed April 22, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 142, these references incorporated by reference herein control.

[00708] In an embodiment, the Kv7 channel activator is a compound according to Formula 142:

Formula 142 wherein, X is selected from a group consisting of oxygen and sulfur; n is 1, 2 or 3;Ri is H or halogen;R2 and R3 are each independently selected from a group consisting of H, D and Ci- C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3- Ce saturated ring;R4 and R5 are each independently selected from a group consisting of H; halogen; Ci-Ce alkyl; C3-C6 cycloalkyl; cyano; alkoxyl; Ci-Ce alkyl substituted by hydroxy, amino, C1-C4 alkoxy, C1-C4 alkylcarbonyl, or halogen; C1-C4 alkoxy substituted by halogen; Ci-Ce alkylcarbonyl; Ci-Ce alkoxycarbonyl; Ci-Ce alkylaminocarbonyl; C2-C6 alkenyl; and C2-C6 alkynyl; provided that R4 and R5 are not simultaneously hydrogen; Re is selected from a group consisting of Ci-Ce alkoxy; Ci-Ce alkylamino; Ci-Ce alkyl; C3-C6 cycloalkyl; C2- Ce alkenyl; C2-C6 alkynyl; Ce-Cio aryl; Ci-Ce alkyl substituted by halogen, cyano, hydroxy, Ci-Ce alkoxyl, di(Ci-C4 alkyl) amino, Ci-Ce alkylcarbonyl, Ci-Ce alkylcarbonylamino, or Ci- Ce alkoxy carbonyl; C3-C6 cycloalkyl substituted by halogen; C2-C6 alkenyl substituted by halogen; C2-C6 alkynyl substituted by halogen; tetrahydrofuranyl; and » — vherein,

R7 and Rs are each independently selected from a group consisting of C1-C4 alkyl.

[00709] In further embodiments, Ri is H or fluorine; R2 and R3 are each independently selected from a group consisting of H and D, or R2 and R3 together with the carbon atom to which they attached form cyclopropyl; one of R4 and R5 is C1-C4 alkyl, and the other is H or C1-C4 alkyl.

[00710] In further embodiments, one of R4 and R5 is methyl, and the other is H or methyl.

Formula 143

[00711] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 143. Such compounds are described in US Patent No. 10,077,245, issued September 18, 2018, and corresponding to US Application No.

15/306,971 filed April 22, 2015; US Patent No. 10,316,008, issued June 11, 2019 and corresponding to US Application No. 15/870,276 filed January 12, 2018; international Publication No. WO2015165352A1, published November 5, 2015, and corresponding to International Application No. PCT/CN2015/077216 filed April 22, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 143, these references incorporated by reference herein control.

[00712] In an embodiment, the Kv7 channel activator is a compound according to Formula 143: Formula 143 ’ wherein, X: is selected from a group consisting of oxygen and sulfur;Ri is H or halogen;R2 and R3 are each independently selected from a group consisting of H, D and Ci- C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3- Ce saturated ring;R4 and R5 are each independently selected from a group consisting of H; halogen; Ci-Ce alkyl; C3-C6 cycloalkyl; cyano; C1-C4 alkoxyl; Ci-Ce alkyl substituted by hydroxy, amino, C1-C4 alkoxy, C1-C4 alkylcarbonyl, or halogen; C1-C4 alkoxy substituted by halogen; Ci-Ce alkylcarbonyl; Ci-Ce alkoxy carbonyl; Ci-Ce alkylaminocarbonyl; C2- Ce alkenyl; and C2-C6 alkynyl; provided that R4 and R5 are not simultaneously hydrogen;Re is selected from a group consisting of Ci-Ce alkoxy; Ci-Ce alkylamino; Ci-Ce alkyl; C3-

Ce cycloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; Ce-Cio aryl; Ci-Ce alkyl substituted by halogen, cyano, hydroxy, Ci-Ce alkoxyl, di(Ci-C4 alkyl) amino, Ci-Ce alkylcarbonyl, Ci-

Ce alkylcarbonylamino, or Ci-Ce alkoxy carbonyl; C3-C6 cycloalkyl substituted by halogen; C2-C6 alkenyl substituted by halogen; C2-C6 alkynyl substituted by halogen; tetrahydrofuranyl; and 9 — \\ herein, R7 and Rs are each independently selected from a group consisting of C1-C4 alkyl.

[00713] In further embodiments, Ri is H or fluorine; R2 and R3 are each independently selected from a group consisting of H and D, or R2 and R3 together with the carbon atom to which they attached form cyclopropyl; one of R4 and R5 is C1-C4 alkyl, and the other is H or C1-C4 alkyl.

Formula 144 - 146

[00714] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to any one of Formulas 144 - 146. Such compounds are described in US Patent No. 10,077,245, issued September 18, 2018, and corresponding to US Application No. 15/306,971 filed April 22, 2015; US Patent No. 10,316,008, issued June 11, 2019, and corresponding to US Application No. 15/870,276 filed January 12, 2018; international Publication No. WO2015165352A1, published November 5, 2015, and corresponding to International Application No. PCT/CN2015/077216 filed April 22, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formulas 144 - 146, these references incorporated by reference herein control.

[00715] In an embodiment, the Kv7 channel activator is a compound according to a formula from the group consisting of 144, 145, and 146: wherein, R2 and R3 are each independently selected from a group consisting of H, D and Ci- C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3-

Ce saturated ring;R4 and R5 are each independently selected from a group consisting of H; Ci- Ce alkyl; C1-C4 alkoxyl; Ci-Ce alkyl substituted by halogen; C1-C4 alkoxy substituted by halogen; provided that R4 and R5 are not simultaneously hydrogen;R9 is selected from a group consisting of Ci-Ce alkyl and C3-C6 cycloalkyl;Rio is selected from a group consisting of Ci- Ce alkyl; Ci-Ce alkyl substituted by halogen, cyano, hydroxy, Ci-Ce alkoxyl, di(Ci-

C4 alkyl)amino, Ci-Ce alkylcarbonyl, Ci-Ce alkylamido, or Ci-Ce alkoxy carbonyl; C3-

G> cycloalkyl; and C3-C6 cycloalkyl substituted by halogen; tetrahydrofuranyl; and wherein, R7 and Rs are each independently selected from a group consisting of C1-C4 alkyl. [00716] In further embodiments, R2 and R3 are each independently selected from a group consisting of H and D, or R2 and R3 together with the carbon atom to which they attached form cyclopropyl; one of R4 and R5 is C1-C1 alkyl, and the other is H or C1-C4 alkyl;Rg is selected from a group consisting of Ci-Ce alkyl and C3-C6 cycloalkyl;Rio is selected from a group consisting of Ci-Ce alkyl; Ci-Ce alkyl substituted by halogen, cyano, hydroxy, Ci- Ce alkoxyl, di(Ci-C4 alkyl)amino, Ci-Ce alkylcarbonyl, Ci-Ce alkylamido, or Ci- Ce alkoxycarbonyl; C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted by halogen; tetrahydrofuranyl; and 6 "“^wherein, R7 and Rs are each independently selected from a group consisting of C1-C4 alkyl. [00717] In further embodiments, R9 is selected from a group consisting of methyl, ethyl and propyl;Rio is selected from a group consisting of C1-C3 alkyl; C1-C3 alkyl substituted by halogen, cyano, hydroxy, C1-C3 alkoxyl, di(Ci-C3 alkyl)amino, C1-C3 alkylcarbonyl, Ci- C3 alkylamido, or C1-C3 alkoxy carbonyl; C3-C6 cycloakyl; C3-C6 cycloakyl substituted by halogen; tetrahydrofuranyl; and — ^ w herein. R7 and Rs are each independently selected from a group consisting of C1-C3 alkyl.

[00718] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: Formula 147

[00719] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 147. Such compounds are described in International Publication No. WO2013165575A1, published November 7, 2013, and corresponding to International Application No. PCT/US2013/030984 filed March 13, 2013; US Patent No. 9,556,114 issued January 31, 2017, and corresponding to US Application No. 14/566,167 filed December 10, 2014; US Publication No. US20170096390A1, published April 6, 2017, and corresponding to US Application No. 15/380,216 filed December 15, 2016; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 147, these references incorporated by reference herein control.

[00720] In an embodiment, the Kv7 channel activator is a compound according to Formula 147: Formula 147 or a pharmaceutically acceptable salt or solvate thereof, wherein: Xi, X ₂ , X3, X4, X5, Xe, X7, and Xs are each independently selected from hydrogen, deuterium, and F; X9 and X10 are each independently selected from hydrogen and deuterium; and n is 1, 2, or 3, wherein at least one of Xi, X ₂ , and X ₃ is F.

[00721] In further embodiments, the Kv7 channel activator is: wherein, A is N or C — X ₃ ; Xi, X ₂ , X ₃ , X4, X5, Xe, X7, and Xs are each independently selected from hydrogen, 19F and 18F; and n is 2 or 3, provided that one of Xi, X ₂ , X ₃ , X4, X5, Xe, X7, and Xs is 18F. [00722] In further embodiments, two of Xi, X2, X3, X4, X5, Xe, X7 and Xx are F.

[00723] In further embodiments, three of Xi, X2, X3, X4, X5, Xe, X7 and Xs are F.

[00724] In further embodiments, the Kv7 channel activator is: wherein, Xi, X2, X3, and Xe are each independently selected from hydrogen, 18F, and 19F, provided that one of Xi, X2, X3, and Xe is 18F.

[00725] In further embodiments, Xe is fluorine and one of Xi, X2, and X3 is fluorine.

[00726] In further embodiments, one of Xi, X2, X3, and Xe is 18F.

[00727] In further embodiments, at least one of Xi, X2, and X3 is 19F.

[00728] In further embodiments, Xe is 19F or 18F.

[00729] In further embodiments, the compound is selected from the group consisting of:

Formula 148

[00730] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 148. Such compounds are described in US Publication No. US20130184294A1, published July 18, 2013, and corresponding to US Application No. 13/822,669 filed September 7, 2011; International Publication No. W02012038850A1, published March 29, 2012, and corresponding to International Application No. PCT/IB2011/053917 filed September 7, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 148, these references incorporated by reference herein control.

[00731] In an embodiment, the Kv7 channel activator is a compound according to Formula 148: Formula 148 wherein, R ¹ is alkyl, cycloalkyl, wherein alkyl or cycloalkyl may be substituted with one or more halogen, alkoxy, aryl, or aryloxy; R ² is cycloalkyl or NR ⁴ R ⁵ ; R ³ is H, halogen, alkyl, or alkoxy, wherein any alkyl may be substituted with one or more halogen atoms; R ⁴ and R ⁵ are independently selected from H, Ci-ealkyl, Cs-ecycloalkyl, or — Ci-ealkyl-Cs-ecycloalkyl, wherein each alkyl or each cycloalkyl may be substituted with one or more halogen, provided that both R ⁴ and R ⁵ are not H simultaneously; or R ⁴ and R ⁵ , together with the N atom to which they are attached, form a heterocycloalkyl; — X — Y — is =CH — CH=, — CH2 — CH2 — , or — CH2 — ; or a pharmaceutically acceptable salt thereof.

[00732] In further embodiments, R ¹ is C5-6 alkyl; R ² is NR ⁴ R ⁵ , wherein one of R ⁴ or R ⁵ is H and the other is Cs-ealkyl, Cs-ecycloalkyl, or — Ci-salkyl-Cs-ecycloalkyl; R ³ is halogen, alkyl, or alkoxy, wherein any alkyl may be substituted with one or more halogen atoms; — X — Y — is =CH — CH= or — CH2 — CH2 — ; or a pharmaceutically acceptable salt thereof.

[00733] In further embodiments, R ¹ is — CH2C(CH3)3; R ³ is chloro, methyl, trifluoromethyl or 1,1 -difluoroethoxy; R ⁴ is H and R ⁵ is isopropyl, isobutyl, 1 -cyclopropylethyl, cyclobutyl or cyclopentyl; — X — Y — is =CH — CH= or — CH2 — CH2 — ; or a pharmaceutically acceptable salt thereof. [00734] In further embodiments, R ¹ is C5-6 alkyl; R ² is Cs-ecycloalkyl; R ³ is halogen, or alkyl, wherein alkyl may be substituted with one or more halogen atoms; — X — Y — is =CH — CH= or — CH2 — CH2 — ; or a pharmaceutically acceptable salt thereof.

[00735] In further embodiments, R ¹ is — CH2C(CH3)3; R ² is cyclopropyl; R ³ is chloro, methyl, trifluoromethyl or 1,1 -difluoroethoxy; — X — Y — is =CH — CH= or — CH2 — CH2 — ; or a pharmaceutically acceptable salt thereof.

Formula 149

[00736] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 149. Such compounds are described in US Patent No. 8,466,201, issued June 18, 2013, and corresponding to US Application No. 12/746,524 filed December 5, 2008; US Patent No. 9,464,052, issued October 11, 2016, and corresponding to US Application No. 13/054,960 filed July 20, 2009; US Patent No.

9,675,567 issued June 13,2017, and corresponding to US Application No. 15/259,064 filed September 8, 2016; US Patent No. 8,466,201 issued June 18, 2013, and corresponding to US Application No. 12/746,524 filed December 5, 2008; International Publication No.

W02009071947A2, published June 11, 2009, and corresponding to International Application No. PCT/GB2008/051158 filed December 5, 2008; International Publication No.

W02010010380A1, published January 28, 2010, and corresponding to International Application No. PCT/GB2009/050887 filed July 20, 2009; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 149, these references incorporated by reference herein control.

[00737] In an embodiment, the Kv7 channel activator is a compound according to Formula 149:

Formula 149 wherein, Ar ¹ and Ar ² are each phenyl; are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5 ; R ¹ is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxy carbonylamino groups, alkyl sulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 5;R ² is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and where b is greater than 1, each substituent R ² may be the same or different; V is selected from the group consisting of (CR ^3a R ^3b ) _p SO2N(R ³ b)X;W is NR ^4a ; X is a substituent selected from the group consisting of hydroxyalkyl groups, and polyalkylene glycol residues; Y and Z are each a group of formula (CR ^5a R ^5b ) _n i, wherein each nl is 0; and p is an integer of from 0 to 2, and wherein V is substituting said Ar ¹ at an ortho position with respect to said Z or said W. [00738] In further embodiments, a is an integer of from 0 to 3.

[00739] In further embodiments, R ¹ is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different.

[00740] In further embodiments, b is an integer of from 0 to 4.

[00741] In further embodiments, R ² is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups.

[00742] In further embodiments, R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups.

[00743] In further embodiments, V is selected from the group consisting of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of from 0 to 2, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, and polyalkylene glycol residues of general formula HO — [(CR (CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is an integer of from 0 to 4, c3 is an integer of from 1 to 20 and R ^6a , R ^6b , R ^6c and R ^6d may be the same or different from each other and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.

[00744] In further embodiments, V is a group of formula of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of 0 or 1, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 4 carbon atoms and polyalkylene glycol residues of general formula HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10 and R ^6a , R ^6b , R ^6c , R ^6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.

[00745] In further embodiments, V is a group of formula of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of 0 or 1, each of R ^3a and R ^3b is a hydrogen atom, and X is a hydroxylalkyl group having from 1 to 4 carbon atoms or a polyalkylene glycol residue of general formula HO — [CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is 1 or 2, c3 is an integer of from 1 to 6 and each of R ^6a , R ^6b , R ^6c and R ^6d is a hydrogen atom.

[00746] In further embodiments, Ar ¹ and Ar ² are each phenyl; a is an integer of from 0 to 3 ; R ¹ is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkyl sulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 4;R ² is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, nitro groups, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups and, where b is greater than 1, each substituent R ² may be the same or different; W is NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms; Y and Z are each a group of formula (CR ^5a R ^5b ) _n i, wherein each nl is 0; and V is selected from the group consisting of (CR ^3a R ^3b ) _p SO2N(R ^3b )X and, wherein p is an integer of from 0 to 2,R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, carbonyl groups, hydroxyl groups and cyano groups, and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, and polyalkylene glycol residues of general formula HO-[(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _C 2]c3 — wherein cl and c2 are the same or different and each is an integer of from 0 to 4, c3 is an integer of from 1 to 20 and R ^6a , R/’ R ^6C and R ^6d may be the same or different from each other and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.

[00747] In further embodiments, Ar ¹ and Ar ² are each phenyl; a is 0 or 1;R ³ is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 3;R ² is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, nitro groups, acylamino groups having from 1 to 4 carbon atoms, alkyl sulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where b is greater than 1, each substituent R ² may be the same or different; W is NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms and 5- or 6- membered aromatic heterocyclic groups containing 1 or 2 sulfur atoms, oxygen atoms and/or nitrogen atoms; Y and Z are each a group of formula (CR ^5a R ^5b ) _n i, wherein each nl is 0; and V is a group of formula of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of 0 or 1, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 4 carbon atoms and polyalkylene glycol residues of general formula HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _C 2]c3 — wherein cl and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10 and R ^6a , R ^6b , R ^bc and R ^6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.

[00748] In further embodiments, Ar ¹ and Ar ² are each phenyl; a is 0 or 1;R ³ is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is 0 to 3;R ² is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups; W is a group of formula NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups; Y and Z are each a group of formula (CR ^5a R ^5b ) _ni wherein each nl is 0; and V is a group of formula of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of 0 or 1, each of R ^3a and R ^3b is a hydrogen atom, and X is a hydroxylalkyl group having from 1 to 4 carbon atoms or a polyalkylene glycol residue of general formula HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _C 2]c3 — wherein cl and c2 are the same or different and each is 1 or 2, c3 is an integer of from 1 to 6 and each of R ^6a , R ^6b , R ^6C and R ^6d is a hydrogen atom.

[00749] In further embodiments, Ar ¹ and Ar ² are each phenyl; a is an integer of from 0 to 3 ; R ¹ is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkyl sulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 4;R ² is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, nitro groups, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkyl sulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups and, where b is greater than 1, each substituent R ² may be the same or different; W is NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms; and V is selected from the group consisting of (CR ^3a R ^3b ) _p SO2N(R ^3b )X wherein p is an integer of from 0 to 2, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7- membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, and polyalkylene glycol residues of general formula HO — [(CR ^6a R ^6c ) _ci — O — (CR ^6c R ^6d ) _C 2]c3 — wherein cl and c2 are the same or different and each is an integer of from 0 to 4, c3 is an integer of from 1 to 20 and R ^6a , R ^6b , R ^6c and R ^6d may be the same or different from each other and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.

[00750] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: l-[2-(2,6-Dichlorophenylamino)phenyl]-N-[2-(2-hydroxyethoxy) ethyl]- methanesulfonamide,N-[2-(2-hydroxyethoxy)ethyl]-C-[2-(2,4,6- tri chi orophenylamino)phenyl]-methanesulfonamide,l-[2-(2,6-dichl oro-4- trifluoromethylphenylamino)phenyl]-N-{2-(2-hydroxyethoxy)eth yl]methanesulfonamide,l- [2-(2,6-dichloro-3-methylphenylamino)phenyl]-N-{2-(2 -hydroxy ethoxy)- ethyl]methanesulfonamide,N-(2-hydroxyethyl)-l-[3-(2,4,6- trichlorophenylamino)phenyl]methane sulphonamide,N-(2-hydroxyethyl)-2-(2,4,6- trichlorophenylamino)benzenesulfonamide,N-(2-hydroxyethyl)-2 -(2,6- dichlorophenylamino)benzene sulfonamide,2-(2,6-dichloro-4-trifluoromethylphenylamino)- N-(2-hydroxyethyl)-benzenesulfonamide,2-(2,6-dichloro-3-meth ylphenylamino)-N-(2- hydroxyethyl)-benzenesulfonamide,2-(2,6-dichloro-4-trifluoro methylphenylamino)-N-[2-(2- hydroxyethoxy)ethyl]-benzenesulfonamide,2-(2,6-dichloro-3-me thylphenylamino)-N-[2-(2- hydroxyethoxy)ethyl]-benzenesulfonamide,2-(3,5-dichloropheny lamino)-N-[2-(2- hydroxyethoxy)ethyl]-benzenesulfonamide, andN-[2-(2-hydroxyethoxy)ethyl]-2-(2,4,6- trichlorophenylamino)-benzenesulfonamide, or a pharmacologically acceptable salt or prodrug thereof.

[00751] In further embodiments, the compound is according to Formula 149 wherein: Ar ¹ and Ar ² are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5; R ¹ is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxy carbonylamino groups, alkyl sulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 5;R ² is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, haloalkoxy groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkyl sulphonyl groups, alkylsulphonylamino groups and cyano groups and where b is greater than 1, each substituent R ² may be the same or different; V is selected from the group consisting of (CR ^3a R ^3b ) _p CON(R ^3b )X and (CR ^3a R ^3b ) _p N(R ^3b )CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z;W is selected from the group consisting of NR ^4a , O, S, S=O, SO2 and C(R ^4a R ^4b )2;X is a substituent selected from the group consisting of hydroxyalkyl groups, alkoxyalkyl groups, haloalkoxyalkyl groups, aryloxyalkyl groups, polyalkylene glycol residues, carboxyalkyl groups, alkoxycarbonylalkyl groups, haloalkoxycarbonylalkyl groups and aralkyloxycarbonylalkyl groups; Y and Z are the same or different and each is a substituent selected from the group consisting of (CR ^5a R ^5b ) _n i, C=O, SO2, C(=O)NR ^5a ;

C(=O)NR ^5a SO ₂ and C=O(R ^5a R ^5b )n2;R ^3a , R ^3b , R ^4a , R ^4b , R ^5a and R ^5b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups, cycloalkyl groups, aryl groups and heteroaryl groups;nl and n2 are the same or different and each is an integer of from 0 to 2; and p is an integer of from 0 to 2.

[00752] In further embodiments, Ar ¹ and Ar ² are the same or different and each is an aryl group having from 5 to 14 carbon atoms or a 5- to 7-membered aromatic heterocyclic group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms.

[00753] In further embodiments, Ar ¹ and Ar ² are the same or different and each is an aryl group having from 6 to 10 carbon atoms or a 5- or 6-membered aromatic heterocyclic group containing 1 or 2 sulfur atoms, oxygen atoms and/or nitrogen atoms.

[00754] In further embodiments, Ar ¹ and Ar ² are each phenyl.

[00755] In further embodiments, R ² is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, haloalkoxy groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups.

[00756] In further embodiments, W is a group of formula NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups.

[00757] In further embodiments, Y and Z are each a group of formula (CR ^5a R ^5b ) _ni wherein each nl is 0. [00758] In further embodiments, V is selected from the group consisting of (CR ^3a R ^3b ) _p CON(R ^3b )X and (CR ^3a R ^3b ) _p N(R ^3b CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z, wherein p is an integer of from 0 to 2, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7- membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, alkoxyalkyl groups comprising alkyl groups having from 1 to 6 carbon atoms which are substituted by at least one alkoxy group having from 1 to 6 carbon atoms, haloalkoxyalkyl groups comprising alkyl groups having from 1 to 6 carbon atoms which are substituted by at least one haloalkoxy group having from 1 to 6 carbon atoms, aryloxy groups having from 5 to 14 carbon atoms, polyalkylene glycol residues of general formula HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _C 2]c3 — wherein cl and c2 are the same or different and each is an integer of from 0 to 4, c3 is an integer of from 1 to 20 and R ^6a , R ^6b , R ^6C and R ^6d may be the same or different from each other and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, carboxyalkyl groups comprising alkyl groups having from 1 to 6 carbon atoms which are substituted with at least one carboxy group, alkoxycarbonylalkyl groups comprising alkyl groups having from 1 to 6 carbon atoms which are substituted with at least one alkoxycarbonyl group having from 2 to 7 carbon atoms, haloalkoxycarbonylalkyl groups comprising carbonylalkyl groups having from 2 to 7 carbon atoms that are substituted with haloalkoxy groups having from 1 to 6 carbon atoms and aralkyloxycarbonylalkyl groups comprising carbonylalkyl groups having from 2 to 7 carbon atoms which are substituted with at least one aralkyloxy group that comprises an alkyl group having from 1 to 6 carbon atoms that is substituted with an aryl group having from 5 to 14 carbon atoms.

[00759] In further embodiments, V is selected from the group consisting of (CR ^3a R ^3b ) _p CON(R ^3b )X and (CR ^3a R ^3b ) _p N(R ^3b )CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z, wherein p is an integer of 0 or 1, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 4 carbon atoms, polyalkylene glycol residues of general formula HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _C 2]c3 — wherein cl and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10 and R ^6a , R ^6b , R ^6c and R ^6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, alkoxyalkyl groups comprising an alkyl group having from 1 to 4 carbon atoms that is substituted with at least one alkoxy group having from 1 to 4 carbon atoms, carboxyalkyl groups comprising an alkyl group having from 1 to 4 carbon atoms that is substituted with at least one carboxy group, carboxyalkyl groups comprising alkyl groups having from 1 to 4 carbon atoms which are substituted with at least one carboxy group and alkoxycarbonylalkyl groups comprising alkyl groups having from 1 to 4 carbon atoms which are substituted with at least one alkoxycarbonyl group having from 2 to 5 carbon atoms.

[00760] In further embodiments, V is selected from the group consisting of (CR ^3a R ^3b ) _p CON(R ^3b )X and (CR ^3a R ^3b ) _p N(R ^3b )CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z, wherein p is an integer of 0 or 1, each of R ^3a and R ^3b is a hydrogen atom, and X is selected from the group consisting of alkyl groups having 1 or 2 carbon atoms which are substituted with a group selected from hydroxyl groups, methoxy groups, ethoxy groups, carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups.

[00761] In further embodiments, the compound is according to Formula 149 wherein: Ar ¹ and Ar ² are each phenyl; a is 0 or 1;R ³ is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, nitro groups, acylamino groups having from 1 to 4 carbon atoms, alkyl sulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is 0 to 3; R ² is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, haloalkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups; W is a group of formula NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups; Y and Z are each a group of formula (CR ^5a R ^5b )ni wherein each nl is 0; and V is selected from the group consisting of (CR ^3a R ^3b ) _p CON(R ^3b )X and (CR ^3a R ^3b ) _p N(R ^3b )CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z, wherein p is an integer of 0 or 1, each of R ^3a and R ^3b is a hydrogen atom, and X is selected from the group consisting of alkyl groups having 1 or 2 carbon atoms which are substituted with a group selected from hydroxyl groups, methoxy groups, ethoxy groups, carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups.

[00762] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-(2-hydroxyethyl)-2-[3-(2,4,6-trichlorophenylamino)phenyl]a cetamide;{2-[5- (3,5-dichlorophenylamino)-2-fluorophenyl]-acetylamino}acetic acid; 2-[4-(2,6-dichloro-4- trifluoromethyl-phenylamino)-phenyl]-N-(2-hydroxyethyl)-acet amide; {2-[4-(3,5- dichlorophenylamino)-phenyl]-acetylamino}acetic acid;N-(2-hydroxy-ethyl)-2-[4-(2,4,6- trichloro-phenylamino)-phenyl]acetamide; 3-(2,6-dichloro-4-trifluoromethyl-phenylamino)- N-(2-hydroxy-ethyl)benzamide; 2-[2-fluoro-5-(2,4,6-trichloro-phenylamino)-phenyl]-N-(2- hydroxy-ethyl)acetamide; 2-[5-(2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro- phenyl]-N-(2-hydroxy-ethyl)acetamide; 2-[5-(2,6-dichloro-4-trifluoromethoxy- phenylamino)-2-fluoro-phenyl]-N-(2-hydroxy-ethyl)acetamide; 2-[4-(2,6-dichloro-4- trifluoromethoxy-phenylamino)-phenyl]-N-(2-hydroxy-ethyl)-ac etamide; 5-(2,6-dichloro-4- trifluoromethyl-phenylamino)-2-fluoro-N-(2-hydroxy-ethyl)-be nzamide; 2-[4-(2,6-dichloro- 4-trifluoromethyl-phenylamino)-phenyl]-N-(2-hydroxy-2-methyl -propyl)acetamide; 2-[5- (2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro-phenyl ]-N-(2-hydroxy-2-methyl- propyl)acetamide; and 2-[4-(2,6-dichloro-4-trifluoromethoxy-phenylamino)-2-fluoro- phenyl]-N-(2-hydroxy-ethyl)propionamide.

[00763] In further embodiments, the compound is according to formula 150 wherein: Ar ¹ and Ar ² are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5; R ¹ is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxy carbonylamino groups, alkyl sulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 5; R ² is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, haloalkoxy groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monoalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkyl sulphonyl groups, alkylsulphonylamino groups and cyano groups and where b is greater than 1, each substituent R ² may be the same or different; V is selected from the group consisting of (CR ^3a R ^3b ) _p CON(R ^3b )X and (CR ^3a R ^3b ) _p N(R ^3b )CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z; W is selected from the group consisting of NR ^4a , O, S, S=O, SO2 and C(R ^4a R ^4b )2; X is a substituent selected from the group consisting of hydrogen atoms, alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, haloalkoxyalkyl groups, aryloxyalkyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, polyalkylene glycol residues, aminoalkyl groups, monoalkylaminoalkyl groups, dialkylaminoalkyl groups; alkyl groups that are substituted with groups of formula NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic group which optionally contains at least one more heteroatom selected from nitrogen, oxygen and sulphur atoms (said saturated or partially unsaturated heterocyclic group optionally further being substituted by one or more substituents selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, nitro groups, amino groups, monoalkylamino groups, dialkylamino groups and hydroxyl groups), carboxyalkyl groups, alkoxycarbonylalkyl groups, haloalkoxycarbonylalkyl groups and aralkyloxycarbonylalkyl groups; Y and Z are the same or different and each is a substituent selected from the group consisting of (CR ^5a R ^5b ) _n i, C=O, SO2, C(=O)NR ^5a ; C(=O)NR ^5a SO ₂ and C=O(R ^5a R ^5b )n2;R ^3a , R ^3b , R ^4a , R ^4b , R ^5a and R ^5b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups, cycloalkyl groups, aryl groups and heteroaryl groups; nl and n2 are the same or different and each is an integer of from 0 to 2; and p is an integer of from 0 to 2.

[00764] In further embodiments, the compound is according to Formula 149 wherein: Ar ¹ and Ar ² are each phenyl; a is 1; R ¹ is halogen; b is an integer of from 0 to 3; R ² is selected from the group consisting of alkyl having from 1 to 3 carbon atoms, halogen, haloalkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3 carbon atoms, haloalkoxy having from 1 to 3 carbon atoms, carboxyl, amino, hydroxyl and cyano, and where b is greater than 1, each substituent R ² may be the same or different; V is (CR ^3a R ^3b ) _p CON(R ^3b )X, wherein said group is in the 3-(meta) or 4-(para) position with respect to the substituent Z;W is NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen, alkyl having from 1 to 3 carbon atoms and phenyl; X is a substituent selected from the group consisting of hydroxyalkyl having from 1 to 4 carbon atoms, polyalkylene glycol residue of general formula:

HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10 and R ^6a , R ^6b , R ^6c and R ^6d may be the same or different and each is a hydrogen or an alkyl having from 1 to 4 carbon atoms, alkoxyalkyl comprising an alkyl having from 1 to 4 carbon atoms that is substituted with at least one alkoxy having from 1 to 4 carbon atoms, carboxyalkyl comprising an alkyl having from 1 to 4 carbon atoms that is substituted with at least one carboxy, carboxyalkyl comprising alkyl having from 1 to 4 carbon atoms which are substituted with at least one carboxy and alkoxycarbonylalkyl comprising alkyl having from 1 to 4 carbon atoms which are substituted with at least one alkoxycarbonyl having from 2 to 5 carbon atoms; Y and Z are each a group of formula (CR ^5a R ^5b ) _ni wherein each nl is 0;R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen and alkyl; and p is an integer of from 0 to 2.

[00765] In further embodiments, V is (CR ^3a R ^3b ) _p CON(R ^3b )X, wherein said groups is in the 3-(meta) or 4-(para) position with respect to the substituent Z, wherein p is an integer of 0 or 1, each of R ^3a and R ^3b is hydrogen, and X is selected from the group consisting of alkyl having 1 or 2 carbon atoms which are substituted with a group selected from hydroxyl groups, methoxy groups, ethoxy groups, carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups.

[00766] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: {2-[5-(3,5-dichlorophenylamino)-2-fluorophenyl]-acetylamino} acetic acid; 2- [5-(2,6-dichloro-4-trifluoromethoxy-phenylamino)-2-fluoro-ph enyl]-N-(2-hydroxy- ethyl)acetamide; 5-(2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro-N-(2 -hydroxy- ethyl)-benzamide; 2-[5-(2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro-p henyl]-N-(2- hydroxy-2-methyl-propyl)acetamide; and 2-[4-(2,6-dichloro-4-trifluoromethoxy- phenylamino)-2-fluoro-phenyl]-N-(2-hydroxy-ethyl)propionamid e.

[00767] In further embodiments, the compound is according to Formula 149 wherein: Ar ¹ and Ar ² are each phenyl; are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5; R ¹ is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups, dialkylamino groups, acylamino groups, alkoxy carbonylamino groups, alkyl sulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 5; R ² is selected from the group consisting of alkyl groups, halogen atoms, haloalkyl groups, alkoxy groups, alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups, dialkylamino groups, nitro groups, acylamino groups, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and where b is greater than 1, each substituent R ² may be the same or different; V is selected from the group consisting of (CR ^3a R ^3b ) _p SO2N(R ³ b)X;W is NR ^4a ;X is a substituent selected from the group consisting of hydroxyalkyl groups, and polyalkylene glycol residues; Y and Z are each a group of formula (CR ^5a R ^5b ) _n i, wherein each nl is 0; and p is an integer of from 0 to 2, and wherein V is substituting said Ar ¹ at an ortho position with respect to said Z or said W. In further embodiments,

[00768] In further embodiments, a is an integer of from 0 to 3.

[00769] In further embodiments, R ¹ is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different.

[00770] In further embodiments, b is an integer of from 0 to 4.

[00771] In further embodiments, R ² is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups.

[00772] In further embodiments, R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups.

[00773] In further embodiments, V is selected from the group consisting of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of from 0 to 2, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, and polyalkylene glycol residues of general formula HO — [(CR (CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is an integer of from 0 to 4, c3 is an integer of from 1 to 20 and R ^6a , R ^6b , R ^6c and R ^6d may be the same or different from each other and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.

[00774] In further embodiments, V is a group of formula of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of 0 or 1, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 4 carbon atoms and polyalkylene glycol residues of general formula HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10 and R ^6a , R ^6b , R ^6c , R ^6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.

[00775] In further embodiments, V is a group of formula of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of 0 or 1, each of R ^3a and R ^3b is a hydrogen atom, and X is a hydroxylalkyl group having from 1 to 4 carbon atoms or a polyalkylene glycol residue of general formula HO — [CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is 1 or 2, c3 is an integer of from 1 to 6 and each of R ^6a , R ^6b , R ^6c and R ^6d is a hydrogen atom.

[00776] In further embodiments, the compound is according to Formula 149 wherein: Ar ¹ and Ar ² are each phenyl; a is an integer of from 0 to 3;R ³ is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 4;R ² is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, nitro groups, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups and, where b is greater than 1, each substituent R ² may be the same or different; W is NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms; Y and Z are each a group of formula (CR ^5a R ^5b )ni, wherein each nl is 0; and V is selected from the group consisting of (CR ^3a R ^3b ) _p SO2N(R ^3b )X and, wherein p is an integer of from 0 to 2,R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms which may optionally be substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, carbonyl groups, hydroxyl groups and cyano groups, and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, and polyalkylene glycol residues of general formula HO-[(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is an integer of from 0 to 4, c3 is an integer of from 1 to 20 and R ^6a , R ^6b , R ^6c and R ^6d may be the same or different from each other and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.

[00777] In further embodiments, the compound is according to Formula 149 wherein: Ar ¹ and Ar ² are each phenyl; a is 0 or 1;R ³ is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 3;R ² is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, nitro groups, acylamino groups having from 1 to 4 carbon atoms, alkyl sulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where b is greater than 1, each substituent R ² may be the same or different; W is NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, aryl groups having from 6 to 10 carbon atoms and 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 sulfur atoms, oxygen atoms and/or nitrogen atoms; Y and Z are each a group of formula (CR ^5a R ^5b ) _n i, wherein each nl is 0; and V is a group of formula of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of 0 or 1, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 4 carbon atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 4 carbon atoms and polyalkylene glycol residues of general formula HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _C 2]c3 — wherein cl and c2 are the same or different and each is an integer of from 1 to 3, c3 is an integer of from 1 to 10 and R ^6a , R ^6b , R ^bc and R ^6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms.

[00778] In further embodiments, the compound is according to Formula 149 wherein: Ar ¹ and Ar ² are each phenyl; a is 0 or 1; R ¹ is selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 4 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 4 carbon atoms, acylamino groups having from 1 to 4 carbon atoms, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is 0 to 3; R ² is selected from the group consisting of alkyl groups having from 1 to 3 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 3 carbon atoms, alkoxy groups having from 1 to 3 carbon atoms, carboxyl groups, amino groups, hydroxyl groups and cyano groups; W is a group of formula NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups; Y and Z are each a group of formula (CR ^5a R ^5b ) _ni wherein each nl is 0; and V is a group of formula of (CR ^3a R ^3b ) _p SO2N(R ^3b )X, wherein p is an integer of 0 or 1, each of R ^3a and R ^3b is a hydrogen atom, and X is a hydroxylalkyl group having from 1 to 4 carbon atoms or a polyalkylene glycol residue of general formula HO — [(CR ^6a R ^6b ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is 1 or 2, c3 is an integer of from 1 to 6 and each of R ^6a , R ^6b , R ^6c and R ^6d is a hydrogen atom.

[00779] In further embodiments, the compound is according to Formula 149 wherein: Ar ¹ and Ar ² are each phenyl; a is an integer of from 0 to 3; R ¹ is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups and, where a is greater than 1, each substituent R ¹ may be the same or different; b is an integer of from 0 to 4; R ² is selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups wherein the alkoxy group has from 1 to 6 carbon atoms, carboxyl groups, hydroxyl groups, amino groups, monalkylamino groups wherein the alkyl group has from 1 to 6 carbon atoms, dialkylamino groups wherein the alkyl groups may be the same or different and each has from 1 to 6 carbon atoms, nitro groups, acylamino groups having from 1 to 6 carbon atoms, alkoxycarbonylamino groups wherein the alkoxy group has from 1 to 6 carbon atoms, alkylsulphonyl groups having from 1 to 6 carbon atoms, alkylsulphonylamino groups having from 1 to 6 carbon atoms and cyano groups and, where b is greater than 1, each substituent R ² may be the same or different; W is NR ^4a , wherein R ^4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms; and V is selected from the group consisting of (CR ^3a R ^3b ) _p SO2N(R ^3b )X wherein p is an integer of from 0 to 2, R ^3a and R ^3b are the same or different and each is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms, aryl groups having from 5 to 14 carbon atoms and 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and X is a substituent selected from the group consisting of hydroxyalkyl groups having from 1 to 6 carbon atoms, and polyalkylene glycol residues of general formula HO — [(CR ^6a R ^6c ) _ci — O — (CR ^6c R ^6d ) _c2 ]c3 — wherein cl and c2 are the same or different and each is an integer of from 0 to 4, c3 is an integer of from 1 to 20 and R ^6a , R ^6b , R ^6c and R ^6d may be the same or different from each other and each is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.

Formula 150

[00780] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 150. Such compounds are described in International Publication No. W02012004698A1, published January 12, 2012, and corresponding to International Application No. PCT/IB2011/052686 filed June 20, 2011; US Patent No. 8,883,812, issued November 11, 2014 and corresponding to US Application No. 13/808,355 filed June 20, 2011; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 150, these references incorporated by reference herein control.

[00781] In an embodiment, the Kv7 channel activator is a compound according to Formula 150:

Formula 150 wherein, n is an integer of 1 or 2; t is 0 or 1; each R ¹ is independently selected from Cn

3 alkoxy, C1-3 alkyl, C1-3 alkyl-0 — C1-3 alkyl; R ² and R ³ are independently C1-3 alkyl, Cn

3 alkoxy, or C3-ecyloalkyl provided that at least one is C1-3 alkoxy; R ⁴ is C1-6 alkyl, C1-3 alkyl- C3-6cyloalkyl, C3-6 heterocycloalkyl; or a pharmaceutically acceptable salt thereof. [00782] In further embodiments, R ¹ , R ² , and R ³ are each C1-3 alkoxy; wherein R ⁴ is C4-6 alkyl, and wherein n and t are each 1, or a pharmaceutically acceptable salt thereof.

[00783] In further embodiments, R ¹ , R ² , and R ³ are each methoxy; R ⁴ is — CFb-t-butyl, and n and t are each 1, or a pharmaceutically acceptable salt thereof.

[00784] In further embodiments, the compound is N-(4,6-dimethoxy-2-(4-methoxypiperidin- l-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide, or a pharmaceutically acceptable salt thereof.

Formula 151

[00785] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 151. Such compounds are described in US Patent No. 9,353,048 issued May 31, 2016, and corresponding to US Application No. 14/353,842 filed October 23, 2012; International Publication No. W02013060097A1, published May 2, 2013, and corresponding to International Application No. PCT/CN2012/001423 filed October 23, 2012; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 152, these references incorporated by reference herein control.

[00786] In an embodiment, the Kv7 channel activator is a compound according to Formula

151 :

Formula 151 wherein, Ri is a radical selected from the group consisting of C2-C8 alkenyl, C5-

C7 cycloalkenyl and C2-C8 alkynyl; wherein, the C2-C8 alkenyl is unsubstituted or optionally substituted by hydroxyl, amino, halogen atom, phenyl or halogenated phenyl; the C2- Cs alkynyl is unsubstituted or optionally substituted by hydroxyl, amino, halogen atom, phenyl or halogenated phenyl; R2 is a radical selected from the group consisting of F, Cl and methoxyl;R3 is a radical selected from the group consisting of H, halogen atom and trifluorom ethyl; Y is not present or Y is O;R4 is a radical selected from the group consisting of Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl and Ce-Cio aryl;Rs is a radical selected from the group consisting of H, halogen atom, amino together with adjacent e alkyl.

[00787] In further embodiments, the Kv7 Channel activator is selected from the group consisting of:

Formula 152

[00788] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 152. In another embodiment, the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in International Publication No. US20100057224A1, published June 3, 2011, and corresponding to International Application No. PCT/US2010/057224 filed November 18, 2010; US Patent No. 8,629,143 published January 14, 2014, and corresponding to US Application No. 12/949,435 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 152, these references incorporated by reference herein control. [00789] In an embodiment, the Kv7 channel activator is a compound according to Formula 152: or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein Z is a ring fused with the pyridazine ring, selected from the group consisting of benzo, cycloalkyl, cycloalkenyl, heterocycle, and heteroary^R ¹ is an optional substituent wherein each occurrence of R ¹ is independently C , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , - S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,-N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , - N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , -(CR ^za R ^zb ) _m -OR ^a , -(CR ^za R ^zb ) _m - OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , -(CR ^za R ^zb ) _m -S(O)R ^a , -(CR ^za R ^zb ) _m - S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , -(CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m - C(O)NR ^a R ^b , -(CR ^za R ^zb )m-NR ^a R ^b ,-(CR ^za R ^zb ) _m -N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , - (CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b , or -(CR^R^m-CP; p is 0, 1, 2, 3, or 4;R ³ is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, -(CR ^3a R ^3b ) _m -G ^3a , or G ^3a ; G ^3a , at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R ⁴ is alkenyl, alkynyl, haloalkyl, G ^4a , -(CR ^4a R ^4b ) _n -G ^4a , or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R ^la ), 0(R ^la ) and N(R ^la ) ₂ ;each occurrence of R ^la is independently hydrogen, (P, -(CR ^za R ^zb ) _m -G ^a , alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G ^4a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G ^3a and G ^4a , at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of G ¹ , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,-N(R ^a )COOR ^b , - N(R ^a )CONR ^a R ^b , -N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -G ^a , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb ) _m -OR ^a , -(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb ) _m -S(O)R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m - N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;G ^a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , - C(O)OR ^a , -C(O)NR ^a R ^b , -N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b ,-N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , -(CR ^za R ^zb )m-OR ^a ,-(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , - (CR ^za R ^zb ) _m -SR ^a , -(CR ^za R ^zb )m-S(O)R ^a ,-(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , - (CR ^za R ^zb ) _m -C(O)R ^a , -(CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , - (CR ^za R ^zb )m-N(R ^a )COOR ^b ,-(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m - N(R ^a )SO ₂ NR ^a R ^b ;R ^za , R ^zb , R ^3a , R ^3b , R ^4a , and R ^4b , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; R ^a and R ^b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; and m and n, at each occurrence, are each independently 1, 2, 3, or 4;with the proviso that when Z ¹ is benzo, p is 0 or 4, R ¹ is halogen, R ³ is G ^3a , and G ^3a is aryl, substituted with 1 or 2 substituents selected from the group consisting of alkyl and unsubstituted aryl, then R ⁴ is other than unsubstituted aryl, unsubstituted alkyl, or haloalkyl. [00790] In further embodiments, Z ¹ is benzo, heteroaryl, or cycloalkyl.

[00791] In further embodiments, R ³ is alkyl, halogen, haloalkyl, G ^3a , or -(CR ^3a R ^3b ) _m -G ^3a . [00792] In further embodiments, R ⁴ is unsubstituted alkyl, haloalkyl, -C(R ^4a R ^4b ) _n -G ^4a , or alkyl substituted with a -S(R ^la ) group.

[00793] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; and R ⁴ is unsubstituted alkyl, haloalkyl, -C(R ^4a R ^4b ) _n -G ^4a , or alkyl substituted with a -S(R ^la ) group. In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; and R ⁴ is -C(R ^4a R ^4b ) _n -G ^4a . [00794] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; R ⁴ is -C(R ^4a R ^4b ) _n - G ^4a ; and R ³ is alkyl, halogen, haloalkyl, G ^3a , or -(CR ^3a R ^3b ) _m -G ^3a .

[00795] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; R ⁴ is -C(R ^4a R ^4b ) _n - G ^4a ;R ³ is alkyl, halogen, haloalkyl, G ^3a , or -(CR ^3a R ^3b ) _m -G ^3a ; andG ^3a is aryl or cycloalkyl. [00796] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; andR ⁴ is unsubstituted alkyl or haloalkyl.

[00797] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; R ⁴ is unsubstituted alkyl or haloalkyl; and R ³ is alkyl, halogen, haloalkyl, G ^3a , or -(CR ^3a R ^3b ) _m -G ^3a .

[00798] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; R ⁴ is unsubstituted alkyl or haloalkyl; R ³ is alkyl, halogen, haloalkyl, G ^3a , or -(CR ^3a R ^3b ) _m -G ^3a ; and G ^3a is aryl or cycloalkyl. [00799] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; and R ⁴ is alkyl substituted with a -S(R ^la ) group.

[00800] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; R ⁴ is alkyl substituted with a -S(R ^la ) group; and R ³ is alkyl, halogen, haloalkyl, G ^3a , or -(CR ^3a R ^3b ) _m -G ^3a . [00801] In further embodiments, Z ¹ is benzo, cycloalkyl, or heteroaryl; R ⁴ is alkyl substituted with a -S(R ^la ) group; R ³ is alkyl, halogen, haloalkyl, G ^3a , or -(CR ^3a R ^3b ) _m -G ^3a ; and G ^3a is aryl or cycloalkyl.

[00802] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(4-chlorophenyl)-N-(4-isopropyl-l-oxophthalazin-2(lH)-yl)a cetamide; 2-( 1 - adamantyl)-N- [4-(4-bromophenyl)- 1 -oxophthalazin-2( 1 H)-yl]acetamide; N-[4-(4- bromophenyl)-l-oxophthalazin-2(lH)-yl]-2-(4-chlorophenyl)ace tamide; 2-(4-chlorophenyl)- N-( 1 -oxo-4-phenylphthalazin-2( 1 H)-yl)acetamide; 2-(3,5-difluorophenyl)-N-(4-isopropyl-

1-oxophthalazin-2(lH)-yl)acetamide; 2-( 1 -adamantyl)-N-(4-isopropyl- 1 -oxophthalazin-2( 1 H)-yl)acetamide; 2-(l-adamantyl)-N-(8-oxo-5-phenylpyrido[2,3-d]pyridazin-7(8H )- yl)acetamide; 2-(l-adamantyl)-N-(4-isopropyl-l-oxo-5,6,7,8-tetrahydro-5,8- ethanophthalazin- 2(1 H)-yl)acetamide; 2-(l-adamantyl)-N-(4-oxo-7-phenylthieno[2,3-d]pyridazin-5(4H )- yl)acetamide; 2-(3,5-difluorophenyl)-N-(4-oxo-7-phenylthieno[2,3-d]pyridaz in-5(4H)- yl)acetamide; 2-(3,5-difluorophenyl)-N-[l-oxo-4-(trifluoromethyl)phthalazi n-2(lH)- yl]acetamide; 2-( 1 -adamantyl)-N-[ 1 -oxo-4-(trifluoromethyl)phthalazin-2(l H)- yl]acetamide; 2-(4-chlorophenyl)-N- [ 1 -oxo-4-(trifluoromethyl)phthalazin-2( 1 H)-yl] acetamide; N-(5,8-difluoro-l-oxo-4-phenylphthalazin-2(lH)-yl)-2-(4-fluo rophenyl)acetamide;

2-(l-adamantyl)-N-(5,8-difluoro-l-oxo-4-phenylphthalazin- 2(lH)-yl)acetamide; 2-(4- chlorophenyl)-N-(5,8-difluoro-l-oxo-4-phenylphthalazin-2(lH) -yl)acetamide; 2-(l- adamantyl)-N-(l-oxo-4-phenylphthalazin-2(lH)-yl)acetamide; 2-(3,5-difluorophenyl)-N-(l- oxo-4-phenylphthalazin-2(lH)-yl)acetamide; N-(4-chloro-l-oxophthalazin-2(lH)-yl)-2-(3,5- difluorophenyl)acetamide; 2-( 1 -adamantyl)-N-(4-chloro- 1 -oxophthalazin-2( 1 H)- yl)acetamide; N-(4-chloro-l-oxophthalazin-2(lH)-yl)-2-(4-chlorophenyl)acet amide; 2-(4- chlorophenyl)-N-(4-cyclopropyl-l-oxophthalazin-2(lH)-yl)acet amide; N-(4-cyclopropyl-l- oxophthalazin-2(lH)-yl)-2-(3,5-difluorophenyl)acetamide; 2-( 1 -adamantyl)-N-(4- cyclopropyl- 1 -oxophthalazin-2( 1 H)-yl)acetamide; 2-(2,3-difluorophenyl)-N-(l-oxo-4- phenylphthalazin-2(lH)-yl)acetamide; 2-(4-fluorophenyl)-N-( 1 -oxo-4-phenylphthalazin-2( 1 H)-yl)acetamide; 2-(2,5-difluorophenyl)-N-(l-oxo-4-phenylphthalazin-2(lH)-yl) acetamide; 2- (4-chlorophenyl)-N-(4-methyl- 1 -oxophthalazin-2( 1 H)-yl)acetamide; 2-(l-adamantyl)-N-(7- oxo-4-phenylthieno[2,3-d]pyridazin-6(7H)-yl)acetamide; 2-[(l S,2S,5S)-6,6- dimethylbicyclo[3.1.1]hept-2-yl]-N-(7-oxo-4-phenylthieno[2,3 - d]pyridazin-6(7H)- yl)acetamide; 2-(4-chlorophenyl)-N-(7-oxo-4-phenylthieno[2,3-d]pyridazin-6 (7H)- yl)acetamide; 2-(4-fluorophenyl)-N-(7-oxo-4-phenylthieno[2,3-d]pyridazin-6 (7H)- yl)acetamide; 2-(3,5-difluorophenyl)-N-(7-oxo-4-phenylthieno[2,3-d]pyridaz in-6(7H)- yl)acetamide; 2-[3,5-dimethyl-l-adamantyl]-N-(4-isopropyl-l-oxophthalazin- 2(lH)- yl)acetamide; 2-(3,5-difluorophenyl)-N-(6-fluoro-l-oxo-4-phenylphthalazin- 2(lH)- yl)acetamide; 2-(4-chlorophenyl)-N-(6-fluoro-l-oxo-4-phenylphthalazin-2(lH )-yl)acetamide; 2-( 1 -adamantyl)-N-(6-fluoro- 1 -oxo-4-phenylphthalazin-2( 1 H)-yl)acetamide; 2-(3,5- difluorophenyl)-N-(4-methyl-l-oxophthalazin-2(lH)-yl)acetami de; 2-[l-(4- chlorophenyl)cyclopropyl]-N-[l-oxo-4-(trifluoromethyl)phthal azin-2(lH)-yl]acetamide; 2- [ 1 -(4-chlorophenyl)cyclobutyl] -N-[ 1 -oxo-4-(trifluoromethyl)phthalazin-2( 1 H)- yl]acetamide; 2-(2-naphthyl)-N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)- yl]acetamide; 3- (4-chlorophenyl)-3-methyl-N-[l-oxo-4-(trifluoromethyl)phthal azin-2(lH)-yl]butanamide; 2- cyclopentyl-N- [ 1 -oxo-4-(trifluoromethyl)phthalazin-2( 1 H)-yl] acetamide; 2.2- difluoro-N- [l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl]-2-phenylaceta mide; 2-cyclobutyl-N-[l-oxo-4- (trifluoromethyl)phthalazin-2(lH)-yl]acetamide; N-[ 1 -oxo-4-(trifluoromethyl)phthalazin- 2(lH)-yl]-2-[4- (trifluoromethyl)phenyl]acetamide; 2- [4-(dimethylamino)phenyl]-N-[l-oxo- 4-(trifluoromethyl)phthalazin-2(lH)-yl] acetamide; 3.3- dimethyl-N-[l-oxo-4- (trifluoromethyl)phthalazin-2(lH)-yl]butanamide; 2-[4-(methylsulfonyl)phenyl]-N-[l-oxo-4- (trifluoromethyl)phthalazin-2(lH)-yl] acetamide; N- [ 1 -oxo-4-(trifluoromethyl)phthalazin-2( 1 H)-yl] -3-phenylpropanamide; N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl]-2-(l- phenylcyclopropyl)acetamide; 3- methyl-N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl]-3- phenylbutanamide; N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl]-2-(3-thieny l)acetamide; N- [ 1 -oxo-4-(trifluoromethyl)phthalazin-2( 1 H)-yl] -2-(2-thienyl)acetamide; 2-(5-chloro-2- thienyl)-N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl]ace tamide; 2-(5-methyl-2-thienyl)- N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl]acetamide; N- [ 1 -oxo-4-

(trifluoromethyl)phthalazin-2( 1 H)-yl] -2-phenylacetamide; (±)-2-(e o-bicyclo[2.2.1]heptan- 2-yl)-N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl] acetamide; 2-(4-chl oro-3 - fluorophenyl)-N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-y l] acetamide; 2-(3- fluoroadamantan- l-yl)-N-(4-isopropyl- 1 -oxophthalazin-2( lH)-yl)acetamide; 2-(3- hydroxyadamantan-l-yl)-N-(4-isopropyl-l-oxophthalazin-2(lH)- yl)acetamide; N-(4-tert-butyl- l-oxophthalazin-2(lH)-yl)-2-cyclopentylacetamide; (±)-2-(e o-bicyclo[2.2. l]heptan-2-yl)-N- (4-tert-butyl-l-oxophthalazin-2(lH)-yl)acetamide; N-(4-tert-butyl- 1 -oxophthalazin-2( 1 H)- yl)-3 -methyl-3-phenylbutanamide; N-(4-tert-butyl-l-oxophthalazin-2(lH)-yl)-2-(4- chlorophenyl)acetamide; 2-[(l S,2S,4R)-bicyclo[2.2. l]hept-2-yl]-N-(4-cyclobutyl-l- oxophthalazin-2(lH)- yl)acetamide; 2-[(l S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl]-N-(4- cyclobutyl-l-oxophthalazin-2(lH)- yl)acetamide; (±)-2-(e o-bicyclo[2.2.1]heptan-2-yl)-N-(4- cyclobutyl-l-oxophthalazin-2(lH)- yl)acetamide; N-(4-cyclobutyl-l-oxophthalazin-2(lH)-yl)- 2-(3,5-difluorophenyl)acetamide; 2-(4-chlorophenyl)-N-(4-cyclobutyl-l-oxophthalazin-2(lH)- yl)acetamide; (±)-2-(e o-bicyclo[2.2. l]heptan-2-yl)-N-(4-cyclopentyl-l-oxophthalazin-2(lH)- yl)acetamide; 2-(4-chlorophenyl)-N-(4-cyclopentyl-l-oxophthalazin-2(lH)-yl )acetamide; N- (4-cyclopentyl-l-oxophthalazin-2(lH)-yl)-2-(3,5-difluorophen yl)acetamide; (±)-2-(e o- bicyclo[2.2. l]heptan-2-yl)-N-(4-cyclohexyl-l-oxophthalazin-2(lH)- yl)acetamide; 2- (adamantan- 1 -yl)-N-(4-cyclohexyl- 1 -oxophthalazin-2( 1 H)-yl)acetamide; 2- (4- chlorophenyl)-N-(4-cyclohexyl-l-oxophthalazin-2(lH)-yl)aceta mide; N-(4-cyclohexyl-l- oxophthalazin-2(lH)-yl)-2-(3,5-difluorophenyl)acetamide; (±)-4-(3- { [(ero-bicyclo[2.2.1 ]heptan-2-yl)acetyl]amino} -4-oxo-3,4- dihydrophthalazin- l-yl)benzoic acid; (±)-methyl 4- (3 - { [ero-bicyclo [2.2.1 ]hept-2-ylacetyl] amino } -4-oxo-3 ,4- dihydrophthalazin- 1 - yl)benzoate; methyl 4-(3- {[(4-chlorophenyl)acetyl]amino}-4-oxo-3,4-dihydrophthalazin- l- yl)benzoate; (±)-4-(3- { [e o-bicyclo[2.2.1]hept-2-ylacetyl]amino}-4-oxo-3,4- dihydrophthalazin-1- yl)-N,N-dimethylbenzamide; 3- methyl-N-(l-oxo-4-phenylphthalazin- 2(lH)-yl)-3-phenylbutanamide; 2-(2,4-dichlorophenyl)-N-(l-oxo-4-phenylphthalazin-2(lH)- yl)acetamide; (±)-2-(e o-bicyclo[2.2. l]heptan-2-yl)-N-[4-(4-bromophenyl)-l-oxophthalazin- 2(1H)- yl]acetamide; N-[4-(4-bromophenyl)-l-oxophthalazin-2(lH)-yl]-3-methyl-3- phenylbutanamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(l- methylcyclopentyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-[l- (trifluoromethyl)cyclopentyl]acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2- [(1 S,2S,5R)-3,3-difluoro-6,6- dimethylbicyclo[3.1. l]hept-2-yl]acetamide; N- [4-(4- chlorophenyl)- 1 -oxophthalazin-2( 1 H)-yl]-3 -methyl-3 -phenylbutanamide; N-[4-(4- chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-fluoro-2-phenylace tamide; N-[4-(4-chlorophenyl)- l-oxophthalazin-2(lH)-yl]-2-phenylacetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)- yl]-2-(morpholin-4-yl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2- (pyri din-3 -yl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(pyridin-2 - yl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(3,4- dichlorophenyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(3,5- dimethoxyphenyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(3,5- dimethylphenyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-[3- (trifluoromethoxy)phenyl]acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-[4- (trifluoromethyl)phenyl]acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-[3- (trifluoromethyl)phenyl]acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-[4- (dimethylamino)phenyl]acetamide; 2-(4-bromophenyl)-N-[4-(4-chlorophenyl)-l- oxophthalazin-2(lH)-yl]acetamide; 2-(3-chlorophenyl)-N-[4-(4-chlorophenyl)-l- oxophthalazin-2(lH)-yl]acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(4- methoxyphenyl)acetamide; N- [4-(4-chlorophenyl)- 1 -oxophthalazin-2( 1 H)-yl] -2-(3 - methoxyphenyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(4- hydroxyphenyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(4- methylphenyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(3- methylphenyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2- cyclopentylacetamide; N- [4-(4-chlorophenyl)- 1 -oxophthalazin-2( 1 H)-yl] -4- methylpentanamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-[4- (methylsulfonyl)phenyl]acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-(5- chloro-2-thienyl)acetamide; (±)-2-(e o-bicyclo[2.2. l]hept-2-yl)-N-[4-(4-chlorophenyl)-l- oxophthalazin-2(lH)- yl]acetamide; 2-(4-chloro-3-fluorophenyl)-N-[4-(4-chlorophenyl)-l- oxophthalazin-2(lH)- yl]acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-2-[(l S,2S,5S)-6,6- dimethylbicyclo[3.1. l]hept-2-yl]acetamide; 2-(adamantan- 1 -yl)-N- [4-(4- chlorophenyl)- 1 -oxophthalazin-2( 1 H)-yl] acetamide; 2-(4-chlorophenyl)-N- [4-(4- chlorophenyl)- 1 -oxophthalazin-2( 1 H)-yl] acetamide; N-[4-(4-chlorophenyl)-l- oxophthalazin-2(lH)-yl]-2-(3,5-difluorophenyl)acetamide; N-[4-(4-chlorophenyl)- 1 - oxophthalazin-2(l H)-yl]-2-( 1 -phenylcyclopentyl)acetamide; N-[4-(4-chlorophenyl)-l- oxophthalazin-2(lH)-yl]-2- phenylcyclopropanecarboxamide; N-[4-(4-chlorophenyl)-l- oxophthalazin-2(lH)-yl]-2-(2-naphthyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin- 2(lH)-yl]-2-(l-naphthyl)acetamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-4,4,4- trifluorobutanamide; N-[4-(4-chlorophenyl)-l-oxophthalazin-2(lH)-yl]-3,3,3- trifluoropropanamide; (±)-2-(e o-bicyclo[2.2. l]hept-2-yl)-N-[4-(3-chlorophenyl)-l- oxophthalazin-2(lH)- yl] acetamide; 2-(adamantan- 1 -yl)-N- [4-(3 -chlorophenyl)- 1 - oxophthalazin-2( 1 H)-yl] acetamide; 2-(4-chlorophenyl)-N- [4-(3 -chlorophenyl)- 1 - oxophthalazin-2( 1 H)-yl] acetamide; N- [4-(3 -chlorophenyl)- 1 -oxophthalazin-2( 1 H)-yl]- 2-(3 ,5 -difluorophenyl)acetamide; 2-[(l S,2S,4R)-bicyclo[2.2.1]hept-2-yl]-N-[4-(4- fluorophenyl)-l-oxophthalazin- 2(1 H)-yl]acetamide; 2-[(l S,2S,4S)-bicyclo[2.2.1]hept-5-en- 2-yl]-N-[4-(4-fluorophenyl)-l-oxophthalazin- 2(1 H)-yl]acetamide; (±)-2-(e o- bicyclo[2.2.1]hept-2-yl)-N-[4-(4-fluorophenyl)-l-oxophthalaz in-2(lH)- yl] acetamide; 2-(4- chlorophenyl)-N-[4-(4-fluorophenyl)-l-oxophthalazin-2(lH)-yl ] acetamide; 2-(3,5- difluorophenyl)-N-[4-(4-fluorophenyl)-l-oxophthalazin-2(lH)- yl]acetamide; (±)-2-(e o- bicyclo[2.2.1]hept-2-yl)-N-[4-(2,4-difluorophenyl)-l-oxophth alazin- 2(1 H)-yl]acetamide; 2- (4-chlorophenyl)-N-[4-(4-methylphenyl)-l-oxophthalazin-2(lH) -yl]acetamide; 2-(3,5- difluorophenyl)-N-[4-(4-methylphenyl)-l-oxophthalazin-2(lH)- yl]acetamide; 2-[(l S,2S,5S)- 6,6-dimethylbicyclo[3.1.1]hept-2-yl]-N-[4-(4-methylphenyl)-l - oxophthalazin-2(lH)- yl]acetamide; 2-(adamantan- 1 -yl)-N- [4-(4-methylphenyl)- 1 -oxophthalazin-2( 1 H)-yl] acetamide; N-(4-benzyl- 1 -oxophthalazin-2( 1 H)-yl)-2- [ 1 -(trifluoromethyl)cyclopentyl] acetamide; N-(4-benzyl- 1 -oxophthalazin-2( 1 H)-yl)-3-methyl-3 -phenylbutanamide; (±)-N- (4-benzyl-l-oxophthalazin-2(lH)-yl)-2-(e o-bicyclo[2.2. l]hept-2-yl)acetamide; N-(4-benzyl-l- oxophthalazin-2(lH)-yl)-2-(4-chlorophenyl)acetamide; N-(4-benzyl-l-oxophthalazin-2(lH)- yl)-2-(3,5-difluorophenyl)acetamide; (±)-2-(e o-bicyclo[2.2. l]hept-2-yl)-N-[4-(4- chlorobenzyl)-l-oxophthalazin-2(lH)- yl] acetamide; N-[4-(4-chlorobenzyl)-l-oxophthalazin- 2(lH)-yl]-2-(4-chlorophenyl)acetamide; N-[4-(4-chlorobenzyl)-l-oxophthalazin-2(lH)-yl]-2- (3,5-difluorophenyl)acetamide; 2- [(1 S,2S,4R)-bicyclo[2.2.1]hept-2-yl]-N-{ l-oxo-4-[4- (trifluoromethyl)phenyl]phthalazin-2(lH)-yl} acetamide; 3- methyl-N- { l-oxo-4-[4- (trifluoromethyl)phenyl]phthalazin-2(lH)-yl}-3- phenylbutanamide; 2-(adamantan-l-yl)-N- { l-oxo-4-[4-(trifluoromethyl)phenyl]phthalazin-2(lH)- yl} acetamide; (±)-2-(exo-bicyclo[2.2.1 ]hept-2-yl)-N- { 1 -oxo-4-[4- (trifluoromethyl)phenyl]phthalazin-2(lH)-yl} acetamide; (±)-2- (e o-bicyclo[2.2.1]hept-2-yl)-N-[4-(4-methoxyphenyl)-l-oxophtha lazin-2(lH)- yl] acetamide; N-[4-(4-methoxyphenyl)-l-oxophthalazin-2(lH)-yl]-2-(4- methylcyclohexyl)acetamide; 2- (3,5-difluorophenyl)-N-[4-(4-methoxyphenyl)-l-oxophthalazin- 2(lH)- yl] acetamide; 2- (adamantan- 1 -yl)-N- [4-(4-methoxyphenyl)- 1 -oxophthalazin-2( 1 H)-yl] acetamide; (±)-2- (e o-bicyclo[2.2.1]hept-2-yl)-N-[4-(2,5-dimethylphenyl)-l-oxoph thalazin- 2(1 H)- yl]acetamide; 2-(adamantan-l-yl)-N-[4-(2,5-dimethylphenyl)-l-oxophthalazin -2(lH)- yl]acetamide; 2-(4-chlorophenyl)-N-[4-(2,5-dimethylphenyl)-l-oxophthalazin -2(lH)- yl]acetamide; 2-(3,5-difluorophenyl)-N-[4-(2,5-dimethylphenyl)-l-oxophthal azin-2(lH)- yl] acetamide; 2-[(l S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl]-N-[4-(2,4-dimethylphe nyl)-l- oxophthalazin-2(lH)-yl]acetamide; (±)-2-(e o-bicyclo[2.2. l]hept-2-yl)-N-[4-(2,4- dimethylphenyl)-l-oxophthalazin- 2(1 H)-yl]acetamide; 2-(4-chlorophenyl)-N-[4-(2,4- dimethylphenyl)-l-oxophthalazin-2(lH)-yl]acetamide; 2-(3,5-difluorophenyl)-N-[4-(2,4- dimethylphenyl)-l-oxophthalazin-2(lH)- yl]acetamide; (±)-2-(e o-bicyclo[2.2.1]hept-2-yl)-N- [4-(3,4-dimethylphenyl)-l-oxophthalazin- 2(1 H)-yl]acetamide; 2-(adamantan-l-yl)-N-[4-(3,4- dimethylphenyl)-l-oxophthalazin-2(lH)-yl]acetamide; 2-(4-chlorophenyl)-N-[4-(3,4- dimethylphenyl)-l-oxophthalazin-2(lH)-yl]acetamide; 2-(3,5-difluorophenyl)-N-[4-(3,4- dimethylphenyl)-l-oxophthalazin-2(lH)- yl]acetamide; (±)-2-(e o-bicyclo[2.2.1]hept-2-yl)-N- [l-oxo-4-(2-phenylethyl)phthalazin-2(lH)- yl]acetamide; (±)-2-(e o-bicyclo[2.2.1]hept-2-yl)- N-[4-(4-isopropylphenyl)-l-oxophthalazin-2(lH)- yl]acetamide; 2-(adamantan-l-yl)-N-[4-(4- isopropylphenyl)-l-oxophthalazin-2(lH)-yl]acetamide; 2-(4-chlorophenyl)-N- [4-(4- isopropylphenyl)- 1 -oxophthalazin-2( 1 H)-yl] acetamide; 2-(3,5-difluorophenyl)-N-[4-(4- isopropylphenyl)-l-oxophthalazin-2(lH)- yl] acetamide; (±)-2-(ero-bicyclo[2.2.1 ]hept-2-yl)- N-[ 1 -oxo-4-(l -phenylcyclopropyl)phthalazin- 2(1 H)-yl]acetamide; 2-(adamantan- 1 -yl)-N- [4-isopropyl- 1 -oxo-7-(trifluoromethyl)phthalazin-2( 1 H)- yl] acetamide; 2-(adamantan- 1 - yl)-N- [7-bromo-4-(4-methoxyphenyl)- 1 -oxophthalazin-2( 1 H)- yl] acetamide; 2- (adamantan- 1 -yl)-N- [6-bromo-4-(4-methoxyphenyl)- 1 -oxophthalazin-2( 1 H)- yl] acetamide; N-[6-bromo-4-(4-methoxyphenyl)-l-oxophthalazin-2(lH)-yl]-2-( 3,5- difluorophenyl)acetamide; N-[7-bromo-4-(4-methoxyphenyl)-l-oxophthalazin-2(lH)-yl]-2- (3,5- difluorophenyl)acetamide; 2-(3-bromoadamantan-l-yl)-N-(7-oxo-4-phenylthieno[2,3- d]pyridazin-6(7H)- yl)acetamide; 2-(3-fluoroadamantan-l-yl)-N-(7-oxo-4-phenylthieno[2,3- d]pyridazin-6(7H)- yl)acetamide; 2-(3-hydroxyadamantan-l-yl)-N-(7-oxo-4- phenylthieno[2,3-d]pyridazin-6(7H)- yl)acetamide; N-[4-(4-chlorophenyl)-5,8-difluoro-l- oxophthalazin-2(lH)-yl]-2-(3,5- difluorophenyl)acetamide; 2-(4-chlorophenyl)-N- [4-(4- chlorophenyl)-5 , 8-difluoro- 1 -oxophthalazin-2( 1 H)- yl]acetamide; 2-(adamantan- l-yl)-N- [4-(4-chlorophenyl)-5,8-difluoro- 1 -oxophthalazin-2(lH)- yl]acetamide; (±)-2-(e o- bicyclo[2.2.1]hept-2-yl)-N-[4-(4-chlorophenyl)-5,8-difluoro- l- oxophthalazin-2(lH)- yl]acetamide; 2-(adamantan-l-yl)-N-(l-oxo-4-phenyl-5,6,7,8-tetrahydrophtha lazin-2(lH)- yl)acetamide; 2-(3,5-difluorophenyl)-N-(l-oxo-4-phenyl-5,6,7,8-tetrahydrop hthalazin-2(lH)- yl)acetamide; 2-(4-chlorophenyl)-N-(l-oxo-4-phenyl-5,6,7,8-tetrahydrophtha lazin-2(lH)- yl)acetamide; 2-(3,5-difluorophenyl)-N-(l-oxo-4-phenyl-l,5,6,7-tetrahydro- 2H- cyclopenta[d]pyridazin-2-yl)acetamide; 2-(adamantan-l-yl)-N-(l-oxo-4-phenyl-l, 5,6,7- tetrahydro-2H- cyclopenta[d]pyridazin-2-yl)acetamide; 2-(4-chlorophenyl)-N-(l-oxo-4- phenyl-l,5,6,7-tetrahydro-2H-cyclopenta[d]pyridazin- 2-yl)acetamide; 2-(methylthio)-N-[l- oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl]acetamide; 2-(adamantan- 1 -ylthio)-N- [ 1 -oxo- 4-(trifluoromethyl)phthalazin-2( 1 H)-yl] acetamide; 2-(adamantan-l-ylthio)-N-(l-oxo-4- phenylphthalazin-2(lH)-yl)acetamide; and 2-( 1 ,3 -benzodioxol-5 -yl)-N- [4-(4- chlorophenyl)- 1 -oxophthalazin-2( 1 H)-yl]acetamide.

Formula 153 [00803] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 153. Such compounds are described in US Patent No. 8,629,143, issued January 14, 2014, and corresponding to US Application No. US8629143B2 filed November 18, 2010; International Publication No. WO2011066168A1, published June 3, 2011, and corresponding to International Application No.

PCT/US2010/057224 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 153, these references incorporated by reference herein control.

[00804] In an embodiment, the Kv7 channel activator is a compound according to Formula 153: or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein, R ¹ is an optional substituent wherein each occurrence of R ¹ is independently CP, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,- N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , -N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb ) _m -OR ^a , -(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb ) _m -S(O)R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b ,-(CR ^za R ^zb ) _m - N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b , or -(CR ^za R ^zb ) _m - G ^a ; p is 0, 1, 2, 3, or 4;R ³ is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, - (CR ^3a R ^3b ) _m -G ^3a , or G ^3a ; G ^3a , at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R ⁴ is alkenyl, alkynyl, haloalkyl, G ^4a , - (CR ^4a R ^4b ) _n -G ^4a , or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R ^la ), 0(R ^la ) and N(R ^la ) ₂ ;each occurrence of R ^la is independently hydrogen, G ¹ , -(CR ^za R ^zb ) _m -G ^a , alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G ^4a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G ^3a and G ^4a , at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of G ¹ , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , - S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,-N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , - N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -G ^a , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , -(CR ^za R ^zb ) _m -OR ^a , - (CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , -(CR ^za R ^zb ) _m -S(O)R ^a , - (CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , -(CR ^za R ^zb ) _m -C(O)OR ^a , - (CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m -N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m - N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;G ^a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , - N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b ,-N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb )m-OR ^a ,-(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb )m-S(O)R ^a ,-(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m - N(R ^a )COOR ^b ,-(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;R ^za , R ^zb , R ^3a , R ^3b , R ^4a , and R ^4b , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; R ^a and R ^b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; and m and n, at each occurrence, are each independently 1, 2, 3, or 4.

Formula 154

[00805] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 154. Such compounds are described in US Patent No. 8,629, 143, issued January 14, 2014, and corresponding to US Application No. US8629143B2 filed November 18, 2010; International Publication No. WO2011066168A1, published June 3, 2011, and corresponding to International Application No.

PCT/US2010/057224 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 154, these references incorporated by reference herein control.

[00806] In an embodiment, the Kv7 channel activator is a compound according to Formula 154: Formula 154 or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, whereinR ¹ is an optional substituent wherein each occurrence of R ¹ is independently G ^:| , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,- N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , -N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb ) _m -OR ^a , -(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb ) _m -S(O)R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b ,-(CR ^za R ^zb ) _m - N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b , or -(CR ^za R ^zb ) _m - G ^a ; p is 0, 1, 2, 3, or 4;R ³ is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, - (CR ^3a R ^3b ) _m -G ^3a , or G ^3a ; G ^3a , at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R ⁴ is alkenyl, alkynyl, haloalkyl, G ^4a , - (CR ^4a R ^4b ) _n -G ^4a , or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R ^la ), 0(R ^la ) and N(R ^la ) ₂ ;each occurrence of R ^la is independently hydrogen, G ^:| , -(CR ^za R ^zb ) _m -G ^a , alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G ^4a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G ^3a and G ^4a , at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of G ^:| , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , - S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,-N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , - N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -G ^a , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , -(CR ^za R ^zb ) _m -OR ^a , - (CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , -(CR ^za R ^zb ) _m -S(O)R ^a , - (CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , -(CR ^za R ^zb ) _m -C(O)OR ^a , - (CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m -N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m - N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;G ^a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , - N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b ,-N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb )m-OR ^a ,-(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb )m-S(O)R ^a ,-(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m - N(R ^a )COOR ^b ,-(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;R ^za , R ^zb , R ^3a , R ^3b , R ^4a , and R ^4b , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; R ^a and R ^b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; and m and n, at each occurrence, are each independently 1, 2, 3, or 4 ; and q is 0, 1, or 2.

Formula 155

[00807] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 155. Such compounds are described in US Patent No. 8,629,143, issued January 14, 2014, and corresponding to US Application No. US8629143B2 filed November 18, 2010; International Publication No. WO2011066168A1, published June 3, 2011, and corresponding to International Application No.

PCT/US2010/057224 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 155, these references incorporated by reference herein control.

[00808] In an embodiment, the Kv7 channel activator is a compound according to Formula 155: or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein R ¹ is an optional substituent wherein each occurrence of R ¹ is independently CP, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,- N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , -N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb ) _m -OR ^a , -(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb ) _m -S(O)R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b ,-(CR ^za R ^zb ) _m - N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b , or -(CR ^za R ^zb ) _m - G ^a ; p is 0, 1, 2, 3, or 4;R ³ is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, - (CR ^3a R ^3b ) _m -G ^3a , or G ^3a ; G ^3a , at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R ⁴ is alkenyl, alkynyl, haloalkyl, G ^4a , - (CR ^4a R ^4b ) _n -G ^4a , or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R ^la ), 0(R ^la ) and N(R ^la ) ₂ ;each occurrence of R ^la is independently hydrogen, G ¹ , -(CR ^za R ^zb ) _m -G ^a , alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G ^4a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G ^3a and G ^4a , at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of G ¹ , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , - S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,-N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , - N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -G ^a , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , -(CR ^za R ^zb ) _m -OR ^a , - (CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , -(CR ^za R ^zb ) _m -S(O)R ^a , - (CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , -(CR ^za R ^zb ) _m -C(O)OR ^a , - (CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m -N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m - N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;G ^a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , - N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b ,-N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb )m-OR ^a ,-(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb )m-S(O)R ^a ,-(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m - N(R ^a )COOR ^b ,-(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;R ^za , R ^zb , R ^3a , R ^3b , R ^4a , and R ^4b , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; R ^a and R ^b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; and m and n, at each occurrence, are each independently 1, 2, 3, or 4 ; and u is 0, 1, 2, or 3. Formula 156

[00809] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 156. Such compounds are described in US Patent No. 8,629,143, issued January 14, 2014, and corresponding to US Application No. US8629143B2 filed November 18, 2010; International Publication No. WO2011066168A1, published June 3, 2011, and corresponding to International Application No.

PCT/US2010/057224 filed November 18, 2010; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 156, these references incorporated by reference herein control.

[00810] In an embodiment, the Kv7 channel activator is a compound according to Formula 156:

Formula 156 or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein R ¹ is an optional substituent wherein each occurrence of R ¹ is independently C , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,- N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , -N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb ) _m -OR ^a , -(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb ) _m -S(O)R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b ,-(CR ^za R ^zb ) _m - N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b , or -(CR ^za R ^zb ) _m - G ^a ; p is 0, 1, 2, 3, or 4;R ³ is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, - (CR ^3a R ^3b ) _m -G ^3a , or G ^3a ; G ^3a , at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R ⁴ is alkenyl, alkynyl, haloalkyl, G ^4a , - (CR ^4a R ^4b ) _n -G ^4a , or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R ^la ), 0(R ^la ) and N(R ^la ) ₂ ;each occurrence of R ^la is independently hydrogen, (P, -(CR ^za R ^zb ) _m -CP, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G ^4a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G ^3a and G ^4a , at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C , alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , - S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b ,-N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b , - N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -G ^a , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , -(CR ^za R ^zb ) _m -OR ^a , - (CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , -(CR ^za R ^zb ) _m -S(O)R ^a , - (CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , -(CR ^za R ^zb ) _m -C(O)OR ^a , - (CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m -N(R ^a )COOR ^b , -(CR ^za R ^zb ) _m - N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;G ^a , at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO ₂ , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -NR ^a R ^b , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , - N(R ^a )COOR ^b , -N(R ^a )CONR ^a R ^b ,-N(R ^a )SO ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -CN, -(CR ^za R ^zb ) _m -NO ₂ , - (CR ^za R ^zb )m-OR ^a ,-(CR ^za R ^zb ) _m -OC(O)R ^a , -(CR ^za R ^zb ) _m -OC(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -SR ^a , - (CR ^za R ^zb )m-S(O)R ^a ,-(CR ^za R ^zb ) _m -S(O) ₂ R ^a , -(CR ^za R ^zb ) _m -S(O) ₂ NR ^a R ^b , -(CR ^za R ^zb ) _m -C(O)R ^a , - (CR ^za R ^zb ) _m -C(O)OR ^a , -(CR ^za R ^zb ) _m -C(O)NR ^a R ^b , -(CR ^za R ^zb ) _m -NR ^a R ^b , -(CR ^za R ^zb ) _m - N(R ^a )COOR ^b ,-(CR ^za R ^zb ) _m -N(R ^a )CONR ^a R ^b , and -(CR ^za R ^zb ) _m -N(R ^a )SO ₂ NR ^a R ^b ;R ^za , R ^zb , R ^3a , R ^3b , R ^4a , and R ^4b , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; R ^a and R ^b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; and m and n, at each occurrence, are each independently 1, 2, 3, or 4 ; v is 1, 2, or 3; and y is absent, a bond, -CH ₂ -, or -CH ₂ CH ₂ -.

Formula 157

[00811] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 157. Such compounds are described in US Publication No. US20110257146A1, published October 20, 2011, and corresponding to US Application No. 12/223, 136 filed January 25, 2007; International Publication No. W02007087424A2, published August 2, 2007, and corresponding to International Application No. PCT/US2007/002116 filed January 26, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 157, these references incorporated by reference herein control. [00812] In an embodiment, the Kv7 channel activator is a compound according to Formula 157:

Formula 157

[00813] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-5,7-Diiodo-8-hydroxyquinoline and zinc-8-Hydroxyquinoline.

[00814] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-pyrrolidine dithiocarbamate, zinc-diethyldithiocarbamate, zinc-di sulfiram and zinc-dimethyldithiocarbamate.

[00815] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-vitamin E and zinc-vitamin A.

Formula 158

[00816] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 158. Such compounds are described in US Publication No. US20110257146A1, published October 20, 2011, and corresponding to US Application No. 12/223,136 filed January 25, 2007; International Publication No. W02007087424A2, published August 2, 2007, and corresponding to International Application No. PCT/US2007/002116 filed January 26, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 158, these references incorporated by reference herein control.

[00817] In an embodiment, the Kv7 channel activator is a compound according to Formula 158: Formula 158 wherein, A is a bond, CH ₂ , CHR _b , CH ₂ S, CHR _b S, CH ₂ O, CH ₂ NRc, or NH; Rb is alkyl; Re is H or S(O) _m -aryl; Ri is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted cycloalkyl, or an optionally substituted heteroaryl; R ₂ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, an optionally substituted cycloalkyl, an optionally substituted heteroaryl, an optionally substituted heterocyclic, an optionally substituted aralkyl,

H or alkyl; each Rd and Re is independently an optionally substituted alkyl, an optionally substituted aryl, or Rd and Re together form an optionally substituted cycloalkyl; and m is 0, 1, or 2.

Formula 159

[00818] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 159. Such compounds are described in US Publication No. US20110257146A1, published October 20, 2011, and corresponding to US Application No. 12/223,136 filed January 25, 2007; International Publication No. W02007087424A2, published August 2, 2007, and corresponding to International Application No. PCT/US2007/002116 filed January 26, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 159, these references incorporated by reference herein control.

[00819] In an embodiment, the Kv7 channel activator is a compound according to Formula 159:

Formula 159 wherein, RUs H, an optionally substituted alkyl, an optionally substituted alkenyl, alkynyl, allyl, or an optionally substituted aryl; Rs is H, hal, or hydroxyl; Re is H, hal, hydroxyl, NH2, a mono- or di-substituted amine, or an optionally substituted alkoxy; R? is H, hal, hydroxyl, an optionally substituted alkoxy, or nitro; X is S or NRa; Y is O, S, or NRa; and each Ra is independently H or an optionally substituted aryl.

[00820] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-Benzo[g]quinolin-4-yl-N'-(2-diethylamino-ethyl)-benzene-l, 4-diamine; 2- [2-(3,4-Dihydroxy-phenyl)-2-oxo-ethylsulfanyl]-4,6-dimethyl- nicotinonitrile; 2-[2-(4- Methoxy-phenyl)-2-oxo-ethylsulfanyl]-4-(5-methyl-furan-2-yl) -5,6,7,8-tetrahydro-quinoline- 3 -carbonitrile; 6-Methyl-4-(5-methyl-furan-2-yl)-2-(2-oxo-2-phenyl-ethylsulf anyl)- nicotinonitrile; 2-(2-Oxo-2-thiophen-2-yl-ethylsulfanyl)-4-pyridin-4-yl-5,6,7 ,8-tetrahydro- quinoline-3 -carbonitrile; 2-(3,5-Diiodo-2-methoxy-phenyl)-2,3,5,6,7,8-hexahydro-lH- benzo[4, 5]thieno[2,3 -d]pyrimidin-4-one; 2,2,2-Trifluoro- 1 -[ 1 -(2,2,2-trifluoro- 1 -hydroxy- 1 - trifluoromethyl-ethyl)-lH-pyrrol-2-yl]-ethanone; l,5-Diphenyl-lH-pyrazole-3-carboxylic acid tert-butyl ami de; 3-(4-Bromo-phenyl)-5-(3-phenyl-allylidene)-dihydro-pyrimidin e-2,4- dione; 2-Amino-7-hydroxy-6-[(2-iodo-phenylimino)-methyl]-4-phenyl-4 H-chromene-3- carbonitrile; 3-(lH-Benzoimidazol-2-yl)-6-nitro-chromen-2-ylideneamine; 6-Methoxy-3-(4- nitro-phenyl)-chroman-2-one; 2-(Benzo[l,2,5]thiadiazol-4-yliminomethyl)- benzo[b]thiophen-3-ol; 4-[3-(4-Bromo-phenyl)-3-oxo-propenylamino]-N-(4,6-dimethyl- pyrimidin-2-yl)-benzenesulfonamide; 2-[(5-Nitro-furan-2-ylmethylene)-amino]-benzamide; 2-Benzo[4,5]imidazo[l,2-c]quinazolin-6-yl-phenylamine; Dimethyl-phenyl)-5-(3-phenyl- allylidene)-pyrimidine-2, 4, 6-trione; 4-(4-Cyclohexyl-phenyl)-thiazol-2-ylamine; or 4-(4- Cy cl ohexy 1 -pheny 1 ) - thi azol -2-y 1 amine .

Formula 160

[00821] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 160. Such compounds are described in International Publication No. W02004060880A1, published July 22, 2004, and corresponding to International Application No. PCT/US2003/039352 filed December 11, 2003; US Patent No. 6,933,308, issued August 23, 2005, and corresponding to US Application No. 10/730,781 filed December 9, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 160, these references incorporated by reference herein control.

[00822] In an embodiment, the Kv7 channel activator is a compound according to Formula 160:

Formula 160 wherein, Ri is Cnealk lkyl, — (CH2)2-4N(Cnealkyl)2,

— (CH2)2-4OCi-ealkyl, hydrogen, Cnealkyl, or — (CH2)2-4OCi-6alkyl; or where R ¹ and R ² taken together are — CH2CH2XCH2CH2 — , where X is a chemical bond, CH2, CHOH, NH, NCH3, NCOCH3, O, or S; R ³ is hydrogen or hydroxy, provided that where R ³ is hydroxy, m is not 0; R ⁴ is hydrogen, Ci-ealkyl, hydroxymethyl, or trifluoromethyl; R ⁵ is halogen, Ci-ealkyl, Ci-2perfluoroalkyl, Ci-ealkoxy, Ci-2perfluoroalkoxy, — N(R ⁴ ) ₂ , N-morpholinyl, or pyridyl; R ⁶ is hydrogen, halogen, or Ci-ealkoxy; m is 0 or 1. [00823] In further embodiments, R ³ is hydrogen and m is 1.

[00824] In further embodiments, R ⁴ is methyl.

[00825] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-[2-(4-morpholinyl)ethyl]-N-[l-[3-(3-pyridinyl)phenyl]ethyl ]-4- (trifluoromethyl)-5-thiazolecarboxamide; N-[l-[3-(dimethylamino)phenyl]ethyl]-2-[2-(l- pyrrolidinyl)ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamid e; 2-[2-(l-pyrrolidinyl)ethyl]-4- (trifluoromethyl)-N-[l-[3-(trifluoromethyl)phenyl]ethyl]-5-t hiazolecarboxamide; 2-[2-[(2- furanylmethyl)methylamino]ethyl]-N-[(lS)-l-[3-(4-morpholinyl )phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[(2-furanylmethyl)methylamino]ethyl]-N-[l- [3-(3-pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazole carboxamide; 2-[2-(l- pyrrolidinyl)ethyl]-N-[l-[3-(trifluoromethoxy)phenyl]ethyl]- 4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-[(2-furanylmethyl)methylamino]ethyl]-N-[l-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazo lecarboxamide; 2-[2- (diethylamino)ethyl]-N-[l-[3-(trifluoromethoxy)phenyl]ethyl] -4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(diethylamino)ethyl]-N-[l-[3-(dimethylamino)phenyl]ethy l]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[ethyl(4-pyridinylmethyl)amino]ethyl]-4- (trifluoromethyl)-N-[l-[3-(trifluoromethyl)phenyl]ethyl]-5-t hiazolecarboxamide; 2-[2-(4- thiomorpholinyl)ethyl]-4-(trifluoromethyl)-N-[l-[3-(trifluor omethyl)phenyl]ethyl]-5- thiazolecarboxamide; 2-[2-[[2-(dimethylamino)ethyl]methylamino]ethyl]-N-[l-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazo lecarboxamide; 2-[2-[[2- (dimethylamino)ethyl]methylamino]ethyl]-4-(trifluoromethyl)- N-[l-[3-

(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-(4-methyl-l-piperazinyl)ethyl]- N-[l-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)- 5-thiazolecarboxamide; 2-[2-(l- piperidinyl)ethyl]-N-[l-[3-(trifluoromethoxy)phenyl]ethyl]-4 -(trifluoromethyl)-5- thiazolecarboxamide; N-[l-[3-(dimethylamino)phenyl]ethyl]-2-[2-(l-piperidinyl)eth yl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(l-piperidinyl)ethyl]-4-(trifluoromethyl)-N-[l- [3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; N-[(lS)-l-[3-(4- morpholinyl)phenyl]ethyl]-2-[2-(l-piperidinyl)ethyl]-4-(trif luoromethyl)-5- thiazolecarboxamide; 2-[2-(4-hydroxy-l-piperidinyl)ethyl]-N-[l-[3- (trifluoromethoxy )phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(4- hydroxy-l-piperidinyl)ethyl]-4-(trifluoromethyl)-N-[l-[3-(tr ifluoromethyl)phenyl]ethyl]-5- thiazolecarboxamide; 2-[2-[(cyclopropylmethyl)propylamino]ethyl]-N-[l-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazo lecarboxamide; 2-[2- [(cyclopropylmethyl)propylamino]ethyl]-N-[l-[3-(dimethylamin o)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[(cyclopropylmethyl)propylamino]ethyl]-4- (trifluoromethyl)-N-[l-[3-(trifluoromethyl)phenyl]ethyl]-5-t hiazolecarboxamide; 2-[2- (diethylamino)ethyl]-N-[(lS)-l-[3-(3-pyridinyl)phenyl]ethyl] -4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(l-piperidinyl)ethyl]-N-[(lS)-l-[3-(3-pyridinyl)phenyl] ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[(l-ethylpropyl)amino]ethyl]-N-[l-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazo lecarboxamide; 2-[2-[(l- ethylpropyl)amino]ethyl]-4-(trifluoromethyl)-N-[l-[3-(triflu oromethyl)phenyl]ethyl]-5- thiazolecarboxamide; 2-[2-[(2-furanylmethyl)amino]ethyl]-N-[(lS)-l-[3-(3- pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarbox amide; 2-[2- (cyclopentylamino)ethyl]-N-[l-[3-(trifluoromethoxy)phenyl]et hyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(cyclopentylamino)ethyl]-N-[(lS)-l-[3-(3- pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarbox amide; 2-[2-[bis(2- methoxyethyl)amino]ethyl]-N-[l-[3-(trifluoromethoxy)phenyl]e thyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-[bis(2-methoxyethyl)amino]ethyl]-4-(trifluoromethyl)-N- [l-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-[bis(2- methoxyethyl)amino]ethyl]-N-[(lS)-l-[3-(3-pyridinyl)phenyl]e thyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(4-morpholinyl)ethyl]-N-[(lS)-l-[3-(4-morpholinyl)pheny l]ethyl]- 4-(trifluoromethyl)-5-thiazolecarboxamide; N-[l-[3-(dimethylamino)phenyl]ethyl]-2-[2-(4- thiomorpholinyl)ethyl]-4-(trifluoromethyl)-5-thiazolecarboxa mide; 2-[2-[[2- (dimethylamino)ethyl]methylamino]ethyl]-N-[l-[3-(dimethylami no)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; and 2-[2-(4-methyl-l-piperazinyl)ethyl]-N-[(l S)-l- [3-(4-morpholinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thi azolecarboxamide.

[00826] In further embodiments, R ³ is hydroxy and m is 1.

[00827] In further embodiments, R ⁴ is methyl.

[00828] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-[l-hydroxy-2-(l-piperidinyl)ethyl]-N-[l-[3-(trifluorometho xy)phenyl]ethyl]- 4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[l -hydroxy -2-(l -pyrrolidinyl)ethyl]-4- (trifluoromethyl)-N-[l-[3-(trifluoromethyl)phenyl]ethyl]-5-t hiazolecarboxamide; 2-[2-[(2- furanylmethyl)methylamino]- 1 -hydroxy ethyl]-4-(trifluoromethyl)-N-[ 1 -[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2- [(cyclopropylmethyl)propylamino]- 1 -hydroxyethyl]-N-[ 1 - [3 - (trifluoromethoxy )phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2- (diethylamino)-l-hydroxyethyl]-N-[(lS)-l-[3-(4-morpholinyl)p henyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(diethylamino)-l-hydroxyethyl]-N-[(lS)-l-[3- (3-pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecar boxamide; 2-[l-hydroxy-2-(4- morpholinyl)ethyl]-N-[l-[3-(trifluoromethoxy)phenyl]ethyl]-4 -(trifluoromethyl)-5- thiazolecarboxamide; 2-[l-hydroxy-2-(4-morpholinyl)ethyl]-4-(trifluoromethyl)-N-[ l-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[l-hydroxy-2-(4-methyl-l- piperazinyl)ethyl]-4-(trifluoromethyl)-N-[l-[3-(trifluoromet hyl)phenyl]ethyl]-5- thi azolecarboxamide; 2-[ 1 -hydroxy-2-(4-methyl- 1 -piperazinyl)ethyl]-N-[( 1 S)- 1 -[3 -(4- morpholinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarb oxamide; 2-[l-hydroxy-2-(4- methyl-l-piperazinyl)ethyl]-N-[(lS)-l-[3-(3-pyridinyl)phenyl ]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[l-hydroxy-2-(l-piperidinyl)ethyl]-4-(trifluoromethyl)-N-[ l-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[l-hydroxy-2-(l- pyrrolidinyl)ethyl]-N-[l-[3-(trifluoromethoxy)phenyl]ethyl]- 4-(trifluoromethyl)-5- thiazolecarboxamide; N-[ 1 -[3 -(dimethylamino)phenyl]ethyl]-2-[ 1 -hydroxy-2-(l - pyrrolidinyl)ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamid e; 2-[l-hydroxy-2-(l- pyrrolidinyl)ethyl]-N-[(lS)-l-[3-(4-morpholinyl)phenyl]ethyl ]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-[(cyclopropylmethyl)propylamino]-l -hydroxy ethyl]-4- (trifluoromethyl)-N-[l-[3-(trifluoromethyl)phenyl]ethyl]-5-t hiazolecarboxamide; and 2-[2-(4- acetyl-l-piperazinyl)-l-hydroxyethyl]-4-(trifluoromethyl)-N- [l-[3- (tri fluor omethy l)pheny 1 ] ethyl ] -5 -thi azol ecarb oxami de .

[00829] In further embodiments, the compound has a stereochemical configuration according to the formula: [00830] In further embodiments, the compound is according to the formula: , , r

— (CH2)2-4OCi-ealkyl; or where R ¹ and R ² taken together are — CH2CH2XCH2CH2 — , where X is a chemical bond, CH2, CHOH, NH, NCH3, NCOCH3, O, or S; R ³ is hydrogen or hydroxy, provided that where R ³ is hydroxy, m is not 0; R ⁴ is hydrogen, Ci-ealkyl, hydroxymethyl, or trifluoromethyl; R ⁵ is halogen, Ci-ealkyl, Ci-2perfluoroalkyl, Cnealkoxy, Ci-2perfluoroalkoxy, — N(R ⁴ )2, N-morpholinyl, or pyridyl; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.

Formula 161

[00832] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 161. Such compounds are described in US Patent No. 7,144,881 issued December 5, 2006, and corresponding to US Application No.

10/919,184 filed November 21, 2003; International Publication No. W02004047738A2, published June 10, 2004, and corresponding to International Application No.

PCT/US2003/037305 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 161, these references incorporated by reference herein control.

[00833] In an embodiment, the Kv7 channel activator is a compound according to Formula 161 :

Formula 161 wherein, R is C1-4 alkyl, CF3 or hydroxymethyl; R ¹ and R ² are each independently hydrogen, C1-4 alkyl, halogen or morpholin-4-yl; R ⁴ is selected from the group consisting of optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent is independently selected from the group consisting of Ci-4alkyl, dimethylamino, hydroxymethyl, chloro and fluoro; R ⁵ is hydrogen or fluoro; or R ⁴ and R ⁵ taken together are — CH=CH — CH=CH — or — CH2CH2O — ; and R ³ , R ⁶ and R ⁷ are each independently selected from hydrogen or fluoro.

Formula 162

[00834] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 162. Such compounds are described in US Patent No. 7,144,881 issued December 5, 2006, and corresponding to US Application No.

10/919,184 filed November 21, 2003; International Publication No. W02004047738A2, published June 10, 2004, and corresponding to International Application No.

PCT/US2003/037305 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 162, these references incorporated by reference herein control.

[00835] In an embodiment, the Kv7 channel activator is a compound according to Formula 162:

Formula 162 wherein, R is methyl or hydroxymethyl; R ¹ and R ² are each independently hydrogen, Ci- 4 alkyl, halogen or morpholin-4-yl; R ⁴ is selected from the group consisting of optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl, in which said substituent is independently selected from the group consisting of Ci-4alkyl, dimethylamino, hydroxymethyl, chloro and fluoro; R ⁵ is hydrogen or fluoro; or R ⁴ and R ⁵ taken together are — CH=CH — CH=CH — or — CH2CH2O — ; and R ³ , R ⁶ and R ⁷ are each independently selected from hydrogen or fluoro.

[00836] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid[l-(2,3-dihydro-benzofuran-5- yl)-ethyl]-amide; 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid[l-(2,3-dihydro- benzofuran-5-yl)-ethyl]-amide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid[l-(2,3- dihydro-benzofuran-5-yl)-ethyl]-amide; 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid(2- hydroxy-1 -naphthal en-2-yl-ethyl)-amide; 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid(2-hydroxy-l -naphthal en-2-yl-ethyl)-amide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid(2-hydroxy-l -naphthal en-2-yl-ethyl)-amide; 2-(2,5-difluoro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy- 1 -naphthal en-2-yl-ethyl)-amide; 2-(2-fluoro- phenyl)-cyclopropanecarboxylic acid[l-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy- ethyl]-amide; 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid[l-(4-fluoro-3-morpholin-4- yl-phenyl)-2-hydroxy-ethyl]-amide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid[l-(4- fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide; 2-(2,5-difluoro-phenyl)- cyclopropanecarboxylic acid[l-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-a mide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid(l -naphthal en-2-yl-ethyl)-amide; 2-(2,5- difluoro-phenyl)-cyclopropanecarboxylic acid(l -naphthal en-2-yl-ethyl)-amide; 2-(4-fluoro- phenyl)-cyclopropanecarboxylic acid{l-[3-(3-dimethylamino-pyrrolidin-l-yl)-phenyl]- ethyll } -amide; 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid{ l-[3-(3-dimethylamino- pyrrolidin- 1 -yl)-phenyl]-ethyl } -amide; 2-(3 -fluoro-phenyl)-cyclopropanecarboxylic acid[ 1 - (3-pyridin-3-yl-phenyl)-ethyl]-amide; 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid[l-(3-pyridin-3-yl-phenyl)-ethyl]-amide; (S)-2-phenyl-cyclopropanecarboxylic acid[l-(3- pyridin-3-yl-phenyl)-ethyl]-amide; (S)-2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid{ 1- [3-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; (S)-2-phenyl-cyclopropanecarboxylic acid{ l-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; and (S)-2-(2-fluoro-phenyl)- cyclopropanecarboxylic acid{l-[3-(2-fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; or a pharmaceutically acceptable salt thereof.

Formula 163

[00837] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 163. Such compounds are described in International Publication No. W02004047743A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037348 filed November 21, 2003; US Patent No. 7,045,551 issued May 16, 2006, and corresponding to US Application No. 10/719,465 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 163, these references incorporated by reference herein control.

[00838] In an embodiment, the Kv7 channel activator is a compound according to Formula 163:

wherein, R ¹ is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, furanyl, C3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; A is — CH=CH — or — (CH2) _n — ; R ² is hydrogen or hydroxymethyl; n is an integer of 0, 1 or 2; R ⁴ is selected from the group consisting of di(Cn 4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, morpholin-4- ylmethyl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents in which said substituent is independently selected from the group consisting of C1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R5 is hydrogen or fluoro; or R ⁴ and R ⁵ taken together is — CH=CH — CH=CH — optionally substituted with a substituent independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, trifluoromethyl and trifluoromethoxy; and R ³ , R ⁶ , and R ⁷ are each independently hydrogen or fluoro.

Formula 164

[00839] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 164. Such compounds are described in International Publication No. W02004047743A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037348 filed November 21, 2003; US Patent No. 7,045,551 issued May 16, 2006, and corresponding to US Application No. 10/719,465 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 164, these references incorporated by reference herein control.

[00840] In an embodiment, the Kv7 channel activator is a compound according to Formula 164: Formula 164 wherein, R ¹ is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, furanyl, C3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; A is — CH=CH — or — (CH2) _n — ; R ² is hydrogen; n is an integer of 0, 1 or 2; R ⁴ is selected from the group consisting of di(Ci-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, morpholin-4-ylmethyl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents in which said substituent is independently selected from the group consisting of C1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R ⁵ hydrogen or fluoro; or R ⁴ and R ⁵ taken together is — CH=CH — CH=CH — optionally substituted with a substituent independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, trifluoromethyl and trifluoromethoxy; and R ³ , R ⁶ , and R ⁷ are each independently hydrogen or fluoro.

[00841] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: (R)-N-[2-hydroxy-l-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl -propionamide; (R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-l-(3-morpholin-4-yl-phe nyl)-ethyl]-acrylamide; (R)- 3-(3-fluoro-phenyl)-N-[2-hydroxy-l-(3-morpholin-4-yl-phenyl) -ethyl]-acrylamide; (R)-3- (2,4-difluoro-phenyl)-N-[2-hydroxy-l-(3-morpholin-4-yl-pheny l)-ethyl]-acrylamide; (R)-N- [l-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(2- fluoro-phenyl)-acrylamide (R)- N-[l-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-( 3-fluoro-phenyl)-acrylamide (R)-N-[l-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl] -3-(4-fluoro-phenyl)- acrylamide (R)-3-(2,4-difluoro-phenyl)-N-[l-(4-fluoro-3-morpholin-4-yl- phenyl)-2-hydroxy- ethyl]-acrylamide (R)-3 -(3 -fluoro-phenyl)-N-(2-hydroxy-l -naphthal en-2-yl-ethyl)- acrylamide; (R)-3-(4-fluoro-phenyl)-N-(2-hydroxy-l -naphthal en-2-yl-ethyl)-acrylamide; (R)- 3 -(2,4-difluoro-phenyl)-N-(2-hydroxy-l -naphthal en-2-yl-ethyl)-acrylamide; (R)-3-(3,4- difluoro-phenyl)-N-(2-hydroxy- 1 -naphthal en-2-yl-ethyl)-acrylamide; (R)-4-fluoro-N-(2- hydroxy-1 -naphthal en-2-yl-ethyl)-benzamide; (R)-2,3-difluoro-N-(2-hydroxy-l-naphthalen- 2-yl-ethyl)-benzamide; (R)-2,4-difluoro-N-(2-hydroxy-l -naphthal en-2-yl-ethyl)-benzamide; (R)-3,4-difluoro-N-(2-hydroxy-l -naphthal en-2-yl-ethyl)-benzamide; (R)-2-(2,4-difluoro- phenyl)-N-(2-hydroxy-l -naphthal en-2-yl-ethyl)-acetamide; (R)-3-(2-fluoro-phenyl)-N-(2- hydroxy-1 -naphthal en-2-yl-ethyl)-propionamide; (R)-3-(3-fluoro-phenyl)-N-(2-hydroxy-l- naphthalen-2-yl-ethyl)-propionamide; (R)-3-(4-fluoro-phenyl)-N-(2-hydroxy-l -naphthal en-2- yl-ethyl)-propionamide; (R)-3 -(2, 4-difluoro-phenyl)-N-(2 -hydroxy- l-naphthalen-2 -yl-ethyl)- propionamide; (R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-l-(7-methoxy-naphthalen -2-yl)-ethyl]- acrylamide; (R)-3-(3-fluoro-phenyl)-N-[2-hydroxy-l-(7-methoxy-naphthalen -2-yl)-ethyl]- acrylamide; (R)-3-(4-fluoro-phenyl)-N-[2-hydroxy-l-(7-methoxy-naphthalen -2-yl)-ethyl]- acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-[2-hydroxy-l-(7-methoxy-naphth alen-2-yl)- ethyl]-acrylamide; (1R, 2S)-N-(2,3-dihydroxy-l-naphthalen-2-yl-propyl)-3-(2-fluoro- phenyl)-acrylamide; (1R, 2S)-3-(2,4-difluoro-phenyl)-N-(2,3-dihydroxy-l-naphthalen-2- yl- propyl)-acrylamide; (1R, 2S)-3-(3,4-difluoro-phenyl)-N-(2,3-dihydroxy-l-naphthalen-2- yl- propyl)-acrylamide; and (1R, 2S)-3-(3,5-difluoro-phenyl)-N-(2,3-dihydroxy-l-naphthalen-2- yl-propyl)-acrylamide; or a pharmaceutically acceptable salt thereof.

Formula 165

[00842] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 165. Such compounds are described in US Patent No. 7,135,472 issued November 14, 2006, and corresponding to US Application No. 10/719,187 filed November 21, 2003; International Publication No. W02004047744A2, published June 10, 2004, and corresponding to International Application No.

PCT/US2003/037349 filed November 21, 2003; US Patent No. 7,135,472 issued November 14, 2006, and Patent Cooperation Treaty application No. US2003/037349 published June 10, 2004, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 165, these references incorporated by reference herein control.

[00843] In an embodiment, the Kv7 channel activator is a compound according to Formula 165: Formula 165 wherein, R ¹ is selected from the group consisting of straight or branched chain C _x _6 alkyl optionally substituted with amino, C alkylamino or di(Ci,4 alkyl) amino, pyridinyl, pyrrodidinyl, piperidinyl, 2-thienyl, furanyl, imidazolyl, indenyl, benzofuran, C3.6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, CM alkyl, C alkoxy, trifluoromethyl, and trifiuoromethoxy; A is - CH=CH-, 1,1 -cyclopropyl, or-(CH2) _n -; R ² is CM alkyl, CF3 or hydroxymethyl; R ³ , R ⁴ , R ⁵ and R ⁶ each are independently hydrogen or fluoro; n is an integer of 0 to 4, inclusive; Het is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and triazolyl optionally substituted with substituents independently selected from the group consisting of CM alkyl, halogen, amino and dimethylaminomethyl; provided that when Het is pyridinyl, pyrimidinyl or pyrazinyl, then A is not -CH=CH-.

Formula 166

[00844] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 166. Such compounds are described in US Patent No. 7,135,472, issued November 14, 2006, and corresponding to US Application No. 10/719,187 filed November 21, 2003; International Publication No. W02004047744A2, published June 10, 2004, and corresponding to International Application No. PCT/US2003/037349 filed November 21, 2003; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 166, these references incorporated by reference herein control.

[00845] In an embodiment, the Kv7 channel activator is a compound according to Formula 166: Formula 166 wherein, R ¹ is selected from the group consisting of straight or branched chain Ci-6 alkyl optionally substituted with amino, C1-4 alkylamino or di(Ci-4 alkyl) amino, pyridinyl, pyrrodidinyl, piperidinyl, 2-thienyl, furanyl, imidazolyl, indenyl, benzofuran, C3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, and trifluoromethoxy; A is — CH=CH — , 1,1 -cyclopropyl, or — (CH2) _n — ; R ² is methyl or hydroxymethyl; R ³ , R ⁴ , R ⁵ and R ⁶ each are independently hydrogen or fluoro; n is an integer of 0 to 4, inclusive; Het is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and triazolyl optionally substituted with substituents independently selected from the group consisting of C1-4 alkyl, halogen, amino and dimethylaminomethyl; provided that when Het is pyridinyl, pyrimidinyl or pyrazinyl, then A is not — CH=CH— .

[00846] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: (S)-3 -(2-fluoro-phenyl)-N-[ 1 -(3 -[ 1 ,2,4]triazol- 1 -yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro-phenyl)-N-[l-(3-thiazol-2-yl-phenyl)-ethyl]- acrylamide; (S)-3-(2-fluoro- phenyl)-N-[l-(3-pyrazol-l-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro-phenyl)-N-[l-(3- imidazol-l-yl-phenyl)-ethyl]-acrylamide; (S)-4-phenyl-N-[l-(3-pyridin-3-yl-phenyl)-ethyl]- butyramide; (S)-N-[l-(3-pyridin-3-yl-phenyl)-ethyl]-benzamide; (S)-lH-imidazole-4- carboxylic acid [l-(3-pyridin-3-yl-phenyl)-ethyl]-amide; (S)-N-[l-(3-imidazol-l-yl-phenyl)- ethyl]-3-phenyl-acrylamide; (S)-N-[l-(3-oxazol-5-yl-phenyl)-ethyl]-3-phenyl-acrylamide; (S)-3-phenyl-N-[l-(3-thiazol-2-yl-phenyl)-ethyl]-acrylamide; (S)-3-phenyl-N-[l-(3-pyrazol- l-yl-phenyl)-ethyl]-acrylamide; and (S)-benzofuran-2-carboxylic acid {l-[3-(6-fluoro- pyridin-3-yl)-phenyl]-ethyl}-amide; or a pharmaceutically acceptable salt thereof.

Formula 167

[00847] In an embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 167. Such compounds are described in International Publication No. W02002096858A1, published December 5, 2002, and corresponding to International Application No. PCT/US2002/017049 filed May 31, 2002; US Patent No. 6,831,080, issued December 14, 2004, and corresponding to US Application No. 10/160,582 filed May 31, 2002; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 167, these references incorporated by reference herein control.

[00848] In an embodiment, the Kv7 channel activator is a compound according to Formula 167:

Formula 167 wherein, R is Ci-4 alkyl or trifluoromethyl; R ¹ is selected from the group consisting of pyridinyl, quinolinyl, thienyl, furanyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, chromanyl, indanyl, biphenylyl, phenyl and substituted phenyl, in which said substituted phenyl is substituted with substituent independently selected from the group consisting of halogen, Cn 4 alkyl, Ci-4 alkoxy, trifluoromethyl, trifluorom ethoxy and nitro; R ² and R ³ are each independently selected from the group consisting of hydrogen, Ci-4 alkyl and halogen; R ⁴ is selected from the group consisting of di(Ci-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents in which said substituent is independently selected from the group consisting of Ci-4alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R ⁵ is hydrogen, chloro or fluoro; or R ⁴ and R ⁵ taken together are — CH=CH — CH=CH — or — X(CH2) _m Y — in which X and Y are each independently selected from the group consisting of QU, (CH2) _n N(R ⁹ ) — and O, wherein m is 1 or 2; n is 0 or 1; R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, chloro and fluoro; and R ⁹ is selected from the group consisting of hydrogen, Cn 4 alkyl, hydroxyethyl, Ci-4 alkoxyethyl, cyclopropylmethyl, — CO2(Ci-4alkyl), and — CH2CH2NR ¹⁰ R ¹¹ in which R ¹⁰ and R ¹¹ are each independently hydrogen or Ci-4 alkyl.

Formula 168 [00849] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 168. Such compounds are described in International Publication No. W02002096858A1, published December 5, 2002, and corresponding to International Application No. PCT/US2002/017049 filed May 31, 2002; US Patent No. 6,831,080 issued December 14, 2004, and corresponding to US Application No. 10/160,582 filed May 31, 2002; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 168, these references incorporated by reference herein control.

[00850] In an embodiment, the Kv7 channel activator is a compound according to Formula 168:

Formula 168 wherein, R ¹ is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, benzodi oxanyl, l,3-benzodioxol-5-yl, chroman-5-yl, indan-5-yl, 4-biphenylyl, phenyl and substituted phenyl, in which said substituted phenyl is substituted with substituent independently selected from the group consisting of halogen, C1-4 alkyl, C -4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R ⁴ is selected from the group consisting of optionally substituted di(Ci-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents in which said substituent is independently selected from the group consisting of Ci-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R ⁵ is hydrogen or fluoro; or R ⁴ and R ⁵ taken together are — CH=CH — CH=CH — or — X(CH2) _m Y — , in which X and Y are each independently selected from the group consisting of CH2, (CH2) _n N(R ⁹ ) — and O, wherein m is 1 or 2; n is 0 or 1; R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, chloro and fluoro; and R ⁹ is selected from the group consisting of hydrogen, C1-4 alkyl, hydroxyethyl, C1-4 alkoxyethyl, cyclopropylmethyl, — CO2(Ci-4alkyl), and — CH2CH2NR ¹⁰ R ⁿ in which R ¹⁰ and R ¹¹ are each independently hydrogen or C1-4 alkyl.

[00851] In further embodiments, R ¹ is substituted phenyl or l,3-benzodioxol-5-yl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C1-4 alkyl, and C1-4 alkoxy; and R ⁴ and R ⁵ taken together are — X(CH2) _m Y — in which X and Y are each O, and m is 1.

[00852] In further embodiments, R ¹ is selected from the group consisting of substituted phenyl, l,3-benzodioxol-5-yl, and indan-5-yl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 alkoxy, trifluoromethoxy and trifluoromethyl; and R ⁴ and R ⁵ taken together are — X(CH2) _m Y — in which X is CH2, Y is O, and m is 1.

[00853] In further embodiments, R ¹ is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy, trifluoromethyl and nitro; R ⁴ is optionally substituted morpholin-4-yl with one or two substituents each independently selected from the group consisting of C1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; and R ⁵ is hydrogen or fluoro.

[00854] In further embodiments, R ¹ is phenyl, fluorophenyl or difluorophenyl.

[00855] In further embodiments, R ¹ is substituted phenyl or l,3-benzodioxol-5-yl in which said substituted phenyl is substituted with one or two substituents each independently selected from halogen or C1-4 alkyl; and R ⁴ and R ⁵ taken together are — X(CH2) _m Y — in which X and Y are O, and m is 2.

[00856] In further embodiments, R ¹ is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from halogen or C1-4 alkyl; R ⁴ and R ⁵ taken together are — X(CH2) _m Y — in which X is (CH2) _n N(R ⁹ ) — ; Y is CH2, and m and n are 1; and R ⁹ is CO2(Ci-4alkyl).

[00857] In further embodiments, R ¹ is substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from halogen; R ⁴ and R ⁵ taken together are — X(CH2) _m Y — in which X is (CH2) _n N(R ⁹ ) — and Y is O wherein m is 2 and n is 0; and R ⁹ is hydrogen, cyclopropylmethyl or Ci-4alkyl.

[00858] In further embodiments, R ¹ is 3-quinolinyl or pyridinyl; R ⁴ is trifluoromethoxy; and R ⁵ is hydrogen.

[00859] In further embodiments, R ¹ is substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen or Ci-4alkyl; R ⁴ and R ⁵ taken together are — X(CH2) _m Y — , in which X is CH2 and Y is (CH2) _n N(R ⁹ ) — wherein m is 1 and n is 0; and R ⁹ is CO2(Ci-4alkyl).

[00860] In further embodiments, R ¹ is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R ⁴ and R ⁵ taken together are — X(CH2) _m Y — , in which X is (CH2) _n N(R ⁹ ) — and Y is CH2 wherein m is 2 and n is 0; and R ⁹ is hydrogen, Ci-4alkyl, acetyl, hydroxyethyl or methoxyethyl.

[00861] In further embodiments, R ¹ is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R ⁴ and R ⁵ taken together are — X(CH2) _n Y — , in which X is CH2 and Y is (CH2) _n N(R ⁹ ) — wherein m is 2 and n is 0; and R ⁹ is hydrogen, Ci-4alkyl, acetyl, hydroxyethyl or methoxyethyl.

[00862] In further embodiments, R ¹ is pyridinyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R ⁴ is optionally substituted pyridinyl with one or two substituents each independently selected from C1-4 alkyl and halogen; and R ⁵ is hydrogen or fluoro.

[00863] In further embodiments, R ¹ is l,3-benzodioxol-5-yl; R ⁴ is di(Ci-4alkyl)amino; and R ⁵ is hydrogen or fluoro.

[00864] In further embodiments, R ¹ is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R ⁴ is pyrimidinyl; and R ⁵ is hydrogen or fluoro.

[00865] In further embodiments, R ¹ is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R ⁴ is pyrazinyl; and R ⁵ is hydrogen or fluoro.

[00866] In further embodiments, R ¹ is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from Ci-4alkyl and halogen; R ⁴ is piperazinyl or 4-methylpiperazinyl; and R ⁵ is hydrogen or fluoro.

[00867] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-Methyl-3-phenyl-but-2-enoic acid (1 -naphthal en-2-ylethyl)-amide; N-(l- Benzo[l,3]dioxol-5-yl-ethyl)-3-(3-methoxy-phenyl)-acrylamide ; N-[l-(2,3- Dihydrobenzofuran-5-yl)ethyl]-3-(3-methoxyphenyl)-acrylamide ; (S)-3-Phenyl-N-[l-(3- morpholin-4-yl-phenyl)ethyl]acrylamide; 3-(3-Fluorophenyl)-N-[l-(2,3- dihydrobenzo[l,4]dioxin-6-yl)-ethyl]acrylamide; (±)-7-{ l-[3-(4- Fluorophenyl)acryloylamino]ethyl}-3,4-dihydro-lH-isoquinolin e-2-carboxylic acid methyl ester; 3-(2-Fluorophenyl)-N-[l-(4-methyl-3,4-dihydro-2H-benzo[l,4]o xazin-6-yl)ethyl]- acrylamide; (S)-N-(l-Naphthalen-2-yl-ethyl)-3-phenyl-acrylamide; (S)-3-(4-Fluoro-phenyl)- N-(l-naphthalen-2-yl-ethyl)-acrylamide; (±)-N-(l-Benzo[l,3]dioxol-5-yl-ethyl)-3-(2,4- difluoro-phenyl)-acrylamide; (±)-N-[l-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3-(2-fluoro- phenyl)-acrylamide; (±)-3-(2,4-Difluoro-phenyl)-N-[l-(2,3-dihydro-benzofuran-5- yl)-ethyl]- acrylamide; (S)-3-(2,4-Difluoro-phenyl)-N-[l-(3-morpholin-4-yl-phenyl)-e thyl]-acrylamide; (S)-N-[l-(3-(2,6-Dimethyl-morpholin)-4-yl-phenyl)-ethyl]-3-p henyl-acrylamide; (S)-3-(2- Fluoro-phenyl)-N-[l-(3-morpholin-4-yl-phenyl)-ethyl]-acrylam ide; (S)-N-[l-(3-Morpholin- 4-yl-phenyl)-ethyl]-3-thiophen-3-yl-acrylamide; (S)-3-(4-Fluoro-phenyl)-N-[l-(3-morpholin-

4-yl-phenyl)-ethyl]-acrylamide; (S)-N-{l-[3-(cis-2,6-Dimethyl-morpholin-4-yl)-phenyl]- ethyl } -3 -(4-fluoro-phenyl)-acrylamide; (S)-3 -(2,4-Difluoro-phenyl)-N- { 1 -[3 -(cis-2,6- dimethyl-morpholin-4-yl)-phenyl]-ethyl} -acrylamide; (S)-3-(3,4-Difluoro-phenyl)-N-{l-[3- (cis-2,6-dimethyl-morpholin-4-yl)-phenyl]-ethyl}-acrylamide; (S)-3-(2,5-Difluoro-phenyl)- N-{l-[3-(cis-2,6-dimethyl-morpholin-4-yl)-phenyl]-ethyl}-acr ylamide; (S)-3-(2-Fluoro- phenyl)-N-{l-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}-acr ylamide; (S)-3-(3-Fluoro- phenyl)-N-{l-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}-acr ylamide; (S)-3-(4-Fluoro- phenyl)-N-{l-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}-acr ylamide; (S)-3-(2,4-Difluoro- phenyl)-N-{ l-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}-acrylamide; (S)-N-{ l-[3-(2-Oxa-

5-aza-bicyclo[2.2.1]hept-5-yl)phenyl]ethyl}-3-phenyl-acry lamide; (S)-N-{l-[3-(2- Hydroxymethyl-morpholin-4-yl)-phenyl]-ethyl}-3-phenyl-acryla mide; (±)-N-[l-(3- Morpholin-4-yl-phenyl)-propyl]-3-phenyl-acrylamide; (±)-3-(2,4-Difluoro-phenyl)-N-[l-(3- morpholin-4-yl-phenyl)-propyl]-acrylamide; (±)-3-(2-Fluoro-phenyl)-N-[l-(3-morpholin-4- yl-phenyl)-propyl]-acrylamide; (±)-3-(3-Fluoro-phenyl)-N-[l-(3-morpholin-4-yl-phenyl)- propyl]-acrylamide; (±)-N-[l-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(2-flu oro- phenyl)-acrylamide; (±)-N-[l-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-flu oro- phenyl)-acrylamide; (±)-3-(2,4-Difluoro-phenyl)-N-[l-(4-fluoro-3-morpholin-4-yl -phenyl)- ethyl]-acrylamide; (±)-N-[l-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-flu oro-phenyl)- acrylamide; (±)-3-(3,4-Difluoro-phenyl)-N-[l-(4-fluoro-3-morpholin-4-yl -phenyl)-ethyl]- acrylamide; (±)-3-(2,5-Difluoro-phenyl)-N-[l-(4-fluoro-3-morpholin-4-yl -phenyl)-ethyl]- acrylamide; (±)-N-[l-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(3-flu oro-phenyl)- acrylamide; (±)-N-[l-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(2-flu oro-phenyl)- acrylamide; (±)-3-(3-Fluoro-phenyl)-N-[l-(l,2,3,4-tetrahydro-quinolin-7 -yl)-ethyl]- acrylamide; (±)-3-(4-Fluoro-phenyl)-N-[l-(l,2,3,4-tetrahydro-quinolin-7 -yl)ethyl]- acrylamide; (±)-3 -(2-Fluoro-phenyl)-N-[ 1 -(1 -methyl- 1 ,2,3 ,4-tetrahydro-quinolin-7- yl)ethyl]acrylamide; (±)-N-{l-[l-(2-Hydroxy-ethyl)-l,2,3,4-tetrahydro-quinolin-7 -yl]-ethyl}- 3-phenyl-acrylamide; (±)-3-(2,5-Difluoro-phenyl)-N-{ 1-[1 -(2 -hydroxy-ethyl)- 1,2, 3,4- tetrahydro-quinolin-7-yl]-ethyl}-acrylamide; (±)-3-(3,5-Difluoro-phenyl)-N-{l-[l-(2- hydroxy-ethyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-ethyl}-acry lamide; (S)-3-Phenyl-N-[l-(3- pyridyl-phenyl)-ethyl]acrylamide; (S)-(2,4-Difluoro-phenyl)-N-[l-(3-pyridin-3-yl-phenyl)- ethyl]-acrylamide; (S)-3-Phenyl-N-[l-(3-pyridin-4-yl-phenyl)-ethyl]-acrylamide; (S)-N-{ 1- [3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-(2-fluoro-phenyl )-acrylamide; (S)-3-Phenyl-N- [l-(3-pyrimidin-5-yl-phenyl)-ethyl]-acrylamide; (S)-3-Phenyl-N-[l-(3-pyridin-2-yl-phenyl)- ethyl]-acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[l-(3-pyridin-2-yl-phenyl)-ethyl]- acrylamide; (S)-3-(2-Fluoro-phenyl)-N-{l-[3-(6-fluoro-pyridin-3-yl)-phen yl]ethyl}-acrylamide; (S)-3-(4- Fluoro-phenyl)-N-{ 1 -[3 -(6-fluoro-pyri din-3 -yl)-phenyl]-ethyl} -acrylamide; (S)-N-{ l-[3-(6- Fluoro-pyridin-3-yl)-phenyl]-ethyl}-3-pyridin-3-yl-acrylamid e; (S)-N-{l-[3-(6-Fluoro- pyridin-3-yl)-phenyl]-ethyl}-3-pyridin-4-yl-acrylamide; (S)-N-{l-[3-(6-Chloro-pyridin-3-yl)- phenyl]-ethyl}-3-(3-fluoro-phenyl)-acrylamide; (S)-N-{l-[3-(6-Chloro-pyridin-3-yl)-phenyl]- ethyl}-3-pyridin-3-yl-acrylamide; (S)-N-{l-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3- pyridin-2-yl-acrylamide; (S)-N-{l-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-pyridin -4-yl- acrylamide; (S)-N-{l-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-(2-fluo ro-phenyl)- acrylamide; (S)-N-{l-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-(2,4-di fluoro-phenyl)- acrylamide; (S)-N-{l-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-(4-fluo ro-phenyl)- acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[l-(3-pyridin-3-yl-phenyl)ethyl]ac rylamide; (S)-N- { l-[3-(6-Fluoro-pyridin-3-yl)-phenyl]-ethyl}-3-phenyl-acrylam ide; (S)-N-{ l-[3-(6-Chloro- pyridin-3-yl)-phenyl]-ethyl}-3-phenyl-acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[l-(3-pyridin- 4-yl-phenyl)ethyl]acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[l-(3-pyrazin-2-yl- phenyl)ethyl]acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[l-(3-pyrimidin-5-yl- phenyl)ethyl]acrylamide; (S)-3-(2-Fluoro-phenyl)-N-{l-[3-(4-methyl-pyridin-3- yl)phenyl]ethyl}acrylamide; (S)-3-(4-Fluorophenyl)-N-{l-[3-(4-methylpiperazin-l- yl)phenyl]ethyl}acrylamide; and (S)-3-(2,3-Difluoro-phenyl)-N-{ l-[3-(4-methyl-piperazin-l- yl)-phenyl]-ethyl} -acrylamide; or a pharmaceutically acceptable salt thereof.

Formula 169

[00868] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 169. Such compounds are described in International Publication No. W02002096858A1, published December 5, 2002, and corresponding to International Application No. PCT/US2002/017049 filed May 31, 2002; US Patent No. 6,831,080, issued December 14, 2004, and corresponding to US Application No. 10/160,582 filed May 31, 2002; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 169, these references incorporated by reference herein control.

[00869] In an embodiment, the Kv7 channel activator is a compound according to Formula 169: Formula 169 wherein, R ¹ is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, benzodi oxanyl, l,3-benzodioxol-5-yl, chroman-5-yl, indan-5-yl, 4-biphenylyl, phenyl and substituted phenyl, in which said substituted phenyl is substituted with substituent independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R ⁴ is selected from the group consisting of optionally substituted di(Ci-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents in which said substituent is independently selected from the group consisting of Ci-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R ⁵ is hydrogen or fluoro; or R ⁴ and R ⁵ taken together are — CH=CH — CH=CH — or — X(CH2) _m Y — , in which X and Y are each independently selected from the group consisting of CH2, (CH2) _n N(R ⁹ ) — and O, wherein m is 1 or 2; n is 0 or 1; R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, chloro and fluoro; and R ⁹ is selected from the group consisting of hydrogen, C4 alkyl, hydroxy ethyl, C1-4 alkoxyethyl, cyclopropylmethyl, — CO2(Ci-4alkyl), and — CH2CH2NR ¹⁰ R ⁿ in which R ¹⁰ and R ¹¹ are each independently hydrogen or C 1-4 alkyl.

[00870] In further embodiments, R ¹ is selected from the group consisting of 2-thienyl, chroman-5-yl, 4-biphenylyl, phenyl and substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy and nitro; and R ⁴ and R ⁵ taken together are — CH=CH — CH=CH — .

[00871] In further embodiments, R ¹ is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy, trifluoromethyl and nitro; R ⁴ is optionally substituted morpholin-4-yl with one or two substituents each independently selected from the group consisting of C1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; and R ⁵ is hydrogen or fluoro.

[00872] In further embodiments, R ¹ is phenyl, fluorophenyl or difluorophenyl. [00873] In further embodiments, R ¹ is pyridinyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R ⁴ is optionally substituted pyridinyl with one or two substituents each independently selected from Ci-4 alkyl and halogen; and R ⁵ is hydrogen or fluoro.

[00874] In further embodiments, R ¹ is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from Ci-4alkyl and halogen; R ⁴ is piperazinyl or 4-methylpiperazinyl; and R ⁵ is hydrogen or fluoro.

Formula 170

[00875] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds according to Formula 170. Such compounds are described in US Patent No. 6,326,385, issued December 4, 2001, and corresponding to US Application No.

09/361,747 filed August 4, 2000; International Publication No. W02001010381A2, published February 15, 2001, and corresponding to International Application No. PCT/US2000/021309 filed August 4, 2000; US Patent No. 6,326,385 issued December 4, 2001, and Patent Cooperation Treaty application No. US2000/021309 published February 15, 2001, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 170, these references incorporated by reference herein control.

[00876] In an embodiment, the Kv7 channel activator is a compound according to Formula 170:

Formula 170 wherein, Ar ¹ and Ar ² are each members independently selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; and X is a member selected from the group consisting of O, S and N — R ¹ , wherein R ¹ is a member selected from the group consisting of H, (Ci-Cs)alkyl, substituted (Ci-Cs)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(Ci-C4)alkyl, substituted aryl(Ci-C4)alkyl, CN, — C(O)R ² , — OR ³ , — C(O)NR ³ R ⁴ , and — S(O)2NR ³ R ⁴ ; wherein R ² is a member selected from the group consisting of (Ci-Cs)alkyl, substituted (Ci-Cs)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(Ci-C4)alkyl and substituted aryl(Ci-C4)alkyl; and R ³ and R ⁴ are each members independently selected from the group consisting of hydrogen, (Ci-Cs)alkyl, substituted (Ci-Cs)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(Ci- C4)alkyl and substituted aryl(Ci-C4)alkyl, or R ³ and R ⁴ can be combined with the nitrogen to which each is attached to form a 5-, 6- or 7-membered ring optionally having additional heteroatoms at the ring vertices.

[00877] In further embodiments, Ar ¹ is a member selected from the group consisting of phenyl, substituted phenyl, indolyl, substituted indolyl, benzofuranyl, substituted benzofuranyl, furanyl, substituted furanyl, thienyl, substituted thienyl, isothiazolyl, substituted isothiazolyl, pyrazolyl and substituted pyrazolyl.

[00878] In further embodiments, Ar ¹ is substituted phenyl, substituted or unsubstituted 2- indolyl and substituted or unsubstituted 2-thienyl.

[00879] In further embodiments, X is O.

[00880] In further embodiments, the Ar ¹ substituents are selected from the group consisting of halogen, alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, nitro, cyano, — NHC(O)R ⁷ , — NHR ⁷ , phenyl and substituted phenyl, wherein R ⁷ is a member selected from hydrogen, (Ci-Cs)alkyl, substituted (Ci-Cs)alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heterocyclyl, substituted hcterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(Ci-C4)alkyl and substituted aryl(Ci-C4)alkyl, or R ⁷ can be combined with the nitrogen to which it is attached to form a 5-, 6- or 7-membered ring optionally having additional heteroatoms at the ring vertices.

[00881] In further embodiments, Ar ² is selected from the group consisting of heteroaryl and substituted heteroaryl.

[00882] In further embodiments, Ar ¹ is substituted aryl; Ar ² is heteroaryl or substituted heteroaryl; and X is O.

[00883] In further embodiments, Ar ² is pyridyl or substituted pyridyl.

[00884] In further embodiments, Ar ² is selected from the group consisting of 6-methyl-3- pyridyl and 2-chloro-5-pyridyl.

[00885] In further embodiments, Ar ¹ is substituted phenyl.

[00886] In further embodiments, the compound is according to the formula:

[00887] wherein, Y is a member selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 substituted alkyl, — OCH3 and — OCF3, and R ⁵ and R ⁶ are members independently selected from the group consisting of H, halogen, alkyl, halo(Ci-C4)alkyl, nitro, cyano and phenyl, with the proviso that both R ⁵ and R ⁶ are not H.

[00888] In further embodiments, R ⁵ and R ⁶ are members independently selected from the group consisting of H, F, and Cl, with the optional proviso that both R ⁵ and R ⁶ are not H.

Further embodiments (Collectively referred to as “Formula 171” for ease of reference in the appended claims. “Formula 171”. as recited in the claims, captures any of the below compounds preceding the glutamate modulators section.)

[00889] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in International Publication No. WO2021055538A1, published March 25, 2021, and corresponding to International Application No. PCT/US2020/051171 filed September 17, 2020; International Publication No. WO2017075222A1, published May 4, 2017, and corresponding to International Application No. PCT/US2016/059128 filed October 27, 2016; International Publication No. WO2021211867A1, published October 21, 2021, and corresponding to International Application No. PCT/US2021/027518 filed April 15, 2021; International Publication No. W02020092577A1, published May 7, 2020, and corresponding to International Application No. PCT/US2019/058878 filed October 30, 2019; International Publication No.

W02021119018A1, published June 17, 2021, and corresponding to International Application No. PCT/US2020/063,822 filed December 8, 2020; International Publication No.

WO2011085351A2, published July 14, 2011, and corresponding to International Application No. PCT/US2011/020784 filed January 11, 2011; US Publication No. US20100286138A1, published November 11, 2010, and corresponding to US Application No. 12/777,935 filed May 11, 2010; US Publication No. US20210262029A1, published August 26, 2021, and corresponding to US Application No. 17/245734 filed April 30, 2021; US Patent No. 11,221,329, issued on January 11, 2022, and corresponding to US Application No. 15/771,857 filed October 27, 2016; which are incorporated by reference in their entirety herein.

[00890] In further embodiments, the compound is selected from the group consisting of N- (l-cyclobutyl-4-fluoro-6-(l- hydroxycyclobutyl)-lH-benzo[d]imidazol-2-yl)-4,4,4-trifluoro - 3,3- dimethylbutanamide; N-(l -(tert-butyl)-6-(difluoromethoxy)- 1H- benzo[d]imidazol-2- yl)-3,3-dimethylbutanamide; N-(6-cyano-l-(l,l,l- trifluoro-2-methylpropan-2-yl)-lH- benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide; N-(l -cyclobutyl -4-fluoro-6-(2- hydroxypropan-2-yl)- 1H- benzo[d]imidazol-2-yl)-2-(l -methyl cy cl opropylj acetamide; N-(6- cyano-1- cy cl obutyl-4-fluoro-lH-benzo[d]imidazol-2-yl)-3, 3 -dimethylbutanamide; N- (1- cyclobutyl-6-fluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbu tanamide; N-(l-(tert-butyl)-6- cyano-4-fluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide; N-(7-cyano-l-(l- methylcyclobutyl)-lH- benzo[d]imidazol -2 -yl)-3 -cyclopropyl-3 -methylbutanamide; N-(6- chloro-7- cyano-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbut anamide; N- (1- cyclobutyl-5-fluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbu tanamide; N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide; N-(6-cyano- 1 - cyclobutyl-7-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)-3, 3 -dimethylbutanamide; N-(6- cyano-4,7-difluoro-l- (l-methylcyclobutyl)-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide; N- (l-(tert-butyl)-5,7-difluoro-lH-benzo[d]imidazol-2-yl)-4,4,4 - trifluoro-3,3- dimethylbutanamide; and N-(l-(tert-butyl)-5,6-difluoro-lH-benzo[d]imidazol- 2- yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide.

[00891] In another embodiment, the Kv7 channel activator is selected from the group consisting of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyra mide in a crystalline form with XRPD reflections at 10.36, 12.67, 28.64 and 29.98 (°20) using CuKai radiation.; N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyra mide in a crystalline form with XRPD reflections at 8.68, 18.09, 22.60 and 30.62 (°20) using CuKai radiation.; N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyra mide in a crystalline form with XRPD reflections at 8.63, 22.26, 23.40 and 30.49 (°20) using CuKai radiation.

[00892] In further embodiments, the Kv7 Channel activator is selected from the group consisting of Chromanol 293B, MIR-1556, UCL2077, JNJ303, L-735821 (L-7), fenofibrate; and a salt or hydrate thereof.

[00893] In further embodiments, the Kv7 Channel activator is selected from the group consisting of a Triaminopyridine or one of its derivatives, an Acrylamide, a Benzamide, a Fenamate, a Dimethoxypyrimidine or one of its derivatives, Oxindole, Celecoxib, zinc pyrithione, ML213, QO58, QO58 lysine, NS1643, Benzbromarone, ZG1732 and ZG2083. [00894] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: NS15370, P-Retigabine, SF0034 or RL648 81 or any combination thereof. [00895] In further embodiments, the Kv7 channel activator is selected from the group consisting of: linopirdine, (l,3-Dihydro-l-phenyl-3,3-bis(4-pyridinylmethyl)-2H-indol-2- one) XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991)), DMP-543 (10,10- bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone (DMP-543)), ML252 ((S)-2-phenyl-N- (2-(pyrrolidin-l-yl)phenyl)butanamide (ML252)) and UCL2077.

[00896] In further embodiments, the Kv7 channel activator is an analog of flupirtine. [00897] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-3-carboxamide ; N- (2,6- dimethylphenyl)bicyclo[2.2. l]heptane-3 -carboxamide; N-(2,5- dimethylphenyl)bicyclo[2.2.1]heptane-3-carboxamide; N-(2-chloro-4,6- dimethylphenyl)pentanamide; N-(2-chloro-4,6-dimethylphenyl)-3,3-dimethylbutanamide; 2- (1 -adamantyl)-N-(2,6-difluorophenyl)acetamide; N-(2-bromo-4-methylphenyl)-2- cyclopentylacetamide; N-(2,3-dimethylphenyl)-2-phenylcyclopropane-l-carboxamide; N- (4- methylphenyl)-2-phenylcyclopropane-l -carboxamide; N-(2,4- dimethoxyphenyl)bicyclo[2.2.1]heptane-3-carboxamide; 7-ethyl-l,3-dimethyl-5-(2-oxo-2- piperidin-1 -ylethyl)sulfanylpyrimido[4,5-d]pyrimidine-2, 4-dione; 1 ,3-dimethyl-7-(2- methylpropyl)-5-(2-oxo-2-piperidin-l -ylethyl)sulfanylpyrimido[4,5-d]pyrimidine-2,4- dione; l,3-dimethyl-5-[2-(4-methylpiperidin-l-yl)-2-oxoethyl]sulfan yl-7- propylpyrimido[4,5- d]pyrimidine-2, 4-dione; 7-ethyl-l ,3-dimethyl-5-[2-(4- methylpiperidin-l-yl)-2- oxoethyl]sulfanylpyriinido[4,5-d]pyrimidine-2, 4-dione; 2-(4- chloro-2-methyl-5-pyrrolidin-l -ylsulfonylphenoxy)-N-cyclohexylacetamide; 2-(4-chloro- 2-methyl-5-thiomo holin-4- ylsulfonylphenoxy)-N-cyclohexylacetamide; 1-[1-(1,3- benzodioxol-5-yl)ethyl]-3- cyclohexylurea; 1-(1 -adamantyl)-3-[l-(l,3-benzodioxol-5- yl)ethyl]urea; 3-(5-bromo-2- hydroxyphenyl)-N-(furan-2-ylmethyl)-3-phenylpropanamide; ethyl 2-benzamido-2-(2,6- dimethylpyran-4-ylidene)acetate; (2,4-dichlorophenyl)methyl 1- benzamido-5- oxopyrrolidine-3 -carboxylate; N-[2-cyano-5-(cyanomethylsulfanyl)-4- phenylthiophen-3-yl]- 2-phenylacetamide; N-(6-bromo-l,3-diethyl-2-oxobenzimidazol-5- yl)-2-phenylpropanamide; N-(2,5-diethoxy-4-mo holin-4-ylphenyl)-2-phenylacetamide _; N-[4-[(5-methylthiophen-2- yl)methylamino]phenyl]butanamide; N-[(2-methylsulfanyl-6- propan-2-ylpyri din-3 - yl)methyl]-3-phenylbutanamide; 4-bromo-N-(thi ophen-2- ylmethylideneamino)-lH-pyrazole- 5-carboxamide; S-[2-[(6-fiuoro-3 -prop-2 -ynyl-1 ,3- benzothiazol-2-ylidene)amino]-2- oxoethyl] ethanethioate; 1 -cyclohexyl-3-[l -(3,4- dimethylphenyl)ethyl]thiourea; N-[4- methyl-1 -oxo-l-(l -phenylethylamino)pentan-2- ylj cyclohexanecarboxamide; 5-chloro-2-[(3- methylphenyl)methylsulfonyl]-N-(5-propyl-1 , 3,4-thiadiazol-2-yl)pyrimidine-4-carboxamide; 2-benzylsulfonyl-5-chloro-N-(5-propan- 2-yl-l ,3,4-thiadiazol-2-yl)pyrimidine-4- carboxamide; and 4-bromo-N-(furan-2- ylmethylideneamino)-lH-pyrazole-5-carboxamide. [00898] In further embodiments, the metal channel activator is QRA-244 as described in Dan Elbaum et al. “TST-20: QRA-244 a Potent, Selective KCNQ2/3 Opener and a Potential Therapy for Motor System Hyperexcitability induced Disease Progression in ALS patients”; 31 ^st International symposium on ALS/MND; Live Poster Session C, December 11, 2020.

GLUTAMATE MODULATORS

[00899] Examples of glutamate modulators are disclosed in Formulas 200 - 463 and the corresponding referenced applications, as well as throughout the specification.

[00900] The glutamate modulator suitable for use in accordance with the present invention include any agents that: (a) promote the modulation, regulation, attenuation or potentiation of; (i) an ionotropic glutamate receptor; (ii) a metabotropic glutamate receptor; or (iii) a glutamate transporter; (b) inhibits glutamate release; or (c) modulates, regulates, attenuates or potentiates the metabolism of glutamate or glutamine. Ionotropic glutamate receptors include NMD A, AMPA and kainite. Metabotropic glutamate receptors include those from group 1 receptors including mGluRl and mGluR5; group II including mGluR2 and mGluR3; and group III including mGluR4, mGluR6, mGluR7, and mGluR8. Glutamate transporters may be expressed in glia or in neurons. Preferably, the glutamate modulators: (i) normalize glutamate levels in the patient; (ii) attenuate or normalize glutamate release in the patient; or (iii) normalize, enhance or potentiates the uptake of glutamate in the patient. The glutamate modulators may cause a reduction in the glutamine/glutamate levels or increase the cycling of glutamate by increasing the expression of excitatory amino acid transporters, causing a reduction in reduce proliferative and effector function.

[00901] Preferred glutamate modulators are selected from riluzole, memantine, n- acetlcysteine, amantadine, topiramate, pregabalin, lamotrigine, ketamine, s-ketamine, AZD8108, AZD 6765 (lanicemine), BHV-4157 (troriluzole), dextromethorphan, AV-101, CERC-301, GLY-13, and pharmaceutically acceptable salts, prodrugs or analogs thereof. Riluzole is currently available in the market as RILUTEK® (riluzole) is available from Sanofi -Aventis, Bridgewater, NJ and has the structure shown below.

6-(trifluoromethoxy)benzothiazol-2-amine.

[00902] The term “riluzole” also refers to all prodrugs, enantiomers, or derivatives and its pharmaceutically acceptable salts, except as otherwise noted. The term “riluzole prodrug” refers to a compound which is a derivative from riluzole with modification therein. A riluzole prodrug may also refer to a compound that is metabolized into an active form of riluzole by the body.

[00903] In additional embodiments, the glutamate modulator is an anticonvulsant including one or more of carbamazepine, felbamate, lamotrigine, pregabalin, phenytoin, tiagabine, and topiramate.

[00904] It should be appreciated that for the disclosed glutamate modulator compounds, substitutional variants which retain glutamate modulatory activity are contemplated. For example, disclosed glutamate modulators may be substituted in one, two, or three, or optionally more positions, and may retain glutamate modulatory activity.

Riluzole and Prodrugs of Riluzole

Formula 200

[00905] In an embodiment, the glutamate modulator is a prodrug of riluzole. Certain preferred riluzole prodrugs have the structure: including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:

R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3,

CH2CCH, CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ )2, CH(CH ₃ )CH ₂ CH3, CH2OH, CH2OCH2PI1, CH2CH2OCH2PI1, CH(OH)CH ₃ , CH ₂ Ph, CH ₂ (cyclohexyl), CH ₂ (4-OH-Ph), (CH ₂ ) ₄ NH2, (CH ₂ )3NHC(NH ₂ )NH, CH ₂ (3 -indole), CH ₂ (5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2. Those skilled in the art will recognize that similar or variant prodrugs can be made from other glutamate modulators. Such agents may be useful as part of the combination of the present invention.

Formula 201

[00906] In an embodiment, the glutamate modulator is a prodrug of riluzole. One especially preferred glutamate modulator, troriluzole, has the following formula:

[00907]

Formula 202

[00908] In an embodiment, the glutamate modulator may be a riluzole prodrug selected from the following compounds according to Formula 202. Such compounds are described in WO 2013/138753, published September 19, 2023 corresponding to PCT/US2013/032292, filed March 15, 2023, US 9,725,427, issued August 8, 2017, US 10,562,870, issued February 18, 2020, US 10,844,026, issued November 24, 2020, US 11,440,893, issued September 13, 2022, and US 2023/0202993, published June 29, 2023, WO 2013/192610, published December 27, 2013, corresponding to PCT/US2013/047315, filed June 24, 2013, US 10,357,497, issued July 23, 2019, US 11,197,864, issued December 14, 2021, and US 2022/0072006, published March 10, 2022 which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 202, these references incorporated by reference herein control.

[00909] In an embodiment, the glutamate modulator is a riluzole prodrug according to formula 202:

, wherein R1 is selected from the group consisting of

0R2, CR3aR3bNH2, CR3aR3bNR7aR7b, CH2CH2CO2R4, CH2CH2CONHR5,

(CR6aR6b)mNR7aR7b, CH2Ar, and optionally substituted phenyl ring;

R2 is selected from the group consisting of optionally substituted C1-C6 alkyl and CH2(CH2)nNR8aR8b; n = 1 or 2;

R3a and R3b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, CH2R4a, optionally substituted phenyl, optionally substituted benzyl, optionally substituted CH2CH2Ar, optionally substituted CH2heteroaryl, CH2OR9,CH(CH3)OR9,CH2SR9,CH2CH2SCH3, CH2CH2SO2CH3, CH2CH2CH2NR10aR10b, CH2COR9a, and CH2CH2COR9a; R3a and R3b are taken together with an atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring comprising two to five carbon atoms and a member selected from the group consisting of O, NR7a, S, and SO2;

R4 is selected from the group consisting of hydrogen and optionally substituted Cl- C6 Alkyl;

R4a is selected from the group consisting of hydrogen, optionally substituted Cl- C6 Alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted four to six membered saturated heterocyclic ring comprising three to five carbon atoms and a member selected from the group consisting of O, NR7a, S, and SO2;

R5 is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, CH2CH2NR10aR10b, and CH2R11;

R6a and R6b are, at each occurrence, independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl;

R6a and R6b are taken together with the atom to which they are bound to form an optionally substituted 6 membered ring; m = 3 or 4; m = 1 or 2; R7a and R7b are each independently selected from the group consisting of hydrogen, methyl, C0R12, and CO2R12;

R3a and R7a are taken together with the atoms to which they are bound to form an optionally substituted three to six membered ring consisting of all carbons and one nitrogen atom;

R3a and R7a are taken together with the atoms to which they are bound to form an optionally substituted 1,2,3,4-tetrahydro-isoquinoline ring system;

R3a and R7a are taken together with the atoms to which they are bound to form an optionally substituted 2,3-Dihydro-lH-isoindole ring system;

R3a and R7a are taken together with the atoms to which they are bound to form a optionally substituted six membered saturated heterocyclic ring comprising four carbons, one nitrogen atom, and a member selected from the group consisting of O, NR7a, S, and SO2;

R6a and R7a are taken together with the atoms to which they are bound to form an optionally substituted three to six membered ring comprising all carbons and one nitrogen atom;

R6a and R7a are taken together with the atoms to which they are bound to form an optionally substituted 1,2,3,4-tetrahydro-isoquinoline ring system;

R6a and R7a are taken together with the atoms to which they are bound to form an optionally substituted 2,3-Dihydro-lH-isoindole ring system;

R6a and R7a are taken together with the atoms to which they are bound to form a optionally substituted six membered saturated heterocyclic ring consisting of four carbons, one nitrogen atom, and a member selected from the group consisting of O, NR7a, S, and SO2;

R8a and R8b are each independently optionally substituted C1-C6 alkyl;

R9 is selected from the group consisting of hydrogen, C1-C6 alkyl, optionally substituted phenyl, optionally substituted benzyl, and optionally substituted CH2CH2Ar;

R9a is selected from the group consisting of OH, C1-C6 alkoxy, and NH2;

RlOa and RlOb are each independently is selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl;

RlOa and R10B and are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms; RlOa and R10B and are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing an oxygen; RlOa and R10B and are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing two nitrogen atoms; R11 is selected from the group consisting of optionally substituted phenyl and optionally substituted heteroaryl;

R12 is C1-C6 alkyl;

Ar is selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl ring;

Ar is optionally substituted with 0-5 moieties selected from the group consisting of deuterium, halogen, trifluoromethyl, trifl ouromethoxy, cyano, NR7aR7b, CONR8aR8b, Cl- C6 alkyl, and C1-C6 alkoxy.

[00910] In further embodiments, the riluzole prodrug has the formula:

, including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein: R12a, R12b, R12c, R12d, and R12e are each independently selected from the group consisting of hydrogen, deuterium, halogen, trifluoromethyl, trifl ouromethoxy, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

[00911] In further embodiments, the riluzole prodrug has the formula: including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R12a, R12b, R12c, R2d, and R12e are each independently selected from the group consisting of hydrogen, deuterium, halogen, trifluoromethyl, trifl ouromethoxy, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

[00912] In further embodiments, the riluzole prodrug is a compound according to: 2-Ajmino-N-(6-trifliKBX)methoxy-benzothiazo)-2-y))-acetamide ;

(R)-2-Amini>-N-<’6-trifluoK>nwlh<)xy-benM&g t;lhi3z<>l-2-yl)-pK>pioniiH»ide; {7JV2'Arnino-3’phenyl-N’(6-irinuoroi>wihoxy-benz<H hjazol-2-yl)’propion amide; (R.j-2-/\Biini>3“benzyli>xy-N-(6-trinuoromeih<oxy -benzothiazo}“2“yl)- propionamide;

(S)-2-Aoiino-N-(6-triflu<BXBnethoxy-benz<«hiazo)-2 -yl)-pr<^>ionatBkfa;

(S)-2-Aniin0-3-BReihyl-N ^! -(6-irinuon)meihoxy-henzxnhiazol-2-y])-butyraniide;

(S)-2-Aniin.0-3-jiienyl-N-(6-tri.nuoK!inedK>xy-beBzodn azol-2-yi)-ptopionaoBde: (5>2-Aniin.o-3-benzyl0xy-N-(6-triftu<>KHBethoxy-bcn z»Xhiaz0l-2-yl)- propionamide;

(5>2-a;Ktno-3-(4-fluofcibenzy!‘>xy.j-N-(6-trifliK >n>medinxy-benz<xhiazo(-2-ylj- propanainide;

(,S>2-ainino-3-(2,4-dtfluombenzyioxy)-N-(6-triniKMX> ;methoxy-benz0thiazol-2-yi)- propanamide;

(5’)-2-amino-3-methoxy-N-(6-tri.fluoK>raethoxy-benzo thiazo1-2-yi)-pfopanamide;

(5>3-tert-buroxy-2-amiiKt‘N-(6-(trifluorc>tBethox y.)ix;nzo[d]thiazo}“2“ y])propanamide;

(6- TrifluoKBncdioxy-benzodiiazoi-l-yn-carbanuc acid niethyi ester;

(6'Trifluorometboxy-benzolhiazol-2-yb-carbanuc acid ethyl ester;

(6-Trifluoromethoxy-benzotliia2o1-2-yl)-earbanuc acid propyl ester;

(6-Trifiuoromethoxy-benzothiazol-2-yl)-carbamic acid butyl ester;

(6-lnfluoK>methoxy-benzothiazol--2-yl)-€arbaniic add isobutyl ester;

(6-Trifluoromeihoxy-benzodtiazol-2-yl)-carbamic acid hexyl ester;

(6-ln.fluoK>tiethoxy*ben«otlwazQl-2-yl)<4rt>aoi ic acid 2-dinieihylatuino-etl:iyl ester,

(6*TritlaoK>methoxy-benzothiazol-2-yl)-cajrbaintc acid 3<litnethylaniint>propyl ester;

N -(6 - Tri fluo romethox y - benzo th i azol-2- y1 ) -s ucci na mic ac id;

N-(6-Trinuoroineihoxy-l>en?Aithiazo.l-2-yl)-succtoaini € acid methyl ester;

N-<(r-1?ril1uoromethoxy-benzoihiazol-2--yl)-succin;iin ic acid tert.- butyl ester;

N-Pyridin.-3-ylmethy1-N'-(6-trinuoroniethoxy-benzothiazxd -2-y])-s«ceinamide;

N '(2-Morpholia-4-yl-eihyl}--N’'(6'trinuoromethoxy-beiizoiht azol-2--yl)-- succinamide;

S-Methylaminopentamic acid <6-trifluiwnredioxy-benz()tliiaz.01-2-yl)-anHcte; 5- Amino-pentanoic acid (6-trifl'uoTt>methoxy-benzothia?x>l-2-yl)-amide;

2-(2-NilTt>phenyl)-N-(6-iriiltK)n>tnethoxy-benzoihi azdl-2-yl)-acetamide;

4-Ajnino-N-(6-trifluoroniethoxy-benzothiazoi-2-y1)-benzam ide;

2“(TAininoiriethyTcyelohexyl)-N-(6-irinuoronieihoxy4xtn zolhiazoT2-yl)- acetamide; or a pharmaceutically acceptable salt thereof. [00913] In further embodiments, the riluzole prodrug is a compound according to: , including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:

R3a and R3b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted CH2CH2Ar, optionally substituted CH2 heteroaryl, CH2OR9, CH(CH3)OR9CH2SR9,CH2CH2SCH3, CH2CH2CH2NR10aR10b, CH2COR9a, and CH2CH2COR9a;

Rlla is selected from group consisting of optionally substituted C1-C6 alkyl, COR4, and CO2R4;

Rlla and R3a are taken together with the atoms to which they are bound to form a 5 membered ring;

Rlla and R3b are taken together with the atoms to which they are bound to form a 5 membered ring.

[00914] In further embodiments, the riluzole prodrug is a compound according to:

, including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00915] In further embodiments, the riluzole prodrug is a compound according to:

, including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00916] In further embodiments, the riluzole prodrug is a compound according to: , including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00917] In further embodiments, the riluzole prodrug is a compound according to: , including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00918] In further embodiments, the riluzole prodrug is selected from: (S>N”(6’tnnu()n)ntethoxy"bemdiiaz()i’2’yl)-pymdid ine’2’e^boxamide; fM-iert-butyl 3-(l?eiizyloxy j-1 -oxo- 1.-(6’trifluon)niethoxy-benzotbiaz.ol’2’ ylamino)-propan-2-ylcart>amate;

(5>2-acetamidc^3-(benzyfoxy>N-(6-trifluo-RMmtboxy-b enzoihiazol-2-yl.)- propanamide; or a phannaceudcaHy acceptable form thereof.

Formula 203

[00919] In an embodiment, the glutamate modulator may be a riluzole prodrug selected from the following compounds according to Formula 203. Such compounds are described in, WO 2016/140878, published September 9, 2016 and corresponding to PCT/US2016/019773, filed February 26, 2016, and WO 2016/140879, published September 9, 2016 and corresponding to PCT/US2016/019787, filed February 26, 2016, US 10,485,791, issued November 26, 2019, US 10,639,298, issued May 5, 2020, US 10,905,681, issued February 2, 2021, US 11,052,070, issued July 6, 2021, US 2021/0236471, published August 5, 2021, and US 2023/0017637, published January 19, 2023, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 203, these references incorporated by reference herein control.

[00920] In an embodiment, the glutamate modulator is a compound according to Formula 203 including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein: R1 is selected from the group consisting of C1-C6 fluoroalkyl, OR2, (CR6aR6b)mNHR7, CR 10a R 10b NR 11 R 12,

R3a and R3b are independently selected from the group consisting of hydrogen, Cl- C6 alkyl, C3- C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and CO2R4; optionally, R3a and R3b cannot both be C1-C6 alkyl;

R3a and R3b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR5, S, and SO2; n is 1 or 2;

R4 is selected from the group consisting of C1-C6 alkyl, C3-C7 branched alkyl, C3- C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted phenyl, and optionally substituted benzyl;

R5 is selected from the group consisting of C1-C6 alkyl, C3-C7 branched alkyl, C3- C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

R6a and R6b are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 branched alkyl, optionally substituted C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; R6a and R6b are taken together with the atom to which they are bound to form an optionally substituted 6 membered ring; m is 1, 2, or 3;

R7 is selected from the group consisting of COCR8aR8b(NHR9),

R8a and R8b are at each occurrence independently selected from the group consisting of hydrogen, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH20H, CH(0H)CH3, CH2Ph, CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3- indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2;

R9 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

Y is at each occurrence independently selected from the group consisting of H2 or O; RlOa and RlOb are at each occurrence independently selected from the group consisting of hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH20H, CH2OCH2Ph, CH(0H)CH3, CH2Ph, CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3 -indole), CH2(5-imidazole), CH2(CCH), CH2(cyclohexyl), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2; RlOa and RlOb are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring;

R11 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, Cl- C6 haloalkyl, and C2-C6 alkynyl;

RlOa and R11 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom, and R12 is not hydrogen; RlOb and R11 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom, and R12 is not hydrogen; or

R12 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, COCR13aR13bNR15aRlb5, COCR13aR13bOR14, SO 3b 2CR13aRl NR15aR15b, COCR13aR13bNHSO2R15a, and (CR19aR19b)qNHR20, and when R12 is hydrogen, R11 cannot be hydrogen;

R11 and R12 are taken together with the atom to which they are bound to form an optionally substituted four to six membered saturated heterocyclic ring containing a nitrogen atom and optionally containing an additional heteroatom from the group consisting of N and O;

R13a and R13b are at each occurrence independently selected from the group consisting hydrogen, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH20H, CH2OCH2Ph, CH2CH2OCH2Ph, CH(0H)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3 -indole), CH2(5- imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2;

R13a and R13b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring;

R13a and R13b are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring with one O atom within the ring;

R13a and R14 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom;

R13a and R15a are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom; Y1 is at each occurrence independently selected from the group consisting of H2, O, and -H/- OCH2Ph;

R14 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

R15a and R15b are at each occurrence independently selected from the group consisting of H, Cl- C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl C1-C6 fluoroalkyl, C0R21, CH2R21, SO2R22, an optionally substituted four to six membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR24 and O, COCHR23 NH2,

R15a and R15b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR5, S, and SO2;

R16 is at each occurrence independently selected from the group consisting of CH2, O, C=O, and NH;

R17 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

R18 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl;

R17 and R18 are taken together with the atoms to which they are bound to form an optionally substituted five or six membered ring containing two nitrogen atoms; R19a and R19b are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3- C7 branched alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl; R19a and R19b are taken together with the atom to which they are bound to form an optionally substituted 3 to 6 membered carbocyclic ring;

R20 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; q is 1, or 2;

R21 is at each occurrence independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 fluoroalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R22 is at each occurrence independently selected from the group consisting of C1-C6 alkyl, C3- C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl;

R23 is selected from the group consisting H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3 -indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2;

R24 is at each occurrence independently selected from the group consisting of H, Cl- C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, COR25, and SO2-C1- 6alkyl;

R25 is at each occurrence independently selected from the group consisting of H, C1-C6 alkyl, C3-C7 branched alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, C1-C6 alkoxy, and C1-C6 alkylamino. [00921] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00922] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof..

[00923] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00924] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00925] In an embodiment, the glutamate modulator is a compound according to; including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00926] In an embodiment,! he glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00927] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [00928] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00929] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00930] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00931] In an embodiment, the glutamate modulator is a compound according to: • , , , including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00932] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00933] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00934] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00935] In an embodiment, the glutamate modulator is a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[00936] In further embodiments, the glutamate modulator is a compound selected from:

2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d] thiazol-2-yl)amino)ethyl) acetamide; (S)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)am ino)ethyl)pyrrolidine-2- carboxamide;

(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thia zol-2-yl)amino)ethyl) propanamide;

3-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d] thiazol-2-yl)amino)ethyl) propanamide; 1- amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d] thiazol-2-yl)amino)ethyl) cyclopropane- 1- carboxamide;

(S)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl )amino)ethyl)azetidine-2- carboxamide; 2-amino-2-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]th iazol-2-yl)amino)ethyl) propanamide; (S)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d ]thiazol-2-yl)amino)ethyl) propanamide;

(R)-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benz o[d]thiazol-2-yl)amino)ethyl) propanamide;

(R)-2-amino-3-hydroxy-N-(2-oxo-2-((6-(trifluoromethoxy)be nzo[d]thiazol-2-yl)amino)ethyl) propanamide;

(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thia zol-2-yl)amino)ethyl)pent-4- ynamide;

(S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thia zol-2-yl)amino)ethyl)pent-4- ynamide; (R)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)am ino)ethyl)pyrrolidine-2- carboxamide; l-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo [d]thiazol-2-yl)amino)ethyl)cyclobutane-l- carboxamide;

(S)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thia zol-2-yl)amino)ethyl) pentanamide;

(R)-2-amino-3-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)ben zo[d]thiazol-2-yl)amino)ethyl) butanamide;

(S)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo [d]thiazol-2-yl)amino)ethyl)pyrrolidine-2- carboxamide;

(S)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl )amino)ethyl)piperidine-2- carboxamide; (S)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)am ino)ethyl)morpholine-3- carboxamide; (R)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)am ino)ethyl)morpholine-3- carboxamide;

(R)-2-amino-4-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)ben zo[d]thiazol-2-yl)amino)ethyl) pentanamide;

(R)-4-oxo-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazo l-2-yl)amino)ethyl)piperidine-2- carboxamide;

4-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d] thiazol-2-yl)amino)ethyl)tetrahydro-2H- pyran- 4-carboxamide;

(R)-2-amino-Nl-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thi azol-2-yl)amino)ethyl) pentanediamide;

(R)-2-amino-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thia zol-2-yl)amino)ethyl)-3-phenyl propanamide;

(R)-2-amino-3-cyclohexyl-N-(2-oxo-2-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) ethyl)propanamide ;

(R)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethox y)benzo[d]thiazol-2-yl)amino) ethyl)propanamide ;

(S)-2-amino-3-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethox y)benzo[d]thiazol-2-yl)amino) ethyl)propanamide; (R)-2-amino-3-(lH-indol-3-yl)-N-(2-oxo-2-((6- (trifluoromethoxy)benzo [d]thiazol-2-yl)amino) ethyl)propanamide ;

(2S,4R)-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethoxy)be nzo[d]thiazol-2-yl)amino)ethyl) pyrrolidine-2-carboxamide;

(S)-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl )amino)ethyl)piperazine-2- carboxamide;

(R)-2-amino-4-(benzyloxy)-N-(2-oxo-2-((6-(trifluoromethox y)benzo[d]thiazol-2-yl)amino) ethyl)butanamide ;

(R)- 1 -(N,N-dimethyl-L-valyl)-N-(6-(trifluoromethoxy)benzo [d]thiazol-2-yl)pyrrolidine-2- carboxamide;

(R)- 1 -(L-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrro lidine-2-carboxamide; (R)- 1 -D- valyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) pyrrolidine-2-carboxamide; (R)-l— glycinyl-N-(6- (trifluoromethoxy )benzo[d]thiazol-2-yl) pyrrolidine-2-carboxamide; (R)-l-N-ethylglycinyl-N-(6- (trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2- carboxamide;

(R)-l-N-isopropylglycinyl-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)pyrrolidine-2- carboxamide; (R)-l-N-t-butylglycinyl-N-(6-(trifluoromethoxy)benzo[d]thiaz ol-2-yl)pyrrolidine-2- carboxamide; (R)-l-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluoromethoxy )benzo[d]thiazol-2-yl) pyrrolidine-2 - carboxamide;

(R)- 1 -( 1 -(aminomethyl)cyclopropane- 1 -carbonyl)-N-(6-(trifluoromethoxy)benzo[d] thiazol-2- yl)pyrrolidine-2-carboxamide ;

(R)- 1 -( 1 -(aminomethyl)cyclopentane- 1 -carbonyl)-N-(6-(trifluoromethoxy)benzo [d] thiazol-2- yl)pyrrolidine-2-carboxamide ;

(R)- 1 -( 1 -(aminomethyl)cyclohexane- 1 -carbonyl)-N-(6-(trifluoromethoxy)benzo [d]thiazol-2- yl)pyrrolidine -2 -carboxamide ;

(S)-l-(3-amino-2,2-dimethylpropanoyl)-N-(6-(trifluorometh oxy)benzo[d]thiazol-2-yl) pyrrolidine-2 - carboxamide;

(S)-l-(l -(aminomethyl)cyclopropane- 1 -carbonyl)-N -(6-(trifluoromethoxy)benzo [d] thiazol-2- yl)pyrrolidine -2 -carboxamide ;

(S)-l-(l -(aminomethyl)cyclopentane- 1 -carbonyl)-N -(6-(trifluoromethoxy)benzo [d]thiazol-2- yl)pyrrolidine -2 -carboxamide ;

(S)-l-(D-valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2- yl)pyrrolidine-2 -carboxamide; (S)-l-(L- valyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidi ne-2-carboxamide; (S)-l -glycyl -N-(6- (trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2 -carboxamide;

(S)-l-(D-alanyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2 -yl)pyrrolidine-2 -carboxamide; (S)-l- (methylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)p yrrolidine-2-carboxamide; (S)-l- (ethylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)py rrolidine-2 -carboxamide; (S)-l- (isopropylglycyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-y l)pyrrolidine-2- carboxamide;

(S)-l-(tert-butylglycyl)-N-(6-(trifluoromethoxy)benzo[d]t hiazol-2-yl)pyrrolidine-2- carboxamide;

(S)-l-(D-leucyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2 -yl)pyrrolidine-2-carboxamide; (S)-l-(3- aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) pyrrolidine-2- carboxamide; (S)-l-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)aze tidine-2 -carboxamide;

(S)-l-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]t hiazol-2-yl)azetidine-2- carboxamide;

(S)- 1 -( 1 -(aminomethyl)cyclopropane- 1 -carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2- yl)azetidine-2-carboxamide;

(S)- 1 -( 1 -(aminomethyl)cyclopentane- 1 -carbonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2- yl)azetidine-2-carboxamide;

(S)-l-glycyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) piperidine-2 -carboxamide;

(S)-l-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]t hiazol-2-yl)piperidine-2- carboxamide;

(S)-l-(3-aminopropanoyl)-N-(6-(trifluoromethoxy)benzo[d]t hiazol-2-yl)piperidine-2- carboxamide; (R)-l-(methylglycyl)-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)piperidine-2-carboxamide; l-(2- aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) cyclopropane-l- carboxamide; l-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl)cyclopropane-l- carboxamide; l-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol- 2-yl)cyclobutane-l- carboxamide; l-(2-(methylamino)acetamido)-N-(6-(trifluoromethoxy) benzo [d]thiazol-2-yl)cyclobutane- 1- carboxamide; l-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)b enzo[d]thiazol-2-yl) cyclobutane- 1 -carboxamide; l-(aminomethyl)-N-(l-((6-(trifluoromethoxy)benzo[d]thiazol-2 -yl)carbamoyl)cyclobutyl) cyclopentane - 1 -carboxamide ; l-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo [d]thiazol-2-yl)cyclobutane-l- carboxamide; l-(2-(isopropylamino)acetamido)-N-(6-(trifluoromethoxy)benzo [d]thiazol-2-yl)cyclobutane-l- carboxamide; l-(aminomethyl)-N-(l-((6-(trifluoromethoxy)benzo[d]thiazol-2 -yl)carbamoyl)cyclobutyl) cyclohexane- 1 -carboxamide;

(R)- 1 -(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo[d]thiazol -2-yl)cyclobutane- 1 - carboxamide;

(R)-l-(2-amino-3-methylbutanamido)-N-(6-(trifluoromethoxy )benzo[d]thiazol-2-yl) cyclobutane- 1- carboxamide;

(S)-2-(2-aminoacetamido)-3-phenyl-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl) propanamide;

(S)-2-(2-(methylamino)acetamido)-3-phenyl-N-(6-(trifluoro methoxy)benzo[d]thiazol-2-yl) propanamide;

(S)-2-((R)-2-aminopropanamido)-3-phenyl-N-(6-(trifluorome thoxy)benzo[d]thiazol-2-yl) propanamide;

(S)-2-((S)-2-aminopropanamido)-3-phenyl-N-(6-(trifluorome thoxy)benzo[d]thiazol-2-yl) propanamide;

(R)-2-amino-3-methyl-N-((S)-l-oxo-3-phenyl-l-((6-(trifluo romethoxy)benzo[d]thiazol-2- yl)amino)propan-2-yl)butanamide ;

(S)-2-amino-2-methyl-N-(l-oxo-3-phenyl-l-((6-(trifluorome thoxy)benzo[d]thiazol-2- yl)amino)propan-2-yl)propanamide;

(S)-l-amino-N-(l-oxo-3-phenyl-l-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)propan- 2- yl)cyclopropane- 1 -carboxamide;

(S)- 1 -amino-N-( 1 -oxo-3 -phenyl- 1 -((6-(trifluoromethoxy) benzo [d]thiazol-2-yl)amino)propan- 2- yl)cyclobutane- 1 -carboxamide; l-(3-amino-2,2-dimethylpropanamido)-N-(6-(trifluoromethoxy)b enzo[d]thiazol-2-yl) cyclobutane- 1- carboxamide; (R)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethoxy)b enzo[d]thiazol-2-yl) propanamide;

(S)-2-(2-aminopropanamido)-2-methyl-N-(6-(trifluoromethox y)benzo[d]thiazol-2-yl) propanamide; 2-(2-aminoacetamido)-2-methyl-N-(6-(trifluoro methoxy)benzo[d]thiazol-2-yl)propanamide; (R)-2- amino-N-(2-methyl-l-oxo-l-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)propan- 2-yl)-3- phenylpropanamide ;

(S)-2-amino-3-(benzyloxy)-N-(2-methyl-l-oxo-l-((6-(triflu oromethoxy)benzo[d]thiazol-2- yl)amino)propan-2-yl)propanamide;

1 -amino-N-(2 -methyl- 1 -oxo- 1 -((6-(trifluoromethoxy)benzo [d]thiazol-2-yl)amino)propan-2- yl)cyclopropane- 1 -carboxamide;

1 -amino-N-(2 -methyl- 1 -oxo- 1 -((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2- yl)cyclobutane- 1 -carboxamide;

2-amino-2-methyl-N-(2 -methyl- 1 -oxo- 1 -((6-(trifluoromethoxy)benzo [d]thiazol-2-yl)amino) propan-2- yl)propanamide;

3-amino-2,2-dimethyl-N-(2-methyl-l-oxo-l-((6-(trifluorome thoxy)benzo[d]thiazol-2-yl) amino)propan-2-yl)propanamide ;

1 -(aminomethyl)-N-(2 -methyl- 1 -oxo- 1 -((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) propan-2- yl)cyclopropane- 1 -carboxamide;

1 -(aminomethyl)-N-(2-methyl- 1 -oxo- 1 -((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) propan-2 - yl)cyclopentane- 1 -carboxamide;

1-(aminomethyl)-N-(2-methyl-l-oxo-l-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) propan-2 - yl)cyclohexane- 1 -carboxamide;

2-methyl-2-(2-(methylamino)acetamido)-N-(6-(trifluorometh oxy)benzo[d]thiazol-2-yl) propanamide; 2-(2-(ethylamino)acetamido)-2-methyl-N-(6-(trifluoromethoxy) benzo[d]thiazol-2-yl) propanamide;

2-(2-(isopropylamino)acetamido)-2-methyl-N-(6-(trifluorom ethoxy)benzo[d]thiazol-2-yl) propanamide;

2-(2-(tert-butylamino)acetamido)-2-methyl-N-(6-(trifluoro methoxy)benzo[d]thiazol-2-yl) propanamide;

(S)-2-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d]t hiazol-2-yl)propanamide;

(S)-2-amino-N-((S)- 1 -oxo- 1 -((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-y l) propanamide;

(R)-2-amino-N-((S)- 1 -oxo- 1 -((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)propan-2-y l) propanamide; 3-Amino-N,2,2-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)ben zo[d]thiazol-2- yl)amino) ethyl)propanamide; l-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)be nzo[d]thiazol-2-yl)amino) ethyl)cyclopropane- 1 -carboxamide; l-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)be nzo[d]thiazol-2-yl)amino) ethyl)cyclopentane - 1 -carboxamide ; 1-(aminomethyl)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)be nzo[d]thiazol-2-yl)amino) ethyl)cyclohexane- 1 -carboxamide ;

N-methyl-2-(methylamino)-N-(2-oxo-2-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) ethyl)acetamide;

2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino) ethyl)acetamide;

2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluorometh oxy)benzo[d]thiazol-2-yl)amino) ethyl)acetamide;

2-(tert-butylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromet hoxy)benzo[d]thiazol-2-yl)amino) ethyl)acetamide;

2-(dimethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluorometho xy)benzo[d]thiazol-2-yl) amino) ethyl)acetamide;

2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d ]thiazol-2-yl)amino)ethyl) acetamide;

(S)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)ben zo[d]thiazol-2-yl)amino) ethyl) propanamide;

(R)-2-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)ben zo[d]thiazol-2-yl)amino) ethyl) propanamide;

3-amino-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d ]thiazol-2-yl)amino)ethyl) propanamide;

2-amino-N-ethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d] thiazol-2-yl)amino)ethyl) acetamide;

2-amino-N-isopropyl-N-(2-oxo-2-((6-(trifluoromethoxy)benz o[d]thiazol-2-yl)amino)ethyl) acetamide;

2-(aminomethyl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2- yl)benzamide; tert-butyl (4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)bu tyl)carbamate;

4-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan amide; (S)-N-(4-oxo-4-((6- (trifluoromethoxy)benzo[d]thiazol-2-yl)amino)butyl)pyrrolidi ne-2- carboxamide;

(S)-2-amino-4-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)ben zo[d]thiazol-2-yl)amino) butyl) pentanamide;

4-(2-aminoacetamido)-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)butanamide;

(S)-4-(2-aminopropanamido)-N-(6-(trifluoromethoxy)benzo [d]thiazol-2-yl)butanamide; (S)-2-amino-

3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol -2-yl)amino) butyl) butanamide;

(S)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazo l-2-yl)amino)butyl) pyrrolidine-2 - carboxamide;

(2S,3S)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) butyl)pentanamide ;

(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo [d]thiazol-2-yl)amino)butyl) amino)pentanoic acid; (S)-2-amino-4-(methylthio)-N-(4-oxo-4-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino) butyl)butanamide ;

(S)-4-(2-amino-3-phenylpropanamido)-N-(6-(trifluoromethox y)benzo[d]thiazol-2-yl) butanamide;

(S)-3-amino-4-oxo-4-((4-oxo-4-((6-(trifluoromethoxy)benzo [d]thiazol-2-yl)amino)butyl) amino)butanoic acid;

(S)-4-amino-5-oxo-5-((4-oxo-4-((6-(trifluoromethoxy)benzo [d]thiazol-2-yl)amino)butyl) amino)pentanoic acid;

(S)-4-(2-amino-3-(lH-indol-3-yl)propanamido)-N-(6-(triflu oromethoxy)benzo[d]thiazol-2- yl)butanamide;

(S)-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol- 2-yl)amino)ethyl)cyclohexyl) methyl)pyrrolidine-2 -carboxamide;

(S)-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol- 2-yl)amino)ethyl)cyclohexyl) methyl)pyrrolidine-2-carboxamide;

(S)-2-amino-4-methyl-N-((l-(2-oxo-2-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)pentanamide;

(S)-2-amino-3-methyl-N-((l-(2-oxo-2-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)butanamide;

2-amino-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thia zol-2-yl)amino)ethyl) cyclohexyl) methyl)acetamide; (S)-2-amino-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thi azol-2- yl)amino)ethyl)cyclo hexyl)methyl)propanamide;

2-(methylamino)-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benz o[d]thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)acetamide ;

(R)-2-amino-3-methyl-N-((l-(2-oxo-2-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)butanamide ;

(S)-5-oxo-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]th iazol-2-yl)amino)ethyl)cyclo hexyl)methyl)pyrrolidine -2 -carboxamide ;

(S)-2-amino-Nl-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d ]thiazol-2-yl)amino)ethyl)cyclo hexyl)methyl)pentanediamide;

(S)-2-amino-4-(methylthio)-N-((l-(2-oxo-2-((6-(trifluorom ethoxy)benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)butanamide;

(S)-2-amino-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d] thiazol-2-yl)amino)ethyl)cyclo hexyl)methyl)-3-phenylpropanamide;

(S)-3-amino-4-oxo-4-(((l-(2-oxo-2-((6-(trifluoromethoxy)b enzo[d]thiazol-2-yl)amino)ethyl) cyclohexyl)methyl)amino)butanoic acid;

(S)-4-amino-5-oxo-5-(((l-(2-oxo-2-((6-(trifluoromethoxy)b enzo[d]thiazol-2-yl)amino) ethyl) cyclohexyl)methyl)amino)pentanoic acid; (S)-2-amino-3-(lH-indol-3-yl)-N-((l-(2-oxo-2-((6-(trifluorom ethoxy)benzo[d]thiazol-2-yl) amino)ethyl)cyclohexyl)methyl)propanamide;

(R)-2-amino-3-methyl-N-(4-oxo-4-((6-(trifluoromethoxy)ben zo[d]thiazol-2-yl)amino) butyl) butanamide;

(R)-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl )amino)butyl)pyrrolidine-2- carboxamide;

(R)-5-oxo-N-(4-oxo-4-((6-(trifluoromethoxy)benzo[d]thiazo l -2-yl)amino)butyl) pyrrolidine-2- carboxamide;

(R)-2-amino-3-methyl-N-((l-(2-oxo-2-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) ethyl)cyclohexyl)methyl)butanamide;

(S)-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol- 2-yl)amino)ethyl)cyclohexyl) methyl)pyrrolidine-2 -carboxamide;

(R)-5-oxo-N-((l-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]th iazol-2-yl)amino)ethyl)cyclohexyl) methyl)pyrrolidine-2-carboxamide;

4-amino-3,3-dimethyl-N-(6-(trifluoromethoxy)benzo[d] thiazol-2-yl)butanamide;

(S)-3-(benzyloxy)-2-morpholino-N-(6-(trifluoromethoxy)ben zo[d]thiazol-2-yl)propanamide; (S)-3- (benzyloxy)-2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d ]thiazol-2-yl) propanamide;

(S)-l-methyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl) pyrrolidine-2-carboxamide;

2-(ethylamino)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino) ethyl)acetamide;

2-(isopropylamino)-N-methyl-N-(2-oxo-2-((6-(trifluorometh oxy)benzo[d]thiazol-2-yl)amino) ethyl)acetamide;

(R)- 1 -( 1 -(aminomethyl)cyclohexane- 1 -carbonyl)-N-(6-(trifluoromethoxy)benzo[d] thiazol-2- yl)pyrrolidine-2 -carboxamide;

N-methyl-2-(methylsulfonamido)-N-(2-oxo-2-((6-(trifluorom ethoxy)benzo[d]thiazol-2-yl) amino)ethyl)acetamide ;

2-(tert-butoxy)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy )benzo[d]thiazol-2-yl)amino) ethyl)acetamide;

N,4,4-trimethyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d] thiazol-2-yl)amino)ethyl) pentanamide; tert-Butyl(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo [d]thiazol-2-yl)amino)ethyl)amino)- 2- oxoethyl)( 1 -(trifluoromethyl)cyclopropyl)carbamate;

N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol -2-yl)amino)ethyl)-2-((l- (trifluoromethyl)cyclopropyl)amino)acetamide;

N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol -2-yl)amino)ethyl)-2-((2,2,2- trifluoroethyl)amino)acetamide hydrochloride;

2-acetamido-N -methyl -N-(2-oxo-2-((6-(trifluoromethoxy) benzo[d]thiazol-2-yl)amino)ethyl) acetamide; N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2 -yl)amino)ethyl)amino)-2- oxoethyl)propionamide ;

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazo l-2-yl)amino)ethyl)amino)-2- oxoethyl)butyramide;

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazo l-2-yl)amino)ethyl)amino)-2- oxoethyl)isobutyramide ;

N-(2-(methyl(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazo l-2-yl)amino)ethyl)amino)-2- oxoethyl)benzamide ;

2,2,2-trifluoro-N-(2-(methyl(2-oxo-2-((6-(trifluoromethox y) benzo[d]thiazol-2-yl)amino)ethyl) amino)-2-oxoethyl)acetamide; N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2- yl)amino)ethyl)-2-(( 1,1,1- trifluoro-2-methylpropan-2-yl)amino)acetamide;

2-(2 -oxopiperazin- 1 -yl)-N-(6-(trifluoromethoxy)benzo [d]thiazol-2-yl)acetamide;

(S)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thi azol-2-yl)amino)ethyl) piperazine- 2- carboxamide;

(R)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thi azol-2-yl)amino)ethyl)piperazine- 2- carboxamide;

Benzyl (2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy )ethyl)carbamate;

2-aminoethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;

Benzyl ethyl (2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamoyl)oxy ) ethyl)carbamate; 2- (Ethylamino)ethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;

Benzylmethyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol-2-y l)carbamoyl)oxy)ethyl) carbamate; 2- (Methylamino)ethyl (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbamate;

Benzylisopropyl(2-(((6-(trifluoromethoxy)benzo[d]thiazol- 2-yl)carbamoyl)oxy)ethyl) carbamate;

2-(Isopropylamino)ethyl (6 -(trifluoromethoxy )benzo[d] thiazol-2-yl)carbamate;

(5-methyl-2 -oxo-1, 3-dioxol-4-yl)methyl(5-(trifluoromethoxy)benzo[d]thiazol-2-y l)carbamate; 4- amino-2,2-dimethyl-N-(6-(trifluoromethoxy)benzo[d]thiazol-2- yl)butanamide;

(S)-2-amino-Nl,N5-bis(6-(trifluoromethoxy)benzo[d]thiazol -2-yl)pentanediamide;

2-(dimethylamino)-N-(6-(trifluoromethoxy)benzo[d]thiazol- 2-yl)acetamide; l,3-bis(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)urea;

2-Amino-N-{[methyl({[6-(trifluoromethoxy)-l,3-benzothiazo l-2- yl] carbamoyl } methyl)carbamoyl]methyl } acetamide ;

N -Methyl-2- [(oxan-4-yl)amino] -N-( { [6-(trifluoromethoxy)- 1 ,3 -benzothiazol-2- yl] carbamoyl } methyl)acetamide ;

2- [(Azetidin-3 -yl)amino] -N -methyl -N -( { [6-(trifluoromethoxy)- 1 ,3 -benzothiazol-2- yl] carbamoyl } methyl) acetamide ;

N-Bethyl-2-[(piperidin-4-yl)amino]-N-({[6-(trifluorometho xy)-l,3-benzothiazol-2- yl] carbamoyl } methyl) acetamide ; 2-[N-Methyl-2-(morpholin-4-yl)acetamido]-N-[6-(trifluorometh oxy)-l,3-benzothiazol-2- yl] acetamide;

2-[N-Methyl-2-(piperazin-l-yl)acetamido]-N-[6-(trifluorom ethoxy)-l,3-benzothiazol-2- yl]acetamide;

(2S)-2-Amino-N-{[methyl({[6-(trifluoromethoxy)-l,3-benzot hiazol-2- yl] carbamoyl } methyl) carbamoyl] methyl } propanamide ;

(2S)-2-Amino-N-{[methyl({[6-(trifluoromethoxy)-l,3-benzot hiazol-2- yl] carbamoyl } methyl) carbamoyl] methyl } -3 -phenylpropanamide ;

(2S)-2-Amino-3-methyl-N-{[methyl({[6-(trifluoromethoxy)-l ,3-benzothiazol-2- yl] carbamoyl } methyl) carbamoyl] methyl } butanamide ;

(2S)-2-Amino-4-methyl-N-{[methyl({[6-(trifluoromethoxy)-l ,3-benzothiazol-2- yl] carbamoyl } methyl)carbamoyl] methyl } pentanamide ;

N-Methyl-2-[(oxetan-3-yl)amino]-N-({[6-(trifluoromethoxy) -l,3-benzothiazol-2- yl] carbamoyl } methyl)acetamide ;

2-tert-Butylamino-N-(2,2,2-trifluoro-ethyl)-N-[(6-trifluo romethoxy-benzothiazol-2- ylcarbamoyl)- methyl] -acetamide ;

2-(Cyclohexylamino)-N-(2-oxo-2-((6-(trifluoromethoxy)benz o[d]thiazol-2- yl)amino)ethyl)acetamide ;

2-[( 1 -Methanesulfonylpiperidin-4-yl)amino] -N -methyl -N -( { [6-(trifluoromethoxy)- 1,3- benzothiazol- 2-yl] carbamoyl } methyl)acetamide ;

2-[( 1 -Amino-2-methylpropan-2-yl)amino] -N-methyl-N-({ [6-(trifluoromethoxy)- 1 ,3- benzothiazol-2- yl] carbamoyl } methyl)acetamide ;

2-{N-Methyl-2-[methyl(piperidin-4-yl)amino]acetamido}-N-[ 6-(trifluoromethoxy)-l,3- benzothiazol- 2-yl]acetamide;

N-Methyl-2-[(l-methylpiperidin-4-yl)amino]-N-({[6-(triflu oromethoxy)-l,3-benzothiazol-2- yl] carbamoyl }methyl)acetamide;

2- [( 1 -Acetylpiperidin-4-yl)amino] -N -methyl -N-( { [6-(trifluoromethoxy)- 1 ,3 -benzothiazol-2- yl] carbamoyl } methyl)acetamide ;

N-Methyl-2-[(4-methylpiperidin-4-yl)amino]-N-({[6-(triflu oromethoxy)-l,3-benzothiazol-2- yl] carbamoyl } methyl) acetamide ; or a pharmaceutically acceptable form thereof.

[00937] In further embodiments, the glutamate modulator has a compound according to: including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein: R23 is selected from the group consisting H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH20H, CH2OCH2Ph, CH2CH2OCH2Ph, CH(0H)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3 -indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2.

[00938] In further embodiments, the glutamate modulator is selected from: yBamino>ihyDamisK)>2<)X0ethyl)pro|iaiiamide;

(R)<2-amiRn-N-<2~UTve&yU2-<>xo-2d(<i"( t.rifi«oromeUK>xy)benzo[d]thiazol-2-- yIjamimyX'thyl)anun?).p2”OX<K‘thybpropMiauddc;

(S)“2-aniiiK>3-niethyl-N-(2*(methyI(2-oxo-24(64tritl uoronwtlH>xy)ben2o(d]?hijjzoI-2" yl )ami no Jethy! iamiuo)- 2 -nxoeth yl )butimam ide ;

(R)«2"aniinO’3’n$ethy1zN<24tr^thy4(2’Oxo~2-((6& lt;miluomn^tte>xy)benz0[d]d».azo1-2' yl)amiaoi£thyl)amhio)*2*<3Xtsclhjd}buianau:ddei

(S)'2xmhnu--N-t2’4nigihyl(2’Oxo~2-((6--{trinuuR>na cd5oxy}benx<}[d]ihi;4i50b2- yl2tn:miK)!sdiyham5noJ-2-<!xt.®lhy:}'3~pht*nylpropEERami de;

(R)-2-amitK)-N-(2-(ntetbyl(2-oxo-24X64'tTU'laoronajthoxy) beiizx»[d]tb.ia<ix>i-2” yI)andno)eihyl)am}!K>)-2-0X<>eihyl.)-3-phcnyipr0p _t inamide:

(S)’2-arai»o4~niethyl-'N’(2“(niediyl(2’OXO"2’( (6’itrifliK)ron’}eihaxy)benzo[djthiazol"2- yI)4anino')eihyl)aniHh))“2-axoeihy] .ipenianamide;

(R)"2"ajY)MK}"4"Riethy!-N“(2--(B^th¥l(2-ox<>24fI >-ttrihucTOnK-ihoxy)henzo[d]thi.3z<>l"2'- y I) ami no .(ethyl Jantino) • 2 - oxoeth y I )pe a tanami de ;

(S)“2--aminG~3-hy<1roxy»N-(2~(methyl(2-oxo~2-((6'(t riflu<^‘<'>m£«.1i0xy)beozo[d]ihiazwl-2“ yl) ami no sc th y 1 kmsiao) -2 -oxoe th y j ) pro pan ami de ;

(R)-2-amiiK>-3"hydr<>xy’N-(2-(inethy1(2-0X(> ;-2^(fi-(tnfli.K>r<>a?ethoxy)benzo[d]ihiM0t-2' yljatruno tcthy ? ^ainjtK>)“2“<>X0ethyi)pr0pa(ia:midet

2-(2-auwnc3acetaB:rido)'N~me^yl>N-{2-0xo-2-{(fi-(trinu ur<>mfJthoxy)fenz0[d]thiazoi’2'- y 1 j : • H ^; ;■ ' K' thy? ? ace < . s m d v : nr a phaniiaeetakally aceepuble form thereof.

[00939] In further embodiments, the glutamate modulator is a compound according to: pharmaceutically acceptable form thereof. [00940] In further embodiments, the glutamate modulator is a peptide (monopeptide, dipeptide, tripeptide, etc.) prodrug of riluzole.

[00941] In further embodiments, the glutamate modulator is a tripeptide prodrug of riluzole.

[00942] In further embodiments, the glutamate modulator is a peptide prodrug of riluzole which may be metabolized to one or more of sarcosine and glycine.

[00943] In an embodiment, the glutamate modulator is troriluzole, or a pharmaceutically acceptable form thereof.

AMPA Receptor Modulators

AMPA receptors bind glutamate and allow the passage of calcium, sodium, and potassium. They primarily function to transmit excitatory signals. AMPA receptors are implicated in diseases of excess neuroexcitation, including neurologic and neurodegenerative diseases. In certain embodiments of the present disclosure, “glutamate modulators” may include AMPA receptor modulators.

Formula 204

[00944] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 204. Such compounds are described in WO 2020/178782, published September 10, 2020 and corresponding to PCT/IB2020/051920, filed March 5, 2020. which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 204, this reference incorporated by reference herein controls.

[00945] In an embodiment, the glutamate modulator is a compound according to Formula 204: wherein R1 is (C6-C10)-aryl, or (C5-C10)-heteroaryl, each of which is optionally substituted with one to three R4 groups; each R4 is independently selected from the group consisting of halo, -CF3, -OCF3, - CN, -NO2, -Ra, -XI -Ra, -ORa, -Xl-ORa, -SRa, -Xl-SRa, -NRaRb, -XI -NRaRb, - NRaRc, -XI -NRaRc, -C(=O)Ra, -Xl-C(=O)Ra, -C(=O)Rc, -Xl-C(=O)Rc, - C(=O)ORa, -NRaC(=O)Rb, -C(=O)NRaRb, -C(=O)NRaRc, -S(=O)2NRaRb, - S(=0)2NRaRc, -NRaS(=O)2Rb, -S(=O)2Ra and -S(=O)CF3; each Ra and Rb is independently selected from the group consisting of H, (C1-C6)- alkyl, (Cl-C6)-haloalkyl (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl, phenyl and benzyl, and each Rc is independently selected from the group consisting of azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, wherein the cyclic portion of Rc is optionally further substituted with a halo, -OH, (Cl-C6)-alkyl, or (Cl-C6)-haloalkyl; each XI is a (Cl-C6)-alkylene;

R2 is (C3-C10)-cycloalkyl, (C3-C10)-heterocycloalkyl, (Cl — C10)-alkyl, (C6-C10)- aryl, or (C5-C10)-heteroaryl, each of which is optionally substituted with one to three R3;each R3 is independently selected from the group consisting of halo, -CF3, - OCF3, - CN,-N02, -Rd, -X2-Rd, -ORd, -X2-0Rd, -SRd, -X2-SRd, -NRdRe, -X2- NRdRe, -NRdRf, -X2-NRdRf, -C(=O)Rd, -X2-C(=O)Rd, -C(=O)Rf, -X2-C(=O)Rf, - C(=O)ORd, -NRdC(=O)Re, -C(=O)NRdRe, -C(=O)NRdRf, -S(=O)2NRdRe, S(=O)2NRdRf, -NRdS(=O)2Re, -S(=O)2Rd or -S(=O)CF3; each Rd and Re are independently selected from the group consisting of H, (C1-C6)- alkyl, (C1-C6)- haloalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C6)-cycloalkyl, phenyl and benzyl, and each Rf is independently selected from the group consisting of azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, and diazepano; each X2 is a (Cl-C6)-alkylene; and pharmaceutically acceptable salts, stereoisomers, and/or solvates thereof.

[00946] In further embodiments, the glutamate modulator has a formula according to:

[00947] In further embodiments, the glutamate modulator has a structure according to:

Formula 205

[00948] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 205. Such compounds are described in, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 205, this reference incorporated by reference herein controls.

[00949] In an embodiment, the glutamate modulator is a compound according to Formula 205: wherein each Rl and each R2 and each R7 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, (Cl-C6)alkoxy, cyano, nitro, amino, (Cl-C6)alkylamino, di(Cl- C6)alkylamino, — (C=0)NH2, — (C=O)NH((C1-C6)alkyl), — (C=O)N((C1- C6)alkyl)2, — O(C=O)— (Cl-C6)alkyl, — (C=O)— O— (Cl-C6)alkyl, (Cl-C6)alkyl, (C6-C10)aryl, (Cl-C9)heteroaryl, (Cl-C9)heterocycloalkyl, (C3-C10)cycloalkyl, or (Cl-C6)alkyl-S(O)2 — NH — , wherein said (Cl-C6)alkoxy, (Cl-C6)alkylamino, di(Cl-C6)alkylamino, — (C=O)NH((C1-C6)alkyl), — (C=O)N— ((Cl-C6)alkyl)2, — (C=O)O— (Cl-C6)alkyl, (Cl-C6)alkyl, (C6-C10)aryl, (Cl-C9)heteroaryl, (Cl- C9)heterocycloalkyl, (C3-C10)cycloalkyl or (Cl-C6)alkyl-SO2 — NH — are each independently optionally substituted with one, two, three or four R8, wherein each R8 is independently selected from the group consisting of halogen, — CN, — OR9, (Cl- C6)alkyl, (C2-C6)alkenyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (Cl- C9)heterocycloalkyl, (C6-C10)aryl, (Cl-C9)heteroaryl, — (C=0)R9, — (C=0)0R9, — 0(C=0)0R9, — (C=O)— N(R9)2, — SO2— N(R9)2, — N(R9)2, — NR9— (C=0)R9, and — N(R9) — S(O)2R9 wherein each of the R8 (Cl-C6)alkyl, (Cl- C9)heterocycloalkyl, (C3-C10)cycloalkyl, (C6-C10)aryl or (Cl-C9)heteroaryl is optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, — R9, — OR9, — N(R9)2, — S(O)tR9, — S(O)2N(R9)2, — N(R9)— SO2R9, — 0(C=0)R9, — (C=O)— OR9, — (C=O)— N(R9)2, — N(R9)— (C=O)— R9, — N(R9)— (C=O)— N— (R9)2, and — (C=0)R9; t is 0, 1 or 2; or when R1 is (C6-C10)aryl or (Cl-C9)heteroaryl, two R8 substituents bonded to adjacent carbon atoms of Rl, together with the adjacent carbon atoms, may be taken together to form a (Cl-C9)heterocyclic or (C3-C10)carbocyclic ring which is optionally substituted with one or more RIO, wherein each R19 is independently selected from the group consisting of hydrogen, — CN, halogen, — (C=0)R9, — (C=O)— N(R9)2, — N(R9)2, — OR9 or — R9; or, two R1 substituents bonded to adjacent carbon atoms of ring “A,” may be taken together with the adjacent carbon atoms, form a (Cl-C9)heterocyclic or (C3- ClOjcarbocyclic ring which is optionally substituted with one or more RIO; m is zero, one, two or three; n is zero, one, two or three; p is zero, one, two or three; q is zero, one, two or three; R3 is hydroxyl; each R4 is independently selected from the group consisting of hydrogen, hydroxyl, (Cl-C6)alkoxy, cyano, nitro, — (C=0)NH2, — (C=O)NH((C1-C6)alkyl), — (C=O)N((C 1 -C6)alkyl)2, — O(C=O)(C 1 -C6)alkyl, — (C=O)— O— (C 1 -C6)alkyl, (Cl-C6)alkyl, (Cl-C6)alkyl-S(O)2 — NH — or two R4 groups on the same carbon atom may be taken together to form an oxo (=0) radical; wherein said (Cl- C6)alkoxy, — (C=O)NH(alkyl), — (C=0)N-(alkyl)2, — (C=0)0— (Cl-C6)alkyl, (Cl-C6)alkyl, or (Cl-C6)alkyl-SO2 — NH — are each independently optionally substituted with one, two, three or four R8, wherein each R8 is independently selected from the group consisting of halogen, — CN, — 0R9, (Cl-C6)alkyl, (C2-C6)alkenyl, — (C=0)R9, — (C=0)0R9, — 0(C=0)0R9, — (C=0)— N(R9)2, — S02— N(R9)2, — N(R9)2, — NR9— (C=0)R9, and — N(R9)— S(O)2R9 wherein each of the R8 (Cl- C6)alkyl is optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, — R9, — 0R9, — N(R9)2, — S(0)qR9, — S(O)2N(R9)2, — N(R9)— SO2R9, — 0(C=0)R9, — (C=0)— 0R9, — (C=0)— N(R9)2, — N(R9)— (C=0)— R9, — N(R9)— (C=0)— N— (R9)2, and — (C=0)R9;

R5 is hydrogen,

R6 is (Cl-C6)alkyl-(C=0)— , [(Cl-C6)alkyl]2N— (C=0)— , (Cl-C6)alkyl-SO2— , (C3-C10)cycloalkyl-SO2 — , or [(Cl-C6)alkyl]2N — S02 — ; wherein said (Cl- C6)alkyl moi eties of said [(Cl-C6)alkyl]2N — (C=0) — and [(Cl-C6)alkyl]2N — S02 — may optionally be taken together with the nitrogen atom to which they are attached to form a three to six membered heterocyclic ring;

R8 is independently selected from the group consisting of halogen, — CN, — 0R9, (Cl-C6)alkyl, (C2-C6)alkenyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (Cl- C9)heterocycloalkyl, (C6-C10)aryl, (Cl-C9)heteroaryl, — (C=0)R9, — (C=0)0R9, — 0(C=0)0R9, — (C=O)N(R9)2, — SO2NR9, — N(R9)2, — N(R9)— (C=0)R9, and — N(R9)2 — SO2R9 wherein each of the R8 (Cl-C6)alkyl, (Cl-C9)heterocycloalkyl, (C3-C10)cycloalkyl, (C6-C10)aryl or (Cl-C9)heteroaryl is optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, — R9, — OR9, — N(R9)2, — S(O)c,R9, — SO2N(R9)2, — NR9SO2R9, — 0(C=0)R9, — (C=0)0R9, — (C=O)N(R9)2, — NR9(C=O)R9, — (NR9)— (C=O)N(R9)2, and — (C=0)R9;

R9 is independently selected from the group consisting of hydrogen, (Cl-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)cycloalkyl, (C6-C10)aryl, (Cl- C9)heterocycloalkyl and (Cl-C6)heteroaryl; wherein each R9 (Cl-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (C6-C10)aryl, (Cl- C9)heterocycloalkyl or heteroaryl is optionally independently substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, (Cl-C6)alkylamino, di(Cl-C6)alkylamino, (Cl- C6)alkyl optionally substituted with one or more halogen or (Cl-C6)alkoxy or (C6- C10)aryloxy, (C6-C10)aryl optionally substituted with one or more halogen or (Cl- C6)alkoxy or (Cl-C6)alkyl or trihalo(Cl-C6)alkyl, (Cl-C9)heterocycloalkyl optionally substituted with (C6-C10)aryl or (Cl-C9)heteroaryl or =0 or alkyl optionally substituted with hydroxy, (C3-C10)cycloalkyl optionally substituted with hydroxy, (Cl-C9)heteroaryl optionally substituted with one or more halogen or (Cl- C6)alkoxy or (Cl-C6)alkyl or trihalo(Cl-C6)alkyl, halo(Cl-C6)alkyl, hydroxy(Cl- C6)alkyl, carboxy, (Cl-C6)alkoxy, (C6-C10)aryloxy, (Cl-C6)alkoxycarbonyl, aminocarbonyl, (Cl-C6)alkylaminocarbonyl and di(Cl-C6)alkylaminocarbonyl;

RIO is independently selected from the group consisting of hydrogen, — CN, halogen, — (C=0)R9, — (C=0)NR9, NR9, — 0R9 or — R9; ring “A” is (C6-C10)aryl, (Cl-C9)heteroaryl, (C4-C10)cycloalkyl, or (Cl- C9)heterocycloalkyl;

“X” is >NH, — O— or >C(R4)2; and

“Y” is absent, >NR11, — NR11— (C=0)— , — O— or >C(R7)2.

[00950] In further embodiments, the glutamate modulator has a structure according to:

[00951] In further embodiments, the glutamate modulator is a compound selected from:

N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenyl]-4-hydroxytetra hydrofuran-3-yl}propane-2- sulfonamide;

N-[(3S,4S)-4-biphenyl-4-yl-4-hydroxytetrahydrofuran-3-yl] propane-2-sulfonamide;

N-{(3R,4R)-4-[4-(5-cyano-2-thienyl)phenyl]-4-hydroxytetra hydrofuran-3-yl}propane-2- sulfonamide;

N-[(3R,4R)-4-biphenyl-4-yl-4-hydroxytetrahydrofuran-3-yl] propane-2-sulfonamide;

[4-(2'-cyano-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3- yl]propane-2-sulfonamide;

N-[4-(2'-cyano-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan- 3-yl]-isobutyramide;

N'-[4-(2'-cyano-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan -3-yl]-N,N-dimethylsulfamide;

[4-(2'-cyano-4'-fluoro-biphenyl-4-yl)-4-hydroxy-tetrahydr o-furan-3-yl]propane-2- sulfonamide;

2-Cyano-4'-[3-hydroxy-4-(propane-2-sulfonylamino)-tetrahy dro-furan-3-yl]-biphenyl-4- carboxylic acid;

[4-(3'-cyano-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3- yl]propane-2-sulfonamide;

[4-(4'-cyano-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3- yl]propane-2-sulfonamide;

[4-(2'-methyl-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3 -yl]propane-2-sulfonamide;

[4-(4'-methyl-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3 -yl]propane-2-sulfonamide;

[4-(2'-fluoro-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3 -yl]propane-2-sulfonamide;

[4-(4'-fluoro-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3 -yl]propane-2-sulfonamide;

[4-(2'-chloro-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3 -yl]propane-2-sulfonamide;

[4-(4'-chloro-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3 -yl]propane-2-sulfonamide;

[4-(Z-hydroxy-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3 -yl]propane-2-sulfonamide; [4-(4'-hydroxy-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3-y l]propane-2-sulfonamide; [4-(2'-methoxy-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3-y l]propane-2-sulfonamide; [4-(2'-ethoxy-biphenyl-4-yl)-4-hydroxy-tetrahydro-furan-3-yl ]propane-2-sulfonamide;

{4-[2'-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-4-hydroxy- tetrahydro-furan-3-yl}propane-2- sulfonamide;

4'-[3-Hydroxy-4-(propane-2-sulfonylamino)-tetrahydro-fura n-3-yl]-biphenyl-2-carboxamide;

{4-hydroxy-4-[2'-(pyrrolidine-l-sulfonyl)-biphenyl-4-yl]- tetrahydro-furan-3-yl}propane-2- sulfonamide;

[4-(2'-methanesulfonylamino-biphenyl-4-yl)-4-hydroxy-tetr ahydro-furan-3-yl]propane-2- sulfonamide;

[4-(2'-methoxymethyl-biphenyl-4-yl)-4-hydroxy-tetrahydro- furan-3-yl]propane-2- sulfonamide;

N-{4'-[3-Hydroxy-4-(propane-2-sulfonylamino)-tetrahydro-f uran-3-yl]-biphenyl-4-yl}- acetamide;

{4-hydroxy-4-[4-(4-methyl-thiophen-2-yl)-phenyl]-tetrahyd ro-furan-3-yl}propane-2- sulfonamide;

[4-hydroxy-4-(4-pyridin-2-yl-phenyl)-tetrahydro-furan-3-y l]propane-2-sulfonamide; [4-hydroxy-4-(4-pyridin-3-yl-phenyl)-tetrahydro-furan-3-yl]p ropane-2-sulfonamide; [4-hydroxy-4-(4-pyridin-4-yl-phenyl)-tetrahydro-furan-3-yl]p ropane-2-sulfonamide; [4-hydroxy-4-(4-pyrimidin-5-yl-phenyl)-tetrahydro-furan-3-yl ]propane-2-sulfonamide; [4-hydroxy-4-(4-pyrrolidin-l-yl-phenyl)-tetrahydro-furan-3-y l]propane-2-sulfonamide;

N-(l-{4-[3-Hydroxy-4-(propane-2-sulfonylamino)-tetrahydro -furan-3-yl]-phenyl}- pyrrolidin-3-yl)-acetamide; and [4-hydroxy-4-(4-phenoxy-phenyl)-tetrahydro-furan-3-yl]propan e-2-sulfonamide, including pharmaceutically acceptable salts thereof.

Formula 206

[00952] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 206. Such compounds are described in WO 2009/053448, pulished April 30, 2009 and corresponding to PCT/EP2008/064407, filed October 24, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 206, this reference incorporated by reference herein controls. [00953] In an embodiment, the glutamate modulator is a compound according to

Formula 206: (where a crossed bond is a single bond indicating both possible stereochemistries at the chiral carbon having hydrogen bound), wherein X is selected from: ;

R1 is selected fromC(O)d-4alkyl and C(O)NR5R6, wherein R5 and R6 are independently selected from hydrogen and Cl-4alkyl; or R5 and R6, together with the nitrogen to which they are attached, form a saturated 4- to 7-membered ring;

R2 is Cl -4 alkyl;

R4 is selected from: C(O)OCi-6alkyl; Cl-6 alkyl sulfonyl; a group (CH2)nC(O)NR7R8 wherein R7 and R8 are independently hydrogen or Cl-6alkyl optionally substituted by hydroxyl; or R7 and R8 form a 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, Cl-6alkyl, hydroxyl and NR9R10; a group (CH2)nY wherein Y is selected from cyano, SO2NR9R10 and NHRI 1, wherein R11 is selected from C(O)Cl-6alkyl, C(O)OhaloCl-6alkyl and Cl - 6alkyl sulfonyl; a group (CH2)Z wherein Z is an N-linked 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, Cl-6alkyl, hydroxyl and NR9R10; o a 5 or 6 membered unsaturated carbocyclic or unsaturated heterocyclic ring, optionally substituted by one or two groups selected from Cl-6alkyl,haloCl- 6alkyl, Cl-6alkoxy and halogen; an N-linked 5 or 6 membered saturated heterocyclic ring substituted by one or two groups selected from oxo, Cl-6alkyl, hydroxyl and NR9R10; an N-linked 5 or 6 membered unsaturated heterocyclic ring fused with a cyclohexane ring or a tetrahydropyran ring and further optionally substituted by haloCl-6alkyl; wherein each R9 and each RIO are independently selected from hydrogen and Cl - 6alkyl, and each n is independently 0 or 1 ; and R3 is hydrogen, or R3 and R4 together form a tetrahydropyranyl or a cyclopentanyl ring.

[00954] In further embodiments, the glutamate modulator is any compond according to:

1-(3-(2“hydroxyethylH-fne(h^-2“{H"(1H“pyrazol"1-yl) ph^^]imino}-2 _> 3^ilhydro-1,3- th iazok5~yl Jethanons

N-i^^'aretyl'S^'dirnethyl-'l jS-thfezol-ZfSHJ-^id^eJaminoJphen^Jacetmtide

N--(4-{[&-acetyl--3--ethy!--4"msthy!--1 ,3-thiaz:Db-2(3H)--yhder!S]a!T3ino>pheriyt)acetam _: ids

N44-{[5"BGStyk3~(2-hydrQxyethytM~metihy!-i,3-thf3zo^2(3H) - yi ide n e]am ino}p h enyi )ace fam ide 1~[2~(2 _! 3-dihydro-1H-ihden~5-yiimmo>3-{2--hydroxyethylH-n3e thyl-2<3-dihydr£)-1 _! 3"th)a2Of-

5-yOethanone

1-[(4-{[5-acefy!~3-eti3yi*4-methyi-1 ,3-thiazoi--2(3H)-yiideneJaminG}-pheeyii)methyl]--2- pyrrolidinone

3- (2-hy4foxyethyl )-N , N ,4-trim ethyl-2*{[4’-( methyloxy)-4 -biphenyly HMnc<}-2 , 3-d i hydro- 1 _: 3- th iazote-S-ca rboxarn tde

1-{3<3thyl"4”methyl'-2~({4~[(4”methyi'-1"piperazin yi)ca!‘bonyi]phenyi}irsMno>2.3'-dihydre~1,3“ th iazol-5-ylJethan one

4’{[5-acetyl-3~(2-hydroxyethyrj-4~methyi-1 ,3-thiazcM-2f3H}-yiidene]amino}benzonitrile ar a salt thereat

Formula 207

[00955] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 207. Such compounds are described in WO 2007/122241, published November 1, 2007, corresponding to PCT/EP2007/054007, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 207, this reference incorporated by reference herein controls.

[00956] In an embodiment, the glutamate modulator is a compound according to formula 207:

(where a crossed bond is a single bond indicating both possible stereochemistries at the chiral carbon having hydrogen bound), wherein R10 is selected from methyl and hydrogen;

X is selected from:

Z is selected from S and O;

R1 is selected from H, Cl-4alkyl, C(O)OCl-4alkyl, C(O)Cl-4alkyl, C(O)haloCl-4alkyl, C(O)NR6R7, cyano, and R6 and R7 are each independently selected from H and Cl-4alkyl; R2 is selected from Cl-4alkyl, C(O)CH3, and CN;

R3 is selected from the group consisting of H, NH2, CH3, (CH2)nOH and (CH2)nCl- 4alkoxy, wherein n is 0 or 1 ; and when R3 is CH3, (CH2)nOH or (CH2)nCl-4alkoxy, then R4 is selected from the group consisting of H, halo, Cl-4alkoxy, haloCl-4alkoxy, Cl-4alkyl, Cl-4alkylthio, HaloCl- 4alkylthio, haloCl-4alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Cl-4alkyl or R8 and R9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;

• when R3 is NH2, then R4 is selected from H, halo, d.4alkoxy, haloCl-4alkoxy, Cl-4alkyl, Cl-4alkylthio, haloCl-4alkylthio, haloCl-4alkyl and NR8R9 wherein R8 and R9 are independently selected from Cl -4 alkyl or R8 and R9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S; • when R3 is H, then R4 is selected from the group consisting of H, Cl-4alkoxy, chloro, bromo, haloCl-4alkoxy, Cl-4alkyl, haloCl-4alkyl, and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Cl -4 alkyl or R8 and R9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S;

• when X is -CH2CF3, then R4 is selected from Cl-4 alkoxy and Cl-4alkyl; when X is methyl, then R4 is selected from Cl-4alkoxy, haloCl-4alkoxy, Cl-4alkyl, haloCl-4alkyl and NR8R9 wherein R8 and R9 are independently selected from hydrogen and Cl-4alkyl or R8 and R9 together with the nitrogen atom to which they are attached form a five- or sixmembered ring which may optionally contain one or more heteroatoms selected from O, N and S; when X is , then R4 is selected from the group consisting of H, halo, Cl-4alkoxy, haloCl-4alkoxy, Cl-4alkyl, haloCl-4alkyl and NR8R9 wherein R8 and R9 are independently selected from Cl-4alkyl or R8 and R9 together with the nitrogen atom to which they are attached form a five or six membered ring which may optionally contain one or more additional heteroatoms selected from O, N and S.

[00957] In further embodiments, the glutamate modulator is a compound selected from:

1-[2-{[4-(ethy!oxyjphefiyf]iminQ}“3-(2-hydroxyeihyi)-4- m&thyi-2,3-dthydro-13- thiazoi-5-yiJethanone

1-[2-((4-ethy!phenyi)imino]-3-(2-hydroxyethyl)-4-mGthy;t- 2,3-<}ihydro-1 ,3-thlazol-5- yljethanone

1-{2-{[4~(ethytoxy)phenylJimino}-4-methyl-3"[2"(methyloxy }ethyl]-2 _I 3-dihydro--1 ,3~ thiazol-5-y Qetha non e

1-{3-(2-hydmxyethyl>4-methyl-2-({<H(trifluoromethyl joxy]phenyl}imino>2,3- d (hydro- 1 , 3-thiazot-5-y Ijetha none

H3^2-hydro)^eriiylH“f’i®th^-2-{H-(trifluoromeihyl)ph enyl|lmino}-2,3-dihydKJ-1 ,3- th iazof*5-y IJsthanan a

1-(3-ethyi-2-{S.4-(etby(Qxy)phenylpm!no}-4-rn®thyi--2 _I 3-dihydro-1 ₍ 3-thiazok5- yijethanone

2-[2-{H“ (athyloxy )phenyQimino)-4 ,5-di methyl- 1 , 3-th iazol-3(2 H}~ y l]e th a no!

1-[2-[(4-l»Jtylph^iy^mino]-3-(24iydfOxyethylH'<o^yl-2 ₅ 3-dihydro-1 _> 3-thjazol-S- yQethanone

1 -[24[4-( ethy toxy )p heny Qi mi no}-3- (3-hyd roxy propyl )-4- meth yl-2, 3-d ihydro-1.3- th iazoi-5-yljet h a no ns

1-(3-(2-hydroxyethyl)-4-meihyl-2-{{4-(4-morphoiinyl)pheny tJimino}-2,3-dihydro-1 _l 3“ th iazol~5-yi)ethano ne

2-{[4-(ethytoxy)frfien^Jimino}»3-(2»hydroxyethyl}4"niet hyi“2,3-dihydro-1 _s 3-thiazde- 5-cariro nitrite

3-ethyl-2-{[4-(ethyloxy)phenylJimino}-44nethyl“2,3-dihy dro-1 _s 3-thiazole-5- carbonitrile

1'-{2-[(4“Chlofopheny0imfno]-3-sthyl“4-methy|-2 _< 3-dshydt’o-1,3-thiazol-5-yl}©thanone

1 -(3-cydo pro py 1-4 ~methyh2-{[4-4 trifluoro m ethyl )p henyl] im i no}-2 ,3-dihy d ro» 1 , 3- th tazoi- 5-yl Jethanone 1 -(3-ethyt-4~methyi'2:-^4-(triffuoromethyi)phenyQimino}“2,3 -dihydro-1 ,34hiazol-5- yl)ethanone

1-(3-ethyl-4-melhyl-2’({4-[(M'fe<xomeih^)oxyjphenyl) imino)-2 _[ 3“dihydra-1 ,3- thiazoi-5-yQsthanone

1 iftuoramethyt)oxy]pheny!}i mine >-3-(2~hyd roxyeth yl }-4-methy 1-2 , 3- dihydro- 1 , 34Nazok5-yQethanone

143-(2-hydroxyethytMd7tethyk2-({44(tritluc»ramethyl)oxyj phen)4}lmino)-2«3- dihydro-1 , 3-thiazol-5»y Ifethanooe

[(3~ethyl-4,5-dimethyi-i,3-thfazo!-2(3/f)-yiideneH4-(trif luoromeihyf)phenyl]amina 1-(3-sthyi-2-{H-(®thy}oxy}phenyl]imino}-4-methyl-2,3-dihydr o-1 _: 3-oxazoi-5- yQsthanona

H24(4-bmmof4ienyl)imfcioI-3-ethyl-4-methyl’2<3-dlhyd ro-1 ,3-thiazol-5-y1}ethanone 1-(3-ethyi-4-methyh24H“Ci-py ^f ' ^J '^^dinyi)phenyljfmino}-2,3-dihydro-1 _! 3’thlazol~5- yljethanone

1 -(3-ethyl-4"mathyl-2-({4-( 1 -piperidinyi)phenyQimino}-2 _s 3-dihydrO"1.S-thiazol-S- yljethanone

3-(2-hydroxyethy1)“N _! N _! 4-tdmathyl-2-04*(trifluoi'omethynph@nyl]i:minQ}-2 _I 3-d(hydro-

1 ,3-thiazole-5-carboxamlde

1-P-[(4-bromopheay})in4no]-3“(2-hydroxyethyt>4-methy l-2 _r 3-dihydrO“1 ,3-thiazol-5- yljethanone 2-{{4-(ethytoxy}ph@nyipmino}-3“(2-hydroxyethyl)-4-methyi-2 _s 3’dihydrO’1 ,3-thiaz{)te-

S-oartoxamide

3“( 2-h yd roxyethy l)-N , N , 4-trimethy l-2-({4»[(trif!uora methy I )oxy] ph e ny l}im ino >2 _; 3- dihy d ro- 1 , 3- thiazote-5-ca rboxa m Id e

1-(3»cydopropyl~4~methyl-2-{[4-(4-morpholsrsy!)phenyl]!m ino}-2 _! 3-dihydro-1 ,3“ th iazol-5-yi )ethanons

3-ethyl-N ₍ N ₍ 4-trimsthyl~2-{[4-(4-mofptK>linyl)|Mienyl]lmino}-2, 3*dihydro-1 _> 3-thfezole-

5-carboxamide

2,2,2-Wfluoro-143>(2~hydfoxyethyl)-4-meft)yl“2“({4 "

((trifluoromethylJoxyjphenyiJiminoj-S^a-dihydfO-^S-thiazo t-S-yfJethanons

3-cyctopropyl-N,N,4-trimethyh2-{(44^" ^mor Pholinyl)phenyl]!mino)-2 _s 3-dihydro-1 ,3- thiazola-5-carboxamide

1 *( 3-(2-hyd roxyethy I H~me thy !-2-{[4-( 1 -pynro I Id i ny tjpheny I] im i no}-2 _: .3-d ih y tto* 1 ,3- thiazo!-5-yQethanone

1-(3-(2-hydroxyetiiyl}-4-methyl-2“{[4-(methjioxy)f^^iyl Jlfnino}~2 _s 3-dlhydro-1,3- thiazol-S-yOethanane

1 -( 3-(2-hydro xyeth yl H~ mefhy k24[4-(methy tth b)pheny I] Im i no}-2.3-d ihydro- 1 , 3- thiazoi-5-yl)ethanone

1-[2-[(3 _< 4-dirnethylpheny0iminoj-3-(24sydroxyethylH“fn®thyl- 2,3-dihydro-1 ,3- thlazoh 5-y I] etha none

1 -[3 ,4-d ime thyl-2- ({4-[(tr ifluoro m e ihyl )o xy] ph e nyljim I no )>2 , 3-d ihyd ro»1 , 3-th iazo l-S- yf|ethanone

1 -{4-me thy i-3»prapy1-2»( {4-( (trifl uoromethy l)oxy] ph e nyljim in a >-2 ,3-dih yd ro- 1 ,3- t h iazo l-5-y l]eth ano ne

1 -[4-methy l»3-{2-(methy foxy )e thy tri f luo ro methy l)oxy} ph en y i}i mi n o )-2 , 3- d i hy d ro- 1 , 3- th iazo l-5-y t]eth a no ne

1»(24(4»(ethyioxy)phenyljimhx)}-3 _r 4--dimethyh2,3-dihydfo-t,3-thiazGh5-yt.tethanone

1“(2-{[4-(elhy}oxy)phenyl]imino}-4-methyb3-propyl-2,3-d ihydi’o-1 _:! 3''thiazoh5- yi)ethanone

1 -( 3 < 4-dirnethyl*2-{[4* ( trifl no romethyl )p heny I] i mi no}-2 , 3-d I hyd ro- 1 , 3-th iazo I-5- yljsthanona

1 -{2-((4-ethy I p he nyl i no]-3 ,4 ~d imeth y I-2 , 3-d lh yd ra- 1 , 3-th I azol- 5~yl}athanon s f -(2“{[4-(dimethylam:ina)phenyi]inwo}“3 _J 4-dimethyi-2 _s 3-dihydrO“1 _i 3--thiazol“5~ yljethanone 1-(3-ethyi-2-{(4-(ethybxy)phenyl]imind}-4“methyi-2 _l 3"dihy'dro-i ,3-th{azok5- yljethandne

1-{2’{H’(di ^e thylamino)phenyi]smino}-3~(2”hydroxyethyl)~4"methyk2 ,3-dihydrO’1 ,3- thiazohS-yljethanone

1-(2-{|4-(diethyiamino)phenylltmino}-3-ethyi-4-meihyi-2 _! 3»dihydro-1 ,3-thiazoh5- yljethanoae

1 -|2- ({4-((difl uoromethy l)oxy]pheny l}lm ino )-3-ethyl-4»methyl- 2 , 3-d ihyd ro- 1 , 3- thiazo i-5-y IJeth a none 1-(3-sthyM-methyU24H*(4'mQrphobnyl}phenyyimino>2,3--dihyd i’t>i3-ih!azol-5» yl)e!har>one

1 -( 3 , 4-d imethyl-24I4-(4-marp hoi I ny I Jphenyfj i mlno}*2 , 3-dihyd ro- 1 ,3-th iazol-5- yljetharone

1-{2-{{4-am!nopheny!)tmirio]-34-dimethyl-2..3-dfhydro-1 ,3-ta2iol-5-yl>ethanone 1-{2-K4*aminophenyl)fminQ]-3-sthyM-methyl"2,3’'dihydi'o-1 _! 3’thiazoh5-yl}ethanone 1-{2-[(4-aminophenyl)iminQ]-3-{2~hydra:xyethyl)-4-niethyi--2 ,3-dihydra’1 _! 3'thiazol-5* yljethanone

1-(2H[4-(dlmeihylamino)phenylpm5no}-3"(2-hyd)‘oxy8thyl) "4-m _: ethyl*2 _i 3-dihydro-1 ,3- thiazol-5-yl]ethanone

Ethyl 2-{[4-(ethy foxy ) ph e nyI]imino}-3-( ,2-hydroxy sthyl)-4- methy 1-2 ,3-4 ihyciro- 1 , 3- thiazate-5-carboxylate

24[4-(ethyloxy)phenyl]imino}-3-(2-hydroxyeihyl)’N,N ₍ 4"trimethyl-2 _; 3--dihydro-1 ₁ 3- thiazote-5-carboxamide

Methyl 2-{|4-(eihytoxy)^enyl]jmino)-3-(24iydFoxyethylH^ethyl~2.3-di hydro-1 _> 3- thiazote-5-cartwylate

3-(2-hydfoxyethythN.N _t 4-trimeihyl-2-{[4-(trifltioram®thyl)phenyl]imino}-2;. 3-dlhydro-

134htazele~5-carboxamide

Methyl 3-(2-hydraxyethyl)-4-meth^*2-{j[4-(tfifluorcwneth^)f^h6nyl]i mino}-2.3- dihydro-^S-tfiiaz^e-S-carbGxylate 1-;3-!'2-hydroxyethyl)-4-methyl-2-((4-methylphenyl)imino]-2 _< 3'-dfhydrci-'! _> 3-th!azof-5- yi}eihanone 1"{3"ethyb2"[(4-ethylphertyl)lmlno]'4-methyl"2,3-dihydr<y 't _; 3-thiazol-5-y{}ethanof-ie |-[3-ethyl-4-rBethyh2-(pher!yfimho)-2,3'dihydrO'-1,3-i:hiazo l-5-yl]ethanortB 143-ethyi-4-Eiiethyh2"[(4--iTiethy1phenyl)lmino]-'2.3-cHhydr o-'l _! 3-thfazol-5- yljetharsone 1-(2-{[4-(d}methylamino^)henyl]imino}’3-ethyt44ne&)yl- 2,3-dSiydro-1 _l 3-thlazok5- yljethanone t~(3-(2-aminoethyl)~2-{[4-(ethyloxy)phenylpmirio}-4-melhy!-2 ,3-d!hydra-1 _l 3--thiazol- 5-yl)ethanone 1-(3-cyclopropyl’2"{(4»(Bthyloxy)phenyl]fFBino}-4’fteth yl-2 _! 3-dlhyclrO"1 ,3-thiazol-5- yljethanone 1-[2-[(4-ethylphenyl)imiriO]'4-methy{’3’(2 _> 2,2’tfffl!Joroethyl)--2 _r 3-dihydro-1 ,3-thiazoF 5-yQethanone 142-n4-(ethyloxy)phenyl];im!no}*4»methyl-3-(2 _: 2,2-trifluoroethyT!-2,3*dihydrD-1,3- th iazol-5-ylJethanone

Formula 208

[00958] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 208. Such compounds are described in WO 2007/090841, published August 16, 2007, corresponding to PCT/EP2007/051136, filed February 6, 2007, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 208, this reference incorporated by reference herein controls.

[00959] In an embodiment, the glutamate modulator may be selected from a compound according to Formula 208: wherein:

Ar is selected from the group consisting of phenyl, pyridyl, furanyl and thienyl, each optionally substituted with one or more groups Y; each Y group is independently selected from the group consisting of: halo, Cl-4alkyl, haloCl-4alkyl, Cl-4alkoxy, cyano, C(O)Cl-4alkyl, NHSO2Cl-4alkyl, NMeSO2Cl-4alkyl, NHCOCl-4alkyl, NMeCOCl-4alkyl, SOCl-4alkyl, SO2Cl-4alkyl, and CO2Cl-4alkyl, or two Y groups together form a cyclic group — 0(CH2)0 — .

[00960] In further embodiments, the glutamate modulator is a compound according to:

[00961] In further embodiments, the glutamate modulator is a compound selected from:

N- { ci s-2- [4-(6-fluoro-3 -pyridinyl)phenyl]tetrahy dro-3 -furanyl } -2-propanesulfonamide N-{cis-2-[4-(6-methyl-3-pyridinyl)phenyl]tetrahydro-3-furany l}-2-propanesulfonamide N- { ci s-2- [4-(5 -fluoro-2-pyridinyl)phenyl]tetrahy dro-3 -furanyl } -2-propanesulfonamide N- { ci s-2- [4-(5 -fluoro-3 -pyridinyl)phenyl]tetrahy dro-3 -furanyl } -2-propanesulfonamide N-{cis-2-[4-(5-methyl-3-pyridinyl)phenyl]tetrahydro-3-furany l}-2-propanesulfonamide N-[cis-2-(4'-fluoro-4-biphenylyl)tetrahydro-3-furanyl]-2-pro panesulfonamide N-[cis-2-(4'-cyano-4-biphenylyl)tetrahydro-3-furanyl]-2-prop anesulfonamide N-[cis-2-(3'-acetyl-4-biphenylyl)tetrahydro-3-furanyl]-2-pro panesulfonamide N-{cis-2-[4-(2-thienyl)phenyl]tetrahydro-3-furanyl}-2-propan esulfonamide and salts and solvates thereof.

Formula 209

[00962] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 209. Such compounds are described in WO 2007/060144, published May 31, 2007, corresponding to PCT/EP2006/068643, filed November 20, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 209, this reference incorporated by reference herein controls.

[00963] In some embodiments, the glutamate modulator is quinoxaline or a quinoxaline derivative compound according to Formula 209: any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically- acceptable addition salt thereof, or an N-oxide thereof, wherein the circle line designates a pyrrolidin-l-yl, azepan-l-yl or azocan- 1-yl group; and R' represents hydrogen, alkyl, cycloalkyl, hydroxy, alkoxy, alkoxy-alkyl, hydroxy- alkyl or carbamoyl; or the circle line designates a piperidin-l-yl group; and

R' represents 2- or 3 -alkyl, cycloalkyl, hydroxy, alkoxy, alkoxy-alkyl, hydroxy-alkyl or carbamoyl.

[00964] In further embodiments, the glutamate modulator is a compound selected from:

Pyrrolidin- 1 -yl-quinoxalin-6-yl-methanone;

(±)-(2-Methyl-pyrrolidin-l -yl)-quinoxalin-6-yl-methanone; or

(±)-(2-Ethyl-pyrrolidin-l -yl)-quinoxalin-6-yl-methanone, including pharmaceutically- acceptable salts thereof.

[00965] In further embodiments, the glutamate modulator is a compound selected from:

(±)-(2-Methyl-piperidin-l -yl)-quinoxalin-6-yl-m ethanone;

(±)-(2-Ethyl-piperidin-l -yl)-quinoxalin-6-yl-m ethanone;

(±)-(3-Methyl-piperidin-l -yl)-quinoxalin-6-yl-m ethanone;

(±)-(3-Ethyl-piperidin-l-yl)-quinoxalin-6-yl-methanone;

(±)-(3-Hydroxy-piperidin-l -yl)-quinoxalin-6-yl-methanone;

(±)-(3-Hydroxy-methyl-piperidin-l -yl)-quinoxalin-6-yl-m ethanone;

(±)-(3 -Methoxy -piperi din- 1 -yl)-quinoxalin-6-yl-methanone; (±)-(3 -Ethoxy -piperi din- 1 -yl)-quinoxalin-6-yl-m ethanone;

(±)-(3 -Methoxy -methyl-piperi din- 1 -yl)-quinoxalin-6-yl-methanone;

(±)-(3 -Ethoxy -methyl-piperi din- 1 -yl)-quinoxalin-6-yl-methanone; or

(±)-(3-Carbamoyl-piperidin-l -yl)-quinoxalin-6-yl-m ethanone, including pharmaceutically- acceptable salts thereof.

Formula 210

[00966] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 210. Such compounds are described in US 7,262,190, issued August 28, 2007, corresponding to US application no. 11/297,260, filed December 8, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 210, this reference incorporated by reference herein controls.

[00967] In an embodiment, the glutamate modulator is a compound according to Formula 210: wherein : R 1 represents a hydrogen atom, a linear or branched (Cl -C6 ) alkyl group or a (C3 -C7 ) cycloalkyl group, R2 represents a hydrogen atom, a halogen atom or a hydroxyl group, A represents a group CR3R4 or a group NR3 , in which R3 represents a hydrogen atom or a linear or branched (Cl -C6) alkyl group, and R4 represents a hydrogen or halogen atom, or A represents a nitrogen atom and forms with the -CHR1 - adjacent group the ring: in which m represents 1, 2 or 3, Y represents a (C2 -C6) alkylene chain optionally substituted with one or more identical or different linear or branched (Cl -C6 ) alkyl groups or halogen atoms, and one of the -CH2 - groups may be replaced by a group in which p is 1, 2, 3 or 4, where Y is a group as defined previously, X represents a group NR5R6 ,S(O)nR7, OR8, C(0)R9 , amidino (optionally substituted by one or two identical or different groups chosen from linear (Cl -C6) alkyl) or branched, hydroxy, linear or branched (Cl -C6) alkoxy, and or a heterocyclic group in which: R5 represents a hydrogen atom, a linear or branched (Cl -C6) alkyl group, S(O)tRl 1 , C0R12 or P(O)OR13OR14 , R6 represents a hydrogen atom, or a linear or branched (Cl -C6) alkyl group, or R5 and R6 together with the nitrogen atom carrying them a heterocyclic group, R8 represents a linear or branched (Cl -C6 ) alkyl group or a C(0)R15 group, R9 represents a linear or branched or amino (Cl -C6) hydroxy or alkoxy group (optionally substituted by one or two identical or different groups, linear or branched (Cl -C6 ) alkyl), R7 , RIO , R11 , R12 , R13 , R14 and R15 , which may be identical or different, each represent a hydrogen atom; a linear or branched (Cl - C6 ) alkyl group optionally substituted with one or more halogen atoms; a linear or branched (Cl -C6 ) arylalkyl group; or an aryl group, n and t, identical or different, represent 0, 1 or 2, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base.

[00968] In further embodiments, R1 represents hydrogen, alkyl or cycloalkyl, R2 represents hydrogen, halogen or hydroxy, A represents CR3R4 or NR3 wherein R3 and R4 are as defined in the description, Y represents an alkylene chain as described in the description, X represents NR5R6, S(O)nR7, OR8, C(O)R9, amidino or a heterocycle, their isomers, and addition salts thereof; and medicinal products containing the same which are useful in the prevention or treatment of diseases associated with AMPA flux.

Formula 211 [00969] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 211. Such compounds are described in US 2004/0254161, published December 16, 2004, corresponding to US 10/865,184, filed June 10, 2004 and issued as US 7,253,162, issued August 7, 2007, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 211, this reference incorporated by reference herein controls.

[00970] In an embodiment, the glutamate modulator is a compound according to Formula 211 : , wherein:

R1 represents hydrogen, halogen, or linear or branched (Cl-C6)alkyl, Ria represents hydrogen or linear or branched (Cl-C6)alkyl, R2 represents hydrogen, halogen, or hydroxy, A represents CR4R5 or NR4, R3 represents hydrogen, linear or branched (Cl-C6)alkyl, or (C3-C7)cycloalkyl, R4 represents hydrogen or linear or branched (Cl-C6)alkyl, or A represents nitrogen and, together with the adjacent — CHR3 — group, forms the ring , wherein m represents 1, 2, or 3, R5 represents hydrogen or halogen, X represents

NR6R7, S(0)nR8, or OR'8, or a heterocyclic group, wherein R6 represents hydrogen, linear or branched (Cl-C6)alkyl, S(O)pR9, C0R9, or P(O)OR9OR10, R7 represents hydrogen, or linear or branched (Cl-C6)alkyl, or R6 and R7, together with the nitrogen atom carrying them, form a heterocyclic group, R8, R9 and RIO, which may be the same or different, represent hydrogen; linear or branched (Cl-C6)alkyl optionally substituted by one or more halogen; aryl-(Cl-C6)alkyl in which the alkyl moiety is linear or branched; or aryl, R'8 represents linear or branched (Cl-C6)alkyl or linear or branched (Cl-C6)acyl, n and p, which may be the same or different, represent 1 or 2, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. [00971] In an embodiment, the glutamate modulator is selected from {3 i{5,S dioxido-2,3,3a,4-tetrahydro-lH-pyrrolo[2,l-c][l,2,4]benzothi adiazin-7- yl)oxy]phenyl}methanamine, N-{3-[(5,5-dioxido-2,3,3a,4-tetrahydro-lH-pyrrolo[2, lC][l,2,4]benzothiadiazin-7-yl)oxy]benzyl}methanesulphonamid e, and N-(4-[(5,5-dioxido- 2,3,3a,4-tetrahydro-lH-pyrrolo[2,l-c][l,2,4]benzothiadiazin- 7- yl)oxy]benzyl}methanesulphonamide, including enantiomers, diastereomers, and pharmaceutically acceptable addition salts thereof.

Formula 212

[00972] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 212. Such compounds are described in US 2004/0254371, published August 7, 2007, corresponding to US 10/865,185, filed June 10, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 212, this reference incorporated by reference herein controls.

[00973] In an embodiment, the glutamate modulator is a compound according to Formula 212: , wherein R1 represents a heterocyclic group, R2 represents hydrogen, halogen, or hydroxy, A represents CR4R5 or NR4, R3 represents hydrogen, linear or branched (Cl-C6)alkyl, or (C3-C7)cycloalkyl, R4 represents hydrogen or linear or branched (Cl-C6)alkyl, or A represents nitrogen and, together with the adjacent —

CHR3 — group, forms the ring wherein m represents 1, 2, or 3,

R5 represents hydrogen or halogen, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base, it being understood that a heterocyclic group may be a monocyclic or bicyclic, aromatic or non-aromatic group containing from one to four identical or different hetero atoms selected from nitrogen, oxygen, and sulphur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (Cl-C6)alkyl, linear or branched (Cl-C6)alkoxy, linear or branched (Cl-C6)polyhaloalkyl, linear or branched (Cl-C6)alkoxy-carbonyl, oxo, thioxo, carboxy, linear or branched (Cl-C6)acyl, linear or branched (Cl-C6)polyhaloalkoxy, hydroxy, cyano, nitro, amino optionally substituted by one or more linear or branched (Cl- C6)alkyl groups, aminosulphonyl optionally substituted by one or more linear or branched (Cl-C6)alkyl groups, and (Cl-C6)alkylsulphonylamino.

[00974] In an embodiment, the glutamate modulator is selected from 7-[3-(lH-tetrazol- 5-yl)phenoxy]-2,3,3a,4-tetrahydro-lH-pyrrolo[2,l-c][l,2,4]be nzothiadiazine 5,5-dioxide; 7- [3-(3-furyl)phenoxy]-2,3,3a,4-tetrahydro-lH-pyrrolo[2,l-c][l ,2,4]benzothiadiazine 5,5- dioxide; and 7-[3-(l,3-oxazol-5-yl)phenoxy]-2,3,3a,4-tetrahydro-lH-pyrrol o[2,l- c][l,2,4]benzothiadiazine, including enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

Formula 213

[00975] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 213. Such compounds are described in WO 2003/053947, published July 3, 2003, corresponding to PCT/FR2002/004484, filed December 20, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 213, this reference incorporated by reference herein controls.

[00976] In an embodiment, the glutamate modulator is a compound according to Formula 213:

R1 represents hydroxy or RCO — O — , R2 represents hydrogen, halogen, hydroxy or R'CO — O — , R and R', which may be identical or different, represent linear or branched (Cl-C6)alkyl optionally substituted by aryl, linear or branched (C2-C6)alkenyl optionally substituted by aryl, linear or branched (Cl-C6)perhaloalkyl, (C3-C7)cycloalkyl, adamantyl, aryl or heteroaryl, R3 represents hydrogen, linear or branched (Cl-C6)alkyl or (C3-C7)cycloalkyl, A represents NR4, R4 represents hydrogen or linear or branched (Cl-C6)alkyl, its isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: R1 represents RCO — O — when it is located in the 5 position of the compound of formula (I), “aryl” may be an aromatic monocyclic group or a bicyclic group in which at least one of the rings is aromatic, each of those groups being optionally substituted by one or more identical or different halogen, linear or branched (Cl-C6)alkyl, linear or branched (Cl-C6)alkoxy, linear or branched (Cl-C6)perhaloalkyl, linear or branched (Cl- C6)-perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (Cl-C6)alkyl), aminosulphonyl (optionally substituted by one or more linear or branched (Cl-C6)alkyl) or phenyl (optionally substituted by one or more identical or different halogen, linear or branched (Cl-C6)alkyl, linear or branched (Cl-C6)perhaloalkyl, hydroxy or linear or branched (Cl-C6)alkoxy),“heteroaryl” may be an aromatic monocyclic group or bicyclic group in which at least one of the rings is aromatic, containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, each of those groups being optionally substituted by one or more identical or different halogen, linear or branched (Cl-C6)alkyl, linear or branched (Cl-C6)alkoxy, linear or branched (Cl- C6)perhaloalkyl, linear or branched (Cl-C6)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (Cl-C6)alkyl) or aminosulphonyl (optionally substituted by one or more linear or branched (Cl-C6)alkyl).

[00977] In an embodiment, the glutamate modulator is l,l-dioxido-3,4-dihydro-2H- l,2-benzothiazin-7-yl benzoate.

Formula 214

[00978] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 214. Such compounds are described in US 2005/0124606, published June 9, 2005, corresponding to US application No. 10/498,948, filed December 20, 2002 as PCT/FR02/04485, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 214, this reference incorporated by reference herein controls.

[00979] In an embodiment, the glutamate modulator is a compound according to Formula 214:

, wherein: R1 represents aryl or heteroaryl,

R2 represents hydrogen, halogen or hydroxy, A represents CR4R5 or NR4, R3 represents hydrogen, linear or branched (Cl-C6)alkyl or (C3-C7)cycloalkyl, R4 represents hydrogen or linear or branched (Cl-C6)alkyl, or A represents nitrogen and, together with the adjacent —

CHR3 — group, forms the ring wherein m represents 1, 2 or 3,R5 represents hydrogen or halogen, its isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: “aryl” may be an aromatic monocyclic group or a bicyclic group in which at least one of the rings is aromatic, each of those groups being optionally substituted by one or more identical or different halogen, linear or branched (Cl- C6)alkyl (optionally substituted by one or more hydroxy groups), linear or branched (Cl- C6)alkoxy, linear or branched (Cl-C6)perhaloalkyl, linear or branched (Cl- C6)alkoxy carbonyl, linear or branched (Cl-C6)alkylthio, carboxy, linear or branched (Cl- C6)acyl, linear or branched (Cl-C6)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (Cl-C6)alkyl or linear or branched (Cl- C6)acyl), aminocarbonyl (optionally substituted by one or more linear or branched (Cl- C6)alkyl), aminosulphonyl (optionally substituted by one or more linear or branched (Cl- C6)alkyl), mono- or di-((Cl-C6)alkylsulphonyl)amino, mono- or di- (trifluoromethylsulphonyl)amino, PO(ORa)(ORb) (wherein Ra, Rb, which may be identical or different, represent hydrogen or linear or branched (Cl-C6)alkyl), benzyloxy, or phenyl (optionally substituted by one or more identical or different halogen, linear or branched (Cl- C6)alkyl, linear or branched (Cl-C6)perhaloalkyl, hydroxy or linear or branched (Cl- C6)alkoxy), “heteroaryl” may be an aromatic monocyclic group, or a bicyclic group in which at least one of the rings is aromatic, containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, each of those groups being optionally substituted by one or more identical or different halogen, linear or branched (Cl-C6)alkyl, linear or branched (Cl-C6)alkoxy, linear or branched (Cl-C6)perhaloalkyl, linear or branched (Cl-C6)alkoxy carbonyl, carboxy, linear or branched (Cl-C6)acyl, linear or branched (Cl-C6)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (Cl-C6)alkyl), aminosulphonyl (optionally substituted by one or more linear or branched (Cl-C6)alkyl), or (Cl-C6)alkylsulphonylamino.

[00980] In an embodiment, the glutamate modulator is a compound selected from 7-(3-methylphenoxy)-2,3,3a,4-tetrahydro-lH-pyrrolo[2,l-c][l, 2,4]benzothiadiazine 5,5- dioxide, 3-[(5,5-dioxido-2,3,3a,4-tetrahydro-lH-pyrrolo[2,l-c][l,2,4] benzothiadiazin-7- yl)oxy]benzoic acid, 3-(5,5-dioxido-2,3,3a,4-tetrahydro-lH-pyrrolo[2,l- c][l,2,4]benzothiazin-7-yl)oxy]aniline, N-[3-(5,5-dioxido-2,3,3a,4-tetrahydro-lH- pyrrido[2, l-c][l,2,4]benzothiazin-7-yl)oxy]phenyl]methanesulphonamide, and ethyl hydrogen 3-[(5,5-dioxido-2,3,3a,4-tetrahydro-lH-pyrrolo[2,l-c][l,2,4] benzothiadiazin-7- yl)oxy]phenylphosphonate, including isomers and pharmaceutically acceptable salts thereof.

Formula 215

[00981] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 215. Such compounds are described in US 2005/0065146, published March 24, 2005, corresponding to US application No. 10/499,164, filed December 20, 2002 as PCT/FR2002/04483, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 215, this reference incorporated by reference herein controls.

[00982] In an embodiment, the glutamate modulator is a compound according to Formula 215: wherein: R1 represents aryl or heteroaryl, R2 represents hydrogen, halogen or hydroxy, X represents oxygen or sulphur, Y represents oxygen, sulphur or NR wherein R represents hydrogen or linear or branched (Cl-C6)alkyl, A represents CR4R5 or NR4, R3 represents hydrogen, linear or branched (Cl-C6)alkyl or (C3- C7)cycloalkyl, R4 represents hydrogen or linear or branched (Cl-C6)alkyl, or A represents nitrogen and, together with the adjacent — CHR3 — group, forms the ring wherein m represents 1, 2 or 3, R5 represents hydrogen or halogen, its isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: “aryl” may be an aromatic monocyclic group, or a bicyclic group in which at least one of the rings is aromatic, each of those groups being optionally substituted by one or more identical or different halogen, linear or branched (Cl-C6)alkyl, linear or branched (Cl- C6)alkoxy, linear or branched (Cl-C6)perhaloalkyl, linear or branched (C1-C6)- perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (Cl-C6)alkyl), aminosulphonyl (optionally substituted by one or more linear or branched (Cl-C6)alkyl), (Cl-C6)alkylsulphonylamino, or phenyl (optionally substituted by one or more identical or different halogen, linear or branched (Cl-C6)alkyl, linear or branched (Cl-C6)perhaloalkyl, hydroxy or linear or branched (Cl-C6)alkoxy), “heteroaryl” may be an aromatic monocyclic group, or bicyclic group in which at least one of the rings is aromatic, containing one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, each of those groups being optionally substituted by one or more identical or different halogen, linear or branched (Cl-C6)alkyl, linear or branched (Cl-C6)alkoxy, linear or branched (Cl-C6)perhaloalkyl, linear or branched (Cl- C6)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (Cl-C6)alkyl), aminosulphonyl (optionally substituted by one or more linear or branched (Cl-C6)alkyl), or (Cl-C6)-alkylsulphonylamino.

[00983] In an embodiment, the glutamate modulator is a compound having R1 selected from aryl, R2 selected from hydrogen, and m = 1.

Formula 216

[00984] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 216. Such compounds are described in WO 2003/031422, published April 17, 2003, corresponding to PCT/DK2002/000654, filed October 2, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 216, this reference incorporated by reference herein controls.

[00985] In an embodiment, the glutamate modulator is a compound according to any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically acceptable salt thereof, wherein R1 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl; and R2 and R3, independently of each another, represent hydrogen, alkyl other than t-butyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and/or a saturated or partially saturated mono- or cyclic heterocyclic ring; or R2 and R3 1 together with the carbon atom to which they are attached, form a saturated or partially saturated monocyclic (spiro) carbocyclic ring; or R2 and/or R3, together with R4 and/or R5, form a saturated or partially saturated monocyclic carbocyclic ring; and R4 and R5, independently of each another, represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and/or a saturated or partially saturated mono- or bi-cyclic heterocyclic ring; or R4 and R5, together with the carbon atom to which they are attached, form a saturated or partially saturated monocyclic carbocyclic (spiro) ring; or R4 and R5, together with R2 and/or R3, form a saturated monocyclic carbocyclic ring; and R6 represents hydrogen, halogen, alkyl, cycloalkyl, haloalkyl or alkoxy; and R7 represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkenyl, alkynyl or halogen, or a group of the formula — RIO — NR9R1, — RIO— NO2— RIO— OR8-R10— SR8 1— RS(=O)R 9, — R9 10-S(=O)2R8, — RIO— S(=O)2OR, — RIO— S(=O)2NR9S(=O)2R8, — RIO— NR11S(=O)2NRR, — R10- CN, — RIO— C(=NR'C(=NNR9)R8, — RIO— C(=NOR9)R8, — R10-C(=O)R8, — R10C (=S)R8-R1-C (=)O)R8-R10— C (=S)OR8, — R10-C(=O)SR8, — R — RIO— C(=0)NR9(0R'), — RIO— C(=S)NR9(OR'), — RIO— C(=O)NR9(SR')-R C(=S)NR9(SR), — R1"-CH(CN)2, — RIO— C(=O)NR9R8, — RIO— NR — NR11 (=O)NR9R8, — RIO— C(=S)NR9R8, — R10-CH[C(=O)R— R 1O‘CH[C(=S)SR8]2, or — R1"-CH[C(=S)NR9R9]2; wherein R8, R8 and R”, independently of each another, represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, hydroxy, aryl or heteroaryl, which aryl or heteroaryl may optionally be substituted one or more times with alkyl, cycloalkyl, alkoxy, halogen, hydroxy, amino, trifluoromethyl, trifluoromethoxy or nitro; or R8 and R9, together with the atoms to which they are bound, form a heterocyclic ring, which heterocyclic ring may optionally be substituted one or more times with alkyl, cycloalkyl, alkoxy, halogen, hydroxy, amino, trifluoromethyl, trifluoromethoxy or nitro, and Rl” is as defined above; and RIO is absent or represents a linker selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl; or R7 represents represents a mono- or polycyclic carbocyclic or heterocyclic group, which carbocyclic or heterocyclic group may optionally be substituted one or more times with substituents selected from alkyl, cycloalkyl, hydroxyalkyl, alkenyl, alkynyl or halogen, or a group of the formula R7-NR8R9, — R10-NO2, — Rl 1-OR9, — R1-SR3, — R2- S(=O)NR9S(=O)R7, — R8 10-S(=O)2R, — RIO— S(=O)2OR, —RIO— S(=O)2NR9S(=O)2R8, — RIO— NR11S(=O)2NR9R1, -RIO- CN, — RC(=NNR 9)R8, — RIO— C(=NOR9)R8, — RIO— C(=O)R8, — Rl C(=S)R 8, — R10-C(=O)OR8, -RIO- C(=S)0R8, — R10-C(=O)SR, — R10-C — RIO— C(=O)NR9(OR), — RIO— C(=S)NR9(OR)-R10— C(=O)NR9(SR2C(=S)NR9(SR8), — R10-CH(CN)2, — R1O- C(=O)NR9R8, — RIO— NR — NR11C(=O)NR9R8, — R10-C(=S)NR9R8 1— R1O- CH[C(=O)R8 — RIO— CH[C(=O)OR]2, — RIO— CH[C(=S)OR]2, — R10-CH[C(=O)SR]2, — R CH[C(=S)SR8]2, or — RIO— CH[C(=S)NR9R8]2; wherein R8, R9 and R”, independently of each another, represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, hydroxy, aryl or heteroaryl, which aryl or heteroaryl may optionally be substituted one or more times with alkyl, cycloalkyl, alkoxy, halogen, hydroxy, amino, trifluoromethyl, trifluoromethoxy or nitro; or R8 and R9, together with the atoms to which they are bound, form a heterocyclic ring, which heterocyclic ring may optionally be substituted one or more times with alkyl, cycloalkyl, alkoxy, halogen, hydroxy, amino, trifluoromethyl, trifluoromethoxy or nitro, and R11 is as defined above; and RIO is absent or represents a linker selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl.

[00986] In an embodiment, the glutamate modulator is a compound selected from: (3RS)-3 -Cyclohexyl-7-(piperidine- 1 -sulfonyl)-3 ,4-dihydro-2H-benzo[e] [ 1 ,2]thiazine- 1,1- dioxide; (3RS)-3-Cyclopentyl-7-(piperidine-l-sulfonyl)-3,4-dihydro-2H - benzofe] [ 1 ,2] thi azine- 1 , 1 -dioxide; (3RS)-3 -Cyclopentyl-7-(4-methyl-piperazine- 1 -sulfonyl)-

3.4-dihydro-2H-benzo[e][l,2]thiazine-l,l-dioxide; (3RS)-3-Cyclohexyl-7-(4-methyl- piperazine- 1 -sulfonyl)-3 ,4-dihydro-2H-benzo[e] [ 1 ,2] thi azine- 1 , 1 -dioxide; (3RS)-3 - Cyclopentyl-6-methyl-7-(piperidine- 1 -sulfonyl)-3 ,4-dihydro-2H-benzo[e] [ 1 ,2] thi azine- 1,1- di oxide; (3RS)-3-Cyclopentyl-6-methyl-7-(morpholine-4-sulfonyl)-3,4-d ihydro-2H- benzofe] [ 1 ,2] thi azine- 1 , 1 -dioxide; (3RS)-3 -Cyclopentyl-6-methyl-7-(4-methyl-piperazine- 1 - sulfonyl)-3,4-dihydro-2H-benzo[e][l,2]thiazine- 1,1 -di oxide; (3RS)-3-Cyclopentyl-6-methyl- 7-(N,N-dimethylamine- 1 -sulfonyl)-3 ,4-dihydro-2H-benzo[e] [ 1 ,2]thi azine- 1 , 1 -dioxide; (3RS)-3-Cyclopentyl-6-methyl-7-(4-hydroxypiperidine-l-sulfon yl)-3,4-dihydro-2H- benzofe] [ 1 ,2] thi azine- 1 , 1 -dioxide; (3RS)-3 -Cyclopentyl-7-(N,N-dimethylamine- 1 -sulfonyl)-

3.4-dihydro-2H-benzo[e] [ 1 ,2]thi azine- 1 , 1 -dioxide; (3RS)-3 -Cyclopentyl-7-(morpholine- 1 - sulfonyl)-3 ,4-dihydro-2H-benzo[e] [ 1 ,2]thi azine- 1 , 1 -dioxide; or [ 1 -(3 -Cyclopentyl- 1 , 1 -dioxo-

1.2.3.4-tetrahydro-lX6-benzo[e][l,2]thiazine-7-sulfonyl)- piperidin-4-yl]-dimethyl-amine; or a pharmaceutically acceptable salt thereof.

Formula 217

[00987] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 217. Such compounds are described in US Patent No. 5,731,348, issued March 24, 1998 and corresponding to US application no. 600,330, filed February 13, 1996, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 217, this reference incorporated by reference herein controls.

[00988] In an embodiment, the glutamate modulator is a compound according to Formula 217:

, wherein R1 is CH or halogen; R2 and R3 are independently selected from the group consisting of H, Cl-C6-alkyl, C3-C4- alkenyl, C3-C5 cycloalkyl,Cl-C6-alkyl-CO-, Cl-C6-alkyl-OCO-Cl-C6-alkyl-NHCO- , -CHO, and C3-C6-alkynyl; R2 and R3 taken together can be -CH2(CH2)pCH2-; p is 0, 1, 2 or 3; including pharmaceutically acceptable salts of these compounds.

[00989] In further embodiments, the glutamate modulator is selected from (2S,4R)-4- methyl glutamic acid, (2S,4S)-4-methyl glutamic acid, (2R,4S)-4-methyl glutamic acid, and (2R,4R)-4-methyl glutamic acid.

Formula 218

[00990] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 218. Such compounds are described in WO 1995/007899, published March 23, 1995, corresponding to PCT/FR1994/001069, filed September 12, 1994which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 218, this reference incorporated by reference herein controls.

[00991] In an embodiment, the glutamate modulator is a compound according to Formula 218:

, wherein R1 is a carboxy radical, alkoxycarbonyl, tetrazolyle, -CO-NH2, -CO-NH-alk, -CO-N(alk)2, -CO-NHOH, -CO- N(alk)OH, -CO-NH-O-RIO, -CO-N(alk)-O-R10, or a group convertible to a carboxy radical in vivo, R2, R3, and R4 are independently selected from hydrogen , halogen, or radical alkyne or alcoxy, R5 is a hydroxyl radical, -NHOH, -NH-C0-NH2, -CH2-NH2, hydroxyalkyl, alcoxyalkyl, or -alk-NOH, R6, R7, R8, and R9 are independently hydrogen, halogen, or adical alkyne or alcoxy, alcoxy, polyfluoroalkyl, amino, nitro, cyano, phenyl, vinyl, polyfluoroalkoxy, alkoxycarbonyl, carboxy, phenylalkoxy, phenylalkyl, benzoylamino, phenylcarbonyl, hydroxy, -NHOH, -NH-C0-NH2, -CH2-NH2, hydroxyalkyl, alcoxyalkyl, - alk=NOH, or subsitituted phenyl or phenoxy, and RIO is a radical alkyl or phenylalkyl, where alk represents a radical alkyl or alkylene.

Metabotropic Glutamate Modulators

[00992] Metabotropic glutamate receptors transmit their signal in response to glutamate binding as opposed to ionotropic receptors which transmit their signal in response to ligand binding by allowing ion passage. Metabotropic glutamate receptors may be classified into three groups. Group I receptors can increase NMDA receptor activity, increase excitotoxicity, and are primarily postsynaptic. Group II receptors can decrease NMDA receptor activity, protect against excitotoxicity activity, and are primarily presynaptic. Group III receptors are similar in function to group II receptors but have different compound sensitives. Group I targeting modulators may target, for example, mGluRl and/or mGluR5. Group II targeting modulators may target, for example, mGluR2 and/or mGluR3. These receptors have been implicated in conditions including Alzheimer’s disease, Huntington’s disease, and multiple sclerosis, as well as various other conditions. It is contemplated that, in some embodiments, the glutamate modulator may be a metabotropic glutamate modulator. In other embodiments, the glutamate modulator may be a non-metabotropic glutamate modulator.

Formula 219

[00993] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 219. Such compounds are described in CN 113861203, published December 31, 2021, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 219, this reference incorporated by reference herein controls.

[00994] In an embodiment, the glutamate modulator is a compound according to Formula 219:

, where ring A is a substituted or unsubstituted phenyl or heteroaryl, and R is any viable substituent affording glutamate modulatory activity. In a further embodiment, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted six-membered heteroaryl, substituted or unsubstituted thiazolyl; r is selected from substituted or unsubstituted phenyl, substituted or unsubstituted six-membered heteroaryl; wherein the substituents are 1,2,3 or 4 substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3- C8 cycloalkyl, C3-C8 halocycloalkyl, cyano, nitro, amino; halogen (F, Cl, Br or I); optionally wherein the six-membered heteroaryl is any one of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl or morpholinyl. R may be any substituent including halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, cyano, nitro, amino; halogen (F, Cl, Br or I), optionally further substituted. [00995] In an embodiment, the glutamate modulator is selected from: n-phenyl-7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-fluorophenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-chlorophenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-iodophenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-methylphenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-methoxyphenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (pyri din-3 -yl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-tert-butylphenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-dimethylaminophenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-trifluoromethoxyphenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine- 6-carboxamide; n- (3 -chlorophenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (3, 4-dichlorophenyl) -7-methyl-4- (phenylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-fluorophenyl) -7-methyl-4- (pyridin-2-ylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-methoxyphenyl) -7-methyl-4- (pyridin-2-ylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-tert-butylphenyl) -7-methyl-4- (pyridin-2-ylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-dimethylaminophenyl) -7-methyl-4- (pyridin-2-ylethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n-phenyl-7-methyl-4- ((4-fluorophenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-fluorophenyl) -7-methyl-4- ((4-fluorophenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine- 6-carboxamide; n- (4-chlorophenyl) -7-methyl-4- ((4-fluorophenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine- 6-carboxamide; n- (4-methylphenyl) -7-methyl-4- ((4-fluorophenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine- 6-carboxamide; n- (4-methoxyphenyl) -7-methyl-4- ((4-fluorophenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-tert-butylphenyl) -7-methyl-4- ((4-fluorophenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-dimethylaminophenyl) -7-methyl-4- ((4-fluorophenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n-phenyl-7-methyl-4- ((4-methoxyphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-fluorophenyl) -7-methyl-4- ((4-methoxyphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-methylphenyl) -7-methyl-4- ((4-methoxyphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-methoxyphenyl) -7-methyl-4- ((4-methoxyphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-tert-butylphenyl) -7-methyl-4- ((4-methoxyphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-dimethylaminophenyl) -7-methyl-4- ((4-methoxyphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n-phenyl-7-methyl-4- ((2-methylthiazol-4-yl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-methylphenyl) -7-methyl-4- ((2-methylthiazol-4-yl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-methoxyphenyl) -7-methyl-4- ((2-methylthiazol-4-yl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n-phenyl-7-methyl-4- ((4-methylphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6- carboxamide; n- (4-fluorophenyl) -7-methyl-4- ((4-methylphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine- 6-carboxamide; n- (4-chlorophenyl) -7-methyl-4- ((4-methylphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-methylphenyl) -7-methyl-4- ((4-methylphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-methoxyphenyl) -7-methyl-4- ((4-methylphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; n- (4-tert-butylphenyl) -7-methyl-4- ((4-methylphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide; and n- (4-dimethylaminophenyl) -7-methyl-4- ((4-methylphenyl) ethynyl) -7H-pyrrolo [2, 3-d ] pyrimidine-6-carboxamide.

Formula 220

[00996] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 220. Such compounds are described in WO 2019/145214, published August 1, 2019 and corresponding to PCT/EP2019/051134, filed January 17, 2019, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 220, this reference incorporated by reference herein controls.

[00997] In an embodiment, the glutamate modulator is a compound according to Formula 220

, wherein R1 is an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group or an optionally substituted linear or branched Cl to C20 alkyl group; and

A is a triple bond, a double bond optionally substituted with a halo group or represents a five- or six-atom heterocyclic group containing from 1 to 4 heteroatoms selected from N, S and O, or represents an alkyl chain (Cl -4), or an alkyl chain substituted with 1 to 3 heteroatoms selected from N, S and O;

R2, R3 are each independently null, a hydrogen, an alkyl group, or a fluorine atom, or R2 and R3 are linked to each other to form a condensed heterocyclic ring containing 1 to 3 heteroatoms selected from N, S and O; n is an integer between 0 and 2;

R4 is a carbonyl, a thiocarbonyl, a sulphonyl group, a bond or null;

B is oxygen, sulphur or nitrogen, wherein the nitrogen is optionally substituted by a C 1-5 alkyl or alkoxy, a bond or null; R5 is an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted mono-, bi- or tricyclic Cl -Cl 3 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O, and S, an optionally substituted C3- C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group or an optionally substituted linear or branched Cl to C20 alkyl group.

[00998] In further embodiments, the optional substituents are independently selected from halogen atoms and C1-C6 alkyl, C1-C6 alkoxy, hydroxy, mercapto, nitro, cyano, oxo, halo(Cl-C6)alkyl, halo(Cl-C6)alkoxy, C1-C6 alkylthio, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonyl, sulphamoyl, C1-C6 alkylsulphamoyl, di(Cl-C6)alkylsulphamoyl, (Cl- C6)alkoxy carbonyl and (Cl-C6)alkylcarbonyl(Cl-C6)alkyl groups, and from groups of the formulae -NR*R*, -C(=O)-NR*R*, -A, -O-A, -C(=O)-A, -(CH2)q-A, -NR**-A, -C(=O)- NR**-A, -NR**C(=O)-A and -O-C(=O)-A wherein each R* independently represents a hydrogen atom or a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl or benzyl group, R** represents a hydrogen atom or a C1-C6 alkyl group, q is an integer from 1 to 6 and A represents a phenyl group or a C1-C8 heterocyclic group containing from 1 to 3 heteroatoms selected from N, O and S; a C1-C6 cycloalkyl group; each group A being optionally substituted with from 1 to 3 groups independently selected from halo, hydroxy, cyano, nitro and C1-C6 alkyl, preferably wherein the optional substituents are selected from the groups consisting of halogen atoms and C1-C6 alkyl groups.

[00999] In further embodiments, the glutamate modulator is a compound selected from:

Formula 221

[001000] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 221. Such compounds are described in WO 2019/002571, published January 3, 2019, corresponding to PCT/EP2018/067628, filed June 29, 2018 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 221, this reference incorporated by reference herein controls.

[001001] In an embodiment, the glutamate modulator is a compound according to Formula 221 :

, wherein R1 is an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O and S, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group or an optionally substituted C1-C6 alkyl group;

A is a carbon-carbon triple bond, a carbon-carbon double bond or A represents a five- or sixmembered heterocyclic group containing from 1 to 4 heteroatoms selected from N, S and O; R2 and R3 are each independently hydrogen, an alkyl group or a fluorine atom, or R2 and R3 are linked to each other to form a C3-C6 cycloalkyl or a C3-C6 heterocyclic ring while simultaneously R7 and R8 are each independently an alkyl group or a fluorine atom, or alternatively R2 or R3 are bonded to R7 or R8 to form a condensed cycloalkyl ring; n and m are each independently an integer selected from 0-2;

R4 is a carbonyl, a thiocarbonyl or a sulphonyl group, or a bond;

B is an oxygen or sulphur atom, a nitrogen atom optionally substituted by a C1-C5 alkyl group or a methoxy group, or B is absent;

R5 is an optionally substituted mono-, bi- or tricyclic C6-C14 aryl group, an optionally substituted mono-, bi- or tricyclic Cl -Cl 3 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O and S, an optionally substituted C3-C6 cycloalkyl group, an optionally substituted C3-C6 cycloalkenyl group or an optionally substituted C1-C6 alkyl group; and

R6 is a hydrogen atom, an optionally substituted C1-C4 alkyl group, or a fluorine atom. [001002] In further embodiments, the phonal substituents are independently selected from the group consisting of halogen atoms, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, mercapto, nitro, cyano, oxo, halo(Cl-C6)alkyl, halo(Cl-C6)alkoxy, C1-C6 alkylthio, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonyl, sulphamoyl, C1-C6 alkylsulphamoyl, di(Cl- C6)alkylsulphamoyl, (Cl-C6)alkoxy carbonyl and (Cl-C6)alkylcarbonyl(Cl-C6)alkyl groups, and from groups of the formulae — NR*R*, — C(=O) — NR*R*, -D, — O-D, — C(=O)-D, — (CH2)q-D, — NR**-D, — C(=O)— NR**-D, — NR**C(=O)-D and — O— C(=O)-D wherein each R* independently represents a hydrogen atom or a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl or benzyl group, R** represents a hydrogen atom or a C1-C6 alkyl group, q is an integer from 1 to 6 and D represents a phenyl group or a C1-C5 heterocyclic group containing from 1 to 3 heteroatoms selected from N, O and S; a C1-C6 cycloalkyl group; each group D being further optionally substituted with from 1 to 3 groups independently selected from halo, hydroxy, cyano, nitro and C1-C6 alkyl, preferably wherein the optional substituents are selected from the groups consisting of halogen atoms and C1-C6 alkyl groups.

[001003] In further embodiments, the glutamate modulator is a compound accortert-butyl (4E)- 3,3-dimethyl-4-[3-(6-methylpyridin-2-yl)prop-2-yn-l-ylidene] piperidine-l-carboxylate; tert-butyl (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidine- 1 -carboxylate; ethyl (4E)-3,3-dimethyl-4-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]piperidine-l-carboxylate; ethyl (4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-dimethylp iperidine-l-carboxylate; tert-butyl (4E)-4-[3-(2-chloropyridin-4-yl)prop-2-yn-l-ylidene]-3,3-dim ethylpiperidine-l- carboxylate; tert-butyl (4E)-3,3-dimethyl-4-[3-(3-methylphenyl)prop-2-yn-l-ylidene]p iperidine-l-carboxylate; tert-butyl (4E)-3,3-difluoro-4-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]piperidine-l-carboxylate; tert-butyl (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -difluoropiperidine- 1 -carboxylate ; tert-butyl (4E)-4-[3 -(4-chloropyridin-2-yl)prop-2-yn- 1 -ylidene] -3 ,3 -difluoropiperidine- 1 -carboxylate ; tert-butyl (4E)-3,3-difluoro-4-[3-(3-methylphenyl)prop-2-yn-l-ylidene]p iperidine-l-carboxylate; ethyl (4E)-3,3-difluoro-4-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]piperidine-l-carboxylate; ethyl (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -difluoropiperidine- 1 -carboxylate; ethyl (4E)-4- [3 -(4-chloropyridin-2-yl)prop-2-yn- 1 -ylidene] -3 ,3 -difluoropiperidine- 1 -carboxylate ; ethyl (4E)-3,3-difluoro-4-[3-(3-methylphenyl)prop-2-yn-l-ylidene]p iperidine-l-carboxylate; ethyl (4E)-4-[3-(2-chloropyridin-4-yl)prop-2-yn-l-ylidene]-3,3-dim ethylpiperidine-l-carboxylate; ethyl (4E)-3,3-dimethyl-4-[3-(3-methylphenyl)prop-2-yn-l-ylidene]p iperidine-l-carboxylate; ethyl (4E)-3,3-dimethyl-4-(3-phenylprop-2-yn-l-ylidene)piperidine- l-carboxylate; ethyl (4E)-4-[3-(4-chloropyridin-2-yl)prop-2-yn-l-ylidene]-3,3-dim ethylpiperidine-l-carboxylate; ethyl (4E)-4-[3-(2,5-difluorophenyl)prop-2-yn-l-ylidene]-3,3-dimet hylpiperidine-l-carboxylate; ethyl (4E)-3,3-dimethyl-4-{3-[6-(trifluoromethyl)pyridin-2-yl]prop -2-yn-l-ylidene}piperidine-l- carboxylate; ethyl (4E)-4-[3-(3-fluorophenyl)prop-2-yn-l-ylidene]-3,3-dimethylp iperidine-l-carboxylate; ethyl (4E)-3 ,3 -dimethyl -4- { 3 -[3 -(trifluoromethyl)phenyl]prop-2-yn- 1 -ylidene }piperidine- 1 - carboxylate; ethyl (4E)-4-[3-(6-methoxypyridin-2-yl)prop-2-yn-l-ylidene]-3,3-di methylpiperidine-l-carboxylate; ethyl (4E)-4- [3 -(3 -methoxyphenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidine- 1 -carboxylate ; ethyl (4E)-4-[3-(4-methoxypyridin-2-yl)prop-2-yn-l-ylidene]-3,3-di methylpiperidine-l-carboxylate; ethyl (4E)-3,3-dimethyl-4-[3-(pyridin-2-yl)prop-2-yn-l-ylidene]pip eridine-l-carboxylate; ethyl (4E)-4- [3 -(3 -cyanophenyl)prop-2-yn- 1 -ylidene] -3 ,3-dimethylpiperidine- 1 -carboxylate ; ethyl (4E)-4-{3-[3-(cyanomethyl)phenyl]prop-2-yn-l-ylidene}-3,3-di methylpiperidine-l-carboxylate; ethyl (4E)-4- [3 -(6-methoxypyridin-3 -yl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidine- 1 -carboxylate; ethyl (4E)-3,3-dimethyl-4-{3-[6-(methylamino)pyridin-2-yl]prop-2-y n-l-ylidene}piperidine-l- carboxylate; ethyl (4E)-4-[3-(4-cyanopyridin-2-yl)prop-2-yn-l-ylidene]-3,3-dime thylpiperidine-l-carboxylate; ethyl (4E)-4-[3 -(3 -cyano-5 -fluorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidine- 1 -carboxylate;

2- { (4E)-3 ,3 -dimethyl -4-[3-(6-methylpyridin-2-yl)prop-2-yn- 1 -ylidene]piperidin- 1 -yl } -6-methyl-3 - nitropyridine;

(3 -chlorophenyl) { (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl} methanone;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3,3 -dimethylpiperidin- 1 -yl } (piperidin- 1 - yl)methanone;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3,3 -dimethylpiperidin- 1 -yl } (pyrrolidin- 1 - yl)methanone;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-N,N,3,3-te tramethylpiperidine-l-carboxamide;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-N,N-diethy l-3,3-dimethylpiperidine-l-carboxamide;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3,3 -dimethylpiperidin- 1 -yl } (furan-2-yl)methanone; methyl (4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-dimethylp iperidine-l-carboxylate;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (morpholin-4- yl)methanone;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-N-methoxy- N,3,3-trimethylpiperidine-l- carboxamide; { (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (3 - methylphenyl)methanone ;

2- { (3E)-3 - [ 1 -(3 -chlorobenzoyl)-3 ,3 -dimethylpiperidin-4-ylidene]prop- 1 -yn- 1 -yl }pyridine-4- carbonitrile;

(3 -chlorophenyl) { (4E)-3 ,3 -dimethyl-4- [3 -(3 -methylphenyl)prop-2-yn- 1 -ylidene]piperidin- 1 - yl} methanone;

(2,5-dimethylfuran-3-yl)[(4E)-4-{3-[3-(hydroxymethyl)phen yl]prop-2-yn-l-ylidene}-3,3- dimethylpiperidin- 1 -yl]methanone ;

[(4E)-3 ,3 -dimethyl -4-(3 - { 3 -[(pyrrolidin- 1 -yl)methyl]phenyl }prop-2-yn- 1 -ylidene)piperidin- 1 -yl] (5 - methylfuran-2-yl)methanone; ethyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]pyrrolidine-l-carboxylate; tert-butyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]pyrrolidine-l- carboxylate; propyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]pyrrolidine-l-carboxylate;

2-methoxyethyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]pyrrolidine-l- carboxylate;

2-methylpropyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]pyrrolidine-l- carboxylate; propan-2 -yl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]pyrrolidine-l- carboxylate;

(3E)-N,N,2,2-tetramethyl-3-[3-(6-methylpyridin-2-yl)prop- 2-yn-l-ylidene]pyrrolidine-l- carboxamide;

{(3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l -ylidene]pyrrolidin-l-yl}(furan-2- yl)methanone;

(3 -chlorophenyl) { (3E)-2,2-dimethyl-3 - [3 -(6-methylpyridin-2-yl)prop-2-yn- 1 -ylidene] pyrrolidin- 1 - yl} methanone;

{(3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l -ylidene]pyrrolidin-l-yl}(piperidin-l- yl)methanone;

{(3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l -ylidene]pyrrolidin-l-yl}(pyrrolidin-l- yl)methanone; methyl (3E)-2,2-dimethyl-3-[3-(6-methylpyridin-2-yl)prop-2-yn-l-yli dene]pyrrolidine-l-carboxylate; tert-butyl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn- 1 -ylidene]pyrrolidine- 1 - carboxylate; ethyl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-l-y lidene]pyrrolidine-l-carboxylate;

2-methoxyethyl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-l-y lidene]pyrrolidine-l- carboxylate; propan-2 -yl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-l-y lidene]pyrrolidine-l- carboxylate; methyl (3E)-2,2-dimethyl-3-[3-(4-methylpyrimidin-2-yl)prop-2-yn-l-y lidene]pyrrolidine-l- carboxylate; tert-butyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-y n-l-ylidene}pyrrolidine-l- carboxylate; ethyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-y n-l-ylidene}pyrrolidine-l- carboxylate; propyl (3E)-2,2-dimethyl-3 - { 3 -[6-(methylamino)pyridin-2-yl]prop-2-yn- 1 -ylidene }pyrrolidine- 1 - carboxylate;

2-methoxyethyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-y n-l- ylidene} pyrrolidine- 1 -carboxylate;

2-methylpropyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-y n-l- ylidene} pyrrolidine- 1 -carboxylate; propan-2 -yl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-y n-l-ylidene}pyrrolidine-

1 -carboxylate; methyl (3E)-2,2-dimethyl-3-{3-[6-(methylamino)pyridin-2-yl]prop-2-y n-l-ylidene}pyrrolidine-l- carboxylate; tert-butyl (3E)-3 -[3 -(4-cyanopyridin-2-yl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidine- 1 - carboxylate; ethyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-l-ylidene]-2,2-dime thylpyrrolidine-l-carboxylate;

2-methoxyethyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-l-ylidene]-2,2-dime thylpyrrolidine-l- carboxylate;

2-methylpropyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidine- 1- carboxylate; propan-2 -yl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-l-ylidene]-2,2-dime thylpyrrolidine-l- carboxylate; methyl (3E)-3-[3-(4-cyanopyridin-2-yl)prop-2-yn-l-ylidene]-2,2-dime thylpyrrolidine-l-carboxylate; tert-butyl (3E)-3 -[3 -(3 -cyano-5 -fluorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidine- 1 - carboxylate; ethyl (3E)-3 - [3 -(3 -cyano-5 -fluorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidine- 1 - carboxylate; propyl (3E)-3 - [3 -(3 -cyano-5 -fluorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidine- 1 - carboxylate;

2-methoxyethyl (3E)-3 -[3 -(3 -cyano-5 -fluorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidine- 1 - carboxylate; 2-methylpropyl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn-l-ylidene]-2,2-d imethylpyrrolidine-l- carboxylate; propan-2 -yl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn- l-ylidene]-2,2-dimethylpyrrolidine- 1- carboxylate; methyl (3E)-3-[3-(3-cyano-5-fluorophenyl)prop-2-yn- l-ylidene]-2,2-dimethylpyrrolidine- 1- carboxylate; tert-butyl (3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-l-ylidene]-2,2-dim ethylpyrrolidine-l- carboxylate;

{ (3E)-3 -[3 -(4-chloropyridin-2-yl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidin- 1 -yl} (furan-2- yl)methanone;

(3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-l-ylidene]-N,N- diethyl-2,2-dimethylpyrrolidine-l- carboxamide;

{ (3E)-3 -[3 -(4-chloropyridin-2-yl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidin- 1 -yl } (pyrrolidin- 1 - yl)methanone;

{ (3E)-3 -[3 -(4-chloropyridin-2-yl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidin- 1 -yl} (piperidin- 1 - yl)methanone;

(3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-l-ylidene]-N,N, 2,2-tetramethylpyrrolidine-l-carboxamide; ethyl (3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-l-ylidene]-2,2-dim ethylpyrrolidine-l-carboxylate; methyl (3E)-3-[3-(4-chloropyridin-2-yl)prop-2-yn-l-ylidene]-2,2-dim ethylpyrrolidine-l-carboxylate;

(3 -chlorophenyl) { (3E)-3 -[3 -(4-chloropyridin-2-yl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidin- 1 - yl} methanone; ethyl (3E)-3-[3-(6-aminopyridin-2-yl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidine- 1 -carboxylate;

(3E)-3-[3-(6-aminopyridin-2-yl)prop-2-yn-l-ylidene]-N,N-d iethyl-2,2-dimethylpyrrolidine-l- carboxamide; methyl (3E)-3-[3-(6-aminopyridin-2-yl)prop-2-yn-l-ylidene]-2,2-dime thylpyrrolidine-l-carboxylate; (3E)-3-[3-(6-aminopyridin-2-yl)prop-2-yn- 1 -ylidene] -N,N,2,2-tetramethylpyrrolidine- 1 -carboxamide; tert-butyl (3E)-3-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-2,2-dimethylp yrrolidine-l-carboxylate;

{ (3E)-3 -[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidin- 1 -yl} (piperidin- 1 - yl)methanone;

{ (3E)-3 -[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidin- 1 -yl} (pyrrolidin- 1 - yl)methanone; ethyl (3E)-3 - [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidine- 1 -carboxylate;

(3E)-3-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-N-ethyl-2, 2-dimethyl-N-(propan-2-yl)pyrrolidine-l- carboxamide;

(3E)-3 -[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -N,N,2,2-tetramethylpyrrolidine- 1 -carboxamide ;

{ (3E)-3 - [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidin- 1 -yl } (furan-2- yl)methanone; methyl (3E)-3-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-2,2-dimethylp yrrolidine-l-carboxylate;

(3 -chlorophenyl) { (3E)-3 -[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -2,2-dimethylpyrrolidin- 1 - yl} methanone;

(3 -chlorophenyl) [(4E)-4- { [5 -(3 -chlorophenyl)- lH-pyrazol-3 -yl] methylidene } -3 ,3 -dimethylpiperidin-

1-yl] methanone; ethyl 2,2,6,6-tetramethyl-4-[3-(6-methylpyridin-2-yl)prop-2-yn-l-y lidene]piperidine-l-carboxylate;

2-methyl-6-[3-(2,2,6,6-tetramethylpiperidin-4-ylidene)pro p-l-yn-l-yl]pyridine; tert-butyl 8- [3 -(6-methylpyridin-2-yl)prop-2-yn- 1 -ylidene] -5 -azaspiro [3 ,5]nonane-5 -carboxylate methyl 8-[3-(6-methylpyridin-2-yl)prop-2-yn-l-ylidene]-5-azaspiro[3 ,5]nonane-5-carboxylate (E:Z mixture);

4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] - 1 ,2,2,6,6-pentamethylpiperidine;

2-methyl-6-[3 -( 1 ,2,2,6,6-pentamethylpiperidin-4-ylidene)prop- 1 -yn- 1 -yl]pyridine; ethyl 3-[3-(6-methylpyridin-2-yl)prop-2-yn-l-ylidene]-8-azabicyclo [3.2.1]octane-8-carboxylate;

8-(6-methyl-3 -nitropyridin-2-yl)-3 - [3 -(6-methylpyridin-2-yl)prop-2-yn- 1 -ylidene] -8- azabicyclo[3.2.1]octane;

3-{(3E)-3-[l-(3-chlorobenzoyl)-3,3-dimethylpiperidin-4-yl idene]prop-l-yn-l-yl}benzonitrile;

3-{(3E)-3-[l-(3-chlorobenzoyl)-3,3-dimethylpiperidin-4-yl idene]prop-l-yn-l-yl}-5- fluorobenzonitrile ;

(3 -chlorophenyl) { (4E)-4-[3 -(3 -methoxyphenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl} methanone;

(3 -chlorophenyl) [(4E) -4 - [3 - { 3 -(hydroxymethyl)phenyl]prop-2-yn- 1 -ylidene } -3 ,3 -dimethylpiperidin- 1-yl] methanone;

(3 -chlorophenyl) { (4E)-4-[3 -(4-fluorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl} methanone;

(3 -chlorophenyl) [(4E)-3 ,3 -dimethyl -4-(3 - { 3 - [(pyrrolidin- 1 -yl)methyl]phenyl }prop-2-yn- 1 - ylidene)piperidin- 1 -yl] methanone;

(3 -chlorophenyl) { (4E)-3 ,3 -dimethyl-4- [3 -(6-methylpyridin-2-yl)prop-2-yn- 1 -ylidene]piperidin- 1 - yl} methanone;

5-{(3E)-3-[l-(3-chlorobenzoyl)-3,3-dimethylpiperidin-4-yl idene]prop-l-yn-l-yl}pyridine-2- carbonitrile;

(3 -chlorophenyl) { (4E)-4-[3 -(6-methoxypyridin-3 -yl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl} methanone;

(3 -chlorophenyl) { (4E)-4-[3 -(3 -fluoro-5 -hydroxyphenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1-yl} methanone;

{ (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (3 - hydroxyphenyl)methanone ; { (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (4-methoxypyridin-2- yl)methanone;

(4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (6-methylpyridin-2- yl)methanone;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-dimeth yl-N-(6-methylpyridin-2-yl)piperidine-l- carboxamide;

{ (4E)-4-[3-(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (2,2- dimethylmorpholin-4-yl)methanone ;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-N-(2,2-dim ethyltetrahydro-2H-pyran-4-yl)-3,3- dimethylpiperidine- 1 -carboxamide ;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-dimeth yl-N-(pyridin-2-yl)piperidine-l- carboxamide;

2-( { (4E)-4-[3 -(3-chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } carbonyl)pyridine-4- carbonitrile;

1 - { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } -2-(2,2- dimethyltetrahydro-2H-pyran-4-yl)ethanone;

{ (4E)-4-[3 -(3 -Chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (4-chloropyridin-2- yl)methanone;

{ (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (4,5 -dimethylfuran-2- yl)methanone;

{ (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (3 - methoxyphenyl)methanone ;

3 -( { (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl } carbonyl)benzonitrile ;

(4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -N -(4-chloropyridin-2-yl)-3 ,3 -dimethylpiperidine- 1 - carboxamide;

2,2-dimethylpropyl (4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-dimethylp iperidine-l- carboxylate;

(4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethyl -N-(3 -methylphenyl)piperidine- 1 - carboxamide;

2-methylpyridin-4-yl (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidine- 1 - carboxylate;

(4E)-4-[3-(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -N -(2, 2-dimethylpropyl)-3 ,3 -dimethylpiperidine- 1 - carboxamide;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (4-hydroxypiperidin- 1 - yl)methanone; ethyl 4-( { (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl } sulfonyl)piperidine- 1 -carboxylate ;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-dimeth yl-l-[(tetrahydro-2H-pyran-2- ylmethyl) sulfonyl] piperidine ;

5 -( { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } sulfonyl)-3 - ethyl [ 1 ,2]oxazolo [5 ,4-b]pyridine ;

(4E)-4-[3-(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethyl- 1 - { [(3 -methyl- 1 ,2-oxazol-5 - yl)methyl] sulfonyl } piperidine ;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-N,3,3-trim ethyl-N-(propan-2-yl)piperidine-l- sulfonamide;

4-( { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } sulfonyl)-2,6- dimethylmorpholine ;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-dimeth yl-l-(phenylsulfonyl)piperidine; (4E)-N-tert-butyl-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidine- 1 -sulfonamide ; 4-( { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } sulfonyl)morpholine; 4-( { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } sulfonyl)- 1 -methyl - 1 H-benzotriazole ;

3 -( { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } sulfonyl)-5 -(propan- 2-yloxy)pyridine;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-N-(cyclopr opylmethyl)-N,3,3-trimethylpiperidine-l- sulfonamide;

5 -( { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } sulfonyl)-2- methoxypyridine ;

3 -( { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } sulfonyl)-6,7- dihydro-5H-pyrazolo [5 , 1 -b] [ 1 , 3 ] oxazine ;

(4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -N-cyclohexyl-N, 3 ,3 -trimethylpiperidine- 1 - sulfonamide;

(4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3,3 -dimethyl- 1 -[(4-methylpiperidin- 1 - yl)sulfonyl]piperidine;

(4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] - 1 - [(2,2-dimethylpropyl)sulfonyl] -3,3- dimethylpiperidine ;

(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-dimeth yl-l-[(tetrahydro-2H-pyran-3- ylmethyl) sulfonyl] piperidine ;

(4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] - 1 - [(3 ,5-dimethyl- 1 ,2-oxazol-4-yl)sulfonyl] -3,3- dimethylpiperidine ;

6-( { (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl } sulfonyl)pyrazolo [ 1 ,5 -a]pyrimidine-3 -carbonitrile; (4E)-4-[3-(3 -chlorophenyl)prop-2-yn- 1 -ylidene] - 1 - [( 1 -ethyl-3 ,5 -dimethyl- lH-pyrazol-4-yl)sulfonyl] - 3 , 3 -dimethylpiperidine ;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (4,6- dimethoxypyrimidin-2-yl)methanone;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3,3 -dimethylpiperidin- 1 -yl } (2-ethyl-5 -methyl-2H- l,2,3-triazol-4-yl)methanone;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (4-methoxypyrimidin-

2-yl)methanone;

{ (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (6,7-dihydro-5H- pyrazolo [5 , 1 -b] [ 1 , 3 ] oxazin-3 -yl)methanone ;

{ (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } ([ 1 ,2,4]triazolo [1,5- a]pyridin-2-yl)methanone;

{ (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (2,6- dimethoxypyrimidin-4-yl)methanone;

4-({(4E)-4-[3-(3-chlorophenyl)prop-2-yn-l-ylidene]-3,3-di methylpiperidin-l-yl}carbonyl)pyridine-2- carbonitrile;

{ (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } ( 1 ,5-dimethyl- 1H- 1,2,3- triazol-4-yl)methanone;

{ (4E)-4- [3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (5 ,6-dihydro-8H- imidazo[2, 1 -c] [ 1 ,4]oxazin-3-yl)methanone;

6-( { (4E)-4-[3-(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } carbonyl)pyridine-2- carbonitrile;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (3 -methoxy- 1 -methyl -

1 H-pyrazol-5 -yl)methanone ;

(3 -chlorophenyl) [(4E) -4 - [3 -(4-methoxypyridin-2-yl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl]methanone;

(3 -chlorophenyl) [(4E) -4 - [3 - [5 -(hydroxymethyl)furan-2-yl]prop-2-yn- 1 -ylidene] -3,3- dimethylpiperidin- 1 -yl]methanone;

(3-chlorophenyl)[(4E)-4-{3-[3-(hydroxymethyl)phenyl]-lH-p yrazol-5-yl}methylidene)-3,3- dimethylpiperidin- 1 -yl]methanone;

3-(5-{(E)-[l-(3-chlorobenzoyl)-3,3-dimethylpiperidin-4-yl idene]methyl}-lH-pyrazol-3- yl)benzonitrile;

(3 -chlorophenyl) [(4E)-3 ,3-dimethyl-4- { [3 -(6-methylpyridin-2-yl)- lH-pyrazol-5 - yl] methylidene } piperidin- 1 -yl] methanone ;

[(4E)-4- { [5 -(3 -chlorophenyl)- lH-pyrazol-3 -yl]methylidene } -3 ,3 -dimethylpiperidin- 1 -yl] (2,5- dimethylfuran-3 -yl)methanone ; (3 -chlorophenyl) { (4E)-3 ,3 -dimethyl -4- [(5 -phenyl- 1 ,2-oxazol-3 -yl)methylidene]piperidin- 1 - yl} methanone;

(3 -chlorophenyl) [(4E)-4- { [5 -(3 -chlorophenyl)- 1 ,3 -oxazol-2 -yl] methylidene } -3 ,3 -dimethylpiperidin- 1 - yl]methanone;

(3 -chlorophenyl) [(4E)-4- { [5 -(3 -chlorophenyl)- 1 ,2,4-oxadiazol-3 -yl]methylidene } -3 ,3 - dimethylpiperidin- 1 -yl]methanone;

(3 -chlorophenyl) [(4E)-4- { [ 5 - (3 -chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl]methylidene } -3 ,3 - dimethylpiperidin- 1 -yl]methanone ;

(3 -chlorophenyl) [(4E)-4-(3 -cyclohexylprop-2-yn- 1 -ylidene)-3 ,3 -dimethylpiperidin- 1 -yl]methanone ;

(3 -chlorophenyl) { (4E)-4-[3 -(4-chloropyridin-2-yl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl} methanone;

(3 -chlorophenyl) [(4E)-3 ,3 -dimethyl -4- { 3 -[6-(trifluoromethyl)pyridin-2-yl]prop-2-yn- 1 - ylidene }piperidin- 1 -yl] methanone;

(3 -chlorophenyl) { (4E)-4-[3-(6-methoxypyridin-2-yl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl} methanone;

(3 -chlorophenyl) { (4E)-4-[3-(3 -hydroxyphenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 - yl} methanone;

[(4E)-3,3-dimethyl-4-(3-phenylprop-2-yn- 1-ylidene )piperidin-l-yl](phenyl)methanone;

3-[(3E)-3-{ l-[(2,5-dimethylfuran-3-yl)carbonyl]-3,3-dimethylpiperidin-4 -ylidene}prop-l-yn-l- yl]benzonitrile;

{ (4E)-4-[3 -(3-chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -dimethylpiperidin- 1 -yl } (phenyl)methanone;

3 - { (3 E) -3 - [3 ,3 -dimethyl- 1 -(3 -methylbenzoyl)piperidin-4-ylidene]prop- 1 -yn- 1 -yl } benzonitrile ;

3-{(3E)-3-[l-(3-methoxybenzoyl)-3,3-dimethylpiperidin-4-y lidene]prop-l-yn-l-yl}benzonitrile;

(4E)-4-[3 - { 3 -(hydroxymethyl)phenyl]prop-2-yn- 1 -ylidene } -3 ,3 -dimethyl -N-(6-methylpyridin-2- yl)piperidine- 1 -carboxamide;

(3 -chlorophenyl) { (4E)-4-[4-(3 -chlorophenyl)but-3 -yn-2 -ylidene] -3 ,3 -difluoropiperidin- 1 - yl} methanone;

(3 -chlorophenyl) { (4Z)-4-[4-(3 -chlorophenyl)but-3 -yn-2 -ylidene] -3 ,3 -difluoropiperidin- 1 - yl} methanone;

3 - [(3 E) - 3 - { 1 -[(2,5 -dimethylfuran-3 -yl)carbonyl] -3 ,3 -dimethylpiperidin-4-ylidene }prop- 1 -yn- 1 -yl] -5 - fluorobenzonitrile ;

(3 -chlorophenyl) { (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -difluoropiperidin- 1 - yl} methanone;

{ (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3,3 -difluoropiperidin- 1 -yl} (4-methoxypyridin-2- yl)methanone;

(3 -chlorophenyl) { (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -difluoropiperidin- 1 - yl} methanone; and { (4E)-4-[3 -(3 -chlorophenyl)prop-2-yn- 1 -ylidene] -3 ,3 -difluoropiperidin- 1 -yl } (4-methoxypyridin-2- yl)methanone.

[001004] D

Formula 222

[001005] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 222. Such compounds are described in, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 222, this reference incorporated by reference herein controls.

[001006] In an embodiment, the glutamate modulator is a negative allosteric modulator of the metabotropic glutamate receptor 5 (mGluR5).

[001007] In an embodiment, the glutamate modulator is a compound selected from:

, and pharmaceutically acceptable salts and solvates thereof, or substituted variants thereof which retain glutamate modulatory activity.

[001008] In an embodiments, the glutamate modulator is a compound selected from: including pharmaceutically acceptable salts and solvates thereof, or substituted variants thereof which retain glutamate modulatory activity.

Formula 223 [001009] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 223. Such compounds are described in WO 2017/071536, published May 4, 2017, corresponding to PCT/CN2016/102946, filed October 21, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 223, this reference incorporated by reference herein controls.

[001010] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein:

R1 is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 1-3 heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 0-3 substituents independently selected from alkyl, halogen, - OH, -CN, nitro, -CF3, -O-CF3, -O-alkyl, -O-aryl, -S-alkyl, -S-aryl, -S (O) -alkyl, -S (O) -aryl, -S (02) -alkyl, -S (02) -aryl, -CH2-aryl, aryl, heteroaryl, -O-CH2-aryl, -N (CH3) 2, cycloalkyl, heterocycloalkyl, -C (O) -alkyl, -C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O- heterocycloalkyl, -C (O) O-aryl, -C (O) O-heteroaryl, -C (O) N-alkyl, -C (O) N-cycloalkyl, - C (O) N-heteroalkyl, -C (O) N-aryl, -C (O) N-heteroaryl or substituted lower alkyl, wherein the substituents may combine to form an optionally substituted 5-7 membered fused and optionally substituted carbocyclic or heterocyclic ring ; or

R1 is a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10-membered aryl ring is optionally substituted with 0-3 substituents independently selected from alkyl, halogen, -OH, -CN, nitro, -CF3, -OCF3, -O-alkyl, -O-aryl, -S-alkyl, -S-aryl, -S (O) -alkyl, -S (O) -aryl, -S (02) -alkyl, -S (02) -aryl, -CH2-aryl, aryl, heteroaryl, -O-CH2-aryl, -N (CH3) 2, cycloalkyl, heterocycloalkyl, -C (O) -alkyl, -C (O) cycloalkyl, -C (O) -heterocycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O- heterocycloalkyl, -C (O) O-aryl, -C (O) O-heteroaryl, -C (O) N-alkyl, -C (O) N-cycloalkyl, - C (O) N-heteroalkyl, -C (O) N-aryl, -C (O) N-heteroaryl or substituted lower alkyl, wherein the substituents may combine to form a 5-7 membered fused and optionally substituted carbocyclic or heterocyclic ring, R2 is alkanoyl, arylalkanoyl, herteroaryl acyl, aryl sulfonyl, heteroaryl sulfonyl, alkoxycarbonyl, -C (O) O-aryl, arylalkoxycarbonyl, acylamino, wherein the aryl or heteroaryl are optionally substituted with 0-3 substituents independently selected from alkyl, halogen, - OH, -CN, nitro, -CF3, -OCF3, -O-alkyl, -O-aryl, , -S-alkyl, -S-aryl, -S (O) -alkyl, S (O) -aryl, -S (02) -alkyl, -S (02) aryl, -CH2-aryl, heteroaryl, -O-CH2-aryl, -N (CH3) 2, cycloalkyl, heterocycloalkyl, -C (O) -alkyl, -C (O) cycloalkyl, -C (O) -heterocycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O-heterocycloalkyl, -C (O) O- aryl, -C (O) O-heteroaryl, -C (O) N-alkyl, -C (O) N-cycloalkyl, -C (O) N-heteroalkyl, -C (O) N-aryl, -C (O) N-heteroaryl or substituted lower alkyl, wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring ; or R2 is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 1-3 heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 0-3 substituents independently selected from alkyl, halogen, - OH, -CN, nitro, -CF3, -O-CF3, -O-alkyl, -O-aryl, -S-alkyl, -S-aryl, -S (O) -alkyl, -S (O) -aryl, -S (02) -alkyl, -S (02) -aryl, -CH2-aryl, aryl, heteroaryl, -O-CH2-aryl, -N (CH3) 2, cycloalkyl, heterocycloalkyl, -C (O) -alkyl, -C (O) cycloalkyl, -C (O) heterocycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O- heterocycloalkyl, -C (O) O-aryl, -C (O) O-heteroaryl, -C (O) N-alkyl, -C (O) N-cycloalkyl, - C (O) N-heteroalkyl, -C (O) N-aryl, -C (O) N-heteroaryl or substituted lower alkyl, wherein the substituents may combine to form an optionally substituted 5-7 membered fused and optionally substituted carbocyclic or heterocyclic ring ; or

R2 is a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10-membered ring system is optionally substituted with 0-3 substituents independently selected from alkyl, halogen, -OH, -CN, nitro, -CF3, -OCF3, -O-alkyl, -O-aryl, -S-alkyl, -S-aryl, -S (O) -alkyl, S (O) -aryl, -S (02) -alkyl, -S (02) aryl, -CH2-aryl, aryl, heteroaryl, -O-CH2-aryl, -N (CH3) 2, cycloalkyl, heterocycloalkyl, -C (O) -alkyl, -C (O) cycloalkyl, -C (O) -heterocycloalkyl, -C (O) -aryl, -C (O) -heteroaryl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O- heterocycloalkyl, -C (O) O-aryl, -C (O) O-heteroaryl, -C (O) N-alkyl, -C (O) N-cycloalkyl, - C (O) N-heteroalkyl, -C (O) N-aryl, -C (O) N-heteroaryl or substituted lower alkyl, wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring.

[001011] In an embodiment, the glutamate modulator is a compound selected from: 3-fluoro-5- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile, 3- (4-fluorophenyl) -1- (pyridin-2-ylethynyl) -3 -azabicyclo [3.1.0] hexane,

1- (pyri din-2 -ylethynyl) -3- (4- (trifluoromethoxy) phenyl) -3 -azabicyclo [3.1.0] hexane, 3 -phenyl- 1- (pyridin-2-ylethynyl) -3 -azabicyclo [3.1.0] hexane,

3- (2-fluorophenyl) -1- (pyridin-2-ylethynyl) -3 -azabicyclo [3.1.0] hexane,

3- (2-chlorophenyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane, 3- (3 -chlorophenyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane, 3- (4-chlorophenyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

3- (3-chloro-5-fluorophenyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane, 3- (4-chloro-2-fluorophenyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane, 3- (4-chl oro-3 -fluorophenyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane, 3- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile,

3- (3, 5 -difluorophenyl) -1- (pyrimidin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

3- (3 -fluorophenyl) -1- (pyrimidin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

3- (1- ( (2-methylthiazol-4-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile,

4- (3- (5-fluoropyri din-3 -yl) -3-azabicyclo [3.1.0] hexan-l-yl) ethynyl) -2-methylthiazole,

3- (1- (pyrimidin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile,

3- (5-fluoropyridin-3-yl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane, 3- (5-fluoropyridin-2-yl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

2- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) isonicotinonitrile,

5- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) -IH-pyrrolo [3, 2-b] pyridine,

5- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) -IH-benzo [d] imidazole,

6- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) picolinonitrile,

3- (5-fluoropyridin-3-yl) -1- ( (6-methylpyridin-2-yl) ethynyl) -3-azabicyclo [3.1.0] hexane, 5- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) nicotinonitrile,

3- (5-fluoropyridin-3-yl) -1- (pyrimidin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

3- (phenyl sulfonyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

(3 -chlorophenyl) (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone, pyridin-2-yl (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone, phenyl (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone,

2-phenyl-l- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) ethanone, (2-chlorophenyl) (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone, 1- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) pentan-l-one,

3-phenyl-l- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) propan-l-one, (4-chlorophenyl) (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone,

3- ( (3 -chlorophenyl) sulfonyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

3- ( (4-chlorophenyl) sulfonyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

3- ( (2-chlorophenyl) sulfonyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

1- (pyri din-2 -ylethynyl) -3 -tosyl-3 -azabicyclo [3.1.0] hexane,

(3 -fluorophenyl) (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone,

3- ( (2-fluorophenyl) sulfonyl) -1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane,

(3 -fluorophenyl) (1- ( (6-methylpyridin-2-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone,

(3 -chlorophenyl) (1- ( (2-methylthiazol-4-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone, cyclopentyl (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone,

2, 2-dimethyl-l- (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) propan-l-one, methyl- 1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane-3 -carboxylate (5-chloropyridin-3-yl) - (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone,

(4-chloropyridin-2-yl) (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone, (6-chl oropyri din-3 -yl) (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone, (3 -chlorophenyl) (1- (pyrimidin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) methanone,

2-methyl-l- (1- ( (6-methylpyridin-2-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) propan-l- one,

1- (1- ( (6-chloropyridin-2-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) -2-methylpropan-l- one,

(1- ( (2-methylthiazol-4-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) (phenyl) methanone,

1- (1- ( (2-methylthiazol-4-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) pentan-l-one,

2-methyl-l- (1- ( (2-methylthiazol-4-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) propan-l- one,

2, 2-dimethyl-l- (1- ( (2-methylthiazol-4-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) propan-l-one,

N-phenyl-1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane-3 -carboxamide, N-propyl-1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexane-3 -carboxamide, (1- (pyridin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) (pyrrolidin-l-yl) methanone, 1- (pyridin-2-ylethynyl) -N- (2, 2, 2-trifluoroethyl) -3-azabicyclo [3.1.0] hexane-3- carboxamide, 3-fluoro-5- (1- (pyrazin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile, 3-fluoro-5- (1- (pyrimidin-2-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile, 3-fluoro-5- (1- ( (3-methylpyridin-2-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile,

3-fluoro-5- (1- (pyridazin-3-ylethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile, 3- (1- ( (2-chloropyridin-4-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) -5- fluorob enzonitril e,

3-fluoro-5- (1- ( (6-methylpyridin-2-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile,

3- (1- (6-chloropyridin-2-yl) -3-azabicyclo [3.1.0] hexan-3-yl) -5-fluorobenzonitrile, 3-fluoro-5- (1- ( (6-methoxypyridin-2-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile, or

3-fluoro-5- (1- ( (2-methylthiazol-4-yl) ethynyl) -3-azabicyclo [3.1.0] hexan-3-yl) benzonitrile, including pharmaceutically acceptable salts thereof, or substituted variants retaining glutamate modulatory activity.

Formula 224

[001012] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 224. Such compounds are described in US 2016/0096833, published January 24, 2017, and issued January 24, 2017 as US 9,550,778 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 224, this reference incorporated by reference herein controls.

[001013] In an embodiment, the glutamate modulator is a compound according to Formula 224:

, wherein Z1 is selected from N and CR6a; wherein

Z2 is selected from N and CR6b; and wherein Z1 and Z2 are not simultaneously N; wherein each of R6a and R6b, when present, is independently selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR40, — NR41aR41b, — SO2R42, and — (C=O)R43; wherein R40, when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R41a and R41b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R41a and R41b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R42, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR44aR44b; wherein each of R44a and R44b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R44a and R44b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R43, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR45aR45b; wherein each of R45a and R45b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R45a and R45b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R1 is heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR60, — NR61aR61b, — SO2R62, and — (C=O)R63; wherein each occurrence of R60, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R61a and R61b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R61a and R61b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R62, when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR64aR64b; wherein each occurrence of each of R64a and R64b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R64a and R64b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R63, when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR65aR65b; wherein each occurrence of each of R65a and R65b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R65a and R65b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R3a and R3b is independently selected from hydrogen and fluoro; wherein Ari is selected from aryl and heteroaryl, and wherein Ari is substituted with 0, 1, 2, or 3 groups independently selected from halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, — OR30, — NR31aR31b, — SO2R32, — (C=O)R33, and cyclopropyl; wherein each occurrence of R30, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R31a and R31b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R3 la and R3 lb, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R32, when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR34aR34b; wherein each occurrence of each of R34a and R34b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R34a and R34b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R33, when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR35aR35b; wherein each occurrence of each of R35a and R35b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R35a and R35b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; or a pharmaceutically acceptable salt thereof.

[001014] In an embodiment, the glutamate modulator is a compound according to:

wherein each of R70a, R70b, R70c, and R70d is independently selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR40, — NR41aR41b, — SO2R42, and — (C=O)R43, provided that at least one of R70a, R70b, R70c, and R70d is hydrogen.

[001016] In an embodiment, the glutamate modulator is a compound according to: , wherein each of R80a and R80b is independently selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR40, — NR41aR41b, — SO2R42, and — (C=O)R43. [001017] In further embodiments, the glutamate modulator is a compound selected from:

, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 225

[001018] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 225. Such compounds are described in WO 2014/065270, published May 1, 2014, corresponding to PCT/JP2013/078553, filed October 22, 2013, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 225, this reference incorporated by reference herein controls.

[001019] In an embodiment, the glutamate modulator is a compound according to: , wherein R1 is halogen, alkyl, methyl, or cyano, R2 and R3 each independently represent H, halogen, Cl -3 alkyl, Cl -3 alkoxy, or cyano, including pharmaceutically acceptable salts thereof.

[001020] In an embodiment, the glutamate modulator is a compound selected from: [2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone;

(3-Chloro-5-fluorophenyl) [2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl ] Methanone;

(2-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone;

(3 -fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone; and

(4-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone , including pharmaceuatically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 226

[001021] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 226. Such compounds are described in, WO 2011/073347, published June 23, 2011, corresponding to PCT/EP2010/069972, filed December 16, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 226, this reference incorporated by reference herein controls.

[001022] In an embodiment, the glutamate modulator is a compound according to: wherein X is selected from CH2 and NR2;

A is selected from the group consisting of 1 ,2-ethanediyl; 1 ,2-ethenediyl; and 1 ,2- ethynediyl;

R1 is selected from the group consisting of phenyl; phenyl substituted with 1 or 2 halo substituents; pyridinyl; and pyridinyl substituted with 1 or two halo substituents; or Rl-A together is 3,4-dihydro-2H-l,4-benzoxazin-7-yl optionally substituted with methyl;

R2 is selected from the group consisting of hydrogen; methyl; methoxyethyl; aryl; benzyl; and benzyl wherein the phenyl part is substituted with 1 or 2 halo substituents; wherein aryl is phenyl, optionally substituted with 1 or 2 substituents selected from the group consisting of methyl, methoxy, cyano, fluoro, chloro, trifluoromethyl and trifluoromethyloxy; or a pharmaceutically acceptable salt or a solvate thereof.

[001023] In an embodiment, the glutamate modulator is a compound selected from:

5.6-dihydro-2-(phenylethynyl)-7(4H)-benzothiazolone;

2- [(5 -f uoro-3 -pyridinyl)ethynyl] -5 ,6-dihydro-7(4H)-benzothiazo lone; 6,7-dihydro-2- (phenylethynyl)- thiazolo[5,4-c]pyridin-4(5H)-one;

6.7-dihydro-5-methyl-2-(phenylethynyl)-thiazolo[5,4-c]pyr idin-4(5H)-one;

5.6-dihydro-2-[(E)-2-phenylethenyl]-7(4H)-benzothiazolone ;

5.6-dihydro-2-(2-phenylethyl)-7(4H)-benzothiazolone;

2-(4-methyl-3 ,4-dihydro-2H- 1 ,4-benzoxazin-7-yl)-5 ,6-dihydro- 1 ,3-benzothiazol- 7(4H)- one;

5.6- dihydro-2-(3-pyridinylethynyl)-7(4H)-benzothiazolone;

6.7- dihydro-5-(2-methoxyethyl)-2-(phenylethynyl)- thiazolo[5,4-c]pyridin-4(5H)- one; and

6.7-dihydro-2-(phenylethynyl)-5-(phenylmethyl)-thiazolo[5 ,4-c]pyridin-4(5H)-one; or a pharmaceutically acceptable salt or a solvate thereof, or substituted variant retaining glutamate modulatory activity.

Formula 227

[001024] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 227. Such compounds are described in US 2015/0266866, published September 24, 2015, corresponding to US 15/664,792, filed March 20, 2015, issued as US 9,533,982, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 227, this reference incorporated by reference herein controls.

[001025] In an embodiment, the glutamate modulator is a compound according to Formula 227:

CR5; wherein R5, when present, is selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR20, — NR21aR21b, — SO2R22, and — (C=O)R23; wherein R20, when present, is selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R21a and R21b, when present, is independently selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R21a and R21b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R22, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, Cl- C3 polyhaloalkyl, cyclopropyl, and, — NR24aR24b; wherein each of R24a and R24b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R24a and R24b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R23, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, Cl- C3 polyhaloalkyl, cyclopropyl, and, — NR25aR25b; wherein each of R25a and R25b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R25a and R25b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR6; wherein R6, when present, is selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR30, — NR31aR31b, — SO2R32, and — (C=O)R33; wherein R30, when present, is selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R3 la and R3 lb, when present, is independently selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R3 la and R3 lb, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R32, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, Cl- C3 polyhaloalkyl, cyclopropyl, and, — NR34aR34b; wherein each of R34a and R34b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R34a and R34b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R33, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, Cl- C3 polyhaloalkyl, cyclopropyl, and, — NR35aR35b; wherein each of R35a and R35b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R35a and R35b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR7, provided that Q and V are not simultaneously N; wherein R7, when present, is selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR40, — NR41aR41b, — SO2R42, and — (C=O)R43; wherein R40, when present, is selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R41a and R41b, when present, is independently selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R41a and R41b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R42, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, Cl- C3 polyhaloalkyl, cyclopropyl, and, — NR44aR44b; wherein each of R44a and R44b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R44a and R44b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R43, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, Cl- C3 polyhaloalkyl, cyclopropyl, and, — NR45aR45b; wherein each of R45a and R45b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R45a and R45b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from — CR8(O)rR9 — , — CR8NR10aR10b — , — (C=O) — , and a structure represented by a formula: wherein Y is selected from — CR8R9 — , — O — , — S(O)q — , and — NR8 — ; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is — CR8R9 — ; wherein the sum of m and n is 2 when Y is — O — , — S(O)q — , and — NR8 — ; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R8, when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is — CR8(O)rR9 — and r is 1, R8 is not halogen; wherein R9, when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is — CR8(O)rR9 — and r is 1, R9 is not halogen; wherein each of RlOa and RlOb, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R12a, R12a, R12a, and R12a, when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R1 is selected from aryl and heteroaryl, and wherein R1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR50, — NR51aR51b, — SO2R52, and — (C=O)R53; wherein each occurrence of R50, when present, is independently selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R51a and R51b, when present, is independently selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R51a and R51b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R52, when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, NR54aR54b; wherein each occurrence of each of R54a and R54b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R54a and R54b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R53, when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, — NR55aR55b; wherein each occurrence of each of R55a and R55b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R55a and R55b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R3 is selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR60, — NR61aR61b, — SO2R62, and — (C=O)R63; wherein R60, when present, is selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R61a and R61b, when present, is independently selected from is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R61a and R61b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R62, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, Cl- C3 polyhaloalkyl, cyclopropyl, and, — NR64aR64b; wherein each of R64a and R64b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R64a and R64b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R63, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, Cl- C3 polyhaloalkyl, cyclopropyl, and, — NR65aR65b; wherein each of R65a and R65b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R65a and R65b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R4a, R4b, R4c, and R4d, is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

[001026] In further embodiments, the glutamate modulator is a compound according to:

, including pharmaceutically acceptable salts thereof, and substituted variants thereof retaining glutamate modulatory activity.

Formula 228

[001027] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 228. Such compounds are described in WO 2015/077246, published May 28, 2015, corresponding to PCT/US2014/066207, filed November 18, 2014 and to US 9,844,542, issued December 19, 2017, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 228, this reference incorporated by reference herein controls.

[001028] In an embodiment, the glutamate modulator is a compound according to Formula 228:

, wherein Q is selected from N and CR5; wherein R5, when present, is selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR30, — NR31aR31b, — SO2R32, and — (C=O)R33; wherein R30, when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R31a and R31b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R31a and R3 lb, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R32, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR34aR34b; wherein each of R34a and R34b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R34a and R34b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R33, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR35aR35b; wherein each of R35a and R35b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R35a and R35b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of Z1 and Z2 is independently selected from N and CR6, provided that Z1 and Z2 are not simultaneously N; wherein each of R6, when present, is independently selected from hydrogen, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR40, — NR41aR41b, — SO2R42, and — (C=O)R43; wherein R40, when present, is selected from hydrogen, C1-C3 alkyl,Cl-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R41a and R41b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R41a and R41b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R42, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR44aR44b; wherein each of R44a and R44b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R44a and R44b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R43, when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR45aR45b; wherein each of R45a and R45b, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R45a and R45b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R1 is heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from deuterium, halogen, — CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, — OR60, — NR61aR61b, — SO2R62, and — (C=O)R63; wherein each occurrence of R60, when present, is independently selected from hydrogen, Cl- C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R61a and R61b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R61a and R61b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R62, when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR64aR64b; wherein each occurrence of each of R64a and R64b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R64a and R64b, when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R63, when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and — NR65aR65b; wherein each occurrence of each of R65a and R65b, when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R65a and R65b, when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R3a, R3b, R3c, and R3d, is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt thereof.

[001029] In further embodiments, the glutamate modulator is a compound selected from:

, including pharmaceutically acceptable salts and substituted variants thereof having glutamate modulatory activity.

Formula 229 [001030] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 229. Such compounds are described in WO 2015/054103, published April 16, 2015 and corresponding to PCT/US2014/059248, filed October 6, 2014, and US 9,688,669, issued June 27, 2017, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 229, these references incorporated by reference herein control.

[001031] In an embodiment, the glutamate modulator is a compound according to Formula 229:

Ri is hydrogen or alkyl; R2 is hydrogen or alkyl ;R3 is R4 is cyano, alkyl, haloalkyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, or thioalkyl, where alkyl, haloalkyl, and cycloalkyl are substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, hydroxy, and alkoxy; or R4 is a bridged [l-4.1-4.0-3]bicycloalkyl; or R4 is alkylcarbonylamino, hal oalky 1 carb ony lamino, cy cl oalkanony 1 , valerolactamyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyloxy, phenyl, or phenoxy; or R4 is amino, alkylamino, dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl; or R4 is pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or indazolyl, and is substituted with 0-2 substituents selected from halo and alkyl; L is a bond, alkylene, or hydroxy alkylene;

Ari is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, and is substituted with 1 R3 substituent and with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; and

Ar2 is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, or benzimidazolyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, and phenyl; or a pharmaceutically acceptable salt thereof

[001032] In an embodiment, the glutamate modulator is a compound according to:

[001033] In an embodiment, the glutamate modulator is a compound according to:

, wherein R1 is selected from:

pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

[001034] In further embodiments, the glutamate modulator is a compound according to: wherein R1 is selected from:

, including pharmaceutically acceptable salts thereof, and substituted variants retaining glutamate modulatory activity.

[001035] In further embodiments, the glutamate modulator is a compound according to:

Formula 230

[001036] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 230. Such compounds are described in JP 2015- 059118, published March 30, 2015 which is incorporated by reference in its entirety herein.

In the case of any conflict of terminology in the context of Formula 230, this reference incorporated by reference herein controls.

[001037] In an embodiment, the glutamate modulator is a compound according to

Formula 230:

, R1 is pyridyl or thiazolyl, wherein the pyridyl may be substituted with halogen, cyano, C 1-3 alkyl optionally substituted with 1 to 5 fluorines, or 1 to 5 fluorines), and wherein the thiazolyl may be substituted with 1 to 2 substituents independently selected from the group consisting of C 1-3 alkoxy and hydroxyl group,

R 2 is a group consisting of halogen, cyano, C 1-3 alkyl optionally substituted with 1 to 5 fluorines, C 1-3 alkoxy optionally substituted with 1 to 5 fluorines, and a hydroxyl group. Represents C 3-8 cycloalkyl, 4-8 membered heterocyclyl, aryl or heteroaryl, optionally substituted with 1-5 substituents independently selected from

R 3 and R 4 each independently represents a hydrogen atom or C 1-3 alkyl,

R 5 represents a hydrogen atom or C 1-3 alkyl, L represents a bond or -C (O)-; n represents 1 or 2] or a pharmaceutically acceptable salt thereof; or optionally R 1 is a group consisting of halogen, cyano, C 1-3 alkyl optionally substituted with 1 to 5 fluorines, C 1-3 alkoxy optionally substituted with 1 to 5 fluorines, and a hydroxyl group. 3-pyridyl or 4-pyridyl optionally substituted with 1 to 4 substituents independently selected from

R 2 is a group consisting of halogen, cyano, C 1-3 alkyl optionally substituted with 1 to 5 fluorines, C 1-3 alkoxy optionally substituted with 1 to 5 fluorines, and a hydroxyl group C 3- 8 cycloalkyl, 4-8 membered heterocyclyl, aryl or monocyclic heteroaryl, optionally substituted with 1-5 substituents independently selected, and n is 1, and R3, R4, R5 are defined as above. [001038] D

[001039] In an embodiment, the glutamate modulator is a compound according to: , wherein R1 and R2 are defined by the respective labeled columns shown below:

pharmaceutically acceptable salts and substituted variants retaining glutamate modulatory activity.

[001040] In further embodiments, the glutamate modulator is a compound according to: , wherein Rl, R2, R3, and R4 are defined according to the respective columns below:

[001041] In further embodiments, the glutamate modulator is a compound according to:

, wherein R1 and R2 are defined by the respective labeled columns shown below:

[001042] In yet further embodiments, the glutamate modulator is a compound according , wherein X , R2, and n are defined by the labeled columns shown below:

Formula 231

[001043] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 231. Such compounds are described in WO 2015/008073, published January 22, 2015, corresponding to PCT/GB2014/052184, filed July 17, 2014 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 231, this reference incorporated by reference herein controls.

[001044] In an embodiment, the glutamate modulator is a compound according to Formula 231 :

alkyl, cyclopropyl, optionally substituted C1-C3 alkoxy, cyano, hydroxyl, nitro or H2; R2 is H or F;

R3 is H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, cyano or a ring N;

R4 is H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, cyano or a ring N and n is 0-3.

[001045] In further embodiments, the glutamate modulator is a compound selected from:

3-chloro-4-fluoro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzo nitrile, 3-chloro-5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzonitrile, 6-[6-(3-chloro-5-cyanophenyl)pyrimidin-4-yl]pyridine-3-carbo nitrile, 3-methyl-5-[6-(pyri din-2 -yl)pyrimidin-4-yl]benzonitrile, 3-chloro-5-[6-(pyridazin-3-yl)pyrimidin-4-yl]benzonitrile, 3-(4,4'-bipyrimidin-6-yl)-5-chlorobenzonitrile, 3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitr ile, 5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzene-l,3-dicarb onitrile, 3-chloro-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitr ile, 3-chloro-5-[6-(5-chloropyridin-2-yl)pyrimidin-4-yl]benzonitr ile, 5-[6-(pyridin-2-yl)pyrimidin-4-yl]benzene-l,3-di carbonitrile, 3-chloro-4-fluoro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl] benzonitrile, 3-methyl-5-[6-(5-methylpyridin-2-yl)pyrimidin-4-yl]benzonitr ile, 3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-(methoxymethyl) benzonitrile, and 3-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]-5-methoxybenzonit rile, including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity. [001046] In further embodiments, the glutamate modulator is a compound selected from:

, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 232

[001047] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 232. Such compounds are described in WO 2013/192346, published December 27, 2013 and corresponding to PCT/US2013/046645, filed June 19, 2013, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 232, this reference incorporated by reference herein controls.

[001048] In an embodiment, the glutamate modulator is a compound selected from: wherein R1 is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein each of R2a and R2b is independently selected from hydrogen and C1-C4 alkyl; wherein R3 is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein each of R4a and R4b is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy(Cl-C4 alkyl), and (Cl- C4 alkyloxy) — (Cl -C4 alkyl) — ; or R4a and R4b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein each of R5a and R5b is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy(Cl-C4 alkyl), and (Cl- C4 alkyloxy) — (CI -C4 alkyl) — ; or R5a and R5b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein each of R6a and R6b is selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy(Cl-C4 alkyl), and (Cl- C4 alkyloxy) — (Cl -C4 alkyl) — ; or R6a and R6b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein R7 is selected from C1-C8 alkyl, Cl- C8 monohaloalkyl, C1-C8 polyhaloalkyl, hydroxy(Cl-C8 alkyl), (C1-C6 alkyl)-O- (C1-C6 alkyl)-, (C1-C6 monohaloalkyl)-0-(Cl-C6 alkyl)-, (C1-C6 polyhaloalkyl)-O-(Cl-C6 alkyl)-, (Cl- C6 alkyl)-NH-(Cl-C6 alkyl)-, (C1-C6 alkyl)(Cl-C6 alkyl)N-(Cl-C6 alkyl)-, Cyl, Cyl - (C2-C6 alkyl)-, and Cyl-C(R9a)(R9b)-; and wherein Cyl, when present, is selected from C3- C8 cycloalkyl, C2-C7 heterocycloalkyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl; and wherein Cyl, when present, is substituted with 0, 1, 2, or 3 non-hydrogen groups each independently selected from halo, cyano, — H2, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, mono(Cl-C6 alkyl)amino, di(Cl-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, and phenyl; wherein each of R9a and R9bis independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, Cl- C8 polyhaloalkyl, and C1-C8 alkoxy; wherein each of R8a and R8b is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy(Cl-C4 alkyl), and (Cl- C4 alkyloxy) — (Cl -C4 alkyl) — ; or R8a and R8b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

[001049] In further embodiments, the glutamate modulator is a compound according to:

[001050] In further embodiments, the glutamate modulator is a compound according to: wherein each of RlOa, RlOb, RIOc, RIOd, and RlOe is independently selected from hydrogen, cyano, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, provided that at least two of RlOa, RlOb, RIOc, RIOd, and RlOe are hydrogen; or a pharmaceutically acceptable salt, solvate or polymorph thereof.

[001051] In further embodiments, the glutamate modulator is a compound according to: wherein each of R4a, R4b, R5a, and R5b is independently selected from hydrogen and methyl; wherein each of RlOa, RlOb, RIOc, RIOd, and RlOe is independently selected from hydrogen, cyano, fluoro, methyl, and methoxy, provided that at least four of RlOa, RlOb, RIOc, RIOd, and RlOe are hydrogen; or a pharmaceutically acceptable salt, solvate or polymorph thereof.

[001052] In further embodiments, the glutamate modulator is a compound according to:

, wherein each of R4a, R4b, R5a, and R5b is independently selected from hydrogen and methyl; wherein each of RlOa, RlOb, RIOc, RIOd, and RlOe is independently selected from hydrogen, cyano, fluoro, methyl, and methoxy, provided that at least four of RlOa, RlOb, RIOc, RIOd, and RlOe are hydrogen; wherein each of Rlla, Rllb, Rile, Rlld, and Rile is independently selected from hydrogen, fluoro, chloro, cyano, methyl, trifluorom ethyl, and methoxy, provided that at least three of Rlla, Rllb, Rile, Rlld, and Rile are hydrogen; or a pharmaceutically acceptable salt, solvate or polymorph thereof.

[001053] In further embodiments, the glutamate modulator is a compound according to:

, with substituents defined according to the below labeled columns, where any undefined substituent in a given row is H:

9L9 , including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

[001054] In a further embodiment, the glutamate modulator is a compound according to:

.. Q

R ■ N - K ..-4— P' ^:

R<B \ Rs2li p4 ,a rj4 ,fc ^£ “>53

' ’ with substituents defined according to the below labeled columns, where any undefined substituent in a given row is H:

salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 233

[001055] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 233. Such compounds are described in WO 2013/192343, published December 27, 2013, corresponding to PCT/US2013/046642, filed June 19, 2013 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 233, this reference incorporated by reference herein controls.

[001056] In an embodiment, the glutamate modulator is a compound according to: wherein R1 is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein each of R2a and R2b is independently selected from hydrogen and C1-C4 alkyl; wherein R3 is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein each of R4a and R4b is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy(Cl-C4 alkyl), and (Cl- C4 alkyloxy) — (Cl -C4 alkyl) — ; or R4a and R4b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein each of R5a and R5b is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy(Cl-C4 alkyl), and (Cl- C4 alkyloxy) — (Cl -C4 alkyl) — ; or R5a and R5b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, hydroxy(Cl-C8 alkyl), (C1-C6 alkyl)-O- (C1-C6 alkyl)-, (C1-C6 monohaloalkyl)-0-(Cl-C6 alkyl)-, (C1-C6 polyhaloalkyl)-O-(Cl-C6 alkyl)-, (Cl- C6 alkyl)- NH-(C1-C6 alkyl)-, (C1-C6 alkyl)(Cl-C6 alkyl)N-(Cl-C6 alkyl)-, Cyl, Cy -(C2-C6 alkyl)-, and Cy -C(R8a)(R8b)-; and wherein Cyl, when present, is selected from C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl; and wherein Cyl, when present, is substituted with 0, 1, 2, or 3 groups each independently selected from halo, cyano, — H2, mono(Cl-C6 alkyl)amino, di(Cl-C6 alkyl)amino, C1-C4 alkyl, C1-C4 alkyloxy, (C1-C4 alkyloxy)-(Cl-4- alkyl)-, (C1-C4 alkyloxy)-(Cl-C4 alkyloxy)-, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, (C1-C4 polyhaloalkyl)-(Cl-C4 alkyloxy)-, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, and phenyl; wherein each of R8a and R8b, when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, and C1-C8 alkoxy; wherein each of R7a and R7b, when present, is selected from hydrogen, halogen, Cl- C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy(Cl-C4 alkyl), and (C1-C4 alkyloxy)-(Cl-C4 alkyl)-; or R7a and R7b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7- membered spirocycloalkyl;or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

[001057] In an embodiment, the glutamate modulator is a compound according to:

, with substituents defined according to the below labeled columns, where any undefined substituent in a given row is H:

[001058] In further embodiments, the glutamate modulator is a compound according to: with substituents defined according to the below labeled columns, where any undefined substituent in a given row is H: .

Formula 234

[001059] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 234. Such compounds are described in WO 2013/192350, published December 27, 2013, corresponding to PCT/US2013/046652, filed June 19, 2013 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 234, this reference incorporated by reference herein controls.

[001060] In some embodiments, the glutamate modulator is a compound according to Formula 234:

, wherein Ari is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, cyano, hydroxyl, — NH2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino; or Ari is monocyclic heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, cyano, hydroxyl, — NH2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino;wherein each of Ria and Rib is independently selected from hydrogen and Cl- C4 alkyl;wherein R2 is — CHR7R8; wherein R7 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy (C1-C4 alkyl), and (C1-C4 alkyloxy) C1-C4 alkyl;wherein R8 is selected from phenyl, monocyclic heteroaryl, and bicyclic heteroaryl; and wherein R8 has 0, 1, 2, or 3 groups independently selected from halogen, cyano, hydroxyl, — NH2, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino;wherein R3 is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, C2-C5 heterocyclyl, C3-C6 cycloalkyl, aryl and heteroaryl; wherein each of R4a and R4b is independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, and (C1-C4 alkyloxy) C1-C4 alkyl; or R4a and R4b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl;wherein each of R5a and R5b is independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, and (C1-C4 alkyloxy) C1-C4 alkyl; or R5a and R5b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein each of R6a and R6b, when present, is independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, and (C1-C4 alkyloxy) C1-C4 alkyl; or R6a and R6b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; and wherein m is 0 or 1; or a pharmaceutically acceptable salt, solvate, or polymorph thereof. [001061] In further embodiments, the glutamate modulator is a compound according to: w ere n eac o a, , an are y rogen; wherein R4a or R5a are selected from hydrogen and methyl, provided that R4a and R5a are not simultaneously methyl; and wherein each of R4b and R5b are hydrogen; wherein R7 is selected from hydrogen and methyl; wherein R8 is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl and thiazolyl, and wherein R8 is substituted with 0, 1, or 2 groups selected from fluoro, chloro, methyl, methoxy, — N(CH3)2, and — CF3; or wherein R8 is unsubstituted and selected from quinolinyl, benzo[d]thiazolyl, and benzo[d]oxazolyl; and wherein each of R9a, R9b, R9c, R9d, and R9e are independently selected from hydrogen, cyano, and methyl, provided that at least four of R9a, R9b, R9c, R9d, and R9e are hydrogen. [001063] In further embodiments, the glutamate modulator is a compound according to: with substituents defined according to the below labeled columns, where any undefined substituent in a given row is H:

ncu ng p armaceuically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

[001064] In further embodiments, the glutamate modulator is a compound according to: other substituents being H.

Formula 235

[001065] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 235. Such compounds are described in EP 2650248, published October 16, 2013, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 235, this reference incorporated by reference herein controls.

[001066] In an embodiment, the glutamate modulator is a compound according to:

, wherein

R ¹ represents and, heteroaryl, cycloCh-ualkyl, cycloCs-ualkenyl, or heterocyclyl;

R ² represents H, F, OH, Cf-salkyl, Ci<>a1koxy, heterocyclyl, or NR ⁶ R ^/ ;

R - represents H, F, or Chalky!; or R ² and R ³ together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cr.f.alkyl, aryl, heteroaryl, cycloCs-ralkyl, Ci-salkoxy, amino, hydroxy, cyano, Ci-ealkoxy carbonyl, Ci-salkylamino, di-(Ci^alkyl)amino, Cusaikyi carbonyl amino, oxo, Ci .f.alkylaminocarbonyl, and di-(Ci.6alkyl)aminocarbonyl;

R ⁴ represents H, F, or Ci-ralkyl; or R ² and R' ^j together with the carbon atoms to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatorns selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, C ■ -ealkyl, aryl, heteroaryl, cycloCs^alkyl, Cj-ralkoxy, amino, hydroxy, cyano, Ci-6alkoxycarbonyl, Cnealkylamino, di-iCnealkylJamino, Ci-ralkylcarbonylamino, oxo, C ■ -ealkylaminocarbonyl, and di-(Ci^.alkyl)aminocarbonyl;

R ³ represents H, F, or Cnsalkyl; or R ⁴ and R ³ together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or tw ⁷ o heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Ci-ealkyl, aryl, heteroaryl, cycloCs-valkyl, Ci-galkoxy, amino, hydroxy, cyano, Ci-salkoxy carbonyl, Ci-ralkylamino, di~(Ci-6.alkyl)aniino, C j.f, alkylcarbonylamino, oxo, C-^al ky I aminocarbonyl, and di-(Ci^alkyl)aminocarbonyl;

R ⁶ represents H, C noalkyl, or acyl;

R ^? represents H or Cj-salkyk

X represents CR ⁸ R ⁹ , Mfr", S, S=O, or SCb;

¥ represents a bond, -CR ⁿ R ^{i 2} -, -CR ⁵³ R ¹⁴ -CH ₂ -, O, -CR ¹⁵ R ⁵⁶ -O-, NR ¹⁷ , or -CR ¹⁸ R ⁱ⁹ -NR ²⁰ -; R ⁸ represents H, Cnoalkyl, acyl, heterocyclyl, heterocyclylsulfmyl; or R ² and R ⁸ together with the carbon atoms to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or tw'O heteroatorns selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoromethoxy, Cnealkyl, aryl, h e ternary 1, cycloChuaikyl, Cnnalkoxy, amino, hydroxy, cyano, Cnsalkoxy carbonyl, Ct .ealkylamino, di- (Cj-ealkyl)amino, Ci -ealkyl carbonyl ami no, oxo, Ci-ealkylantinocarbonyl, and di-(Cn eal ky I lammocarbonyl; or R ² and R ⁸ together with the carbon atoms to which they are attached form a 5-6 membered aromatic or heteroaromatic ring, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, tri fluoroethyl, trifluoropropyh trifluoromethoxy, Ci^alkyl, Cj ^alkoxy, amino, hydroxy, cyano, Cnsalkoxy carbonyl, C: .ealkylamino, di-(C _; .ealky l)ami no, C: .ealkylcarbonylamino, oxo, C j -ealkylami nocarbonyl, and di-(Ci<>a1ky1)aminocart)onyl, in which case the R ^J and R ⁹ substituents are absent; or R ⁴ and R ⁸ together with die carbon atoms to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluorornethyl, trifluoromethyl, trifluoromethoxy, Cue.alkyl, aryl, heteroaryl, cycloC3.7alkyl, Cusalkoxy, amino, hydroxy, cyano, Cw alkoxycarbonyl, Ci^alkylamino, di-(Ci^alkyl)amino, Cusaikyi carbonyl amino, oxo, Ci xalkylaminocarbonyl, and di-(Ci.6alkyl)aminocarbonyl;

R ⁹ represents H or Cusalkyl, or R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, tri fluorometh oxy, C>..6alkyl, aryl, heteroaryl, cycloCmalkyl, Ci-salkoxy, amino, hydroxy, cyano, Ci-salkoxy carbonyl, Cusalkylamino, di-(Cu6alkyl)amino, Cusalkyl carbonyl amino, oxo, Ci^alkylaminocarbonyh and di-(Cj^a1ky1)aminocarbonyl;

R ¹⁰ represents hydrogen, Cj.salkyl, acyl, -C(O)-C(O)-Ci x.alkoxy, Ci -ealkylsulfinyl, Ci- ealkyl sulfonyl, cycloC3.7alkylsulfor1yl, heteroeyclyl sulfonyl, arylsulfonyl, di~(Ci- 6alkyl)aminosulfonyl, aryl, or heteroaryl; or R ² and R ^t0 together with the atoms to which they are attached form a 3-7 membered ring which may he saturated or unsaturated, wherein the ring may optionally contain one or two additional heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifiuoromethoxy, Cix.alkyl, aryl, heteroaryl, cycloCs-ralkyl, Ci-salkoxy, amino, hydroxy, cyano, Cj^alkoxycarbonyl, Ci^alkylamino, di-(Ci^alkyl)araino, Cusaikyi carbonyl amino, oxo, Ci xalkylaminocarbonyl, and di-(Ci.6alkyl)aminocarbonyl; or R ⁴ and R ¹⁰ together with the atoms to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two additional heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluorornethyl, trifluoromethyl, trifiuoromethoxy, Ci-salkyl, aryl, heteroaryl, cycloCs^alkyl, Cj-salkoxy, amino, hydroxy, cyano, Ci-salkoxycarbonyl, Cuealkyl amino, di-(Cj^a1ky1)amino, Cj.salkylcarbonylamino, oxo, Ci^alkylaminocarbonyl, and di-(Ci .f.alkyl)aminocarbonyl;

R ^{f i} represents H, Cj^alkyl, acyl or heteroeyclyl; or R ⁴ and R ¹¹ together with the carbon atoms to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein die ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyi, trifluoromethyl, trifluoromethoxy, Cusalkyl, and, heteroaryl, cycloCwalkyl, Ci-f.alkoxy, amino, hydroxy, cyano, Ci-ealkoxy carbonyl, Ci-ralkylarnino, di- (Cu6alkyl)amino, Curalkylcarbonylamino, oxo, (h-6alkylami nocarbonyl, and di-(Cu f.alkyl)ami nocarbonyl -, or R ² and R ⁿ together with the carbon atoms to which they are attached form a 5-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyi, trifluoromethyl, trifluoromethoxy, Ci-salkyl, and, heteroaryl, cycloCs-valkyl, Ci -ealkoxy, amino, hydroxy, cyano, Ci^alkoxy carbonyl, Cnralkyl amino, di- (Ci-6alkyl)arnino, Ci-ralkylcarbonylamino, oxo, Ci-ealkylaminocarbonyl, and di-(Ci- 6alkyl)ami nocarbonyl , or R ⁸ and R ⁿ together with the carbon atoms to which they are attached form a 4-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyi, trifluoromethyl, trifluorom ethoxy, Cj-f,alkyl, aryl, heteroaryl, cycloCsoalkyl, Caealkoxy, amino, hydroxy, cyano, Ci-f.alkoxy carbonyl, Cuealkylamino, di- (Chralkyllamino, Cnralkyicarbonylammo, oxo, Cusalkyl aminocarbonyl, and di-(Cn ral kyl)aminocarbonyl;

R ^{J ?} represents H or Cnealkyk or R ¹¹ and R ⁱ² together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen, wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyi, trifluoromethyl, trifluorom ethoxy, Cj-f,alkyl, aryl, heteroaryl, cycloCsoalkyl, Ci-ealkoxy, amino, hydroxy, cyano, Ci-f.alkoxy carbonyl, Cuealkylamino, di- (Cj-6alkyl)amino, Cnealkyl carbonyl ami no, oxo, Ci-calkylaminocarbonyl, and di-(Cn ral kyl)aminocarbonyl;

R ^ki represents H, Cj^alkyl, acyl or heterocyclyl; R ¹⁴ represents H or Ci-galkyl;

R ⁱ⁵ represents H, Cj^alkyl, acyl or heterocyclyl;

R ^lb represents H or Ci-ealkyl;

R ¹⁷ represents H, Ci-f.alkyl, acyl, aryl, or heteroaryl;

R ^ls represents H, Cuealkyl, acyl or heterocyclyl;

R ¹⁹ represents H or Ci- ealkyl;

R ²⁰ represents H, Cj. ealkyl, acyl, aryl, or heteroaryl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorph s th ereof.

[001067] In further embodiments, the compound is selected from:

(rac)-5-Methoxy-3-(phenylethynyl)-5,6,7,8-tetrahydroquino line, 5-Methoxy-3- (phenylethynyl)-5,6,7,8-tetrahydroquinoline,

(rac)-6-((5-Methoxy-5,6,7,8-tetrahydroquinolin-3-yl)ethyn yl)pyridin-2-amine, (rac)-5- Methoxy-7,7-dimethyl-3-(phenylethynyl)-5,6,7,8-tetrahydroqui noline, (rac)-6-((5 -Methoxy - 7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)ethynyl)pyridin -2-amine,

(rac)-3-(Imidazo[l,2-a]pyridin-2-ylethynyl)-5-methoxy-7, 7-dimethyl-5,6,7, 8- tetrahydroquinoline,

(rac)-6-((4-Methoxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2, 3-b]pyridin-6- yl)ethynyl)pyridin-2-amine,

(rac)- 6-(Imidazo[l,2-a]pyridin-2-ylethynyl)-4-m ethoxy-2, 2-dimethyl-3, 4-dihydro-2H- pyrano[2,3-b]pyridine,

4-Methoxy-l-methyl-6-(phenylethynyl)-l,2,3,4-tetrahydro-l ,8-naphthyridine, (rac)-3'- (Phenylethynyl)-7',8'-dihydro-6'H-spiro[oxazolidine-5,5'-qui nolin]-2-one, (rac)-3-Methyl-3'- (phenylethynyl)-7',8'-dihydro-6'H-spiro[oxazolidine-5,5'-qui nolin]-2-one,

(rac)-3-Phenyl-3'-(phenylethynyl)-7',8'-dihydro-6'H-spiro [oxazolidine-5,5'-quinolin]-2-one, (rac)-cis+-4-Methyl-9-(phenylethynyl)-3,4,4a,5,6,10b-hexahyd ro-2H-[l,4]oxazino[2,3- f] quinoline,

(rac)-cis-4-Ethyl-9-(phenylethynyl)-3,4,4a,5,6,10b-hexahy dro-2H-[l,4]oxazino[2,3- f] quinoline,

(rac)-cis-9-(Phenylethynyl)-4-propyl-3,4,4a,5,6,10b-hexah ydro-2H-[l,4]oxazino[2,3- f] quinoline, cis-9-(Phenylethynyl)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-[ l,4]oxazino[2,3-f]quinoline, cis-9-(Phenylethynyl)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-[ l,4]oxazino[2,3-f]quinoline, (rac)-cis-9-((2-Fluorophenyl)ethynyl)-4-propyl-3,4,4a,5,6,lO b-hexahydro-2H-

[l,4]oxazino[2,3-f]quinoline, (rac)-cis-9-((3-Fluorophenyl)ethynyl)-4-propyl-3,4,4a,5,6,10 b-hexahydro-2H-

[l,4]oxazino[2,3-f]quinoline, (rac)-cis-9-((4-Fluorophenyl)ethynyl)-4-propyl-3,4,4a,5,6,10 b-hexahydro-2H-

[l,4]oxazino[2,3-f]quinoline,

(rac)-cis-4-Propyl-9-(m-tolylethynyl)-3,4,4a,5,6,10b-hexa hydro-2H-[l,4]oxazino[2,3- f] quinoline, (rac)-trans-9-(Phenylethynyl)-4-propyl-3,4,4a,5,6,10b-hexahy dro-2H-[l,4]oxazino[2,3- f] quinoline, (rac)-cis-4-Isobutyl-9-(phenylethynyl)-3,4,4a,5,6,10b-hexahy dro-2H-[l,4]oxazino[2,3- f] quinoline, (rac)-cis-9-(Phenylethynyl)-4-(2,2,2-trifluoroethyl)-3,4,4a, 5,6,10b-hexahydro-2H-

[l,4]oxazino[2,3-f]quinoline, (rac)-cis-9-(Phenylethynyl)-4-(3,3,3-trifluoropropyl)-3,4,4a ,5,6,10b-hexahydro-2H-

[l,4]oxazino[2,3-f]quinoline,

(rac)-cis-Methyl 9-(phenylethynyl)-4a,5,6,10b-tetrahydro-2H-[l,4]oxazino[2,3- f]quinoline- 4(3H)-carboxylate, (rac)-cis-N,N-Dimethyl-9-(phenylethynyl)-4a,5,6,10b-tetrahyd ro-2H-[l,4]oxazino[2,3- f]quinoline-4(3H)-carboxamide,

1-Methyl-8-(phenylethynyl)-4,5-dihydro-lH-pyrazolo[3,4-f] quinoline,

(rac)-cis-Methyl 8-(phenylethynyl)-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo[2,3-f]q uinoline-l- carboxylate,

Methyl 8-(phenylethynyl)-3,3a,4,5-tetrahydro-lH-pyrrolo[3,4-f]quino line-2(9bH)- carboxylate,

Methyl 8-((3-fluorophenyl)ethynyl)-3,3a,4,5-tetrahydro-lH-pyrrolo[3 ,4-f]quinoline-2(9bH)- carboxylate,

(rac)-cis-Methyl 3-((3-fluorophenyl)ethynyl)-6a,7,9,9a-tetrahydro-5H-pyrrolo[ 3,4- h]quinoline-8(6H)-carboxylate,

2-Methyl-l-(3-(phenylethynyl)-7,8-dihydro-l,6-naphthyridi n-6(5H)-yl)propan-l-one, 2,2-Dimethyl-l-(3-(phenylethynyl)-7,8-dihydro-l,6-naphthyrid in-6(5H)-yl)propan-l-one, l-(3-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydro-l,6-naphthyr idin-6(5H)-yl)-2,2- dimethylpropan- 1 -one,

(3-Methyloxetan-3-yl)(3-(phenylethynyl)-7,8-dihydro-l,6-n aphthyridin-6(5H)-yl)methanone, (rac)-6-(tert-Butylsulfinyl)-3-(phenylethynyl)-5,6,7,8-tetra hydro-l,6-naphthyridine, 6-(Cyclopropylsulfonyl)-3-(phenylethynyl)-5,6,7,8-tetrahydro -l,6-naphthyridine, 3-(Phenylethynyl)-6-(phenylsulfonyl)-5,6,7,8-tetrahydro-l,6- naphthyridine,

Ethyl 3-(phenylethynyl)-7,8-dihydro-l,6-naphthyridine-6(5H)-carbox ylate, Isobutyl 3-(phenylethynyl)-7,8-dihydro-l,6-naphthyridine-6(5H)-carbox ylate, tert-Butyl 3-(phenylethynyl)-7,8-dihydro-l,6-naphthyridine-6(5H)-carbox ylate, Phenyl 3-(phenylethynyl)-7,8-dihydro-l,6-naphthyridine-6(5H)-carbox ylate, N,N-Dimethyl-3-(phenylethynyl)-7,8-dihydro-l,6-naphthyridine -6(5H)-carboxamide, 3-((3-Fluorophenyl)ethynyl)-N,N-dimethyl-7,8-dihydro-l,6-nap hthyridine-6(5H)-carboxam ide, 3-((3-Cyanophenyl)ethynyl)-N,N-dimethyl-7,8-dihydro-l,6-naph thyridine-6(5H)-carboxam ide, 3-((6-Aminopyridin-2-yl)ethynyl)-N,N-dimethyl-7,8-dihydro-l, 6-naphthyridine-6(5H)- carboxam ide, 3-((3-Cyanophenyl)ethynyl)-N,N-diethyl-7,8-dihydro-l,6-napht hyridine-6(5H)-carboxam ide,

3-(Phenylethynyl)-N,N-bis(2,2,2-trifluoroethyl)-7,8-dihyd ro-l,6-naphthyridine-6(5H)- carboxam ide,

(3 -(Phenylethynyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl)(piperidin- 1 -yl)methanone, 3-((6-(Piperidine-l-carbonyl)-5,6,7,8-tetrahydro-l,6-naphthy ridin-3-yl)ethynyl)benzonitrile, N,N-Dimethyl-3-(phenylethynyl)-7,8-dihydro-l,6-naphthyridine -6(5H)-sulfonamide, 3-(Phenylethynyl)-6-(pyrrolidin-l-ylsulfonyl)-5,6,7,8-tetrah ydro-l,6-naphthyridine,

3-(Phenylethynyl)-6-(piperidin-l-ylsulfonyl)-5,6,7,8-tetr ahydro-l,6-naphthyridine,

4-((3-(Phenylethynyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl)sulfonyl)morpholine, 6-(Azepan-l-ylsulfonyl)-3-(phenylethynyl)-5,6,7,8-tetrahydro -l,6-naphthyridine, (rac)-8-Methyl-3 -(phenylethynyl)-9, 10, 1 Oa, 11 -tetrahydro-5H-pyrimido[ 1,6- g] [ 1 ,6]naphthyridin-7(8H)-one,

(rac)-Methyl 3-(phenylethynyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohept a[b]pyridine-10- carboxylate,

(rac)-Methyl 3-((3-fluorophenyl)ethynyl)-6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[b]pyridine-10-carboxylate,

(rac)-cis-Methyl 3-(phenylethynyl)-7,8,9,9a-tetrahydro-5H-cyclopenta[h][l,6]n aphthyridine- 6(6aH)-carboxylate, (rac)-cis-Methyl 3-((3-fluorophenyl)ethynyl)-7,8,9,9a-tetrahydro-5H- cyclopenta[h][l,6]naphthyridine-6(6aH)-carboxylate,

(rac)-cis-Methyl 3-(phenylethynyl)-6a,7,8,9,10,10a-hexahydrobenzo[h][l,6]naph thyridine- 6(5H)-carboxylate,

(rac)-cis-Methyl 3-((3-fluorophenyl)ethynyl)-6a,7,8,9,10,10a- hexahydrobenzo[h][l,6]naphthyridine-6(5H)-carboxylate, (rac)-3-Propyl-3'-(m-tolylethynyl)-7',8'-dihydro-6'H-spiro[o xazolidine-5,5'-quinolin]-2-one, (rac)-cis-Azetidin-l-yl-(9-(phenylethynyl)-5,6-dihydro-2H-[l ,4]oxazino[2,3-f]quinolin- 4(3H,4aH, 1 ObH)-yl)m ethanone,

(rac)-3'-((3-Fluorophenyl)ethynyl)-3-propyl-7',8'-dihydro -6'H-spiro[oxazolidine-5,5'- quinolin] -2-one,

(rac)-3'-((3-Fluorophenyl)ethynyl)-3-phenyl-7',8'-dihydro -6'H-spiro[oxazolidine-5,5'- quinolin] -2-one,

3-(m-Tolylethynyl)-7,8-dihydro-5H-thiopyrano[4,3-b]pyridi ne 6,6-dioxide, 3-((3-Fluorophenyl)ethynyl)-7,8-dihydro-5H-thiopyrano[4,3-b] pyridine 6,6-dioxide, 3-((4-Fluorophenyl)ethynyl)-7,8-dihydro-5H-thiopyrano[4,3-b] pyridine 6,6-dioxide,

(6aR, 9aR)-Methyl 3-(phenylethynyl)-6,6a,9,9a-tetrahydro-5H-pyrrolo[2,3-h]quin oline- 7(8H)-carboxylate,

(6aR,9aR)-Methyl 3-((3-fluorophenyl)ethynyl)-6,6a,9,9a-tetrahydro-5H-pyrrolo[ 2,3- h]quinoline-7(8H)-carboxylate,

(rac)-cis-Methyl 3-((3-fluorophenyl)ethynyl)-5a,6,8,8a- tetrahydropyrrolo[3',4':4,5]cyclopenta[l,2-b]pyridine-7(5H)- carboxylate, (rac)-3- Cyclopropyl-3'-(phenylethynyl)-7',8'-dihydro-6'H-spiro[oxazo lidine-5,5'-quinolin]-2-one, 5,5-Dimethyl-3-(phenylethynyl)-7,8-dihydro-5H-thiopyrano[4,3 -b]pyridine-6,6-dioxide, (rac)-3-Cyclopropyl-3'-((3-fluorophenyl)ethynyl)-7',8'-dihyd ro-6'H-spiro[oxazolidine-5,5'- quinolin] -2-one,

Ethyl 2-oxo-2-(3-(phenylethynyl)-7,8-dihydro-l,6-naphthyridin-6(5H )-yl)acetate, 6-((4- Methylpiperazin-l-yl)sulfonyl)-3-(phenylethynyl)-5,6,7,8-tet rahydro-l,6-naphthyridine, (rac)-Methyl 3-(phenylethynyl)-5a,6,8,8a-tetrahydropyrrolo[3',4':4,5]cycl openta[l,2- b]pyridine-7(5H)-carboxylate,

(rac)-cis-Methyl 7-(phenylethynyl)-2,3,3a,4,5,9b-hexahydro-lH-pyrrolo[3,2-h]q uinoline-l- carboxylate, and 6-(Isopropylsulfonyl)-3-(phenylethynyl)-5,6,7,8-tetrahydro-l ,6-naphthyridine, (rac)-3'- (Phenylethynyl)-3-propyl-7',8'-dihydro-6'H-spiro[oxazolidine -5,5'-quinolin]-2-one, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 236

[001068] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 236. Such compounds are described in US 2013/0245043, published September 19, 2013 and corresponding to US 13/420,333, filed March 14, 2012, and issued as US 8,865,725 on October 21, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 236, this reference incorporated by reference herein controls.

[001069] In an embodiment, the glutamate modulator is a compound according to formula 236: wherein - is an optional covalent bond, wherein valence is satisfied; wherein Ari is phenyl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Ari is monocyclic heteroaryl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when - is present and Al and A2 are joined by a covalent double bond, Al is

CRla, and A2 is CR2a; wherein Ria is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein R2a is selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; wherein when - is not present and Al and A2 are joined by a covalent single bond, Al is

CRlbRlc, and A2 is CR2bR2c; wherein each of Rib and Rlc are independently selected from hydrogen, fluoro, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or Rib and Rlc are covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein each of R2b and R2a are independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, or R2b and R2c are covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein Ria and R2a, when present, are optionally covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered fused cycloalkenyl; wherein Rib and R2b, when present, are optionally covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered fused cycloalkyl; wherein R3, when - is present, is selected from hydrogen, C1-C6 alkyl; C1-C6 alkyloxy;

C1-C6 monohaloalkyl; C1-C6 polyhaloalkyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; (C3-C8 cycloalkyl)-Cl-C6 alkyl-; (C3-C8 heterocycloalkyl)-Cl-C6 alkyl-, and aromatic moiety Ar2; wherein Ar2 is phenyl or benzyl or — (C2-C6)-phenyl, and substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, — NH2, — NH(C1-C4 alkyl), and — N(C1-C4 alkyl)(Cl-C4 alkyl), or Ar2 is monocyclic heteroaryl substituted with 0-3 substituents independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, — NH2, — NH(C1-C4 alkyl), and — N(C1-C4 alkyl)(Cl-C4 alkyl); and, wherein R3, when - is not present, is Ar2; wherein R4 is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, and C1-C4 alkoxy; wherein each of R5a and R5b is independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

[001070] In further embodiments, the glutamate modulator is a compound according to: wherein R7 and R8 are independently selected from H and Cl -C4 alkyl, wherein R6 is Cl -C4 alkyl, wherein R7 and R8 are independently selected from H and C1-C4 alkyl, and , wherein R6 is C1-C4 alkyl.

[001071] In further embodiments, the glutamate modulator is a compound selected from:

Formula 237

[001072] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 237. Such compounds are described in WO 2013/049255, published April 4, 2013, corresponding to PCT/US2012/057395, filed September 26, 2012 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 237, this reference incorporated by reference herein controls.

[001073] In an embodiment, the glutamate modulator is a compound according to Formula 237:

, wherein Q is N or N — 0 ; wherein R1 is selected from -Ari, -(C1-C6 alkyl-Arl, -(C1-C6 alkyl-O-Arl, -Cyl, -(C1-C6 alky -Cyl, -(C1-C6 alkyl-O-Cyl, -C(OH)R3R4, -C(0H)R3Arl, and -C(OH)R3Cyl; wherein Ari is phenyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, - NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or monocyclic heteroaryl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, — NH2, C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, or C1-C6 polyhaloalkyl, Cl- C6 alkylamino, and C1-C6 dialkylamino; wherein Cyl is C3-C6 cycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or C3-C6 heterocycloalkyl substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein R3 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; wherein R4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and Cl- C6 polyhaloalkyl; or wherein R1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, and Cl -6 polyhaloalkyl, and substituted with 0-3 substituents selected from halo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; wherein each of R2a and R2b is independently selected from hydrogen, — Ar2, — (C1-C6 alkyl)- Ar2, -Cy2, -(C1-C6 alkyl)-Cy2, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl; and wherein each of R2a and R2b is independently substituted with 0-3 substituents selected from halo, hydroxyl, cyano, -NH2, C1-C6 alkyl, C1-C6 alkoxy, Cl- C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl; wherein Ar is phenyl or monocyclic heteroaryl; wherein Cy is C3-C6 cycloalkyl or C3-C6 heterocycloalkyl; or wherein R2a and R2b are covalently bonded and, together with the intermediate carbons, comprise a 3- to 7-membered heterocycloalkyl, and substituted with 0-3 substituents selected from halo, hydroxyl, cyano, - NH2, C1-C6 alkyl, C1-C6 alkoxy, Cl - C6 haloalkyl, or C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[001074] In further embodiments, the glutamate modulator is a compound according to:

[001075] In further embodiments, the glutamate modulator is a compound selected from:

acceptable salts thereof and substituted variants having glutamate modulatory activity.

Formula 238

[001076] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 238. Such compounds are described in WO 2012/172093, published December 20, 2012, corresponding to PCT/EP2012/061527, filed June 15, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 238, this reference incorporated by reference herein controls.

[001077] In an embodiment, the glutamate modulator is a compound according to Formula 238: wherein R1 represents aryl, heteroaryl, cycloC3-

7alkyl or heterocyclyl, wherein the cycloC3-7alkyl or heterocyclyl group may be optionally fused with an aryl or heteroaryl ring;

R2 and R3, which may be the same or different, each independently represent H, Cl-6alkyl, F, OH, Cl-6alkoxy, or R2 and R3 together with the carbon atom to which they are attached form a carbonyl group, or R2 and R3 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from Cl -6 alkyl, F, oxo, and acyl;

R4 and R5, which may be the same or different each independently represent H, Cl-6alkyl or F or R4 and R5 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from Cl -6 alkyl, F, oxo, and acyl;

X represents CR6R7 or NR8; R6 and R7, which may be the same or different, each independently represent H, Cl-6alkyl, F, amino, Cl-6alkylamino or di-(Cl-6alkyl)amino or R6 and R7, together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from d-6 alkyl, F, oxo, and acyl; or R3 and R6, together with the carbon atoms to which they are attached, may form a 4 to 7 membered ring wherein the ring may optionally contain one or two heteroatoms selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from Cl -6 alkyl, F, oxo, and acyl;

R8 represents H, Cl-6alkyl, acyl, aryl, heteroaryl, aryl-Cl-6alkyl, heteroaryl-Cl-6alkyl, or di-(Cl-6 alkyl)aminosulfonyl; or R2 and R8 together with the atoms to which they are attached, may form a 4 to 7 membered ring wherein the ring may optionally contain one or two additional heteroatoms selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from Cl -6 alkyl which is optionally substituted by one or more halogen atoms, F, oxo, and acyl; Y represents a bond, CR9R10 or -CR9R10-CH2-;

R9 and RIO, which may be the same or different, each independently represent H, Cl-6alkyl or F or R9 and RIO, together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from Cl-6alkyl, F, oxo, and acyl;

Rl l represents H, halogen, Cl-6alkyl, aryl, heteroaryl, cycloC3-7alkyl or heterocyclyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[001078] In further embodiments, the glutamate modulator is a compound selected from: ©-((S-FiuorophenyOethynyi^S-m^thyl-Si.S-dihydro-l H-pyrrolizin-1-one, e-flS-FluorophenjdJethynyl^^-dimethyl^.S-clihydro-IH-pyn^izI n-l-one, 6-((6-Aminopyridin-2-yl>&thynyl)-2,2-dimethy1-2,3-dih ydro-1 H-pyrroiiZfri-1 -one, 6“((6-Aminc4)yridin"2-yl)etiiynyl)“2-methyl-2,3“dihydr o-1 W-pyrrolizin-1-CHTe,

6-((6-AfTiinopyridin-2-yf)ethynyl)-2,3-dihydro-1 H-py!TOiizin-'l-one _: ,

2-((6-Amin<^)yridln-2-yl)ethynyl)-7,8-dihydFO-5H-pynol o(1,2-a|azepin-9(6H)-<Mie,

2-(Pheny1ethyny)-7,8-dihydro-5H-pyrro!o[1 ,2-a]azepin-9(6H)-one,

S,8-D}Hiethyi-2-(phenytethyny[)-7,8-dshydro-5W-pyfToto[1 ,2-a]azepin-9(6H>one, 24(6^min<^yridin’2-yl)ethynyl)^ ₎ 8<l!methyS-7,8-dihyclraH5H'^>yTOto[1 ₎ 2-a]az^)in- 9(6H)-one,

8-((6-Aminopyridin-2“yi)&thynyl)-2.3 _; 4,5“tetrahydro-1/-Apyrroto[1 ,2-a][1 ,4]diazepin-

1-one,

8-((6-Arninopyridtn-2-yf)ethynyl)-2-methyi-2,3,4,5-tetrah ydfD-1H-pyrrota[1 ,2- a][1 ,4]diazepin-1 -one,

2-Methyl“8-(phenyleihynyQ-2,3 _r 4,54etrahydrc>-'] H-pyrroto[1 ,2-a][1 ,4]diazepin-1 - one,

8-(Phen^e(hynyl)-2,3,4,5-tetrahydro-1 H-pyrrolo[1 ,2-a][l ,4Jdiazepin-1 -one,

7- ( P h enyieth y n yi )-3 ,4-d ih yd nopyrrolo [1 ,2-a] py razi n - 1 (2H)-on e , 2-Meth^"7-(phenylethynyl)-3,4-dihydropyrrolo[1 _! 2"S]pyrazln”1(2H>-one _!

7 - ((6 -Am inopynd in-2-yl Jethynyl )- 2-m ethyl -3 ,4 -d I hyd ropyrrok>[ 1 .2-a] pyraztn- 1 ( 2 H)~ one,

7-((6-Amlnopyrid8n-2-y!)ethynyl)-3 _l 4-dlhydropyrroto[1 _! 2-a]pyrazin-1 (;2H)-one _l

1 -(7-((6-Amlnop^ki!n-2-yl)ethyTiyl)’3,4-dlhydropyrri^o[1 ,2-a]pyrazin-2(1 H)-yi )-2,2- dimethylpropan-1 -one, 7-((6-Am5nopyTidFn“2»yQethynyl)-N,N-dimethyl"3,4”d^ihyd ropyrroton ,2-a]pyrazine-

2(1 H)-carboxam ide,

N, N-D ii m ethyl-7’( phe nyi ethynyl )-3 , 4-d ihyd ropy rro lo[ 1 , 2 -a]pyrazine-2( 1 H)- carboxamide, 2 _} 2~Dfmethyi-1--(7-(phenytethynyl)-3,4-dihydropyrroio[1 _J 2-s|pyrazhi-2(1 H)" ^)propan-1-one,

2- ( P h enylethy nyi )-5 ,6 ,7 , 8-tetra h yd no indo! lain e ,

6- ( P h enylethy n yl )-2 , 3 -d ih yd no- 1 H-pyrroi izi n e , 2-(Phenylethynyl ^6,7,8 ,94etrahydrO’5Hpyrro lo[1 ,2-a]azepine _t "((2"F§uorQphen^)ethyE^yi)-23<nhydro-iH’pyrroHzin»1� �One, -((4-F^oroph6nyi)ethyriyi>2,3<ifhyxirO“W"PyrroHaisv1 -one, -((6-(Methy!amino}pyridfn-2-y!)ethynyl )-2,3-dthydro-1 H-pyrohzin-1 -one. -Methyl-6-(m-tolyiethynyi)-2,3-dihydro-1 H-pyrroiizin-1 -one, -((2-FkJoro-3--methyiphenyl)ethyriyi)"6,7--dihydfomdofl?Jn� �8(5H)”Of>e, “((2“F^Qro*5-m6thy!phenyl)64hynyi)-6,7-dihydroincio!izfn *8(5H)-cine, -((3-F^oro-2-methyiphenyl)ethyriyQ-6 _i 7-dihydrotndoHzin-8(5H)-one _i ’((4-F!uono3^nethylphenyl^th^yi>-6 ₍ 7’dihydFojndoliz^’8(5H>one _< .2-Dimelhyl-6^|^en^e8lyn^)-2 _s 3-dihydro«1 H-pyiT0lizh’1-<»ie _> .2-Diniethyi“6-(m”toi ylethynyl >2 , 3-d th yd ro- 1 H-pyrrol iztn- 1 -one . ”((3-Fkioi’opheny!)eJhynyi)--5,6 ₁ 7 _> 8'-tetrahydrc>indolizin-S--oh -f(2-F^orO'4-methy!pheriyl)ethynytF6,7-dihydrofndoNzin-8(5H) 'One. -((4-F^Joro-2-methyiphenyl)ethynyi)-67'dihydrotnciotsin-8(5H )-one, ”((3"F^oro*4-'methylphenyl)ethynyi)-'6 _[ 7-’dihydrojndo!!zin-'8(5H)-'One, -((3-F^oro-5-methylphenyl)ethynyt)-6,7-dihydroindoHztti-8(5H )-one, -((5-Fiuoro-2-methyiphenyl)eihyiiyi)-6 _I 7-dihydroindofizin-8(5H)-one, -(!midazo[1 ,2-a']pyndin-2-^ethynyl)-6,7-dihydroindoi:zin-8(5H)-one _>

2"(lmidazo:1 ,2-3]pyi‘idin-2-yleJhynyn"7,7-ditYteJhyk8 _! 7-dihydfi3indo^zin-8(5H)-one, 2-((2-FkJoro-6-methylphenyi)ethyiiyi)-6 _i 7-dthydroi!idoltetn-8(5H)-one _i 2-('(5‘Cbtorothiophen-2-yl )ethyE^ylF6,7-dihy'droiE^doiiz)n-8(5H)-one.

2-(lmjdazon ₎ 2-a]pyridjn-2-yieihyny!)-6-rTsethyF6.7~dthydro!ridotEi n-8(6H)-one,

2-({6-Amin<^yfidin-2-yl)ethynyl)-7.8-dihydno-5W-p^Trto n.2-alazepin-9(eWhMie,

3-(Phenylethynyl)’2.3.4 _! 5-tetrahydrO’1H’pyiT^o[1 ,2'8][1.4]diazepjn’1«one, 2-((3-Hydroxypheny()ethynyf)-6 _! 7--dthydrotndQSiz:n-8(5H)-one _J

S-tX^'HydroxyphenyljethynyiFS./'dthydrojndotein-BCSHJ-one ,

2-Methyj'B-(phenyiethynyi)-2,3,4,5"tetTahydro-1H-pyrralon ,2--a^'! ,4]diazepin-1- one,

2-(lmlda2o[1.2-aJpyridin-2-^efhyn^)-7-methyl-6,7-dlhydroi ndoliz!n-8(5H)-one,

2-(Phenylethynyi)-7,8-dihydro-5H"pyrro!o[1,2-a]8zeptn-9(6 H)-one,

3-((1 -Oxo-2-propyl-l ,2,3,4-tetrahydropyrrolon ,2-a]pyrazin-7- yl)eth yny I Jbenzon itrite , 2-MethyF7-(phenyiethynyi)-3 _l 4-dthydropyrro!opL2-ajpyrazin-1(2H)-one,

3-((2-Meb]4-1-oxo-t,2,3,4-tetrahydropyrrdo[1,2-a]pyrazin- 7- yl jethynyl benzonitrile,

7-(('3-FSuorophenyi)ethynyl)-2~rnethy-3,4-dinyci ^: ropyrrolo[1 _s 2-a]pyrazin-1(2H)-one,

2-Methyi-7-(m4olylethyriyi}-3,4-dihydropyrrolo[1 ,2-a]pyrazin-1(2H>one,

2-Benzyi-7-((3-fluorophenyl)ethynyl)-3,4-dihy<lropyrro loJ'i ,2-a]pyrazin-1(2H)-one, 2-Benzyl-7-(phenytebyn^>3,4-dihydropyr«^o[1 ,2-8|pyrabn-1(2H)-one.

2-BanzyP7-(m-toiyiethynyl)-3 _; 4-<!ihydfopyrrotan ^-aJpyrgzin-I^HJ-one, 3"((2-Benxyl-1-oxo-'! ,2,3,44®trahydropyrro!o£1 ,2-a]pyrazin-7- yi jethynyi benzonitrile,

7-(Phenylethyny!)-2-propyl-3 _> 4-dihyclropyrroiOi1 _r 2-a]pyrazsn-t(2H)-one,

2-Propyl-7-(m-tolyi8thynyi}-3,4-ciihydropyETolot1:,2-a]py razin-1(2H)-one,

6-((B-Amirtapyridin-2-y()ethynyl3-2-!ri8ihyl-2,3 ₁ 4,5-t8trahydra-1 H-pyrrolo[1 ,2- a][1 ,4]diazepin-1-one.

2-Etiyt-7-(phenytethynyl )-3,4-dihydropyrroio{1 ,2-a]pyraz;n-1 (SHJ-one,

2-B!jtyl-7-(phenylethyr!yl}-3,4-<iihydropyrroio{1 ,2-3]pyt’azin-'(2H)-one,

2-But^-7-((3'fluoropheny!)ethyn^}-3,4-<jbydropyrFolon ,2-a)pyr8zin-1(2H)-one,

7“((3-Fluorophenyt)ethynyl)-2';sopropyl-3 ₁ 4-di:hydropyrrciio[1 ,2-a]pyr8zin-1 (2H)- one,

2-4sopropyl-7-(m4olylethynyi)--3,4-dih5<iropyrroton -2-slpyf’3zin--1 (2H)-one,

8 _J 8-Dimethyl'2-(ph«nylethytiyl)--7 _t 8--db;ydrO"5H-pyrrolo[1 ,2-a]azeptn-9{6H}-one, 2~Phef'iyl-7-(phenytethynyl)-3,.4-d!hydropyrrclon _i 2-a]pyrazift-1 (2H)-one.

7'((3-Fluorophenyl)ethynyQ-2-phenyl-3 _; 4'-dihyeiropyrrolo[1 ,2-3]pyrazin-1(2H)-or)e _<

2-Ph«i^-7-(m4^jdethynjrf)-3,4-dthydK)p^T^£^1 _> 2-alpyraz3n-1(2H)-one,

7-(PhenyiethynyO-3,4-dihydropyrrolo[1 ,2-a]pyrazin-1(2H)-Qrse _s

7-((3-Fluorc>phenyi)ethynyl)-3,4-dihydro-pyrrol9n >2-^pyrazin-': (2H)-one,

2-((6-Aminopyndi ^: n-2-yl)ethynyl)-8 _! 8-dirriethyl-7 _J 8-<iihydfO“5H-pyrrolo{1 .2-a]azepin- 9(6H)-one,

2-(i ^: midazo[1 ,2-a]pyr:din-2-ylethynyl )-6,6-dfmethyP6,7“Ciihyc^roifidolizin“8(5Mj-orie.

2,2- Dimethyl- 1 ■'(7-{phefiylethynyl)-3,4-dihydropyrroto[1 ,2-3]pyrazsn-2{1 H)- yl)propan-1-one,

S-Bromo-S^phenylethynyiJ-BJ-dihydroindolizfri-SfSHbone,

S-Cyclopropyl^^phenylethynyn-e.Z-dih^roindolizin-SfSHJ-on e,

M,W"Dimethy[-7-(phenyiethynyi)-3,4-dihydropyrroto[1 ,2-a]pyra?:ine-20 H)- carboxamide,

2-(2'Methylbenzyi)-7-(phenylethy!iyi)-3,4'dihydrapyn'olon ,2-a]pyrazin-1 (2H)-one, 7-({3-Fluoropheny!)eihyny!)-2-(2-meihy§befizyr)-3,4-dihydro pyrroto[1,2-a]pyrazin- 1<2H)-one,

2-(3-MethylbenzyO-7-(phenytethynyB-3,4-dihyciropyrrolo[1 ,2-a}pyrazin-i(2H)-on8, 2-(3-Methyibenz^ )'?-(m-tolyiethynyi )-3,4'd ihydropyrrolo[1.2-aJpyrazin-l (2H)-one, 7-((3-F!uorophenyl)ethyr!yi)-2-(3-metfiySbenzyi)-3,4-di7iydr opy:To!o^,2- _t ^r 3]pyraz.in- 1(2H)-one,

2-(4-Metliytberizyn-7-(ph8nyi8thyny!)-3,4'dihydropyrrolo{ l ,2-a]pyrazin-'l(2 ₍ 4)'One, 2-(4-Methyfbenz\,4)-7-(<’T!-to!ylethynyn-3 _r 4-dihydrapyrrolo{1 ,2-a]pyrazin-1(2H)-one, 7“((3“Fiuorophenyl)eihyny!)“244-methy§benzyl)"3,4-dih ydropyTOlon,2-a]pyrazin“ 1(2H)-one,

2’(2-Fiuorobenzyl)~7-(phenytethyriyl)-3,4-dfhydropy:TOl o[1 ,2-a]pyraz:n-1(2H)-one, 2-(2-RuorobenEy0-7-(mdo!ylethynyl)-3,4<Hhydropymoto[1 ,2-a]pyrazind(2Hyone, 2-(2-FiLioroberszyl)-7”((3"fluoropheny}jeihynyi)'3 _; 4-'dih>'clropyrrolo[1,2--s]pyrazin- 1(2H)*one,

Phen^^T-Cphen^ethynyfJ-aX-dihydropym^ofl^-alpyrazin-Zfl f^-yt^netharKMie, (KJ”2-’('i -PI’ienytet!iyi}-7-(phenyiethynyi}-3,4-dihydropyrroSo(1 _I 2-a]pyrazin-1(2H)- one, (R}-2-(1--Phenytelhyf)“7-(m-tolyiethy’iyf)“3,4-<lih ydropyn’otoJ1 ,2-s]pyraztn"1(2M)-- one,

(/^y7-((3-FiiJOrophenyi jethynyi)-2-(1 -phenyleshyi )-3 ,4<f ihydropyrrcto[1 ,2-aJpyrazin-

1 (2A0-one,

2-(3-Fiuorobenz:yl)-7-(phenytethynyl)-3,4-dfhydropyrrolo^ ,2“3]pyr3zin-1 (2H)-one, 2-(3*Huorobenzyl)-7-(m-tolylethynyl)-3,4-dihydropyrfoto[1 ,2'a]pyrazin-1 (2H)-one, 2-(3-F^orobenzyl)'7'((3-fluorophenyl>ethy'nyl)-3 _; 4-dihydrapyTrajo^ ,2-a]pyraz!n-

1 (2H)-one,

2-(4-FiuofOt<enzyl)-7-(pheriyiethyfiyl)-3,4-dfhydropyr rolon ,2"a]pyrazin-1 (2H)-one, 2“(4*Fiuorobenzyl)-7“(m“tolylethynyl)“3,4“dihy'clr opyrfoio['i ,2-a]pyrazin-1 (2H'}-one, 2-(4-Fluorobenzyl)-7-((3-fluorophenyl)ethynyi)-3,4-dihydropy rn3lon ,2-ajpyrazin- 1(2H)-one,

■•Pheny§ethyi)-7-(m4o(ylethyny))"3,4-dihyd:DpyrrQlon ,2-a1pyrazfa-1 (2H> one, (SJ-Z-fl -Phenyteth^)’7-(phetiylethynyl)-3.4'dihydropyrrolon ,2-a'ipyrazfH’l (2H)- one,

(S)-7-((3-FI ^: uoropheny!)ethyny!)-2-0-phenyiethy!)-3,4-dihydropyrro! o[1 ,2-a]pyrazin- 1(2Hj-cne,

(7-(Phenylethyn^)-3,4-<iB3ydropy!T^o[1 ,2-aJpyrazin-2(1 HJ-yiXpyrrolidin-1 - yl)m ethanone,

Methyl 7’{phenylethynylj"3 _l 4-<jihydrapyrroloJ1 ,2-aJpyrazine-2{1H)<:att)oxylate.

2'-(Phenyiethynyi>6',7'-d!hyciro-5'H-spiro[jmiclazolfd ine-4.8'-indGlizineJ-2,5-dtone _s 1,3’Dimethyi-2'-(phenyiethynyi)-6'7'’djhydro-5'H-spiro[i midazoitdine-4,8'- indoiizine]-2,5'dione, ciis-9-(Phenyte&iynyl)-4’prop^-3 _l 4,4a,5,6,1(»i'hexahydro-2H-[1,4]oxazkio[3,2’ gjindolizine, eiS’9'(Phenyiethyftyl)4-(3,3,3-tr^uoro{» ^, ^>^)’3,4,4a,5,6,i0b4TexahydFO'2H’

[1.4]oxazino[3.2-gpndolizine..

CiS-9-(Phenytethyr>yl)-4~(2 _> 2.,2-trifltioroethyi)-3,4,4a,5 ₁ 6,Wb-hexahydro’2H- [1 , 4 joxazino[3 , 2 -gj indol izin e , c/s-4-(2,2’DifiLioroethy0’9-(phenytethy4iy^-3 _> 4,4a _[ 5,6 ₁ T0b’hexahydro-2H’

[1.4]oxazino[3,2-ff]indoli2lne, olM-(2-Fluoroethyt)-9-{phenyfethynyO-3.4 ,48,5,6 , 10b-hexahydro-2H-

[1.4]oxazino[3,2-g]indo!izine, c/s-Methyl g-fphenyiethynylJ^s.S.SJOb-tetrahydro-SH-n ^loxazsnofS.Z- gJindolizine“4(3H)*carljoxy}ate _t c/s-M,/^-Dimeihyl-9-(phenyiethynyrs-4a,5,6,10b-tetrahydro-2H ’[1 ,4]oxazino[3 _s 2- g]indolizine-4(3W)-carboxamide, Azetidin-1-yl(cfe-9-(^enyiethyn^)-5 _t 6-<iihyd«>-2H41,4]oxazHio[3,2-g ^! ]hdoli^n‘ 4(3H,48HJ0bH)-yl)methanone,

W.N-Dimethyl’7^p^enylefri^»yl}-3,4-dihydrt^3yrFC^o[1,2 -a]p)!r8J3ne-2(1H)- sulfonamide, 7-(Phen^eth^y!)-2-(pyrimid!n«2-y!)«1 <2,3,4<tetrahydropyrrok>n >2*s]pyrazine, Morphol ino(7-(ph6nytethynyf)-3,4-dihydropyfroto[1 ,2-s]pyrazin-2( 1 Hy yi) methanone,

7^(3^luwo^i^)ethyn^)~2’Phenethyl’3,4-dihydn3pyrok)[1 ,2-a]^azfn-1 (2H)’ one,

2-Phenethyl-7~(phenytethynyl )-3,4-dthydropyrrolon ,2-a]pyrazin-1 (2H}one, 2*Phenethyl“7*(rMoiytethynyl)-3 _< 4fothydropyrrofon >2“3jpyrazfn-1(2H)"On6,

, including optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof, and including substituted variants retaining glutamate modulatory activity. [001079] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 239. Such compounds are described in WO 2012/170845, published December 13, 2012, corresponding to PCT/US2012/041595, filed June 8, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 239, this reference incorporated by reference herein controls.

[001080] In an embodiment, the glutamate modulator is a compound according to Formula 239: wherein

Q is CR9 or N; m and n are each independently 0 or 1 ;

X is F, CI, Br, or I;

Rl, R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen, X, alkyl, heteroalkyl, or alkenyl; or any two of Rl, R2, R3, R4, R5 and R6 together with the atoms to which they are attached, form a cycloalkyl ring; and

R9 is hydrogen or alkyl; provided that at least one of Rl, R2, R3, R4, R5, R6, R7, and R8 is either X, or alkyl or heteroalkyl substituted with at least one X; or a cycloalkyl ring formed by any two of Rl, R2, R3, R4, R5 and R6 together with the atoms to which they are attached is substituted with at least one X; at least one of R3 and R4 is not hydrogen; when m and n are both 1, Q is CH, and Rl, R2, R4, R5, and R6 are all H, then R3 is not CF3 or F; when m and n are both 1, Q is CH, and Rl, R2, R5, and R6 are all H, then R3 and R4 are not both F; when m and n are both 1, Q is CH, Rl, R2, R5, and R6 are all H, and R3 is unsubstituted alkyl, then R4 is not F; and when m is 1, n is 0, Q is CH, Rl, R2, R5, and R6 are all H, and R3 is H or F, then R4 is optionally not F. [001081] In further embodiments, the glutamate modulator is a compound according to:

Q is CR7 or N;

G is CH2 or O;

R1 and R2 are independently hydrogen, alkyl, cyano, or heteroalkyl; or R1 and R2 together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; and

R7 is selected from hydrogen and alkyl provided that when Q is N and G is CH2, then at least one of R1 and R2 is not hydrogen; when Q is N, G is CH2, and one of R1 and R2 is methyl, then the other of R1 and R2 is not hydrogen or methyl; when Q is N, G is CH2, and one of R1 and R2 is hydroxymethyl or methoxymethyl, then the other of R1 and R2 is not hydrogen; and when Q is N, G is CH2, and R1 and R2 together with the atom to which they are attached form a heterocycloalkyl ring, then R1 and R2 together are optionally not -(CH2)20(CH2)2-. [001082] In further embodiments, the glutamate modulator is a compound according to: heteroalkyl, or cyano; or R1 and R2 or R3 and R4 together with the atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; or

R2 and R3 together with the atoms to which they are attached form a cycloalkyl ring; R5 is hydrogen or alkyl; R6, R7, and R8 are each independently hydrogen, CN, heteroalkyl, alkyl, or X; and

X is F, CI, Br, or I; when Rl, R2, R3, and R4 are all hydrogen, then at least one of R5, R6, R7, and R8 is not hydrogen when both Rl and R2 are methyl, then at least one of R3, R4, R5, R6, R7, and R8 is other than hydrogen; when both R3 and R4 are methyl, then at least one of Rl, R2, R5, R6, R7, and R8 is not hydrogen; when one of Rl, R2, R3, and R4 is methyl, and the other three of Rl, R2, R3, and R4 are all hydrogen, then at least one of R5, R6, R7, and R8 is not hydrogen; when one of Rl and R2 is hydroxymethyl or methoxymethyl and the other of Rl and R2 is hydrogen, then at least one of R3, R4, R5, R6, R7, and R8 is not hydrogen; when one of R3 and R4 is hydroxymethyl, hydroxy, methoxy, methoxymethyl, or fluoro, and the other of R and R is hydrogen, then at least one of R , R , R , R , R , and R8 is not hydrogen; when one of R3 and R4 is methyl and the other of R3 and R4 is hydroxyl or methoxy, then at least one of Rl, R2, R5, R6, R7, and R8 is not hydrogen; when R3 and R4 are both F, then at least one of Rl, R2, R5, R6, R7, and R8 is not hydrogen. [001083] In further embodiments, the glutamate modulator is a compound according to: wherein m and n are each independently 0 or 1 ;

Rl, R2, R3, R4, R5, and R6 are each independently hydrogen, alkyl, or heteroalkyl; or

Rl and R2, R3 and R4, or R5 and R6 together with the atom to which they are bonded form a cycloalkyl or heterocycloalkyl ring;provided that at least one of Rl, R2, R3, R4, R5, and R6 is not hydrogen; when m and n are both 1 or both m and n are 0, one of R3 and R4 is methyl, and the other of R3 and R4 is hydrogen, then at least one of Rl, R2, R5, and R6 is not hydrogen; when m is 0, n is 1 , and both R5 and R6 are methyl, then at least one of Rl, R2, R3, and R4 is not hydrogen; when m is 1, n is 0, and both R3 and R4 are methyl, then at least one of Rl, R2,

R5, and R6 is not hydrogen; when m and n are both 0 and both R3 and R4 are methyl, then at least one of Rl, R2, R5 and R6 is not hydrogen; and when m and n are both 0, one of R5 and R6 is hydroxymethyl or methoxymethyl, and the other of R5 and R6 is hydrogen, then at least one of Rl, R2, R3, and R4 is not hydrogen. [001084] In further embodiments, the glutamate modulator is a compound according to:

Z is

Rl, R2, R3, R4, R5, and R6 are each independently hydrogen or alkyl;

Q is O or S;

R7 and R8 are hydrogen or alkyl; or R7 and R8 together with the atoms to which they are attached form a cyclolalkyl, heterocycloalkyl, aryl, or heteroaryl ring; provided that when m is 1, n is 1, Z is ’, Q is S, R7 is methyl and R8 is hydrogen, one of R3 and R4 is methyl, and the other of R3 and R4 is hydrogen, then at least one of Rl, R2, R5 and R6 is optionally not hydrogen.

[001085] In further embodiments, the glutamate modulator is a compound according to: wherein m and n are independently

0 or 1 ; L is -R8C=CR8-, -OC(R9)2-, C(0)NR10-, or -NRIOC(O)-;

X is F, CI, Br, or I;

Rl, R2, R3, R4, R5, and R6 are each independently hydrogen, alkyl, or X;

R7 is hydrogen or cyano; each R8 is hydrogen or X;

R9 and RIO are each independently hydrogen or alkyl.

[001086] In further embodiments, the glutamate modulator is a compound according to:

[001087] In further embodiments, the glutamate modulator is a compound selected from:

, additionally including substituted variants thereof retaining glutamate modulatory activity.

Formula 240

[001088] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 240. Such compounds are described in WO 2012/162635, published November 29, 2012, corresponding to PCT/US2012/039639, filed May 25, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 240, this reference incorporated by reference herein controls.

[001089] In an embodiment, the glutamate modulator is a compound according to

Formula 240: wherein

Yl, Y2, and Y3 are each independently CR4 or N;

R1 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R2 and R4 is independently hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, or heteroaryl;

R3 is hydrogen, alkyl, heteroalkyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;

L is -C=C-, -R4C=CR4-, -C(R4)2-C(R4)2-, -C(0)-CR5R6-, -CH(OH)-CR5R6, - CR5R6-

C(O)-, -C0-6alkyl-O-C0-6alkyl-, -NR6S0-, -S0NR6-, -NR6SO2-, -SO2NR6-, -NR6-,

W 1 and W2 are each independently N or CH,

W3 is O, S, or NR5; and

R5 and R6 are each independently hydrogen or alkyl.

[001090] In further embodiments, the glutamate modulator is a compound according to:

, wherein Yla, Y2a, and Y3a are each independently CR4a or N’

Ria is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R3a is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

R4a is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, or heteroaryl.

[001091] In further embodiments, the glutamate modulator is a compound according to: , wherein Yla, Y2a, and Y3a are each independently CR4a or N;

R3a is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;

R4a is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, or heteroaryl; and

R12a is alkyl, heterocyclic, heteroaryl, cycloalkyl, acyl, alkoxycarbonyl, heteroarylalkyl, heterocyclicalkyl or aralkyl.

[001092] In further embodiments, the glutamate modulator is a compound selected from:

2-cyclopentyl-5-(4-((3-fluorophenyl)ethynyl)phenyl)-l,3,4 -oxadiazole;

2-(sec-butyl)-5-(4-((3-fluorophenyl)ethynyl)phenyl)-l,3,4 -oxadiazole;

2-(pentan-3-yl)5-(4-(pyridine-4-ylethynyl)phenyl)-l,3,4-o xadiazole;

2-(4-((3 -fluorophenyl)ethynyl)phenyl)-5 -(pentan-3 -yl)- 1 ,3 ,4-oxadiazole ;

2-(4-(phenylethynyl)phenyl)-3a,4,5,6,7,7a-hexahydro-lH-be nzo[d]imidazole;

3-(4-((4-fluorophenyl)ethynyl)phenyl)-l,5,6,7,8,8a-hexahy drolinidazo[l,5-a-]pyridine;

2-(4-(phenylethynyl)phenyl)-3a, 4,5,6,7,7a-hexahydro-lH-benzo [d] imidazole;

3(4((4-fluorophenyl)ethynl)phenyl)-5,6,7,8-tetrahydronnid azo[l,5-a]pyridine;

3 -cyclopentyl-5-4-((3-fluorophenyl)ethynyl)phenyl)-4H-l,2,4-t riazole;

2-(4-methyl-5 -(pyrrolidin- 1 -yl)ethyl)-4H- 1 ,2,4-triazol-3 -yl)-5 -(pyridi-n-2-ylethynyl)pyridine;

3-(4-((4-fluorophenyl)ethynyl)phenyl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[-4,3-a]pyridine; l-(sec-butyl)-4-(4-(pyridin-4-ylethynyl)phenyl)-lH-l,2,4-tri azol-5(4H)-one;

3-(tert-butyl)-5-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2, 4-oxadiazole;

3-cyclopentyl-5-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4 -oxadiazole;

3-(sec-butyl)-5-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4 -oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4-oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4-oxadiazole;

5-ethyl-3-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4-oxadi azole;

3 -(4 -( (3 -fluorophenyl)ethynyl)phenyl)-5 -propyl- 1 ,2,4-oxadiazole ;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-isopropyl-l,2,4-o xadiazole; 5 -cyclopropyl-3 -(4 -( (3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazole ;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-isobutyl-l,2,4-ox adiazole;

5 -(tert-butyl)-3 -(4- ((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazole;

5-cyclobutyl-3-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4- oxadiazole;

5 -5 -(sec-butyl)-3 -(4 - ((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazole ;

(S)-5-(sec-butyl)-3-(4-((3-fluorophenyl)ethynyl)phenyl)-l ,2,4-oxadiazole;

(R)-5-(sec-butyl)-3-(4-((3-fluorophenyl)ethynyl)phenyl)-l ,2,4-oxadiazole;

5-cyclopentyl-3-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4 -oxadiazole;

5 -cyclohexyl-3 -(4-((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazole ;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(pentan-3-yl)-l,2 ,4-oxadiazole;

5-benzyl-3-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4-oxad iazole;

5 -benzyl-3 -(4- ((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-((tetrahydrofuran -2-yl)methyl)-l,-2,4-oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(furan-2-ylmethyl )-l,2,4-oxadiazole;

3 -(4-((3 -fluorophenyl)ethynyl)phenyl)-5 -(tetrahydrofuran -2 -yl)- 1 ,2,4-oxadiazole ;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(2-methoxyethyl)- l,2,4-oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(tetrahydro-2H-py ran-4-yl)-l,2,4-oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(furan-2-yl)-l,2, 4-oxadiazole;

3 -(4-((3 -fluorophenyl)ethynyl)phenyl)-5 -(tetrahydrofuran-3 -yl)- 1 ,2,4-oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(l-methoxypropyl) -l,2,4-oxadiazole;

3 -(4-((3 -fluorophenyl)ethynyl)phenyl)-5 -( 1 -methylpiperidin-4-yl)- 1 ,2,4-oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(l-methylpyrrolid in-2-yl)-l,2,4-oxadiazole;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(l-methylpyrrolid in-2-yl)-l,2,4-oxadiazole;

5 -( 1 -ethylpyrrolidin-2-yl)-3 -(4 - ((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazole ;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(l-isopropylpyrro lidin-2-yl)-l,2,-4-oxadiazole;

5 -( 1 -cyclobutylpyrrolidin-2-yl)-3 -(4 - ((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2-,4-oxadiazole

5 -( 1 ,2-dimethylpyrrolidin-2-yl)-3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-y-l)- 1 ,2,4-oxadiazole ;

5 -( 1 -(azetidin- 1 -yl)ethyl)-3 -(4-((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazole;

3 -(4-((3 -fluorophenyl)ethynyl)phenyl)-5 -( 1 -(pyrrolidin- 1 -yl)ethyl)- 1 ,2,4-oxadiazole ;

N-( 1 -(3 -(4-((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)ethyl)-N - methylcyclopropanamine ; ethyl 3— (4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4-oxadiazole-5-carbo xylate; l-(3-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4-oxadiazol-5-y l)ethanone;

1 -(3 -(4-((3 -fluorophenyl)ethynyl)phenyl)- 1 ,2,4-oxadiazol-5 -yl)ethanol;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-5-(l-methoxyethyl)- l,2,4-oxadiazole;

3 -(4 -( (3 -fluorophenyl)ethynyl)phenyl)5 -(pyrrolidin- 1 -yl)- 1 ,2,4-oxadiazole ;

4-(3-(4-((3-fluorophenyl)ethynyl)phenyl)-l,2,4-oxadiazol- 5-yl)morpholine; N -ethyl-3 -(4-((3 -fluorophenyl)ethynyl)phenyl)-N-methyl- 1 ,2,4-oxadiazol-5 -amine ;

3-(4-((3-fluorophenyl)ethynyl)phenyl)-N-methyl-l,2,4-oxad iazol-5-amine;

3-(4-((4-fluorophenyl)ethynyl)phenyl)-5-isopropyl-l,2,4-o xadiazole;

5-(sec-butyl)-3-(4-((4-fluorophenyl)ethynyl)phenyl)-l,2,4 -oxadiazole;

5-cyclopentyl-3-(4-((4-fluorophenyl)ethynyl)phenyl)-l,2,4 -oxadiazole;

5-(tert-butyl)-3-(4-((4-fluorophenyl)ethynyl)phenyl)-l,2, 4-oxadiazole;

5-(tert-butyl)-3-(4-((4-fluorophenyl)ethynyl)phenyl)-l,2, 4-oxadiazole;

5-(l-methoxyethyl)-3-(4-(pyridin-2-ylethynyl)phenyl)-l,2, 4-oxadiazole;

5-(l-methoxypropyl)-3-(4-(pyridin-2-ylethynyl)phenyl)-l,2 ,4-oxadiazole;

5-(l-methylpyrrolidin-2-yl)-3-(4-(pyridin-2-ylethynyl)phe nyl)-l,2,4-oxadiazole;

5-(sec-butyl)-3-(4-(pyridin-4-ylethynyl)phenyl)-l,2,4-oxa diazole;

(S)-5-(sec-butyl)-3-(4-(pyridin-4-ylethynyl)phenyl)-l,2,4 -oxadiazole;

(R)-5-(sec-butyl)-3-(4-(pyridin-4-ylethynyl)phenyl)-l,2,4 -oxadiazole;

5-(l-methoxyethyl)-3-(4-(pyridin-4-ylethynyl)phenyl)-l,2, 4-oxadiazole;

5 -(pentan-3 -yl) - 3 -(4-(pyridin-4-ylethynyl)phenyl)- 1 ,2,4-oxadiazole ;

5-( 1 -methoxypropyl) -3 -(4-(pyridin-4-ylethynyl)phenyl)- 1 ,2,4-oxadiazole ;

3-(4-(pyridin-4-ylethynyl)phenyl)-5-(pyrrolidin-2-yl)-l,2 ,4-oxadiazole;

5-( 1 -methylpyrrolidin-2-yl)-3-(4-(pyridin-4-ylethynyl)phenyl)- 1 ,2,4-oxadiazole;

N-methyl-l-(3-(4-(pyridin-4-ylethynyl)phenyl)-l,2,4-oxadi azol-5-yl)ethanamine;

N,N-dimethyl-l-(3-(4-(pyridin-4-ylethynyl)phenyl)-l,2,4-o xadiazol-5-yl)ethanamine;

5-(sec-butyl)-3-(4-(pyridin-3-ylethynyl)phenyl)-l,2,4-oxa diazole;

5-(sec-butyl)-3-(6-((3-fluorophenyl)ethynyl)pyridin-3-yl) -l,2,4-oxadiazole;

5 -cyclopentyl-3 -(6 - ((3 -fluorophenyl)ethynyl)pyridin-3 -yl)- 1 ,2,4-oxadiazole ;

3 -(6 -( (3 -fluorophenyl)ethynyl)pyridin-3 -y 1) -5 -( 1 -methoxyethyl)- 1 ,2,4-oxadiazole ;

3 -(6 -( (3 -fluorophenyl)ethynyl)pyridin-3-yl)-5 -( 1 -methoxypropyl)- 1 ,2,4-oxadiazole ;

5 -(sec-butyl)-3 -(6-(pyridin-2-ylethynyl)pyridin-3 -yl)- 1 ,2,4-oxadiazole ;

5-(pentan-3-yl)-3-(6-(pyridin-2-ylethynyl)pyridin-3-yl)-l ,2,4-oxadiazole;

5 -( 1 -methoxyethyl)-3 -(6-(pyridin-2-ylethynyl)pyridin-3 -yl)- 1 ,2,4-oxadiazole;

5-(l-methoxypropyl)-3-(6-(pyridin-2-ylethynyl)pyridin-3-y l)-l,2,4-oxadiazole;

5-(sec-butyl)-3-(6-(pyridin-4-ylethynyl)pyridin-3-yl)-l,2 ,4-oxadiazole;

5 -(pentan-3 -y 1) - 3 -(6-(pyridin-4-ylethynyl)pyridin-3 -yl)- 1 ,2,4-oxadiazole;

5-( 1 -methoxyethyl)-3-(6-(pyridin-4-ylethynyl)pyridin-3-yl)- 1 ,2,4-oxadiazole;

5 -(pentan-3-yl)-3 -(6-(pyridin-4-ylethynyl)pyridin-3 -yl)- 1 ,2,4-oxadiazole ;

5-(sec-butyl)-3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl) -l,2,4-oxadiazole;

5-cyclopentyl-3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl) -l,2,4-oxadiazole;

3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-5-(l-methoxye thyl)-l,2,4-oxadiazole;

3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -( 1 -methoxypropyl)- 1 ,2,4-oxadiazole; 3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-5-(l-methoxyprop yl)-l,2,4-oxadiazole; tert-butyl 2-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxadiaz ol-5-yl)azeti-dine-l- carboxylate;

5-(azetidin-2-yl)-3-(5-((3-fluorophenyl)ethynyl)pyridin-2 -yl)-l,2,4-oxadiazole;

3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -( 1 -methylazetidin-2-yl)- 1 ,2,4-oxadiazole;

1 -(3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5 -yl)-N-methylmethanamine ; l-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxadiaz ol-5-yl)-N,N -dimethylmethanamine; l-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxadiaz ol-5-yl)-N,N -dimethylethanamine;

(R)-l-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4- oxadiazol-5-yl)-N,N -dimethylethanamine;

(S)-l-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4- oxadiazol-5-yl)-N,N -dimethylethanamine;

1-(3-(5-(3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxadi azol-5-yl)-N-methylethanamine;

3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -( 1 -(pyrrolidin- 1 -yl)ethyl)- 1 ,2,4-oxadiazole N-(l-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxad iazol-5-yl)ethyl)cyclopropanamine; N-( 1 -(3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5 -yl)ethyl)propan-2-amine; N,N-diethyl- 1 -(3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazo- 1 -5-yl)ethanamine;

2-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxad iazol-5-yl)-N-methylpropan-2-amine;

2-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxad iazol-5-yl)-N,N-dimethylpropan-2-amine;

1 -(3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5-yl)propan- 1 -amine; l-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxadiaz ol-5-yl)-N-methylpropan-l-amine;

1 -(3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5 -yl)-N,N-dimethylpropan- 1 -amine ; N-(l-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxad iazol-5-yl)propyl) cyclopropanamine;

1-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxad iazol-5-yl)-N,N - dimethylcyclopropanamine ;

3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -(pyrrolidin-2-yl)- 1 ,2,4-oxadiazole;

(R)-3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -(pyrrolidin-2-yl)- 1 ,2,4-oxadiazole ;

(S)-3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -(pyrrolidin-2-yl)- 1 ,2,4-oxadiazole ;

3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-5-(2-methylpy rrolidin-2-yl)-l,2,4-oxadiazole;

3-(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -(3 ,3,3 -trifluoropropyl)p-yrrolidin-2-yl) - 1 ,2,4- oxadiazole;

3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -( 1 -(prop-2 -yn- 1 -yl)pyrrolidin-2-yl)- 1 ,2,4-oxadiazole ;

2-(2-(3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5 -yl)pyrrolidin- 1 -yl)acetonitrile;

5 -( 1 -cyclobutylpyrrolidin-2-yl)-3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-y-l)- 1 ,2,4-oxadiazole; (S)-3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -(4-methylenepyrrolidin-2-yl)- 1 ,2,4-oxadiazole ;

(4R) -tert-butyl 2-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4-oxadiaz ol-5-yl)-4- hydroxypyrrolidine- 1 -carboxylate;

(3R,5 S)-5 -(3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5 -yl)pyrrolidin-3 -ol; (3R,5S)-5-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l,2,4 -oxadiazol-5-yl)-l-methylpyrrolidin-3- ol;

(3R,5R)-5 -(3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5 -yl)pyrrolidin-3 -ol;

(3R,5R)-5-(3-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-l, 2,4-oxadiazol-5-yl)-l-methylpyrrolidin-3- ol;

3 -(5 -((3 -fluorophenyl)ethynyl)pyridin-2-yl)-5 -((2R,4R)-4-methoxypyrrolidi-n-2-yl)- 1 ,2,4-oxadiazole ; 5-(sec-butyl)-3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l,2,4- oxadiazole;

5 -( 1 -methoxyethyl)-3 -(5 -(pyridin-2-ylethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazole ;

5-(pentan-3-yl)-3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l ,2,4-oxadiazole;

5-cyclopentyl-3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l,2 ,4-oxadiazole;

5-(l-methoxypropyl)-3-(5-(pyridin-2-ylethynyl)pyridin-2-y l)-l,2,4-oxadiazole;

5 -( 1 -(2,2-dimethylpyrrolidin- 1 -yl)ethyl)-3-(5 -(pyridin-2-ylethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazole; N-(l-(3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l,2,4-oxadiazo l-5-yl)ethyl)-propan-2 -amine;

2-methyl-N-(l-(3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l, 2,4-oxadiazol-5-yl)ethyl)propan-2-amine;

3 -(5 -(pyridin-2-ylethynyl)pyridin-2-yl)-5 -( 1 -(pyrrolidin- 1 -yl)ethyl)- 1 ,2,-4-oxadiazole;

N,N-dimethyl-l-(3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l ,2,4-oxadiazol-5-yl)ethanamine;

N-methyl-2-(3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l,2,4 -oxadiazol-5-yl)-propan-2-amine;

N,N-dimethyl-2-(3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l ,2,4-oxadiazol-5-yl)propan-2-amine; ethyl(l-(3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l,2,4-oxadi azol-5-yl)propyl)carbamate;

N-methyl-l-(3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-l,2,4 -oxadiazol-5-yl)-propan-l-amine;

N,N-dimethyl- 1 -(3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5-yl)propan- 1 -amine;

N-( 1 -(3 -(5 -(pyridin-2-ylethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazol-5 -yl)propyl) cyclopropanamine;

5 -( 1 -methylazetidin-2-yl)-3 -(5 -(pyridin-2-ylethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazole ;

3-(5-(pyridin-2-ylethynyl)pyridin-2-yl)-5-(pyrrolidin-2-y l)-l,2,4-oxadiazole;

5-(5,5-dimethylpyrrolidin-2-yl)-3-(5-(pyridin-2-ylethynyl )pyridin-2-yl)-l-,2,4-oxadiazole;

3 -(5 -(pyridin-2-ylethynyl)pyridin-2-yl)-5 -( 1 ,5 ,5 -trimethylpyrrolidin-2-yl-)- 1 ,2,4-oxadiazole;

(R)-5-(4,4-difluoro-l-methylpyrrolidin-2-yl)-3-(5-(pyridi n-2-ylethynyl)py-ridin-2-yl)-l,2,4- oxadiazole;

(S)-5-(4,4-difluoro-l-methylpyrrolidin-2-yl)-3-(5-(pyridi n-2-ylethynyl)py-ridin-2-yl)-l,2,4- oxadiazole;

5 -((2R,4S)-4-fluoro- 1 -methylpyrrolidin-2-yl)-3 -(5 -(pyridin-2-ylethynyl)py-ridin-2-yl)- 1 ,2,4- oxadiazole;

5-((2S,4S)-4-methoxypyrrolidin-2-yl)-3-(5-(pyridin-2-ylet hynyl)pyridin-2-yl)-l,2,4-oxadiazole;

5-(sec-butyl)-3-(5-(pyridin-4-ylethynyl)pyridin-2-yl)-l,2 ,4-oxadiazole;

5-(lmethoxyethyl)-3-(5-(pyridin-4-ylethynyl)pyridin-2-yl) -1.2.4-oxadiazole;

5-(pentan-3-yl)-3-(5-(pyridin-4-ylethynyl)pyridin-2-yl)-l ,2,4-oxadiazole;

5 -( 1 -methoxypropyl)-3 -(5 -(pyridin-4-ylethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazole; 3-(5-(pyridin-4-ylethynyl)pyridin-2-yl)-5-(pyrrolidin-2-yl)- l,2,4-oxadiazole

N-methyl-l-(3-(5-(pyridin-4-ylethynyl)pyridin-2-yl)-l,2,4 -oxadiazol-5-yl)-ethanamine;

3 -(5 -(pyridin-3 -ylethynyl)pyridin-2-yl)-5 -(pyrrolidin-2-yl)- 1 ,2,4-oxadiazole ;

3 -(5 -(phenylethynyl)pyridin-2-yl)-5 -(pyrrolidin-2-yl)- 1 ,2,4-oxadiazole;

3 -(5 ((3 -chlorophenyl)ethynyl)pyridin-2-yl)-5 -(pyrrolidin-2-yl)- 1 ,2,4-oxadiazole ;

3-(5-(phenylethynyl)pyridin-2-yl)-5-(pyrrolidin-2-yl)-l,2 ,4-oxadiazole;

3-fluoro-5-((6-(5-(pyrrolidin-2-yl)-l,2,4-oxadiazol-3-yl) pyridin-3-yl)ethynyl)benzonitrile;

5 -((2R4R)-4-fluoro- 1 -methylpyrrolidin-2-yl)-3 -(5 -(pyridin-2-ylethynyl)pyridin-2-yl)- 1 ,2,4- oxadiazole;

5 -(2-azabicyclo [3.1.0]hexan- 1 -y 1) -3 -(5 -(pyridin-2-ylethynyl)pyridin-2-yl)- 1 ,2,4-oxadiazole ;

5-((lS,5R)-2-methyl-2-azabicyclo[3,1.0]hexan-l-yl)-3-(5-( pyridin-2-ylethynyl)pyridin-2-yl) -1,2,4- oxadiazole;

5-(l-azabicyclo[2.2.1]heptan-2-yl)-3-(5-(pyridin-2-ylethy nyl)pyridin-2-yl-)-l,2,4-oxadiazole;

5 -( 1 -azabicyclo [2.2.1 ]heptan-2-yl)-3 -(5 -(pyridin-2-ylethynyl)pyridin-2-yl-)- 1 ,2,4-oxadiazole; and

5-(hexahydro-lH-pyrrolizin-7a-yl)-3-(5-(pyridin-2-ylethyn yl)pyridin-2-yl) -1,2,4-oxadiazole, or a pharmaceutically acceptable salt thereof, or a substituted variant thereof retaining glutamate modulatory activity.

Formula 242

[001093] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 242. Such compounds are described in WO 2012/118563, published September 7, 2012, corresponding to PCT/US2012/000119, filed March 5, 2012 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 242, this reference incorporated by reference herein controls.

[001094] In an embodiment, the glutamate modulator is a compound according to; wherein A is CR2 or N; wherein R1 is selected from methyl and ethyl; wherein R2, when present, is selected from hydrogen, halogen, CN, C1-C3 alkyl, Cl- C3 haloalkyl, C1-C3 polyhaloalkyl, and C3 cycloalkyl; wherein R3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, Cl- C3 polyhaloalkyl, and C3 cycloalkyl; wherein each of R4, R5, and R6 is independently selected from hydrogen, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 polyhaloalkyl, and C3 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[001095] In further embodiments, the glutamate modulator is a compound according to:

[001096] In further embodiments, the glutamate modulator is a compound selected from:

Formula 243

[001097] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 243. Such compounds are described in WO 2012/097182, published July 19, 2012, corresponding to PCT/US2012/021123, filed January 12, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 243, this reference incorporated by reference herein controls.

[001098] In an embodiment, the glutamate modulator is a compound according to Formula 243: wherein one of

Y 1 and Y2 is N, and the other is C — R3a; wherein Y3 is O, N — R7, or a covalent bond; wherein one of LI and L2 is — O — , and the other is — C(Rla, Rib) — ; provided that when Y1 is N, LI is — O — and L2 is — C(RlaRlb) — ; wherein Ari is phenyl with 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy, or Ari is monocyclic heteroaryl having 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy; wherein each of Ria and Rib is independently selected from hydrogen and C1-C4 alkyl; wherein R2 is selected from hydrogen; C1-C6 alkyl; (C1-C6 alkyloxy) C1-C6 alkyl;

C3-C8 cycloalkyl; (C3-C8 cycloalkyl) C1-C6 alkyl; C2-C5 heterocyclyl; phenyl with 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy; and monocyclic heteroaryl having 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy; wherein R3a is selected from hydrogen, halogen, cyano, and C1-C4 alkyl; wherein R3b is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, or R3a and R3b are substituted on adjacent carbons and are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused ring selected from 4- to 7-membered cycloalkenyl, 5- to 7-membered heteroaryl, and 6-membered aryl; wherein R4a and R4b are independently selected from hydrogen and C1-C4 alkyl, or R4a and R4b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein R5a and R5b are independently selected from hydrogen and C1-C4 alkyl; or R5a and R5b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; or R4a and R5a are optionally covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered fused cycloalkyl; wherein R6a and R6b are independently selected from hydrogen and C1-C4 alkyl, or R6a and R6b together comprise an exocyclic double bond, or R6a and R6b are covalently bonded and, together with the intermediate carbon, comprise cyclopropyl; and wherein R7 is selected from hydrogen and C1-C6 alkyl; and or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[001099] In further embodiments, the glutamate modulator is a compound selected from:

, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 244

[001100] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 244. Such compounds are described in WO 2012/092530, published July 5, 2012, corresponding to PCT/US2011/067997, filed December 29, 2011 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 244, this reference incorporated by reference herein controls.

[001101] In further embodiments, the glutamate modulator is a compound according to:

wherein each - is independently an optional covalent bond, wherein valence is satisfied; wherein one of Y1 and Y2 is N, and the other is C — R3a; wherein one of Z1 and Z2 is C-L-Arl, and the other is C — R3b; wherein L is — O — C(RlaRlb) — or — C(RlaRlb) — O — ; wherein Ari is phenyl with 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy, or Ari is monocyclic heteroaryl having 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy; wherein each of Ria and Rib is independently selected from hydrogen and C1-C4 alkyl; wherein R2 is selected from hydrogen; C1-C6 alkyl; (C1-C6 alkyloxy) C1-C6 alkyl;

C3-C8 cycloalkyl; (C3-C8 cycloalkyl) C1-C6 alkyl; C2-C5 heterocyclyl; phenyl with 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy;

(C1-C2 alkyl)phenyl with 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy; and monocyclic heteroaryl having 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy; wherein R3a is selected from hydrogen, halogen, cyano, and C1-C4 alkyl; wherein R3b is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, or R3a and R3b are substituted on adjacent carbons and are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused ring selected from 4- to 7-membered cycloalkenyl, 5- to 7-membered heteroaryl, and 6-membered aryl; wherein R4a is selected from hydrogen and C1-C4 alkyl; wherein R4b, when present, is selected from hydrogen and C1-C4 alkyl, or R4a and R4b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; wherein R5a is selected from hydrogen and C1-C4 alkyl; wherein R5b, when present, is selected from hydrogen and C1-C4 alkyl, or R5a and R5b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; and wherein R4a and R5a are optionally covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered fused cycloalkyl; or a pharmaceutically acceptable salt thereof, wherein the compound exhibits potentiation of mGluR5 response to glutamate as an increase in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.

[001102] In further embodiments, the glutamate modulator is a compound according to: pharmaceutically acceptable salts or substituted variants thereof retaining glutamate modulatory activity.

[001103] In further embodiments, the glutamate modulator is a compound selected from:

, including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

Formula 245

[001104] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 245. Such compounds are described in WO 2012/085167, published June 28, 2012, corresponding to PCT/EP2011/073712, filed December 21, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 245, this reference incorporated by reference herein controls. [001105] In an embodiment, the glutamate modulator is a compound according to:

, wherein

X represents CR6(C=0)R7 or NR8; R1 represents H, Cl-6alkyl, or F; R2 represents H, Cl-6alkyl, or F; or R1 and R2 together with the carbon atom to which they are attached form a carbonyl group; or R1 and R2 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl- 6alkyl, Cl-6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl- 6alkyl)amino, Cl-6alkylcarbonylamino, and oxo;

R3 represents H, Chalkyl, or F;

R4 represents H, Cl-6alkyl, or F; or R3 and R4 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl-6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl- 6alkyl)amino, Cl-6alkylcarbonylamino, and oxo;

R5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl;

R6 represents H, Cl-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl-6alkylamino, and di-(Cl-6alkyl)amino, or F;

R7 represents Cl-6alkyl, which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl-6alkylamino, and di-(Cl-6alkyl)amino, cycloC3-6alkyl, heterocyclyl, or NR11 R12; or R6 and R7 together with the carbon atoms to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl- 6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl- 6alkyl)amino, Cl-6alkylcarbonylamino, and oxo;

R8 represents Cl-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl-6alkylamino, and di-(Cl-6alkyl)amino, cycloC3-6alkyl, heterocyclyl, aryl, heteroaryl, Cl-6alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C-l-6alkoxy, amino, hydroxy, Cl-6alkylamino, and di- (Cl-6alkyl)amino, cycloC3- 6alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroaryl carbonyl, Cl- 6alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl-6alkylamino, and di-(Cl-6alkyl)amino, aminocarbonyl, N-Cl- 6alkylaminocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl- 6alkoxy, amino, hydroxy, C-l-6alkylamino, and di-(Cl-6alkyl)amino, N,N-di-(Cl- 6alkyl)aminocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, Cl-6alkoxy carbonyl, cyano, amino, hydroxy, Cl-6alkylamino, and di- (Cl-6alkyl)amino, N-Cl-6alkyl-N- cycloC3-6alkylaminocarbonyl, N-C-l-6alkyl-N- cycloC 1 -6alkyl-C- 1 -6alkylaminocarbonyl, aminothiocarbonyl, N-C 1 - 6alkylaminothiocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl-6alkylamino, and di-(Cl-6alkyl)amino, N,N-di-(Cl- 6alkyl)aminothiocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, C-l-6alkylamino, and di- (C-l-6alkyl)amino, Cl- 6alkylsulfonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl- 6alkoxy, amino, hydroxy, Cl-6alkylamino, and di- (Cl-6alkyl)amino, cycloC3- 6alkylsulfonyl, aminosulfonyl, N-Cl-6alkylaminosulfonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl-6alkylamino, and di-(Cl-6alkyl)amino, or N,N-di-(Cl-6alkyl)aminosulfonyl, wherein the alkyl moi eties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl-6alkylamino, and di-(C 1 -6alkyl)amino;

R9 represents H, Cl-6alkyl, or F; RIO represents H, Cl-6alkyl, or F; or R9 and RIO together with the carbon atom to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl-6alkoxy, amino, hydroxy, cyano, acyl, C-l-6alkylamino, di-(C-l-6alkyl)amino, Cl-6alkylcarbonylamino, and oxo; Rl l represents H, Cl-6alkyl, or cycloC3-6alkyl;

R12 represents H, Cl-6alkyl, or cycloC3-6alkyl; or R11 and R12 together with the nitrogen atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl-6alkoxy, amino, hydroxy, cyano, acyl, C-l-6alkylamino, di-(C-l-6alkyl)amino, Cl-6alkylcarbonylamino, and oxo; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; it being understood that: if R1 and R2 together with the carbon atom to which they are attached form a carbonyl group, then R8 may also represent H. [001106] In further embodiments, the glutamate modulator is a compound selected from:

.\ ^f -(3-Chfoffiphsnyi)-6-(1 -meihyl-1 H4rnidazo!-2-yi)-5,6,7,84£rtrahydropyrido{4,3- d]pyrimidin-2-amine ₍

3-((6-(2-Ethyibuf3noyi)-5,S,7,8-letrahydropyrido[4,3-c!]p yrfmidfn-2- yl)amino)benzonitrile.

^Buty4-2-{(3-cyanophenyi)smino)-W-methyt-7 _! 8-dihydropyrido[4,3-dlpyf’!mjdins-

6(5W)-carboxam ide,

2"((3-Cyannphsnyi)amino)--A.''-cycIoprapyi-N-mst:hyi*7.8- dihydrapyrido[4 _! 3“ d]pyrimidin®-6(6H)--carbQxstYtide,

S-ifS-ChiorophenyrjafninoJ-W-ethyi^V-propyl-Z^B-dihydfopy ricloH.S-dlpyrimidine-

6(5H)-carboxam ide, (rac)-3-((6-<3~Methy^py!rroHdjne-1 -cafbonyi)-5 _s 6,7.8-tetrahydropyrido(4.3- d]pyrimfdin-2-y!)aminojbenzonitrile _r (racJ-3-i‘(6-(2-Methyipyn‘Oiidine-1-carbony!)-5 _: 6 _[ 7,8-tefrahydropyrido[4.3- d] pyr im id i n -2 -y I jam i no jbenzonitr iie .

3"((6"(3.3-Difneihyiaz&tidtne-1 -carbony^-5, 6 7.8-tetrahydrapyridos4,3-d3pyrimidin- 2-yl)amino)benzonitrife, 2-((3~Cyanophenyi)amirto)*A _l '-'ethyi~A'-propyi-7 _; 8-clihydropyrjdo[4,3-d]pyrtmidjne- 6(5H)-cart>oxamide, (rac)-1-{24(3-Chiorophenyl)aminc)-5-methyl-7 _! 8~clihydrapyrido[4,3-d]pyTtmidin- 6(5H}-yl)-2,2-dimethylpropan-1-one, (rac}-1 -(24(3-ChiO:rophenyl)amino)-7-methyl-7 _: 8<iihydropyrido[4,3-d]pyfimidin-

StSHJ-yD^^-dimethylpropan-l-one, 2-((3’Cyanopheny0amino)-,VA/-bis('2 _; 2 _i 2-trifluoroethyi)~7,8-dthydropyrido[4.3- d ] py rim id i ne-6( 5H ) -carbox amide.

Azetidin-1-y!(2*((3-dstorqihen^)amino)-7.8-d^iydrop^ickX4 _l 3-d]pyrimidin-6(5H)- yl)methanone.

Methyl 2-(2~((3-chloropheny!)aminoj-W-methyl-5,6,7,8-tetrahydropyri do[4.3- djpyrirn idine-6-carboxam idojacetate, N'-(2’Cyanoethyl)’2-((3'€yar;opheriyQamfno)-ftrimethyi '-7,8-d ^: ihydropyricio[4 _; 3’ djpyrimidine"6(5H)-carboxamjda, 2>((3-Cyanophenyi)atnino)»W'-(2-methoxyethyl3-Af'-methyh 7,8-dihydropyric!o[4,3* d]pyrimsdme-6(5H)--cartoxamicfe, 2-(2“(P“Tolylamir!o}-7 _: 8*dihydropyrtdo[4 _[ 3“d]pydmidin*6(5H)-yl)nicotinonitrite

2”((3-Cyanophenyi)amino}“W“methy4-M-propy!-7.8-ciih ydropyrido[4,3“d]pyrjmidine- 6(5H}-cart>oxatnide, 6-424(3-Cyariopher!yl}amino)~7,8-d!hydrQpyridQK.3-'d]pyTimid in-6(5Ath yQpicoltnonitrife, 2-(2-{(3"CyanDphenyriainino)”?,8"dihydropyTidoH.3-d]pyiimi din”6(5H)- yl)isontcotinonitri!e.

2-(2-({3-Cyanophenyl}amino)-7,8-dihydropyrido[4:3-d]pyri! Ti ^: idin-6(5Wj-y})-6- m ethy in icotinon it ri te, Azetidfn--7-yi(2-{.m-tolylamino)-7.8-dihydropyrido[4.3-djpyT !midin-6(5H)- yl)methanone.

/V-E thy l-M-m ethy 1-2 -( m-to ly lam i no )- 7 , 8-d ihy drop y rido[4 , 3-d]py rim id i ne-6 ( 5 H)- carboxamide.

N-Methyt-/V-propyl''2-(m-tolylamfno)'7,8-dihydrapyrido[4, 3-d]pyrimidine-6(5H)- carboxamide,

2-((3-Chiorophenyl)amkTO)-W-mettyi-W-|Mx^yl-7 _i 8-d^ydrop^-ick^4.3-cllpyrtrnidin8- 6(5H)*carboxam ide. a-^S-ChtorcphmylJaminoJ-W-ethyi-N-rnethyl-Z.S-dihydropyridoH .S-dlpyrffnidine-

S(5H)-carboxam ide,

34(6-(1-lsoprapyM H-!midazol-2-yi)-5,6,7.8-tetrahydropyrido[4,3-djpyrimidin-2- y ! Jam jnojbenzonit rile,

(2-( ( 3-C h io raphe n y I Jan ino)-7 , 8-d ihy dropy rido[4.3-djpy ri m id ln-6(5H)-y i)( 3- m elhy loxe ta n ■ 3-y I )<rt ethanone.

(3-Methyioxetan-3-yP(2-(m-tolylamino)-7 _! 8'<iihydropyrido[4 _! 3-cl]pyrimidin'6(5H}- yljrnethanone, and pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 246

[001107] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 246. Such compounds are described in WO 2012/085166, published June 28, 2012, corresponding to PCT/EP2011/073711, filed December 21, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 246, this reference incorporated by reference herein controls.

[001108] In an embodiment, the glutamate modulator is a compound according to Formula 246:

X represents CH2 or C=0; Y represents CR6R7, NR8, 0 or S; R1 represents H, Cl-6alkyl, or F; R2 represents H, Cl-6alkyl, or F; or R1 and R2 together with the carbon atom to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl-6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl-6alkyl)amino, d- 6alkylcarbonylamino, and oxo;

R3 represents H, Cl-6alkyl, or F;

R4 represents H, Cl-6alkyl, or F; or R3 and R4 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl-6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl- 6alkyl)amino, Cl-6alkylcarbonylamino, and oxo;

R5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl;

R6 represents H, Cl-6alkyl, or F;

R7 represents H, Cl-6alkyl, or F; or R6 and R7 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl-6alkoxy, amino, hydroxy, cyano, acyl, C-l-6alkylamino, di-(C-l- 6alkyl)amino, Cl-6alkylcarbonylamino, and oxo;

R8 represents H, Cl-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl- 6alkylamino, and di-(Cl-6alkyl)amino, C3-6cycloalkyl, Cl-6alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, C-l-6alkylamino, and di-(Cl-6alkyl)amino, C3-6cycloalkylcarbonyl, Cl-6alkoxy carbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, C-l-6alkylamino, and di-(Cl-6alkyl)amino, aminocarbonyl, N-C-l- 6alkylaminocarbonyl wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, C-l-6alkylamino, and di-(C-l-6alkyl)amino, N,N-di-(C-l-6alkyl)aminocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkoxy, amino, hydroxy, Cl- 6alkylamino, and di-(Cl-6alkyl)amino; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[001109] In further embodiments, the glutamate modulator is a compound selected from:

pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

Formula 247

[001110] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 247. Such compounds are described in WO 2012/088365, published June 28, 2012, corresponding to PCT/US2011/066690, filed December 22, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 247, this reference incorporated by reference herein controls.

[001111] In an embodiment, the glutamate modulator is a compound according to formula 247:

, wherein L is — NHCO — or — CONH — ; and

R1 and R2 are each independently alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, aryl or heteroaryl, which is optionally mono-, di-, or tri-substituted independently with alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-R3, — NHR3, — N(alkyl)R3, — C(0)NHR3, — C(O)N(alkyl)R3, — NHC(0)R3, — N(alkyl)C(O)R3, —OH or — OR3, wherein:

R3 is Cl-C6alkyl or Cl-C6cycloalkyl, which is optionally substituted with halogen, — CN, — NH2, — NH(C1-C3 alkyl), — N(Cl-C3alkyl)2, Cl-C3alkylheterocyclyl, Cl- C3 alkylcarbamate, — C(O)NH(C1-C3 alkyl), — C(O)N(C1-C3alkyl)2, — NHC(O)— Cl-C3alkyl, — N(Cl-C3alkyl)-C(O)— Cl -C3 alkyl, OH, or — O— Cl-C6alkyl; or a pharmaceutically acceptable salt thereof.

[001112] In further embodiments, the glutamate modulator is a compound selected from:

variants thereof.

Formula 248

[001113] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 248. Such compounds are described in WO 2012/083224, published June 21, 2012, corresponding to PCT/US2011/065598, filed December 16, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 248, this reference incorporated by reference herein controls.

[001114] In an embodiment, the glutamate modulator is a compound according to formula 248:

, wherein each

Figure US20120225844 Al -20120906-P00001 is independently an optional covalent bond, wherein valence is satisfied; wherein Ari is phenyl with 0-3 substituents selected from halogen, cyano, hydroxyl, — NH2, C1-C4 alkyl, hydroxy C1-C4 alkyl, C1-C4 alkyloxy, amino C1-C4 alkyl, Cl- C4 alkylamino, C1-C4 dialkylamino, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; or Ari is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl and has 0-3 substituents selected from halogen, cyano, hydroxyl, — NH2, C1-C4 alkyl, hydroxy C1-C4 alkyl, C1-C4 alkyloxy, amino C1-C4 alkyl, C1-C4 alkylamino, C1-C4 dialkylamino, monohalo C1-C4 alkyl, and polyhalo C1-C4 alkyl; wherein each of Ria and Rib is independently selected from hydrogen and C1-C4 alkyl; wherein R2 is selected from hydrogen; C1-C6 alkyl; hydroxy C1-C6 alkyl, (C1-C6 alkyloxy) C1-C6 alkyl; monohalo C1-C6 alkyl; polyhalo C1-C6 alkyl; C3-C8 cycloalkyl; (C3-C8 cycloalkyl) C1-C6 alkyl; (halo C3-C8 cycloalkyl) C1-C6 alkyl, (polyhalo C3-C8 cycloalkyl) C1-C6 alkyl, C2-C5 heterocyclyl, (C2-C5 heterocyclyl) C1-C6 alkyl; aryl with 0-3 substituents selected from halogen, cyano, hydroxyl, — NH2, C1-C4 alkyl, hydroxy C1-C6 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, polyhalo C1-C4 alkyl, amino C1-C4 alkyl, C1-C4 alkylamino, C1-C4 dialkylamino, halo C1-C4 alkyloxy, polyhalo C1-C4 alkyloxy, (C1-C4 alkyloxy) C1-C4 alkyl, (Cl- C4 alkyloxy) C1-C4 alkyloxy, C2-C5 heterocycloalkyl, and C3-C6 cycloalkyl; and heteroaryl with 0-3 substituents selected from halogen, cyano, hydroxyl, — NH2, Cl- C4 alkyl, hydroxy C1-C6 alkyl, C1-C4 alkyloxy, monohalo C1-C4 alkyl, polyhalo C1-C4 alkyl, amino C1-C4 alkyl, C1-C4 alkylamino, C1-C4 dialkylamino, halo Cl- C4 alkyloxy, polyhalo C1-C4 alkyloxy, (C1-C4 alkyloxy) C1-C4 alkyl, (C1-C4 alkyloxy) C1-C4 alkyloxy, C2-C5 heterocycloalkyl, and C3-C6 cycloalkyl; wherein Y is N or C — R3, wherein R3, when present, is selected from hydrogen, halogen, cyano, C1-C4 alkyl, monohalo C1-C4 alkyl, polyhalo C1-C4 alkyl, C2-C5 heterocyclyl, C3-C6 cycloalkyl, aryl and heteroaryl; wherein R4a is selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, and (C1-C4 alkyloxy) C1-C4 alkyl; wherein R4b, when present, is selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, and (C1-C4 alkyloxy) C1-C4 alkyl; or R4a and R4b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7- membered spirocycloalkyl; wherein R5a is selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, and (C1-C4 alkyloxy) C1-C4 alkyl; and wherein R5b, when present, is selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkyloxy, hydroxy C1-C4 alkyl, and (C1-C4 alkyloxy) C1-C4 alkyl; or R5a and R5b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7- membered spirocycloalkyl; or a pharmaceutically acceptable salt thereof.

[001115] In further embodiments, the glutamate modulator is a compound according to: pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

Formula 249 [001116] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 249. Such compounds are described in WO 2012/064603, published May 18, 2012, corresponding to PCT/US2011/059339, filed November 4, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 249, this reference incorporated by reference herein controls.

[001117] In an embodiment, the glutamate modulator is a compound according to Formula 249:

R1 is hydrogen or alkyl;

R2 is hydrogen or alkyl;

A

R3 is

Ari is phenyl or a 5 or 6 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, in which Ari is substituted with 1 R3 substituent and with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;

Ar2 is aryl or heteroaryl, and is substituted with 0-3 substituents selected from halo, cyano, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, and phenyl; and

Ar3 is aryl or heteroaryl, and is substituted with 0-3 substituents selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylthio, amino, alkylamino, and dialkylamino; or a pharmaceutically acceptable salt thereof.

[001118] In further embodiments, the glutamate modulator is a compound selected from: (4R,5R)-5-phenyl-4-(6-(phenylethynyl)-2-pyridinyl)-l,3-oxazo lidin-2-one;

(4R,5R)-5-phenyl-4-(2-(phenylethynyl)-4-pyridinyl)-l,3-ox azolidin-2-one; (4R,5R)-5 -(3 -fluorophenyl)-4-(5 -(phenylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-5-phenyl-4-(2-(3-pyridinylethynyl)-4-pyridinyl)-l ,3-oxazolidin-2-one;

(4R,5R)-5-(3-methoxyphenyl)-4-(5-(phenylethynyl)-3-pyridi nyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-fluorophenyl)-4-(5-(3-pyridinylethynyl)-3-py ridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-methoxyphenyl)-4-(2-(phenylethynyl)-4-pyridi nyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-phenyl-4-(5-(phenylethynyl)-3-pyridinyl)-l,3-ox azolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-(phenylethynyl)-3-pyridin yl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-(3-pyridinylethynyl)-3-py ridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-((5-fluoro-3-pyridinyl)et hynyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-methoxyphenyl)-4-(3-(2-pyridinylethynyl)phen yl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-methoxyphenyl)-4-(3-(4-pyridinylethynyl)phen yl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-methoxyphenyl)-4-(3-((6-methoxy-2-pyridinyl) ethynyl)phenyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-methoxyphenyl)-4-(3-(l,3-thiazol-4-ylethynyl )phenyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(3-((6-fluoro-3-pyridinyl)ethynyl)phenyl)-5-(3- methoxyphenyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(3-((2-fluoro-4-pyridinyl)ethynyl)phenyl)-5-(3- methoxyphenyl)-l,3-oxazolidin-2-one;

5-((3-((4R,5R)-5-(3-methoxyphenyl)-2-oxo-l,3-oxazolidin-4 -yl)phenyl)ethynyl)nicotinonitrile;

(4R,5R)-4-(3 -((5 -fluoro-3 -pyridinyl)ethynyl)phenyl)-5 -(3 -methoxyphenyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-5-phenyl-4-(3-(phenylethynyl)phenyl)-l,3-oxazolid in-2-one;

(4R,5R)-5-(3,4-dimethylphenyl)-4-(3-(phenylethynyl)phenyl )-l,3-oxazolidin-2-one;

(4R,5S)-4-(3-(phenylethynyl)phenyl)-5-(2-thienyl)-l,3-oxa zolidin-2-one;

(4R,5R)-5-(4-methylphenyl)-4-(3-(phenylethynyl)phenyl)-l, 3-oxazolidin-2-one;

(4R,5R)-5-(2-fluorophenyl)-4-(3-(phenylethynyl)phenyl)-l, 3-oxazolidin-2-one;

(4R,5R)-5-(3-fluorophenyl)-4-(3-(phenylethynyl)phenyl)-l, 3-oxazolidin-2-one;

(4R, 5 R) -5 -(4-fluorophenyl) -4-(3 -(phenylethynyl)phenyl)- 1 , 3 -oxazolidin-2-one ;

(4R,5R)-4-(3-(phenylethynyl)phenyl)-5-(3-pyridinyl)-l,3-o xazolidin-2-one;

(4R,5R)-4-(3-((2-fluorophenyl)ethynyl)phenyl)-5-(3-methox yphenyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(3-((3-fluorophenyl)ethynyl)phenyl)-5-(3-methox yphenyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(6-(phenylethynyl)-2-pyridin yl)-l,3-oxazolidin-2-one;

(4R,5R)-4-methyl-5-phenyl-4-(5-(phenylethynyl)-3-pyridiny l)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-fluorophenyl)-4-(2-fluoro-5-(3-pyridinylethy nyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(2-fluoro-5 -((5 -fluoro-3 -pyridinyl)ethynyl)-3 -pyridinyl)-5 -(3 -fluorophenyl)- 1 ,3 - oxazolidin-2-one ;

(4R,5R)-4-(2-fluoro-5 -((2-fluoro-4-pyridinyl)ethynyl)-3 -pyridinyl)-5 -(3 -fluorophenyl)- 1 ,3 - oxazolidin-2-one ;

(4R,5R)-5 -(4-fluorophenyl)-4-(2-fluoro-5 -(3 -pyridinylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-4-(2-fluoro-5-((5-fluoro-3-pyridinyl)ethynyl)-3-p yridinyl)-5-(4-fluorophenyl)-l,3- oxazolidin-2-one ; (4R,5R)-4-(5 -fluoro-2-((5 -fluoro-3 -pyridinyl)ethynyl)-4-pyridinyl)-5 -(4-fluorophenyl)- 1 ,3- oxazolidin-2-one ;

(4R,5R)-5 -(4-chlorophenyl)-4-(2-fluoro-5 -(3 -pyridinylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-4-(2-fluoro-5-((6-fluoro-2-pyridinyl)ethynyl)-3-p yridinyl)-5-(4-fluorophenyl)-l,3- oxazolidin-2-one;

(4R, 5 R) -5 -(3 , 5 -difluorophenyl) -4-(5 -(phenylethynyl)-3 -pyridinyl)- 1 , 3 -oxazolidin-2-one ;

(4R,5R)-5-(3,4-difluorophenyl)-4-(5-(phenylethynyl)-3-pyr idinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3,4-difluorophenyl)-4-(5-(3-pyridinylethynyl)- 3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3,4-difluorophenyl)-4-(5-((5-fluoro-3-pyridiny l)ethynyl)-3-pyridinyl)-l,3-oxazolidin-2- one;

3-((5-((4R,5R)-5-(3,4-difluorophenyl)-2 -oxo-1, 3-oxazolidin-4-yl)-3-pyridinyl)ethynyl)benzonitrile;

(4R,5R)-5-(2,4-difluorophenyl)-4-(5-(phenylethynyl)-3-pyr idinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5 -(2,4-difluorophenyl)-4-(5-((5 -fluoro-3 -pyridinyl)ethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2- one;

(4R,5R)-5 -(2,4-difluorophenyl)-4-(5 -(3 -pyridinylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-5 -(2,5 -difluorophenyl)-4-(5 -(phenylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one;

(4R,5R)-5 -(2,5 -difluorophenyl)-4-(5 -((5 -fluoro-3 -pyridinyl)ethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2- one;

(4R,5R)-4-(3-((4-fluoro-2-pyridinyl)ethynyl)phenyl)-5-(3- methoxyphenyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(3 -((3 -fluoro-2-pyridinyl)ethynyl)phenyl)-5 -(3 -methoxyphenyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-4-(5 -(phenylethynyl)-3 -pyridinyl)-5 -(3 -pyridinyl)- 1 ,3 -oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-5-methyl-4-(5-(phenylethynyl)- 3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5S)-5-(4-fluorophenyl)-5-methyl-4-(5-(phenylethynyl)- 3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-((5-fluoro-3-pyridinyl)et hynyl)-3-pyridinyl)-5-methyl-l,3- oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-((3-fluoro-2-pyridinyl)et hynyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-(2-pyrazinylethynyl)-3-py ridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-(4-pyridinylethynyl)-3-py ridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-((2-fluoro-4-pyridinyl)et hynyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

3-((5-((4R,5R)-5-(4-fluorophenyl)-2 -oxo-1, 3-oxazolidin-4-yl)-3-pyridinyl)ethynyl)benzonitrile;

(4R,5R)-5-(4-fluorophenyl)-4-(5-((6-fluoro-2-pyridinyl)et hynyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-fluorophenyl)-4-(6-(phenylethynyl)-2-pyridin yl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-methyl-4-(5-(phenylethynyl)- 3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-fluorophenyl)-5-methyl-4-(5-(phenylethynyl)- 3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5 S)-4-methyl-5 -phenyl-4-(5 -(phenylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-5 -methyl-5 -phenyl-4-(5 -(phenylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-4-(5-((3-fluoro-2-pyridinyl)ethynyl)-3-pyridinyl) -4-methyl-5-phenyl-l,3-oxazolidin-2-one; (4R,5S)-4-(3-(phenylethynyl)phenyl)-5-(2-pyridinyl)-l,3-oxaz olidin-2-one;

(4R,5R)-5-(4-pyridinyl)-4-(3-(2-pyridinylethynyl)phenyl)- l,3-oxazolidin-2-one;

(4R,5R)-4-(3-(phenylethynyl)phenyl)-5-(4-pyridinyl)-l,3-o xazolidin-2-one;

(4R,5 S)-4-(3 -(phenylethynyl)phenyl)-5 -(4-pyrimidinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-5 -(3 -fluorophenyl)-4-(5 -((5 -fluoro-3 -pyridinyl)ethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one;

(4R,5R)-5-(3-fluorophenyl)-4-(2-(3-pyridinylethynyl)-4-py ridinyl)-l,3-oxazolidin-2-one;

(4R, 5 R) -5 -(3 -fluorophenyl) -4-(2-(phenylethynyl)-4-pyridinyl)- 1 , 3 -oxazolidin-2-one ;

(4R,5R)-5-(3-fluorophenyl)-4-(2-(phenylethynyl)-4-pyrimid inyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2,3-difluorophenyl)-4-(5-(phenylethynyl)-3-pyr idinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2,5-difluorophenyl)-4-(5-((4-fluorophenyl)ethy nyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2,5-difluorophenyl)-4-(5-((2-fluorophenyl)ethy nyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2,3-difluorophenyl)-4-(5-((2-fluorophenyl)ethy nyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2,3-difluorophenyl)-4-(5-((4-fluorophenyl)ethy nyl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(5-(phenylethynyl)-3-pyridinyl)-5-(2,4,6-triflu orophenyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(5-(phenylethynyl)-3-pyridinyl)-5-(2,3,4-triflu orophenyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(4-(phenylethynyl)-2-pyridin yl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-fluorophenyl)-4-(2-fluoro-5-(phenylethynyl)- 3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5 -(3 -fluorophenyl)-4-(2-methoxy-5 -(phenylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-5-(2,5-difluorophenyl)-4-(5-fluoro-2-(phenylethyn yl)-4-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2,5-difluorophenyl)-4-(2-fluoro-5-(phenylethyn yl)-3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2-fluorophenyl)-4-(5-fluoro-2-(phenylethynyl)- 4-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2,4-difluorophenyl)-4-(6-(phenylethynyl)-2-pyr idinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2,4-difluorophenyl)-4-(6-((3-fluorophenyl)ethy nyl)-2-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(5 -(phenylethynyl)-3 -pyridinyl)-5 -(4-pyrimidinyl)- 1 ,3 -oxazolidin-2-one ;

(4R,5R)-5-(2,3-dichlorophenyl)-4-(5-(phenylethynyl)-3-pyr idinyl)-l,3-oxazolidin-2-one;

(4S,5R)-5-(l-methyl-lH-pyrazol-5-yl)-4-(5-(phenylethynyl) -3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(4-fluorophenyl)-4-(5-((3-fluoro-2-pyridinyl)et hynyl)-3-pyridinyl)-4-methyl-l,3- oxazolidin-2-one;

(4R,5 S)-4-(5 -(phenylethynyl)-3 -pyridinyl)-5 -(2 -thienyl)- 1 ,3 -oxazolidin-2-one ;

(4R, 5R)-5-(4-fluorophenyl)-4-(4-((2-fluorophenyl)ethynyl)-2 -pyridinyl)- l,3-oxazolidin-2 -one;

(4R,5R)-5-(4-fluorophenyl)-4-(4-((3-fluorophenyl)ethynyl) -2 -pyridinyl)- l,3-oxazolidin-2 -one;

(4R,5R)-5-(4-fluorophenyl)-4-(4-((4-fluorophenyl)ethynyl) -2 -pyridinyl)- l,3-oxazolidin-2 -one;

(4R,5R)-5-(4-chlorophenyl)-4-(5-(phenylethynyl)-3-pyridin yl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(3-chlorophenyl)-4-(5-(phenylethynyl)-3-pyridin yl)-l,3-oxazolidin-2-one;

(4R,5 S)-5 -(2-chlorophenyl)-4-(5 -(phenylethynyl)-3 -pyridinyl)- 1 ,3 -oxazolidin-2-one ;

4-((4R,5R)-2-oxo-4-(5-(phenylethynyl)-3-pyridinyl)-l,3-ox azolidin-5-yl)benzonitrile;

(4R,5R)-5-(4-fluorophenyl)-4-(6-((3-fluoro-2 -pyridinyl)ethynyl)-2 -pyridinyl)- l,3-oxazolidin-2 -one; (4R,5R)-5-(4-fluorophenyl)-4-(6-((2-fluoro-4-pyridinyl)ethyn yl)-2-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(2 -fluoro-5-(phenylethynyl)pyridin-3-yl)-5-(2 -fluorophenyl)- l,3-oxazolidin-2 -one;

(4R,5R)-5-(2,5-difluorophenyl)-4-(5-(2-pyrazinylethynyl)- 3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(5 -((2-chlorophenyl)ethynyl)-3 -pyridinyl)-5 -(3 -fluorophenyl)- 1 ,3 -oxazolidin-2-one ;

(4R, 5 R) -5 -(3 -fluorophenyl) -4-(5-((3 -fluorophenyl)ethynyl) -3 -pyridinyl) - 1 ,3 -oxazolidin-2-one ;

(4R,5R)-5-(3-fluorophenyl)-4-(5-((3-methylphenyl)ethynyl) -3-pyridinyl)-l,3-oxazolidin-2-one;

(4R,5R)-4-(5-((3-chlorophenyl)ethynyl)-3-pyridinyl)-5-(3- fluorophenyl)-l,3-oxazolidin-2-one;

(4R,5R)-5-(2-fluorophenyl)-4-(5-(phenylethynyl)-3-pyridin yl)-l,3-oxazolidin-2-one; and

(4R,5R)-5-(2,5-difluorophenyl)-4-methyl-4-(5-(phenylethyn yl)-3-pyridinyl)-l,3-oxazolidin-2-one; or a pharmaceutically acceptable salt thereof, or a substituted variant thereof retaining glutamate modulatory activity.

[001119] In further embodiments, the glutamate modulator is (4R,5R)-5-(2,5- difluorophenyl)-4-(5-(phenylethynyl)-3-pyridinyl)-l,3-oxazol idin-2-one:

, or a pharmaceutically acceptable salt thereof, or a substituted variant thereof retaining glutamate modulatory activity.

Formula 250

[001120] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 250. Such compounds are described in WO 2012/061019, published May 10, 2012, corresponding to PCT/US2011/056981, filed October 20, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 250, this reference incorporated by reference herein controls.

[001121] In an embodiment, the glutamate modulator is a compound according to: wherein:

A is selected from the group consisting of phenyl, naphthyl and heteroaryl;

X is selected from N, O, S and C(R8), Y is selected from N, O, S and C(R8), wherein X is N and Y is O, to form a oxadiazole ring, or

X is O and Y is N, to form a oxadiazole ring, or

X is C(R8) and Y is S to form a thiazole ring, or

X is S and Y is C(R8) to form a thiazole ring, or

X is C(R8) and Y is N to form an imidazole ring, or

X is N and Y is C(R8) to form an imidazole ring, or

X is C(R8) and Y is O to form an oxazole ring, or

X is O and Y is C(R8) to form an oxazole ring, or

X is N and Y is N to form a triazole ring;

Q is selected from C and N,

V is selected from C and N,

K is — CH2— ,

Z is selected from — CH2— , — CH(CH3)— , —CHF—, — CF2— , — CH(OH)— , — O— , — S— , — S(O)— , — NH— , and — N(CH3)— , or

K is — CH(OH)— and Z is — CH(OH)— , or

K and Z taken together form — CH=CH — , or

K and Z taken together form a cyclopropyl ring;

Ria, Rib and Rlc may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) — (C=O)m — On — Cl-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,

(5) — (C=0)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,

(6) — (C=0)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,

(7) — (C=0)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13, (8) — (C=O)m — On-phenyl or — (C=O)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,

(9) — (C=O)m — On-heteroaryl, where the heteraryl is unsubstituted or substituted with one or more substituents selected from R13,

(10) — (C=0)m — NR10R11, wherein RIO and R11 are independently selected from the group consisting of:

(a) hydrogen,

(b) Cl-6alkyl, which is unsubstituted or substituted with R14,

(c) C3-6alkenyl, which is unsubstituted or substituted with R14,

(d) C3-6alkynyl, which is unsubstituted or substituted with R14,

(e) C3-6cycloalkyl which is unsubstituted or substituted with R14,

(f) phenyl, which is unsubstituted or substituted with R14, and

(g) heteroaryl, which is unsubstituted or substituted with R14,

(11) — S(O)2— NR10R11,

(12) — S(O)q — R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of RIO and R11,

(13) — CO2H,

(14) — CN, and

(15) — NO2;

R2a, R2b and R2c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) — (C=0)m — On — Cl-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,

(5) — (C=0)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,

(6) — (C=0)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,

(7) — (C=0)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13, (8) — (C=O)m — On-phenyl or — (C=O)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,

(9) — (C=O)m — On-heteroaryl, where the heteroaryl is unsubstituted or substituted with one or more substituents selected from R13,

(10) — (C=0)m— NR10R11,

(11) — S(O)2— NR10R11,

(12) — S(O)q— R12,

(13) — CO2H,

(14) — CN, and

(15) — NO2;

R8 is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) Cl-6alkyl, which is unsubstituted or substituted with R13,

(4) C3-6alkenyl, which is unsubstituted or substituted with R13,

(5) C3-6alkynyl, which is unsubstituted or substituted with R13,

(6) C3-6cycloalkyl which is unsubstituted or substituted with R13,

(7) phenyl, which is unsubstituted or substituted with R13, and

(6) heteroaryl, which is unsubstituted or substituted with R13,

R13 is selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3) — (C=0)m — On — Cl-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,

(4) — On — (Cl-3)perfluoroalkyl,

(5) — (C=0)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,

(6) — (C=0)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,

(7) — (C=0)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R14, (8) — (C=O)m — On-phenyl or — (C=O)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R14,

(9) — (C=O)m — On-heteroaryl, where the heteroaryl is unsubstituted or substituted with one or more substituents selected from R14,

(10) — (C=0)m— NR10R11,

(11) — S(O)2— NR10R11,

(12) — S(O)q— R12,

(13) — CO2H,

(14) — CN, and

(15) — NO2;

R14 is selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) Cl-6alkyl,

(4) — C3-6cycloalkyl,

(5) — O— C 1-6 alkyl,

(6) — O(C=O)— Cl-6alkyl,

(7) — NH— Cl -6 alkyl,

(8) phenyl,

(9) heteroaryl,

(10) — CO2H, and

(11) — CN; or a pharmaceutically acceptable salt thereof.

[001122] In further embodiments, the glutamate modulator is a compound according to: [001123] In further embodiments, the glutamate modulator is a compound selected from:

3 -(3 -(4-methyl- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl)- 1,3, 4, 11, 12,12a-hexahydrobenzo [e]pyrido [1,2- a]azepin-6(2H)-one; cis-(3S,12aS)-3-(3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol -5-yl)-l, 3, 4, 11,12,12a- hexahydrobenzo[e]pyrido[l,2-a]azepin-6(2H)-one; cis-(3R,12aR)3-(3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol- 5-yl)-l,3,4,ll,12,12a- hexahydrobenzo [e]pyrido [ 1 ,2-a] azepin-6(2H)-one;

9-Fluoro-3 - [3 -(4-methyl- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3 S, 12aS)-9-fluoro-3 -[3 -(4-methyl- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5-yl] -1,3,4,11,12,12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

9-fluoro-3 - [3 -(4-chloro lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3 S, 12aS)-9-fluoro-3 -[3 -(4-chloro lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -1,3, 4, 11, 12,12a- hexahydropyridof 1,2-b] [2]benzazepin-6(2H)-one;

9-fluoro-3 -(4-(5-fluoropyridin-2-yl)oxazol-2-yl)- 1 ,3 ,4, 11 , 12, 12a-hexahydrobenzo [e]pyrido [1,2- a]azepin-6(2H)-one; cis-(3 S, 12aS)-9-fluoro-3 -(4-(5 -fluoropyridin-2-yl)oxazol-2-yl)- 1,3, 4, 11, 12,12a- hexahydrobenzo [e]pyrido [ 1 ,2-a]azepin-6(2H)-one ; cis-(3R,12aR)-9-fluoro-3-(4-(5-fluoropyridin-2-yl)oxazol-2-y l)-l, 3, 4, 11,12,12a- hexahydrobenzo [e]pyrido [ 1 ,2-a]azepin-6(2H)-one ;

9-fluoro-3 -(5 -(5-fluoropyridin-2-yl)- 1 ,2,4-oxadiazol-3 -yl)- 1,3, 4, 11, 12,12a- hexahydrobenzo[e]pyrido[l,2-a]azepin-6(2H)-one; cis-(3 S, 12aS)-9-fluoro-3 -(5 -(5 -fluoropyridin-2-yl)- 1 ,2,4-oxadiazol-3 -yl)- 1,3, 4, 11, 12,12a- hexahydrobenzo[e]pyrido[l,2-a]azepin-6(2H)-one; cis-(3R, 12aR)-9-fluoro-3 -(5 -(5 -fluoropyridin-2-yl)- 1 ,2,4-oxadiazol-3 -yl)- 1,3, 4, 11, 12,12a- hexahydrobenzo [e]pyrido [ 1 ,2-a] azepin-6(2H)-one;

8-(3-(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5-yl)-3-fluoro-8,9, 10, 10a, 11 , 12- hexahydrodipyrido [ 1 ,2-a: 3 ',4'-e] azepin-5(7H)-one;

(±) trans-8-(3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5-yl)-3 -fluoro-8,9,10,10a,l l,12- hexahydrodipyrido [ 1 ,2-a: 3 ',4'-e] azepin-5 (7H)-one; cis-(8 S, 10aS)-8-(3 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -y 1) -3 -fluoro-8,9, 10, 10a, 11,12- hexahydrodipyrido [ 1 ,2-a: 3 ',4'-e]azepin-5 (7H)-one ; cis-(8R,10aR)-8-(3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol -5-yl)-3-fluoro-8,9,10,10a,l l,12- hexahydrodipyrido[l,2-a:3',4'-e]azepin-5(7H)-one;

3-fluoro-8-(3-(4-methyl- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5-yl)-8,9, 10, 1 Oa-tetrahydrodipyrido[ 1 ,2- a: 3 ',4'-e]azepin-5 (7H)-one ;

(±) cis-3-fluoro-8-(3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol- 5-yl)-8,9,10,10a- tetrahydrodipyrido [ 1 ,2-a: 3 ',4'-e] azepin-5 (7H)-one;

(±) cis-(Z)-3-[3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5-yl] -l,3,4,12a-tetrahydropyrido[l,2- b] [2]benzazepin-6(2H)-one ;

9-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5-yl]-12-o xo-5,6,6a,7,8,9,10,12-octahydropyrido[2,l- c] [ 1 ,4]benzodiazepine;

(6aS,9S)-9-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5 -yl]-12-oxo-5,6,6a,7,8,9,10,12- octahydropyrido[2, 1-c] [ l,4]benzodiazepine;

9- [3 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -y 1] -6, 6a, 7, 8,9, 10-hexahydro- 12H-pyrido [2,1- c] [ 1 ,4]benzoxazepin- 12-one;

(6aS,9S)-9-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5 -yl]-6,6a,7,8,9,10-hexahydro-12H- pyrido [2, 1 -c] [ 1 ,4]benzoxazepin- 12-one ;

(6aR,9R)-9-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5 -yl]-6,6a,7,8,9,10-hexahydro-12H- pyrido [2, 1 -c] [ 1 ,4]benzoxazepin- 12-one ;

2-chloro-8-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5 -yl]-8,9,10,10a,l l,12- hexahydrodipyrido [l,2-a:2',3'-e] azepin-5 (7H) -one ;

(8S,10aS)-2-chloro-8-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-o xadiazol-5-yl]-8,9,10,10a,l l,12- hexahydrodipyrido [ 1 ,2-a: 2 ', 3 '-e] azepin-5 (7H) -one ;

(8R,10aR)-2-chloro-8-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-o xadiazol-5-yl]-8,9,10,10a,l 1,12- hexahydrodipyrido [ 1 ,2-a: 2 ', 3 '-e] azepin-5 (7H) -one ;

8- [3 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -2-methoxy-8,9, 10, 10a, 11 , 12- hexahydrodipyrido[l,2-a:2',3'-e]azepin-5(7H)-one;

(8S,10aS)-8-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol- 5-yl]-2-methoxy-8,9,10,10a,ll,12- hexahydrodipyrido[l,2-a:2',3'-e]azepin-5(7H)-one;

8-[3-(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5-yl]-2-fluoro-8,9, 10, 10a, 11 , 12- hexahydrodipyrido[l,2-a:2',3'-e]azepin-5(7H)-one;

(8S,10aS)-8-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol- 5-yl]-2-fluoro-8,9,10,10a,l l,12- hexahydrodipyrido [ 1 ,2-a: 2', 3 '-e] azepin-5 (7H)-one;

2-fluoro-8-[3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5 -yl]-8,9,10,10a,l 1,12- hexahydrodipyrido [ 1 ,2-a: 2', 3 '-e]azepin-5 (7H)-one ;

(8S,10aS)-2-fluoro-8-[3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-o xadiazol-5-yl]-8,9,10,10a,l l,12- hexahydrodipyrido [ 1 ,2-a: 2', 3 '-e]azepin-5 (7H)-one ; 2-fluoro-8-[3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl]-8 ,9,10,10a,l l,12-hexahydrodipyrido[l,2- a: 2', 3 '-e]azepin-5 (7H)-one ;

(8S,10aS)-2-fluoro-8-[3-(5-fluoropyridin-2-yl)-l,2,4-oxad iazol-5-yl]-8,9,10,10a,l l,12- hexahydrodipyrido[l,2-a:2',3'-e]azepin-5(7H)-one;

9-fluoro-3 -[4-(pyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3,4,11,12, 12a-hexahydropyrido [ 1 ,2-b] [2]benzazepin- 6(2H)-one;

(3S,12aS)-9-fluoro-3-[4-(pyridin-2-yl)-l,3-thiazol-2-yl]- l,3,4,l 1,12, 12a-hexahydropyrido[ 1,2- b] [2]benzazepin-6(2H)-one ;

(3R, 12aS)-9-fluoro-3 - [4-(pyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

9-cyano-3- [3 -(4-chloro lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

(±) cis-9-cyano-3 -[3 -(4-chloro lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -1,3, 4, 11, 12, 12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

10-methoxy-3-[3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol -5-yl]-l,3,4,l 1,12,12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

(±) cis-10-methoxy-3-[3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazo l-5-yl]-l, 3, 4,11,12,12a- hexahydropyrido[l,2-b][2]benzazepin-6(2H)-one;

9,11,1 l-trifluoro-3-[3-(5-fluoropuridin-2-yl)-l,2-4-oxadiazol-5-yl }-l,3,4,l 1,12,12a- hexahydropyrido[l,2-b][2]benzazepin-6(2H)-one;

(±) cis-9,11,1 l-trifluoro-3-[3-(5-fluoropuridin-2-yl)-l,2-4-oxadiazol-5-yl }-l,3,4,l 1,12,12a- hexahydropyrido[l,2-b] [2]benzazepin-6(2H)-one;

9,11,1 l-trifluoro-3-[3-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5 -yl]-l,3,4,l 1,12,12a- hexahydropyrido[l,2-b] [2]benzazepin-6(2H)-one;

(±)cis-9,l 1,1 l-trifluoro-3-[3-(4-methyl-lH-pyrrol-2-yl)-l, 2, 4-oxadiazol-5-yl]-l, 3, 4,11,12,12a- hexahydropyrido[l,2-b][2]benzazepin-6(2H)-one;

9-fluoro-3 - [ 3 - (5 -fluoropyridin-2-yl)- 1 ,2-4-oxadiazol-5 -yl } - 11 , 12-dihydroxy- 1,3, 4, 11, 12,12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

(±) cis-9-fluoro-3 - [3 -(5 -fluoropyridin-2-yl)- 1 ,2-4-oxadiazol-5 -yl } - 11 , 12-dihydroxy- 1,3,4,11,12,12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

9-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5-yl]-3-fl uoro-6,6a,7,8,9,10-hexahydrodipyrido[l,2- a:4',3'-e]azepin-12(5H)-one; cis-9-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5-yl]-3-f luoro-6,6a,7,8,9,10- hexahydrodipyrido [ 1 ,2-a: 4', 3 '-e]azepin- 12(5H)-one ;

(6aS,9S)-9-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5 -yl]-3-fluoro-6,6a,7,8,9,10- hexahydrodipyrido [ 1 ,2-a: 4', 3 '-e]azepin- 12(5H)-one ; (6aR,9R)-9-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-5-yl ]-3-fluoro-6,6a,7,8,9,10- hexahydrodipyrido[l,2-a:4',3'-e]azepin-12(5H)-one;

3-fluoro-9-[5-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-3-yl ]-6,6a,7,8,9,10-hexahydrodipyrido[l,2- a: 4', 3 '-e]azepin- 12(5H)-one ; cis-3-fluoro-9-[5-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-3-y l]-6,6a,7,8,9,10-hexahydrodipyrido[l,2- a:4',3'-e]azepin-12(5H)-one;

(6aS,9S)-3-fluoro-9-[5-(5-fluoropyridin-2-yl)-l,2,4-oxadi azol-3-yl]-6,6a,7,8,9,10- hexahydrodipyrido[l,2-a:4',3'-e]azepin-12(5H)-one;

(6aR,9R)-3-fluoro-9-[5-(5-fluoropyridin-2-yl)-l,2,4-oxadi azol-3-yl]-6,6a,7,8,9,10- hexahydrodipyrido [ 1 ,2-a: 4', 3 '-e] azepin- 12(5H)-one;

9-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3-yl]-3-fl uoro-6,6a,7,8,9,10-hexahydrodipyrido[l,2- a:4',3'-e]azepin-12(5H)-one;

(6aS,9S)-9-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-3-fluoro-6,6a,7,8,9,10- hexahydrodipyrido [ 1 ,2-a: 4', 3 '-e]azepin- 12(5H)-one ;

(6aR,9R)-9-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-3-fluoro-6,6a,7,8,9,10- hexahydrodipyrido[l,2-a:4',3'-e]azepin-12(5H)-one;

9-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3-yl]-6,6a ,7,8,9,10-hexahydro-12H-pyrido[2,l- c] [ 1 ,4]benzothiazepin- 12-one ;

(6aS,9S)-9-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-6,6a,7,8,9,10-hexahydro-12H- pyrido [2, 1 -c] [ 1 ,4]benzothiazepin- 12-one;

(6aR,9R)-9-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-6,6a,7,8,9,10-hexahydro-12H- pyrido[2, 1-c] [l,4]benzothiazepin-12-one;

(6aS,9S)-9-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-6,6a,7,8,9,10-hexahydro-12H- pyrido [2, 1 -c] [ 1 ,4] benzothiazepin- 12-one 5 -oxide ;

9-[5-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3-yl]-6,6a ,7,8,9,10-hexahydro-12H-pyrido[2,l- c] [ 1 ,4]benzothiazepin- 12-one;

(6aS,9S)-9-[5-(4-methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-6,6a,7,8,9,10-hexahydro-12H- pyrido [2, 1 -c] [ 1 ,4]benzothiazepin- 12-one;

(6aR,9R)-9- [5 -(4-methyl- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -6, 6a, 7, 8, 9, 10-hexahydro- 12H- pyrido [2, 1 -c] [ 1 ,4]benzothiazepin- 12-one;

9-[5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-6,6a,7,8,9,10 -hexahydro-12H-pyrido[2,l- c] [ 1 ,4] benzothiazepin- 12-one ;

(6aS,9S)-9-[5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-6,6a ,7,8,9,10-hexahydro-12H-pyrido[2,l- c] [ 1 ,4]benzothiazepin- 12-one ;

(6aR,9R)-9-[5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-6,6a ,7,8,9,10-hexahydro-12H-pyrido[2,l- c] [ 1 ,4]benzothiazepin- 12-one ;

Ill 9-fluoro-3 -[5 -(4-iodo- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -y 1] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3 S, 12aS)-9-fluoro-3 - [5 -(4-iodo- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -1,3,4,11,12, 12a- hexahydropyrido[l,2-b] [2]benzazepin-6(2H)-one;

9-fluoro-3 -[4-(pyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

(3 S, 12aS)-9-fluoro-3 - [4-(pyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

(3R, 12aS)-9-fluoro-3- [4-(pyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

3 - {4-[4-(difluoromethoxy)phenyl] - 1 ,3 -thiazol-2-yl } -9-fluoro- 1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

(3 S, 12aS)-3 - {4-[4-(difluoromethoxy)phenyl] - 1 ,3 -thiazol-2-yl } -9-fluoro- 1,3, 4, 11, 12,12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

9-fluoro-3-[4-(thiophen-2-yl)-l,3-thiazol-2-yl]-l,3,4,l 1,12, 12a-hexahydropyrido[ 1,2- b] [2]benzazepin-6(2H)-one ;

(3S,12aS)-9-fluoro-3-[4-(thiophen-2-yl)-l,3-thiazol-2-yl] -l,3,4,ll,12,12a-hexahydropyrido[l,2- b] [2]benzazepin-6(2H)-one;

3 - [4 -( 5 -chloropyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -9-fluoro- 1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3 S, 12aS)-3 - [4 -(5 -chloropyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -9-fluoro- 1,3,4,11,12,12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

9-fluoro-3-[4-(4-fluorophenyl)-l,3-thiazol-2-yl]-l,3,4,l 1,12, 12a-hexahydropyrido[ 1,2- b] [2]benzazepin-6(2H)-one;

(3 S, 12aS)-9-fluoro-3 -[4-(4-fluorophenyl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

9-fluoro-3 - [4 - (5 -methylpyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3 S, 12aS)-9-fluoro-3 - [4-(5 -methylpyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a- hexahydropyrido[l,2-b] [2]benzazepin-6(2H)-one;

9-fluoro-3 - [4 - (5 -methylpyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

(3 S, 12aS)-9-fluoro-3 - [4-(5 -methylpyrimidin-2-yl)- 1 ,3-thiazol-2-yl] -1,3,4,11,12,12a- hexahydropyrido[l,2-b][2]benzazepin-6(2H)-one;

3-[4-(5-bromopyrimidin-2-yl)-l,3-thiazol-2-yl]-9-fluoro-l ,3,4,l l,12,12a-hexahydropyrido[l,2- b] [2]benzazepin-6(2H)-one ; (3 S, 12aS)-3 - [4 -( 5 -bromopyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -9-fluoro- 1,3, 4, 11, 12,12a- hexahydropyrido[l,2-b] [2]benzazepin-6(2H)-one;

9-fluoro-3 - [4 - (5 -fluoropyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3,4,11,12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3 S, 12aS)-9-fluoro-3 - [4-(5 -fluoropyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a- hexahydropyrido[l,2-b] [2]benzazepin-6(2H)-one;

9-chloro-3 -[4-(pyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3,4,11,12,12a-hexahydropyrido [ 1 ,2-b] [2]benzazepin- 6(2H)-one;

(3 S, 12aS)-9-chloro-3 - [4-(pyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11,12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

9-chloro-3 -[4-(pyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

(3 S, 12aS)-9-chloro-3 - [4-(pyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

3-[4-(5-bromopyridin-2-yl)-l,3-thiazol-2-yl]-9-fluoro-l,3 ,4,l l,12,12a-hexahydropyrido[l,2- b] [2]benzazepin-6(2H)-one ;

(3 S, 12aS)-3 - [4- (5 -bromopyridin-2-yl)- 1 ,3 -thiazol-2-yl] -9-fluoro- 1,3, 4, 11, 12,12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

9-fluoro-3-[4-(4-methoxyphenyl)-l,3-thiazol-2-yl]-l,3,4,l 1,12, 12a-hexahydropyrido[ 1,2- b] [2]benzazepin-6(2H)-one;

(3S,12aS)-9-fluoro-3-[4-(4-methoxyphenyl)-l,3-thiazol-2-y l]-l,3,4,l l,12,12a-hexahydropyrido[l,2- b] [2]benzazepin-6(2H)-one;

9-fluoro-3 - [4-(thiophen-3 -yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3S,12aS)-9-fluoro-3-[4-(thiophen-3-yl)-l,3-thiazol-2-yl] -l,3,4,l l,12,12a-hexahydropyrido[l,2- b] [2]benzazepin-6(2H)-one;

9-fluoro-3 - [4 - (5 -fluoropyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3,4,11,12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3R, 12aS)-9-fluoro-3 - [4-(5 -fluoropyridin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a- hexahydropyrido[l,2-b] [2]benzazepin-6(2H)-one;

3- [4-(5 -bromopyridin-2-yl)- 1 ,3 -thiazol-2-yl] -9-fluoro- 1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

(3R,12aS)-3-[4-(5-bromopyridin-2-yl)-l,3-thiazol-2-yl]-9- fluoro-l,3,4,l l,12,12a- hexahydropyrido[l,2-b][2]benzazepin-6(2H)-one;

3-[4-(5-bromopyrimidin-2-yl)-l,3-thiazol-2-yl]-9-fluoro-l ,3,4,l l,12,12a-hexahydropyrido[l,2- b] [2]benzazepin-6(2H)-one ; (3 S, 12aS)-3 - [4 -( 5 -bromopyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -9-fluoro- 1,3, 4, 11, 12,12a- hexahydropyrido[l,2-b] [2]benzazepin-6(2H)-one;

9-fluoro-3 -[4-( lH-pyrrol-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one;

(3S,12aS)-9-fluoro-3-[4-(lH-pyrrol-2-yl)-l,3-thiazol-2-yl ]-l,3,4,l l,12,12a-hexahydropyrido[l,2- b] [2]benzazepin-6(2H)-one ;

9-fluoro-3 -[4-(pyrazin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3,4,11,12,12a-hexahydropyrido [ 1 ,2-b] [2]benzazepin- 6(2H)-one;

(3 S, 12aS)-9-fluoro-3 - [4-(pyrazin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11,12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

9-fluoro-3 - [4- (5 -fluoropyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b] [2]benzazepin-6(2H)-one ;

(3 S, 12aS)-9-fluoro-3 - [4-(5 -fluoropyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3,4,11,12,12a- hexahydropyrido [ 1 ,2-b] [2]benzazepin-6(2H)-one ;

9-fluoro-3 - [4 -(5 -fluoropyrimidin-2-yl)- 1 ,3 -thiazol-2-yl] -1,3, 4, 11, 12,12a-hexahydropyrido [1,2- b][2]benzazepin-6(2H)-one; and (3R,12aS)-9-fluoro-3-[4-(5-fluoropyrimidin-2-yl)-l,3-thiazol -2-yl]-l,3,4,l l,12,12a- hexahydropyrido[l,2-b][2]benzazepin-6(2H)-one, including pharmaceutically acceptable salts thereof and substituted variants thereof retaining glutamate modulatory activity.

Formula 251

[001124] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 251. Such compounds are described in, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 251, this reference incorporated by reference herein controls.

[001125] In an embodiment, the glutamate modulator is a compound according to Formula 251 :

,R1 represents aryl, heteroaryl, cycloC3-12alkyl, cycloC5-12alkenyl, or heterocyclyl; R2 represents hydrogen, fluorine, or Cl-6alkyl;

R3 represents hydrogen, fluorine, or Cl-6alkyl; or R2 and R3 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl- 6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl-6alkyl)amino, Cl- 6alkylcarbonylamino, and oxo;

W represents

Y represents CR-12R-R13, or NR14;

R4 represents hydrogen, fluorine, or Cl-6alkyl;

R5 represents hydrogen, fluorine, or Cl-6alkyl; or R4 and R5 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl- 6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl-6alkyl)amino, Cl- 6alkylcarbonylamino, and oxo;

R6 represents hydrogen, fluorine, or Cl-6alkyl;

R7 represents hydrogen, fluorine, or Cl-6alkyl; or R6 and R7 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl- 6alkoxy, amino, hydroxy, cyano, acyl, C-l-6alkylamino, di-(C-l-6alkyl)amino, Cl- 6alkylcarbonylamino, and oxo;

R8 represents hydrogen, Cl-6alkyl, or acyl;

R9 represents hydrogen, fluorine, or Cl-6alkyl;

RIO represents hydrogen, fluorine, or Cl-6alkyl; or R9 and RIO together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl- 6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl-6alkyl)amino, Cl- 6alkylcarbonylamino, and oxo;

R11 represents hydrogen, Cl-6alkyl, or acyl;

R12 represents hydrogen, fluorine, Cl-6alkyl, amino, Cl-6alkylamino, di-(C 1 - 6alkyl)amino, acylamino, or heterocyclyl;

R13 represents hydrogen, fluorine, or Cl-6alky; or R12 and R13 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, Cl- 6alkoxy, amino, hydroxy, cyano, acyl, Cl-6alkylamino, di-(Cl-6alkyl)amino, Cl- 6alkylcarbonylamino, and oxo; and

R14 represents hydrogen, Cl-6alkyl, aryl, or heteroaryl; wherein the term "aryl" optionally means phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, hydroxyCl-6alkyl, C2-6alkenyl, Cl-6alkoxy, Cl-6alkoxyCl-6alkyl, amino, hydroxy, nitro, cyano, formyl, Cl-6alkylcarbonyl, Cl-6alkoxy carbonyl, Cl-6alkylcarbonyloxy, Cl- 6alkylcarbonyloxyCl-6alkyl, C-l-6alkylamino, di-(Cl-6alkyl)amino, cycloC3-12alkylamino, Cl-6alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N-Cl-6alkylaminocarbonyl, di-N,N-Cl-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloC3-12alkyl, pyridinyl, and Cl-6alkylenedioxy; the term "heteroaryl" means an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, hydroxyCl- 6alkyl, C2-6alkenyl, Cl-6alkoxy, amino, hydroxy, nitro, cyano, Cl-6alkylcarbonyl, Cl- 6alkoxy carbonyl, Cl-6alkoxy carbonyloxy, Cl-6alkylamino, and di-(Cl-6alkyl)amino, cycloC3-12alkylamino, Cl-6alkylcarbonylamino, aminocarbonyl, N-C-l- 6alkylaminocarbonyl, di-N,N-Cl-6alkyl- aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC3-12alkyl, Cl-6alkylenedioxy, aryl, and pyridinyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. [001126] In further embodiments, the glutamate modulator is a compound selected from:

W~(34(7 , 7-D sm ethyl-5'Oxcs-5 , 67.8-tetrahydraqujnolm-3- yl)ethynyi}phenyl)acetarnide, 3-47 _[ 7-’DifnethyF5-oxo--5,6.7.8-tetfahydtoquiRo:iin-3-yl) ethyo _: yi}-4-fliJdrobe!iEOf’i:trile _: 34(5-Ahiino-24iuorophenyl}athynyih7.7-dtmethyl-7.8-dthydroqu inoiin-5(8h"pc'na. 34(34tydroxy-S-methy^henyl}®Hiyn^}-7,7-dsinethyl-7,8-dthydr aquin^in-5(8H}- one, one,

7.7-Bimethyt-3’{(67p>peddh7 ’yl)pyf1din7’yHeihynyl)7.8--dJhydraquiriol!n--5(6/yj-- one.

7 _; 7-Dimelhyi-3-{pyddsn-35!ethynyl)-7,8-s!ihydraqMsnobo-5 '6H)-ofiS;

3-((5-Flijas-Gpy'r!din-3-ypsthynyl)-7,7-dSnisthyP7 B-<jihydraqui!‘TOiir>5(@A'yonfi _t

M(77-DimetbyF5^x<?-5 _f 6,7 _; 8-teirahydroquino!in"3"yi)ethjflT:yt)nic0ttn0nitrite ₁

7,7-Djmethy!-3-{pyrjdjn'4'yiethynyf)7,8’dinydraquinojin -5(6M}<sn& _;

3--((2-FiLK3rap^hdsn-4-yt)ethyrsy])-7,7--d!!nethyi--7,8-d ihydraquin<iNn--5(8A ^, )-one _i

774)imetiiyi-3-{(2-^eth^jyridin-4-yl)ethyn^)’7,8-dihydK X?^T<^in’5(6H}-we,

4’((7,7“Dimethy^5-ox&-5 ₎ S.7 ₇ 8'tetr8hydraquinaiin"3"yl)ethynyt3pjcot!rionitrite.

3qX2Afetho:<ypyndtn^-yl)®thynyO'72?“dii’r3®-thyi -?/‘ _; 8-dihyd!'oquir>Gtjfv5{6H)<<ns.

3Ai2-Af?iinopyr!dsn-4-yJ)ethynyl)-7 _! 7-d!fnsthyi-7 _; a-dihydraqusno|jn-5f6Mj-one,

7j-Dipiethyi^(24ni®thyiarnino)pyridin-4-yl)ethynyt)*7,8- cfihydroqumlin-5{6^- one,

S-((2-Amtnopynrnidin-4-yl)ethyny!)-7.7-d!methyt-7,8-dihyd roquinoiin-5t8W><3ne. yj-Dirnethyi-^-^S'fmethyiarrithoJpyritriidin^-ylJethynytj^^i hycIr&qutmlin-SfSH}- one.

, optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, polymorphs thereof, including substituted variants retaining glutamate modulatory activity. Formula 252 [001127] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 252. Such compounds are described in WO 2010/124055, published October 28, 2010, corresponding to PCT/US2010/032001, filed April 22, 2010 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 252, this reference incorporated by reference herein controls.

[001128] In an embodiment, the glutamate modulator is a compound according to

Formula 252: , wherein:

Al is selected from the group consisting of phenyl, naphthyl and heteroaryl;

A2 is selected from the group consisting of phenyl, naphthyl and heteroaryl;

X is selected from N, O and C(R13),

Y is selected from N and O, wherein X is N and Y is O, to form a oxadiazole ring, or X is O and Y is N, to form a oxadiazole ring, or X is C(R13) and Y is O to form an oxazole ring;

Ria, Rib and Rlc may be absent if the valency of Al does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) — (C=0)m — On — Cl-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,

(5) — (C=0)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,

(6) — (C=0)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,

(7) — (C=0)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,

(8) — (C=0)m — On-phenyl or — (C=0)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,

(9) — (C=0)m — On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,

(10) — (C=0)m — NR10R11, wherein RIO and R11 are independently selected from the group consisting of: (a) hydrogen,

(b) Cl-6alkyl, which is unsubstituted or substituted with R13,

(c) C3-6alkenyl, which is unsubstituted or substituted with R13,

(d) C3-6alkynyl, which is unsubstituted or substituted with R13,

(e) C3-6cycloalkyl which is unsubstituted or substituted with R13,

(f) phenyl, which is unsubstituted or substituted with R13, and

(g) heterocycle, which is unsubstituted or substituted with R13,

(11) — S(O)2— NR10R11,

(12) — S(O)q — R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of RIO and R11,

(13) — CO2H,

(14) — CN, and

(15) — NO2;

R2a, R2b and R2c may be absent if the valency of A2 does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) — (C=0)m — On — Cl-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,

(5) — (C=0)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,

(6) — (C=0)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,

(7) — (C=0)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,

(8) — (C=0)m — On-phenyl or — (C=0)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,

(9) — (C=0)m — On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,

(10) — (C=0)m— NR10R11,

(11) — S(O)2— NR10R11,

(12) — S(O)q— R12, (13) — CO2H,

(14) — CN, and

(15) — NO2;

R3 is Cl-6alkyl;

R13 is selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3) — (C=0)m — On — Cl-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,

(4) — On — (Cl-3)perfluoroalkyl,

(5) — (C=0)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,

(6) — (C=0)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,

(7) — (C=0)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R14,

(8) — (C=0)m — On-phenyl or — (C=0)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R14,

(9) — (C=0)m — On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R14,

(10) — (C=0)m— NR10R11,

(11) — S(O)2— NR10R11,

(12) — S(O)q— R12,

(13) — CO2H,

(14) — CN, and

(15) — NO2;

R14 is selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) Cl-6alkyl,

(4) — C3-6cycloalkyl,

(5) — O— Cl-6alkyl,

(6) — O(C=O)— Cl-6alkyl, (7) — NH— Cl-6alkyl,

(8) phenyl,

(9) heterocycle,

(10) — CO2H, and

(11) — CN; or a pharmaceutically acceptable salt thereof.

[001129] In further embodiments, the glutamate modulator is a compound selected from:

(2S,5R)-l-(4-fluorobenzoyl)-5-[5-(4-fluorophenyl)-l, 2, 4-oxadiazol-3-yl]-2 -methylpiperidine;

(2R,5S)- l-(4-fluorobenzoyl)-5-[5-(4-fluorophenyl)-l, 2, 4-oxadiazol-3-yl]-2 -methylpiperidine;

(2S,5R)-5-[5-(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3-yl] - 1 -(4-fluorobenzoyl)-2- methylpiperidine ;

(2R,5 S) -5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] - 1 -(4-fluorobenzoyl)-2- methylpiperidine ;

5-fluoro-2-{3-[(3S,6R)-l-(4-fluorobenzoyl)-6-methylpiperi din-3-yl]-l,2,4-oxadiazol-5-yl}pyridine;

(2R,5 S ) -5 -[3 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] - 1 -(4-fluorobenzoyl)-2- methylpiperidine ;

2,4'-bipyridin-4-yl{(2R,5S)-5-[5-(4-chloro-lH-pyrrol-2-yl )-l,2,4-oxadiazol-3-yl]-2-methylpiperidin- 1-yl} methanone;

2,2'-bipyridin-4-yl{(2R,5S)-5-[5-(4-chloro-lH-pyrrol-2-yl )-l,2,4-oxadiazol-3-yl]-2-methylpiperidin- 1-yl} methanone;

(4-fluorophenyl){(2R,5S)-5-[4-(4-fluorophenyl)-l,3-oxazol -2-yl]-2-methylpiperidin-l-yl}methanone;

(4-fluorophenyl) { (2R,5 S)-5 - [4 -(5 -fluoropyridin-2-yl)- 1 ,3 -oxazol-2-yl] -2-methylpiperidin- 1 - yl} methanone;

(2R,5S)-l-(3-chlorobenzoyl)-5-[5-(4-fluorophenyl)-l, 2, 4-oxadiazol-3-yl]-2 -methylpiperidine;

4-({(2R,5S)-5-[5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-2 -methylpiperidin-l-yl}carbonyl)-2- methoxypyridine ;

(2R,5 S)-5-[5-(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3-yl] - 1 -(4-fluorobenzoyl)-2- methylpiperidine ;

(2R, 5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] - 1 -(4-fluorobenzoyl)-2- methylpiperidine ;

(2R,5S)-l-(4-fluorobenzoyl)-2-methyl-5-[5-(4-methyl-lH-py rrol-2-yl)-l,2,4-oxadiazol-3- yl]piperidine;

(2S,5R)-l-(4-fluorobenzoyl)-2-methyl-5-[5-(4-methyl-lH-py rrol-2-yl)-l,2,4-oxadiazol-3- yl]piperidine; 4-({(2R,5S)-5-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-2-methylpiperidin-l-yl}carbonyl)-

2-fluoropyridine;

4-({(2R,5S)-5-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazo l-3-yl]-2-methylpiperidin-l-yl}carbonyl)-

2-methoxypyridine;

5 -( { (2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -y 1] -2-methylpiperidin- 1 -yl } carbonyl)- 2-fluoropyridine;

2-fluoro-5-({(2R,5S)-2-methyl-5-[5-(4-methyl-lH-pyrrol-2- yl)-l,2,4-oxadiazol-3-yl]piperidin-l- yl } carbonyl)pyridine ;

4-({(2R,5S)-5-[5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl]-2 -methylpiperidin-l-yl}carbonyl)-2,3- dimethoxypyridine ;

4-( {(2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } carbonyl)-

5-fluoro-2-methoxypyridine;

4-({(2R,5S)-5-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazo l-3-yl]-2-methylpiperidin-l-yl}carbonyl)-

3-fluoro-2 -methoxypyridine;

2- { 3- [(3 ,6-cis)- 1 -(4-fluorobenzoyl)-6-methylpiperidin-3 -yl] - 1 ,2,4-oxadiazol-5 -yl} -5-methylpyridine ;

2- { 3 -[(3 ,6-cis)- 1 -(3 -chlorobenzoyl)-6-methylpiperidin-3 -yl] - 1 ,2,4-oxadiazol-5 -yl} -6-methylpyridine;

2- { 3 -[(3 ,6-cis)- 1 -(3 -chlorobenzoyl)-6-methylpiperidin-3 -yl] - 1 ,2,4-oxadiazol-5 -yl } -6-fluoropyridine ; (2R,5S)- l-(4-fluorobenzoyl)-5-[3-(4-fluorophenyl)-l, 2, 4-oxadiazol-5-yl]-2 -methylpiperidine;

5-({(2R,5S)-5-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazo l-5-yl]-2-methylpiperidin-l-yl}carbonyl)- 2-fluoropyridine

4-( { (2R,5 S)-5 -[3 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -2-methylpiperidin- 1 -yl } carbonyl)- 2-fluoropyridine;

(2R,5 S)- 1 -(3 -chlorobenzoyl)-5 - [3 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -2- methylpiperidine ;

(2R,5 S)-5 -[3-(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] - 1 -(3 ,4-difluorobenzoyl)-2- methylpiperidine ;

4-( { (2R,5 S)-5 -[3 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -2-methylpiperidin- 1 -yl } carbonyl)-

2-methoxypyridine;

4-({(2R,5S)-5-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazo l-5-yl]-2-methylpiperidin-l-yl}carbonyl)-

5-fluoro-2 -methoxypyridine;

4-({(2R,5S)-5-[3-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazo l-5-yl]-2-methylpiperidin-l-yl}carbonyl)-

3-fluoro-2 -methoxypyridine;

2- { 5 - [(3 S,6R)- 1 -(4-fluorobenzoyl)-6-methylpiperidin-3-yl]- 1 ,2,4-oxadiazol-3-yl}pyridine;

5-fluoro-2-{5-[(3S,6R)-l-(4-fluorobenzoyl)-6-methylpiperi din-3-yl]-l,2,4-oxadiazol-3-yl}pyridine;

4-( { (2R,5 S)-5 - [5 -(4-chloro- IH-pyrrol -2 -yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 - yl } carbonyl)benzonitrile ; 3-({(2R,5S)-5-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-2-methylpiperidin-l- yl } carbonyl)benzonitrile ;

{(2R,5S)-5-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-2-methylpiperidin-l-yl}(4-methyl-l,3- thiazol-5 -yl)methanone ;

4-( { (2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -y 1] -2-methylpiperidin- 1 - yl } carbonyl)pyridine-2 -carbonitrile ;

{ (2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } [2-(pyrazin-2- yl)pyridin-4-yl] methanone ;

2,3 '-bipyridin-4-yl { (2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3-yl] -2-methylpiperidin- l-yl( methanone;

{ (2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl} [2-( 1H- pyrazol-4-yl)pyridin-4-yl]methanone;

{ (2R,5 S)-5 - [5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } [2-( 1 -methyl - lH-pyrazol-4-yl)pyridin-4-yl]methanone;

(3,5-difluoro-2-methoxypyridin-4-yl){(2R,5S)-2-methyl-5-[ 5-(4-methyl-lH-pyrrol-2-yl)-l,2,4- oxadiazol-3 -yl]piperidin- 1 -yl (methanone ;

(5-fluoro-2-methoxypyridin-4-yl){(2R,5S)-2-methyl-5-[5-(4 -methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol-

3 -yl] piperidin- 1 -yl } methanone ;

(3-fluoro-2-methoxypyridin-4-yl){(2R,5S)-2-methyl-5-[5-(4 -methyl-lH-pyrrol-2-yl)-l,2,4-oxadiazol-

3 -yl] piperidin- 1 -yl } methanone ;

(4-fluoro-3-methoxyphenyl){(2R,5S)-2-methyl-5-[5-(4-methy l-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3- yl] piperidin- 1 -yl } methanone ;

(4-fluorophenyl) { (2R,5 S)-5 -[3 -(4-fluoro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5 -yl] -2-methylpiperidin- 1 - yl (methanone;

{ (2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } (4-fluoro-2- methoxyphenyl)methanone ;

{(2R,5S)-5-[5-(4-chloro-lH-pyrrol-2-yl)-l,2,4-oxadiazol-3 -yl]-2-methylpiperidin-l-yl}(2-methoxy-4- methylphenyl)methanone ;

(3 -chloro-4-fluorophenyl) { (2R,5 S)-5 -[5 -(5 -fluoropyridin-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2- methylpiperidin- 1 -yl } methanone ;

(5-fluoro-2-methoxypyridin-4-yl) { (2R,5 S)-5 - [5 -(5 -fluoropyridin-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2- methylpiperidin- 1 -yl} methanone;

{ (2R,5 S)-5- [5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } (2,3 - dimethoxyphenyl)methanone ;

(2,4-difluorophenyl) { (2R,5 S)-5 -[5 -(5 -fluoropyridin-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 - yl} methanone; { (2R,5 S)-5- [5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } (2- ethoxyphenyl)methanone ;

{ (2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } [2- (trifluoromethoxy)phenyl]methanone;

{ (2R,5 S)-5 -[5 -(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } (4- fluorophenyl)methanone ;

{ (2R,5 S)-5 -[5 -(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 -yl } (2- methoxypyridin-3 -yl)methanone ;

(5 -chloro-2-methoxyphenyl) { (2R,5 S)-5 - [5 -(4-chloro- IH-pyrrol -2 -yl)- 1 ,2,4-oxadiazol-3 -yl] -2- methylpiperidin- 1 -yl } methanone ;

{(2R,5S)-5-[5-(2,5-difluorophenyl)-l,2,4-oxadiazol-3-yl]- 2-methylpiperidin-l-yl}(4- fluorophenyl)methanone ;

(4-fluorophenyl) { (2R,5 S)-5 -[5 -(2-hydroxyphenyl)- 1 ,2,4-oxadiazol-3 -yl] -2-methylpiperidin- 1 - yl} methanone;

(4-chloro- lH-pyrrol-2-yl) {(2R,5 S)-5-[3-(4-chloro- lH-pyrrol-2-yl)- 1 ,2,4-oxadiazol-5-yl] -2- methylpiperidin-l-yl}methanone; and

(4-fluorophenyl) {(2R,5S)-2-methyl-5-[5-(4-methyl-lH-imidazol-2-yl)-l, 2, 4-oxadiazol-3-yl]piperidin- 1-yl} methanone; or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate modulatory activity.

Formula 253

[001130] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 253. Such compounds are described in WO 2011/087758, published July 21, 2011, corresponding to PCT/US2010/061288, filed December 20, 2010 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 253, this reference incorporated by reference herein controls.

[001131] In an embodiment, the glutamate modulator is a compound according to Formula 253: wherein: R1 and R2 are each independently aryl, heteroaryl, alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, acyl, alkoxy, which is optionally mono-, di-, or tri- substituted independently with alkyl, halogen, hydroxy, cyano, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy; and

L is -CO-N(X)-, -NH-C(0)-N(Y)-, -(W)N-C(O)O-, -OC(O)N(Z)-, -NHS02-, -NH-, -heteroaryl or a bond; wherein:

X is hydrogen, or a bond that is linked to R2 and taken together with the N to which it is attached forms a heterocycle;

Y is hydrogen or a bond that is linked to R2 and taken together with the N to which it is attached forms a heterocycle;

W is hydrogen or a bond that is linked to R2 and taken together with the N to which it is attached forms a heterocycle; and

Z is hydrogen or a bond that is linked to R2 and taken together with the N to which it is attached forms a heterocycle; or a pharmaceutically acceptable salt thereof.

[001132] In further embodiments, the glutamate modulator is a compound selected from:

6-Methyl-pyridine-2 -carboxylic acid [3-(2-hydroxyphenylcarbamoyl)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2 -carboxylic acid (3-isopropylcarbamoyl-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid [3 -(2-oxo-propylcarbamoyl)-adamantan- 1 -yl]- amide;

6-Methyl-pyridine-2-carboxylic acid (3-methylcarbamoyl-adamantan- 1 -yl)-amide;

6-Methyl-pyridine-2-carboxylic acid (3-carbamoyl-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(2 -hydroxy -2 -phenyl -ethylcarbamoyl)- adamantan- 1 -yl] - amide;

Pyridine-2 -carboxy ic acid 3-(3-cyano-phenylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(3-chloro-phenylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(6-methyl-pyridin-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(2-hydroxy-ethylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid (3-cyclohexylcarbamoyl-adamantan-l-yl)-amide;

Pyridine-2 -carboxy ic acid 3 -(3 -hydroxy-azetidine- 1 -carbonyl)-adamantan- 1 -yl] -amide;

Pyridine-2 -carboxy ic acid 3-(pyridin-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(benzothiazol-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(4-methyl-thiazol-2-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(lH-benzimidazol-2-ylcarbamoyl)-adamantan-l-yl]-amide; Pyridine-2 -carboxy ic acid 3-( 1 -methyl- lH-benzimidazol-2-ylcarbamoyl)-adamantan- 1 - yl] - amide;

Pyridine-2 -carboxy ic acid 3-(quinolin-3-ylcarbamoyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxy ic acid 3-(4,5-dimethyl-thiazol-2-ylcarbamoyl)-adamantan-l-yl]- amide;

Pyridine-2 -carboxy ic acid 3-(2-hydroxy-2-methyl-propylcarbamoyl)-adamantan-l-yl]- amide;

Pyridine-2 -carboxy ic acid 3-(3,3-difluoro-cyclobutylcarbamoyl)-adamantan-l-yl]- amide; 3 -(3 - Chloro-benzoylamino)-adamantane- 1 -carboxylic acid (3 -chloro-phenyl)-amide;

3 -(3 -Chloro-benzoylamino)-adamantane-l -carboxylic acid pyridin-2-ylamide;

3 -(3 -Chloro-benzoylamino) -adamantane- 1 -carboxylic acid (6-methyl-pyridin-2-yl)- amide; 6-Methyl-pyridine-2-carboxylic acid (3-dimethylcarbamoyl-adamantan- 1 -yl)-amide;

6-Methyl-pyridine-2 -carboxylic acid [3-((R)-3-fluoro-pyrrolidine-l-carbonyl)- adamantan-l-yl]- amide;

Pyridine-2 -carboxylic acid [3 -((R)-fluoro-pyrrolidine- 1 -carbonyl) -adamantan- 1 -yl] - amide; 6-Methyl-pyridine-2-carboxylic acid [3 -(4-hydroxy-piperidine- 1 -carbonyl) -adamantan- 1 - yl] - amide;

6-Methyl-pyridine-2-carboxylic acid [3-(morpholine-4-carbonyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(morpholine-4-carbonyl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(piperidine-l-carbonyl)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3 -(pyrrolidine- l-carbonyl)-adamantan-l-yl] -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3 -(3 -propyl -ureido)-adamantan- 1 -yl] -amide;

6-Methyl-pyrazine-2-carboxylic acid [3-(3-propyl-ureido)-adamantan-l-yl]-amide;

6-(3- {3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-ur eido)-hexanoic acid ethyl ester; 6-Methyl -pyridine-2 -carboxylic acid [3-(3-ethyl-ureido)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3-propyl-ureido)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3-butyl-ureido)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(3-phenyl-ureido)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(3-propyl-ureido)-adamantan- 1 -yl] -amide;

Pyridine-2 -carboxylic acid [3-(3-cyclopropyl-ureido)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3 -(3 -butyl -ureido)-adamantan- 1 -yl] -amide;

Morpholine-4-carboxylic acid {3-[(pyridine-2-carbonyl)-amino]-adamantan-l-yl} -amide; Pyridine-2 - carboxylic acid { 3 - [(piperidine-l-carbonyl)-amino] -adamantan-l-yl } -amide;

Pyridine-2-carboxylic acid {3-[(pyrrolidine-l-carbonyl)-amino]-adamantan-l-yl} -amide;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 2-(2- hydroxy-ethoxy)- ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 3,3,3- trifluoro-propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 3-fluoro- propyl ester; {3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl}-ca rbamic acid 4,4,4- trifluoro-butyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 2,2,2- trifluoro-ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 2-(2- methoxy-ethoxy) - ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 3-morpholin- 4-yl-propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid cyclopropylmethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 2,2-difluoro- propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 2 -hydroxy - ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 3-chloro- propyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 2-methoxy- ethyl ester;

{3-[(6-Methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid hexyl ester;

{3-[(Pyridine-2-carbonyl)-amino]-adamantan-l-yl} -carbamic acid 2,2,2-trifluoro-ethyl ester; 6- Methyl-pyridine-2 -carboxylic acid [3-(2-oxo-[l,3]oxazinan-3-yl)-adamantan-l-yl]- amide;

Pyridine-2 -carboxylic acid (3-benzenesulfonylaminoadamantan-l-yl)-amide;

Ethyl-carbamic acid 3-[(pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

6-Methyl-pyridine-2 -carboxylic acid[3-(pyridin-2-ylamino)-adamantan-l-yl]-amide;

Pyridine -2 -carboxylic acid { 3 - [(pyridin-2-ylmethyl) -amino] -adamantan-l-yl } -amide ;

Pyridine-2 -carboxylic acid (3 -benzylamino-adamantan- 1 -yl)-amide;

Pyridine-2 -carboxylic acid [3-(5-chloro-lH-benzimidazol-2-yl)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid (3-benzoxazol-2-yl-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(lH-benzimidazol-2-yl)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(6-fluoro-lH-benzimidazol-2-yl)-adamantan-l- yl] -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(lH-imidazo[4,5-b]pyridin-2-yl)-adamantan-l- yl] -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3H-imidazo[4,5-c]pyridin-2-yl)-adamantan- 1 - yl] -amide;

6-Methyl-pyridine-2-carboxylic acid [3-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)- adamantan-l-yl] - amide;

6-Methyl-pyridine-2 -carboxylic acid [3-(4-methyl-lH-imidazol-2-yl)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2 -carboxylic acid [3-(l,3-dihydro-isoindol-2-yl)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2 -carboxylic acid [3-(3-oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)- adamantan-l- yl] -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3 -(3 -oxo- 1 ,3 -dihydro-pyrrolo [3 ,4-c]pyridin-2- yl)- adamantan-l-yl] -amide; 5-Fluoro-pyridine-2 -carboxylic acid [3-(3-oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)- adamantan-1- yl] -amide; 4-Methyl-pyrimidine-2 -carboxylic acid [3 -(3 -oxo- 1 ,3 -dihydro-pyrrolo [3 ,4-c]pyridin- 2- yl)-adamantan- 1 -yl] -amide;

4- Fluoro-pyridine-2-carboxylic acid [3-(3-oxo-l,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)- adamantan- 1 -yl] -amide;

N-[3 -(3 -Oxo-1, 3 -dihydro-pyrrolo [3 ,4-c]pyridin-2-yl)-adamantan-l-yl] -nicotinamide;

5- Fluoro-pyridine-2 -carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)- adamantan- 1 -yl] -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6- yl)- adamantan- 1 -yl] -amide;

N-[3-(5-Oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-adama ntan-l-yl]-nicotinamide;

Isoxazole -5 -carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)- adamantan-l-yl] - amide;

Thiazole-2-carboxylic acid [3 -(5 -oxo-5 ,7-dihydro-pyrrolo [3 ,4-b]pyridin-6-yl)-adamantan-

1- yl] -amide;

2- Methyl-thiazole-4-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)- adamantan-l- yl] -amide;

6- Methyl-pyridine-2-carboxylic acid [3-(5-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)- adamantan-

1-yl] -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3-(7-oxo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6- yl)- adamantan- 1 -yl] -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3-(2-methyl-5-oxo-5,7-dihydro-pyrrolo[3,4- b]pyridin-6-yl)- adamantan- 1 -yl] -amide;

6-Methyl-pyridine-2 -carboxylic acid [3-(2-methyl-5-oxo-5,7-dihydro-pyrrolo[3,4- b]pyridin-6-yl)- adamantan- 1 -yl] -amide;

5 -Fluoro-pyridine-2 -carboxylic acid [3-(2-methyl-5-oxo-5,7-dihydro-pyrrolo[3,4- b]pyridin-6-yl)- adamantan- 1 -yl] -amide;

Pyridine-2 -carboxylic acid [3-(l-oxo-l,3-dihydro-isoindol-2-yl)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-yl)- adamantan-l-yl] - amide; 6-Methyl-pyridine-2-carboxylic acid [3 -(5 -phenyl- [1,3,4] oxadiazol-2-y l)-adamantan-l- yl] - amide;

6-Methyl-pyridine-2-carboxylic acid { 3 - [5 -(4-methoxy -phenyl)- [ 1 ,3 ,4]oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid { 3 - [5 -(3 -methoxy -phenyl)- [ 1 ,3 ,4]oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid {3 - [5 -(3 -chloro-phenyl)- [ 1 ,3 ,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide; 6-Methyl-pyridine-2 -carboxylic acid {3 - [5 -(4-chloro-phenyl)- [ 1 ,3 ,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2 -carboxylic acid { 3 - [5 -(4-fluoro-phenyl)-[ 1 ,3 ,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2 -carboxylic acid { 3 - [5 -(3 -fluoro-phenyl)-[ 1 ,3 ,4] oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2 -carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]- amide;

6-Methyl-pyridine-2 -carboxylic acid [3-(5-pyridin-4-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid [3 -(5 -pyridin-3 -yl- [ 1 ,3 ,4]oxadiazol-2-yl)- adamantan-l-yl]- amide;

6-Methyl-pyrazine-2-carboxylic acid [3-(5-pyridin-3-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]- amide;

6-Methyl-pyrazine-2-carboxylic acid [3-(5-pyridin-4-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]- amide;

6-Methyl-pyrazine-2-carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2-yl)- adamantan-l-yl]- amide;

Pyridine-2-carboxylic acid [3-(5-pyridin-3-yl-[l,3,4]oxadiazol-2-yl)-adamantan-l-yl]- amide;

Pyridine-2-carboxylic acid [3-(5-pyridin-2-yl-[l,3,4]oxadiazol-2-yl)-adamantan-l-yl]- amide;

Pyrazine-2-carboxylic acid [3-(5-pyridin-3-yl-[l,3,4]oxadiazol-2-yl)-adamantan-l-yl]- amide;

2-Methyl-pyrimidine-4-carboxylic acid [3 -(5 -pyridin-3 -yl- [1,3,4] oxadiazol-2-yl)- adamantan- 1 - yl] -amide;

Pyridine-2-carboxylic acid {3 - [5 -(6-methyl -pyridin-3 -yl)- [ 1,3,4] oxadiazol-2-yl] - adamantan- 1 - yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] - adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] - adamantan- 1 -yl} - amide;

6-Methyl-pyrazine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] - adamantan- 1 -yl} -amide;

Pyridine-2-carboxylic acid {3 - [5-(5-methyl-pyridin-3 -yl)- [ 1,3,4] oxadiazol-2-yl] - adamantan- 1 - yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid {3-[5-(5-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] - adamantan- 1 -yl} -amide;

Pyridine-2 -carboxylic acid {3 - [5 -(6-trifluoromethyl -pyridin-3 -yl)- [ 1 ,3 ,4]oxadiazol-2-yl] - adamantan- 1 -yl} -amide; 2-Methyl-pyrimidine-4-carboxylic acid {3-[5-(6-trifluoromethyl-pyridin-3-yl)- [ 1 ,3,4]oxadiazol-2- yl]-adamantan- 1 -yl} -amide;

6-Methyl-pyridine-2-carboxylic acid {3-[5-(6-ethyl-pyridin-3-yl)-[l,3,4]oxadiazol-2-yl]- adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid {3-[5-(6-ethyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] - adamantan- 1 -yl} -amide;

5 -Fluoro-pyridine-2 -carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol-2- yl] - adamantan- 1 -yl} -amide; Pyrazine-2-carboxylic acid {3-[5-(6-methyl-pyridin-3-yl)-[l,3,4]oxadiazol- 2-yl]- adamantan- 1 -yl} -amide;

Pyrimidine-4-carboxylic acid {3 - [5-(6-methy l-pyridin-3 -yl)- [ 1 ,3 ,4]oxadiazol-2-yl] - adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid { 3 - [3 -(3 -fluoro-phenyl)- [ 1,2,4] oxadiazol-5-yl] - adamantan- 1 -yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid [3-(3-pyridin-3-yl-[l,2,4]oxadiazol-5-yl)- adamantan-l-yl]- amide;

Pyrazine-2-carboxylic acid [3-(3-pyridin-3-yl-[l,2,4]oxadiazol-5-yl)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid [3 -(3 -pyridin-3 -yl- [ 1 ,2,4]oxadiazol-5-yl)- adamantan-l-yl]- amide;

6-Methyl-pyridine-2 -carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-[l,2 ,4]oxadiazol-5-yl] adamantan- 1-yl} -amide;

2-Methyl-pyrimidine-4-carboxylic acid { 3 - [3 -(6-methyl-pyridin-3 -yl)-[ 1 ,2,4]oxadiazol-5 - yl] - adamantan- 1 -yl} -amide;

Pyridine-2 -carboxylic acid {3 - [3 -(6-methyl-pyridin-3 -yl)- [ 1 ,2,4] oxadiazol-5 -yl] - adamantan- 1 -yl} -amide;

Pyrimidine-4-carboxylic acid {3 - [3 -(6-methy l-pyridin-3 -yl)- [ 1 ,2,4] oxadiazol-5 -yl] - adamantan- 1 -yl} -amide;

Pyrazine-2 -carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-[l,2,4]oxadiazol-5-yl]- adamantan- 1 -yl} - amide;

6-Methyl-pyrazine-2-carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-l,2,4-oxadiazol-5- yl] - adamantan- 1 -yl} -amide;

5- Fluoro-pyridine-2 -carboxylic acid {3-[3-(6-methyl-pyridin-3-yl)-[l,2,4]oxadiazol-5- yl] - adamantan- 1 -yl} - amide;

6- Methyl-pyridine-2 -carboxylic acid {3-[5-(3-chloro-phenyl)-oxazol-2-yl]-adamantan-l- yl} -amide; 6-Methyl-pyridine-2-carboxylic acid (3 -benzenesulfonylamino-adamantan- 1 -yl)-amide;

6-Methyl-pyrazine-2-carboxylic acid (3 -benzenesulfonylamino-adamantan- 1 -yl)-amide;

Pyridine-2 -carboxylic acid [3-(2-fluoro-benzenesulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2-carboxylic acid [3-(3-fluoro-benzenesulfonylamino)-adamantan-l-yl]-amide; Pyridine-2 -carboxylic acid [3-(4-fluoro-benzenesulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid (3-methanesulfonylamino-adamantan-l-yl)-amide;

Pyridine-2 -carboxylic acid (3 -ethanesulfonylamino-adamantan- 1 -yl)-amide;

Pyridine-2 -carboxylic acid (3-cyclopropylmethanesulfonylamino-adamantan-l-yl)-amide;

Pyridine-2 -carboxylic acid (3-cyclobutanesulfonylamino-adamantan-l-yl)-amide;

Pyridine-2 -carboxylic acid [3-(tetrahydro-pyran-4-sulfonylamino)-adamantan-l-yl]- amide;

Pyridine-2 -carboxylic acid [3-(pyridine-2-sulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(pyridine-3-sulfonylamino)-adamantan-l-yl]-amide;

Pyridine-2 -carboxylic acid [3-(pyridine-4sulfonylamino)-adamantan- 1 -yl]-amide;

Pyridine-2 -carboxylic acid [3-(thiazole-2-sulfonylamino)-adamantan-l-yl]-amide;

Ethyl-carbamic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

Ethyl-carbamic acid 3-[(6-methyl-pyrazine-2-carbonyl)-amino]-adamantan-l-yl ester;

Cyclopropyl-carbamic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

Azetidine-l-carboxylic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

Piperidine- 1 -carboxylic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

Morpholine-4-carboxylic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantan-l-yl ester;

4-Methyl-piperazine- 1 -carboxylic acid 3-[(6-methyl-pyridine-2-carbonyl)-amino]- adamantan-l-yl ester; 6-Methyl-pyridine-2-carboxylic acid [3-(cyclohexylmethyl-amino)-adamantan- 1 -yl] - amide; 6-Methyl -pyridine-2 -carboxylic acid [3-(cyclopentyhnethyl-amino)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid [3-(cyclobutylmethyl-amino)-adamantan-l-yl]- amide;

6-Methyl-pyridine-2-carboxylic acid (3-benzylamino-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(2-fluoro-benzylamino)-adamantan-l-yl]-amide;

6-Methyl -pyridine-2-carboxylic acid [3-(3-fluoro-benzylamino)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(4-fluoro-benzylamino)-adamantan-l-yl]-amide;

6-Methyl-pyridine-2-carboxylic acid [3-(thiazol-2-ylamino)-adamantan- 1 -yl] -amide;

6-Methyl-pyridine-2-carboxylic acid (3-isobutylamino-adamantan-l-yl)-amide;

6-Methyl-pyridine-2-carboxylic acid (3 -propylamino-adamantan- 1 -yl)-amide;

6-Methyl-pyridine-2-carboxylic acid{3-[(tetrahydro-pyran-4-ylmethyl)-amino]- adamantan-l-yl} - amide; or

6-Methyl-pyridine-2-carboxylic acid [3-(tetrahydro-pyran-4-ylamino)-adamantan-l-yl]- amide; or a pharmaceutically acceptable salt thereof or substituted variants retaining glutamate modulatory activity.

Formula 254

[001133] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 254. Such compounds are described in WO 2011/073339, published June 23, 2011, corresponding to PCT/EP2010/069957, filed December 16, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 254, this reference incorporated by reference herein controls.

[001134] In some embodiments, the glutamate modulator is a compound according to Formula 254: or a stereoisomeric form thereof, wherein n is 1 or 2;

A is selected from the group consisting of — CH2O — and — O — CH2 — ;

R1 is selected from the group consisting of phenyl and phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of Cl-6alkyl, trifluoromethyl, cyano and halo; and

R2 is selected from the group consisting of hydrogen; Cl-8alkyl;

(Cl-6alkyloxy)Cl-3alkyl; C3-8cycloalkyl; (C3-8cycloalkyl)Cl-3alkyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of Cl-6alkyl, Cl-3alkyloxy, halo and Cl-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; (phenyl)C 1-3 alkyl; (phenyl)C 1-3 alkyl wherein the phenyl part is substituted with 1, 2 or 3 independently selected halo substituents; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of Cl-6alkyl, Cl-3alkyloxy, halo and Cl-3alkyl substituted with 1, 2 or 3 independently selected halo substituents; and (tetrahydro-2H-pyranyl)-m ethyl; or a pharmaceutically acceptable salt thereof.

[001135] In further embodiments, the glutamate modulator is a compound selected from: 5-(4-fluorophenyl)-6,7-dihydro-2-(phenylmethoxy)-thiazolo[5, 4-c]pyridin-4(5H)-one,

6.7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H )-one,

6.7-dihydro-2-(phenoxymethyl)-5-[(tetrahydro-2H-pyran-4-y l)methyl]-thiazolo[5,4-c]pyridin-4(5H)- one,

6.7-dihydro-5-(2-methoxyethyl)-2-(phenoxymethyl)-thiazolo [5,4-c]pyridin-4(5H)-one,

6.7-dihydro-5-(5-methyl-2-pyridinyl)-2-(phenoxymethyl)-th iazolo[5,4-c]pyridin-4(5H)-one, 2-[(4-fluorophenoxy)methyl]-5-(4-fluorophenyl)-6,7-dihydro-t hiazolo[5,4-c]pyridin-4(5H)-one,

2- [(3 -fluorophenoxy )methyl] -6,7-dihydro-5 -[( 1 R)- 1 ,2,2-trimethylpropyl] -thiazolo [5 ,4-c]pyridin- 4(5H)-one,

6.7-dihydro-5-methyl-2-(phenoxymethyl)-thiazolo[5,4-c]pyr idin-4(5H)-one,

5-(4-fluorophenyl)-6,7-dihydro-2-(phenoxymethyl)-thiazolo [5,4-c]pyridin-4(5H)-one, 5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepi n-4-one, 5-(4-fluorophenyl)-5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-t hiazolo[5,4-c]azepin-4-one, 5-(2,4-difluorophenyl)-6,7-dihydro-2-(phenylmethoxy)-thiazol o[5,4-c]pyridin-4(5H)-one,

5-[(2,4-difluorophenyl)methyl]-6,7-dihydro-2-(phenylmetho xy)-thiazolo[5,4-c]pyridin-4(5H)-one,

5-[(4-fluorophenyl)methyl]-6,7-dihydro-2-(phenylmethoxy)- thiazolo[5,4-c]pyridin-4(5H)-one,

5-[(3-fluorophenyl)methyl]-6,7-dihydro-2-(phenylmethoxy)- thiazolo[5,4-c]pyridin-4(5H)-one, 5-[(2-fluorophenyl)methyl]-6,7-dihydro-2-(phenylmethoxy)-thi azolo[5,4-c]pyridin-4(5H)-one, 5-(2,4-difluorophenyl)-2-[(3-fluorophenyl)methoxy]-6,7-dihyd ro-thiazolo[5,4-c]pyridin-4(5H)-one, 5-(2,4-difluorophenyl)-2-[(2-fluorophenyl)methoxy]-6,7-dihyd ro-thiazolo[5,4-c]pyridin-4(5H)-one,

5-(4-fluorophenyl)-2-[(3-fluorophenyl)methoxy]-6,7-dihydr o-thiazolo[5,4-c]pyridin-4(5H)-one,

3-[[[5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-4-oxothiaz olo[5,4-c]pyridin-2-yl]oxy]methyl]- benzonitrile,

5-(2,4-difluorophenyl)-6,7-dihydro-2-[3-methylphenyl)meth oxy]-thiazolo[5,4-c]pyridin-4(5H)-one, 5 -(4-fluorophenyl)-2- [(2-fluorophenyl)methoxy] -6,7-dihydro-thiazolo [5 ,4-c]pyridin-4(5H)-one, 5-(2,4-difluorophenyl)-2-[(2,4-difluorophenyl)methoxy]-6,7-d ihydro-thiazolo[5,4-c]pyridin-4(5H)- one,

6.7-dihydro-5-methyl-2-(phenylmethoxy)-thiazolo[5,4-c]pyr idin-4(5H)-one,

2-[(3-fluorophenoxy)methyl]-5-(4-fluorophenyl)-6,7-dihydr o-thiazolo[5,4-c]pyridin-4(5H)-one,

2-[(3 -fluorophenyl)methoxy] -6,7-dihydro-5 -[4-(trifluoromethyl)phenyl] -thiazolo [5 ,4-c]pyridin- 4(5H)-one,

5 -(3 -fluorophenyl)-2-[(3 -fluorophenyl)methoxy] -6,7-dihydro-thiazolo[5 ,4-c]pyridin-4(5H)-one,

5 -(2,4-difluorophenyl)-2-[(3 -fluorophenoxy)methyl] -6,7-dihydro-thiazolo [5 ,4-c]pyridin-4(5H)-one, 5-(2,4-difluorophenyl)-6,7-dihydro-2-(phenoxymethyl)-thiazol o[5,4-c]pyridin-4(5H)-one,

2 - [( 3 -fluorophenyl)methoxy] -6,7-dihydro-5 -[3 -(trifluoromethyl)phenyl] -thiazolo [5, 4-c]pyridin- 4(5H)-one, 2-[(2-fluorophenoxy)methyl]-5-(4-fluorophenyl)-6,7-dihydro-t hiazolo[5,4-c]pyridin-4(5H)-one, 5-(2,4-difluorophenyl)-2-[(4-fluorophenoxy)methyl]-6,7-dihyd ro-thiazolo[5,4-c]pyridin-4(5H)-one,

2-[(2 -fluorophenoxy )methyl]-6,7-dihydro-5-[(lR)-l, 2, 2 -trimethylpropyl] -thiazolo [5, 4-c]pyridin-

4(5H)-one,

2-[(4-fluorophenoxy)methyl]-6,7-dihydro-5-[(lR)-l,2,2-tri methylpropyl]-thiazolo[5,4-c]pyridin-

4(5H)-one,

6.7-dihydro-2-(phenoxymethyl)-5-[(lR)-l,2,2-trimethylprop yl]-thiazolo[5,4-c]pyridin-4(5H)-one, -[(2 -fluorophenoxy )methyl]-6,7-dihydro-5-(2-methoxyphenyl)-thiazolo[5,4-c]pyri din-4(5H)-one,- [(3 -fluorophenoxy )methyl] -6,7-dihydro-5 -(2-methoxyphenyl)-thiazolo [5 ,4-c]pyridin-4(5H)-one,,6,7,8-tetrahydro-5-methyl-2-(phenoxy methyl)-4H-thiazolo[5,4-c]azepin-4-one,-(cyclopropylmethyl)- 6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-o ne, -cyclopropyl -2-[(3 -fluorophenoxy )methyl] -6,7-dihydro-thiazolo [5 ,4-c]pyridin-4(5H)-one,-(cyclopropylmethyl)-2-[(3-fluorophen oxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,-(c yclopropylmethyl)-2-[(2-fluorophenoxy)methyl]-6,7-dihydro-th iazolo[5,4-c]pyridin-4(5H)-one,-(cyclopropylmethyl)-2-[(4-fl uorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H) -one,-cyclopropyl-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4 -c]pyridin-4(5H)-one, .7-dihydro-2-(phenoxymethyl)-5-(2-pyridinyl)-thiazolo[5,4-c] pyridin-4(5H)-one, .7-dihydro-5-(6-methyl-2-pyridinyl)-2-(phenoxymethyl)-thiazo lo[5,4-c]pyridin-4(5H)-one,-(5-fluoro-2-pyridinyl)-6,7-dihyd ro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one, .7-dihydro-2-(phenoxymethyl)-5-(3-pyridinyl)-thiazolo[5,4-c] pyridin-4(5H)-one, .7-dihydro-2-(phenoxymethyl)-5-(4-pyridinyl)-thiazolo[5,4-c] pyridin-4(5H)-one, -(3-fluoro-2-pyridinyl)-6,7-dihydro-2-(phenoxymethyl)-thiazo lo[5,4-c]pyridin-4(5H)-one, .7-dihydro-5-(4-methyl-2-pyridinyl)-2-(phenoxymethyl)-thiazo lo[5,4-c]pyridin-4(5H)-one,.7-dihydro-5-(3-methyl-2-pyridiny l)-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin-4(5H)-one,- [(4-fluorophenoxy)methyl] -5 -(5 -fluoro-2-pyridinyl)-6,7-dihydro-thiazolo [5 ,4-c]pyridin-4(5H)-one,- [(3 -fluorophenoxy )methyl] -5 -(5 -fluoro-2-pyridinyl)-6,7-dihydro-thiazolo [5 ,4-c]pyridin-4(5H)-one,-[(2-fluorophenoxy)methyl]-5-(5-fluor o-2-pyridinyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one, -ethyl-6,7-dihydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridin- 4(5H)-one, -(5-fluoro-3-pyridinyl)-6,7-dihydro-2-(phenoxymethyl)-thiazo lo[5,4-c]pyridin-4(5H)-one, -(3-fluoro-4-pyridinyl)-6,7-dihydro-2-(phenoxymethyl)-thiazo lo[5,4-c]pyridin-4(5H)-one, -(2, 4-difluorophenyl)-2-[(2-fluorophenoxy)methyl] -6,7-dihydro-thiazolo [5 ,4-c]pyridin-4(5H)-one,-[(4-chlorophenoxy)methyl]-5-(4-fluor ophenyl)-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one, -cyclopropyl -2- [(2 -fluorophenoxy )methyl]-6,7-dihydro-thiazolo[5,4-c]pyridin-4(5H)-one,-cyclo propyl-2-[(4-fluorophenoxy)methyl]-6,7-dihydro-thiazolo[5,4- c]pyridin-4(5H)-one, .7-dihydro-5-(l-methylethyl)-2-(phenoxymethyl)-thiazolo[5,4- c]pyridin-4(5H)-one, -[(3-fluorophenoxy)methyl]-6,7-dihydro-5-(l-methylethyl)-thi azolo[5,4-c]pyridin-4(5H)-one,.7-dihydro-2-(phenylmethoxy)-t hiazolo[5,4-c]pyridin-4(5H)-one, -fluoro-5-[[(4,5,6,7-tetrahydro-4-oxothiazolo[5,4-c]pyridin- 2-yl)oxy]methyl]-benzonitrile,.7-dihydro-2-[(2-methylphenyl) methoxy]-thiazolo[5,4-c]pyridin-4(5H)-one, .7-dihydro-2-[(3-methylphenyl)methoxy]-thiazolo[5,4-c]pyridi n-4(5H)-one, - [(2-fluorophenyl)methoxy] -6,7-dihydro-thiazolo [5 ,4-c]pyridin-4(5H)-one, -[(2-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridi n-4(5H)-one trifluoroacetate,-[(3-fluorophenyl)methoxy]-6,7-dihydro-thia zolo[5,4-c]pyridin-4(5H)-one, -[(3-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyridi n-4(5H)-one trifluoroacetate, 2-[(4-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyrid in-4(5H)-one, 2-[(4-fluorophenyl)methoxy]-6,7-dihydro-thiazolo[5,4-c]pyrid in-4(5H)-one trifluoroacetate, 6,7-dihydro-2-[(4-methylphenyl)methoxy]-thiazolo[5,4-c]pyrid in-4(5H)-one, 5-(2,4-difluorophenyl)-2-[(3,5-difluorophenyl)methoxy]-6,7-d ihydro-thiazolo[5,4-c]pyridin-4(5H)- one,

5 -(2,4-difluorophenyl)-2- [(3 ,4-difluorophenyl)methoxy] -6,7-dihydro-thiazolo [5 ,4-c]pyridin-4(5H)- one,

4-[[[5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-4-oxothiaz olo[5,4-c]pyridin-2-yl]oxy]methyl]- benzonitrile, 2-[[[5-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-4-oxothiazolo [5,4-c]pyridin-2-yl]oxy]methyl]- benzonitrile, 2-[(3-fluorophenyl)methoxy]-6,7-dihydro-5-[(lR)-l,2,2-trimet hylpropyl]-thiazolo[5,4-c]pyridin- 4(5H)-one,

5-(2,4-difluorophenyl)-6,7-dihydro-2-[[4-(trifluoromethyl )phenyl]methoxy]-thiazolo[5,4-c]pyridin- 4(5H)-one, 5-(2,4-difluorophenyl)-6,7-dihydro-2-[(2-methoxyphenyl)metho xy]-thiazolo[5,4-c]pyridin-4(5H)-one, 5 -(2,4-difluorophenyl)-6,7-dihydro-2- [(3 -methoxyphenyl)methoxy] -thiazolo [5 ,4-c]pyridin-4(5H)-one, and 5-(2,4-difluorophenyl)-6,7-dihydro-2-[[2-(trifluoromethyl)ph enyl]methoxy]-thiazolo[5,4-c]pyridin- 4(5H)-one, and the stereoisomeric forms, the pharmaceutically acceptable salts thereof, including substituted variants which retain glutamate modulatory activity.

Formula 255

[001136] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 255. Such compounds are described in WO 2011/073347, published June 23, 2011, corresponding to PCT/EP2010/069972, filed December 16, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 255, this reference incorporated by reference herein controls.

[001137] In an embodiment, the glutamate modulator is a compound according to Formula 255: wherein

X is selected from CH2 and NR2;

A is selected from the group consisting of 1 ,2-ethanediyl; 1 ,2-ethenediyl; and 1 ,2- ethynediyl;

R1 is selected from the group consisting of phenyl; phenyl substituted with 1 or 2 halo substituents; pyridinyl; and pyridinyl substituted with 1 or two halo substituents; or Rl-A together is 3,4-dihydro-2H-l,4-benzoxazin-7-yl optionally substituted with methyl;

R2 is selected from the group consisting of hydrogen; methyl; methoxyethyl; aryl; benzyl; and benzyl wherein the phenyl part is substituted with 1 or 2 halo substituents; wherein aryl is phenyl, optionally substituted with 1 or 2 substituents selected from the group consisting of methyl, methoxy, cyano, fluoro, chloro, trifluoromethyl and trifluoromethyloxy; or a pharmaceutically acceptable salt or a solvate thereof.

Formula 256

[001138] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 256. Such compounds are described in WO 2011/053575, published May 5, 2011, corresponding to PCT/US2010/054054, filed October 26, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 256, this reference incorporated by reference herein controls.

[001139] In an embodiment, the glutamate modulator is a compound according to Formula 256: wherein: R1 and R2 are each independently aryl, heteroaryl, alkyl, cycloalkyl, ketocycloalkyl, or heterocyclyl, which is optionally mono-, di-, or tri-substituted independently with alkyl, cycloalkyl, alkoxy, hydroxy, halogen, cyano, trifluoroalkyl, amino, acyl, aryl, heteroaryl, heterocyclyl, — C(O)NHR30, — C(O)N(R30)R31, — NHC(O)30, — N(R30)C(O)R31, — NHR30, — N(R30)R31, or — OR30; wherein:

R30 and R31 are each independently Cl-C6alkyl or Cl-C6cycloalkyl that is optionally substituted with acyl, halogen, — CN, — NH2, — NH(C1-C3 alkyl), — N(Cl-C3alkyl)2, Cl-C3alkylheterocyclyl, C1-C3 alkylcarbamate, — C(O)NH(C1- C3 alkyl), — C(O)N(C1-C3alkyl)2, — NHC(O)— Cl -C3 alkyl, — N(Cl-C3alkyl)- C(O)— Cl -C3 alkyl, OH, or — O— Cl-C6alkyl; and each aryl, heteroaryl, heterocyclyl substituent is optionally substituted with Cl-3alkyl, C3-5cycloalkyl, Cl-3alkoxy, hydroxy, halogen, cyano, trifluoroalkyl, or amino;

R3, R4, R5 and R6 are each independently H, Cl-3alkyl, C3-5cycloalkyl, halogen, or hydroxy;

R7 is H; or

R1 and R7 taken together with the — C(O)N — to which they are attached form a mono- or bicyclic 4- to 12-membered heterocycloalkyl or heteroaryl, which optionally contains 1-3 additional heteroatoms; or a pharmaceutically acceptable salt thereof.

Formula 257

[001140] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 257. Such compounds are described in WO 2011/050063, published April 28, 2011, corresponding to PCT/US2010/053379, filed October 20, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 257, this reference incorporated by reference herein controls.

[001141] In an embodiment, the glutamate modulator is a compound according to Formula 257:

wherein:

X is — CONR3R4, — CH2NR3R4, — CH(0H)R5, — CO2R3, — C0R5, or — C(OH)R5R6, wherein:

R3 is hydrogen or Cl-C6alkyl;

R4 is Cl-C6alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, arylalkyl, or aryl, each of which is optionally mono-, di-, or tri -substituted independently with Cl- C6alkyl, halogen, cycloalkyl, and aryl; or

R3 and R4 taken together with the N to which they are attached to form a 4 to 10 membered heterocyclyl, which optionally contains at least one additional heteroatom and optionally is mono-, di-, or tri -substituted independently with Cl-C6alkyl, hydroxy, C1-C6 alkoxy, Cl-C6alkoxyalkyl, Cl-C6cycloalkyl, CO2Cl-C6alkyl, hydroxyalkyl, — CN, — NH2, — NH(C1-C3 alkyl), — N(Cl-C3alkyl)2, — NHCOC I - C6alkyl, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-Cl-C6alkyl, =0, and halogen;

R5 is Cl-C3alkyl, CF3, CHF2, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, or heterocyclyl that is attached via a carbon having from 1 to 3 substitutions, which are selected from a group consisting of Cl-C6alkyl, halogen, cycloalkyl, aryl, hydroxy, Cl-C6alkoxy, hydroxyalkyl, — CN, — NH2, — NH(C1-C3 alkyl), — N(Cl-C3alkyl)2, acyl, heteroaryl, heterocyclyl, and carbonyl; and

R6 is hydrogen, Cl-C3alkyl, CF3, CHF2, or C3-C6cycloalkyl;

R1 is hydrogen, Cl-C6alkyl, C3-C6cycloalkyl, aryl or heteroaryl, which is optionally mono-, or di -substituted independently with Cl-C3alkyl, Cl-C3alkoxy, hydroxyl, CF3, CHF2, CN and halogen;

R2 is hydrogen, Cl-C3alkyl, CF3, CHF2, or halogen; with the proviso that X and R2 are attached either to the fourth or fifth carbon of the thiazole ring and when X is attached to the fourth carbon, R2 is attached to the fifth carbon and vice versa; or a pharmaceutically-acceptable salt thereof.

[001142] In further embodiments, the glutamate modulator is a compound according to:

Formula 258

[001143] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 258. Such compounds are described in WO 2011/035209, published March 24, 2011, corresponding to PCT/US2010/049400, filed September 17, 2010, or in WO 2011035214, published March 24, 2011, corresponding to PCT/US2010/049407, filed September 17, 2010, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 258, these references incorporated by reference herein control.

[001144] In some embodiments, the glutamate modulator is a compound according to formula 258: wherein A is CR2 or N; wherein L is O or NR7, wherein W is CR6 or N; wherein Z is CR6a or N; provided that only one of W and Z is N; wherein R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R1 is substituted with 0-3 of R9; wherein R2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, Cl- C6 haloalkoxy, amino, hydroxyl, alkylamino, dialkylamino, NO2, CN, SO2R8, or COR8; wherein R3 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN; wherein R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, CN, SO2R8, and COR8, with the proviso that when A is N, then R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO2R8, and COR8; wherein R5 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO2R8, and COR8; wherein R6, when present, is selected from hydrogen, halogen, CN, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl; wherein R6a, when present, is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R6b is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, and C1-C6 haloalkoxy; wherein R6c is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, and C1-C6 haloalkoxy; wherein R7 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R8 is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; and wherein each R9, when present, is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3- C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO2, CN, SO2R8, or COR8; or wherein A is CR2 or N; wherein L is O or NR7, wherein R1 is a five-membered or six-membered monocyclic heteroaromatic ring substituted with 0-3 of R9; wherein R2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, Cl- C6 haloalkoxy, amino, hydroxyl, alkylamino, dialkylamino, NO2, CN, SO2R8, or COR8; wherein R3 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN; wherein R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, CN, SO2R8, and COR8, with the proviso that when A is N, then R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO2R8, and COR8; wherein R5 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO2R8, and COR8; wherein R6 is selected from hydrogen, halogen, CN, C1-C6 alkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl and C1-C6 haloalkyl; wherein each of R6a, R6b, and R6c is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy; wherein R7 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R8 is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; and wherein each R9, when present, is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3- C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO2, CN, SO2R8, or COR8.

[001145] In further embodiments, the glutamate modulator is selected from:

, or a pharmaceutically acceptable salt or prodrug thereof, or a substituted variant retaining glutamate modulatory activity.

Formula 259 [001146] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 259. Such compounds are described in WO 2011/035186, published March 24, 2011, corresponding to PCT/US2010/049373, filed September 17, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 259, this reference incorporated by reference herein controls.

[001147] In further embodiments, the glutamate modulator is a compound according to: wherein A is CR2 or N; wherein L is O or NR7, wherein W is CR6 or N; wherein Z is CR6a or N; provided that only one of W and Z is N; wherein R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; wherein R1 is substituted with 0-3 of R9; wherein R2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, Cl- C6 haloalkoxy, amino, hydroxyl, alkylamino, dialkylamino, NO2, CN, SO2R8, or COR8; wherein R3 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and CN; wherein R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, and C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, CN, SO2R8, and COR8, with the proviso that when A is N, then R4 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO2R8, and COR8; wherein R5 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, CN, SO2R8, and COR8; wherein R6, when present, is selected from hydrogen, halogen, CN, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkyl, and C1-C6 haloalkyl; wherein R6a, when present, is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; wherein R6b is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, and C1-C6 haloalkoxy; wherein R6c is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, and C1-C6 haloalkoxy; wherein R7 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein R8 is C1-C6 alkyl, C1-C6 cycloalkyl, amino, alkylamino, or dialkylamino; and wherein each R9, when present, is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3- C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxyl, amino, alkylamino, dialkylamino, NO2, CN, SO2R8, or C0R8;

Formula 260

[001148] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 260. Such compounds are described inWO 2011/035324, published March 24, 2011, corresponding to PCT/US2010/049697, filed September 21, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 260, this reference incorporated by reference herein controls.

[001149] In an embodiment, the glutamate modulator is a compound according to formula 260: wherein R1 is an Cl to C9 organic residue selected from alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl, wherein R1 is optionally substituted with one or more of halide, hydroxyl, trifluoromethyl, cyano, Cl to C4 alkoxy, thiol, Cl to C4 alkylsulfonyl, or Cl to C4 sulfonamide; wherein R3 represents 0-1 substituents independently selected from Cl to C4 alkyl, Cl to C4 haloalkyl, halide, hydroxyl, trifluoromethyl, cyano, Cl to C4 alkoxy, thiol, Cl to C4 alkyl sulfonyl, Cl to C4 carboxamide, and Cl to C4 sulfonamide; wherein R4 and R5 are independently hydrogen or an Cl to C6 organic residue selected from alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl, optionally substituted with one or more of halide, hydroxyl, trifluoromethyl, cyano, Cl to C4 alkoxy, thiol, Cl to C4 alkylsulfonyl, or Cl to C4 sulfonamide, or R4 and R5, together with the intermediate carbon, comprise an optionally substituted C3 to C6 cycloalkyl or heterocycloalkyl; wherein A is an optionally substituted C3 to C9 cyclic organic residue selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl; or a pharmaceutically acceptable salt or N-oxide thereof.

Formula 261

[001150] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 261. Such compounds are described in WO 2010/124047, published October 28, 2010, corresponding to PCT/US2010/031982, filed April 22, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 261, this reference incorporated by reference herein controls.

[001151] In an embodiment, the glutamate modulator is a compound according to Formula 261 : or a pharmaceutically acceptable salt thereof, wherein

Wl, W2, W3, W4, W5, XI, X2, X3, X4, Y and Zl, Z2, Z3, Z4, Z5 are each independently selected from C, N, S, and O; Figure US20100273772 Al -20101028-P00001 is independently a single bond or a double bond; n is 1 or 2; m is 0 or 1; p is 1 or 2;

R1 and R2 are each independently selected from H, hydroxyl, halogen, cyano, Cl- C6alkyl, halo-Cl-C6alkyl, and — O(Cl-C6alkyl);

R3 is selected from H, halogen, Cl-C6alkyl, halo-Cl-C6alkyl, — O(Cl-C6alkyl), halo-Cl-C6alkoxy, and hydroxyl;

R4 and R5 are each independently selected from H, Cl-C6alkyl, C3-C6cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, Cl-C6alkylNR7R8 and the Cl-C6alkyl, C3-C6cycloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, Cl- C6alkylNR7R8 and groups are optionally independently substituted with from 1 to 4-Cl-C6alkyl, halo- Cl-C6alkyl, — OH, or — NH2; or R4 and R5 and the atoms to which they are attached form a ring;

R6 is from 1 to 4 groups each independently selected from H, halogen, oxo, cyano, Cl-C6alkyl, halo-Cl-C6alkyl, — O(Cl-C6alkyl), heterocyclyl, NO2, and amino; and R7 and R8 are each independently selected from H, Cl-C6alkyl, aryl and R7 and R8 can be taken together with the nitrogen to which they are attached to form a saturated heterocycle containing 5-7 atoms independently selected from C, N, O, or S.

Formula 262

[001152] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 262. Such compounds are described in WO 2010/124055, published October 28, 2010, corresponding to PCT/US2010/032001, filed April 22, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 262, this reference incorporated by reference herein controls. [001153] In an embodiment, the glutamate modulator is a compound according to formula 262: wherein:

Al is selected from the group consisting of phenyl, naphthyl and heteroaryl;

A2 is selected from the group consisting of phenyl, naphthyl and heteroaryl;

X is selected from N, O and C(R13),

Y is selected from N and O, wherein X is N and Y is O, to form a oxadiazole ring, or X is O and Y is N, to form a oxadiazole ring, or X is C(R13) and Y is O to form an oxazole ring;

Ria, Rib and Rlc may be absent if the valency of Al does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) — (C=O)m — On — Cl-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,

(5) — (C=0)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,

(6) — (C=0)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,

(7) — (C=0)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,

(8) — (C=0)m — On-phenyl or — (C=0)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,

(9) — (C=0)m — On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13, (10) — (C=O)m — NR10R11, wherein RIO and R11 are independently selected from the group consisting of:

(a) hydrogen,

(b) Cl-6alkyl, which is unsubstituted or substituted with R13,

(c) C3-6alkenyl, which is unsubstituted or substituted with R13,

(d) C3-6alkynyl, which is unsubstituted or substituted with R13,

(e) C3-6cycloalkyl which is unsubstituted or substituted with R13,

(f) phenyl, which is unsubstituted or substituted with R13, and

(g) heterocycle, which is unsubstituted or substituted with R13,

(11) — S(O)2— NR10R11,

(12) — S(O)q — R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of RIO and R11,

(13) — CO2H,

(14) — CN, and

(15) — NO2;

R2a, R2b and R2c may be absent if the valency of A2 does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) — (C=0)m — On — Cl-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,

(5) — (C=0)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,

(6) — (C=0)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,

(7) — (C=0)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,

(8) — (C=0)m — On-phenyl or — (C=0)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,

(9) — (C=0)m — On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,

(10) — (C=0)m— NR10R11, (11) — S(0)2— NR10R11,

(12) — S(O)q— R12,

(13) — CO2H,

(14) — CN, and

(15) — NO2;

R3 is Cl-6alkyl;

R13 is selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3) — (C=O)m — On — Cl-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,

(4) — On — (Cl-3)perfluoroalkyl,

(5) — (C=O)m — On — C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,

(6) — (C=O)m — C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,

(7) — (C=O)m — C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R14,

(8) — (C=O)m — On-phenyl or — (C=O)m — On-napthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R14,

(9) — (C=O)m — On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R14,

(10) — (C=0)m— NR10R11,

(11) — S(O)2— NR10R11,

(12) — S(O)q— R12,

(13) — CO2H,

(14) — CN, and

(15) — NO2;

R14 is selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) Cl-6alkyl,

(4) — C3-6cycloalkyl, (5) — O— Cl-6alkyl,

(6) — O(C=O)— Cl-6alkyl,

(7) — NH— Cl-6alkyl,

(8) phenyl,

(9) heterocycle,

(10) — CO2H, and

(11) — CN; or a pharmaceutically acceptable salt thereof.

[001154] In further embodiments, the glutamate modulator is a compound according to:

, including pharmaceutically acceptable salts and substituted variants retaining glutamate modulatory activity.

Formula 263

[001155] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 263. Such compounds are described in WO 2010/114971, published October 7, 2010, corresponding to PCT/US2010/029575, filed April 1, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 263, this reference incorporated by reference herein controls.

[001156] In an embodiment, the glutamate modulator is a compound according to formula 263 : or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;

R2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted;

R3 and R4 are each independently hydrogen, halogen, or lower alkyl; or when R3 and R4 are attached to the same carbon atom, CR3R4 is C=O, or R3 and R4 may be combined with the carbon atom to which they are attached to form a 3- to 7- membered Spiro cycloalkyl; or when R3 and R4 are attached to different carbon atoms, R3 and R4 may be combined with the carbon atoms to which they are attached to form a 3- to 7-membered bridged or fused cycloalkyl;

LI is a bond, — S— , —SO—, — SO2— , — O— , — NR9— , — CR5R6— , — CR5R6 — CR7R8 — , optionally substituted cycloalkyl, optionally substituted heterocyclyl; optionally substituted aryl, or optionally substituted heteroaryl; L2 is a bond, — O— , — NR9— , — CR5R6— or — CR5R6— CR7R8— ;

X is C or N;

Y is O, S, N, NR10, or CR10;

Z is O, S, N, NR10, or CR10; wherein Y and Z are not both O or both S;

R5 and R6 are each independently hydrogen, halogen, or lower alkyl, or CR5R6 is C=O; or R5 and R6 may be combined with the carbon atom to which they are attached to form a 3- to 7-membered cycloalkyl;

R7 and R8 are each independently hydrogen, halogen, or lower alkyl, or CR7R8 is C=O; or R7 and R8 may be combined with the carbon atom to which they are attached to form a 3- to 7-membered cycloalkyl;

R9 and RIO are each independently hydrogen or lower alkyl;

G is N or CH; o is 0, 1, or 2; and p is 1 or 2.

Formula 264

[001157] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 264. Such compounds are described in WO 2010/101648, published September 10, 2010, corresponding to PCT/US2010/000669, filed March 4, 2010 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 264, this reference incorporated by reference herein controls.

[001158] In an embodiment, the glutamate modulator is a compound according to formula 264: wherein

R4 is selected from the set consisting of H, Cl, Br, F, CH3, OCH3, CF3, OCF3, and phenyl;

R6 is selected from the group consisting of H, CH3CO, COPh, COCH2Ph, COC6H4NO2(p), COC6H4OH(p), COC6H4NH2(p), CON(CH3)2, CON(CH2CH3)2, CON(CH3)(CH2CH3), CON(CH2Ph)2, CON(CH3)(CH2Ph), 1- pyrrolidinecarbonyl, 2-carboxy- 1 -pyrrolidincarbonyl, (2S)-2-carboxy- 1 - pyrrolidinecarbonyl, (2R)-2-carboxy-l -pyrrolidinecarbonyl, 1 -morpholinecarbonyl, 4- methyl-1 -piperazinecarbonyl, sarcosine-N-carbonyl, CO — N-Me-Ala-OH, CO — N- Me-Val-OH, CO— N-Me-Leu-OH, CO— N-Me-Ile-OH, CO— N-Me-Val-OH, CO— N-Me-Met-OH, CO— N-Me-Phe-OH, CO— N-Me-Trp-OH, CO-Pro-OH, CO— N- Me-Gly-OH, CO— N-Me-Ser-OH, CO— N-Me-Thr-OH, CO— N-Me-Cys-OH, CO— N-Me-Tyr-OH, CO— N-Me-Asn-OH, CO— N-Me-Gln-OH, CO— N-Me-Asp-OH, CO— N-Me-Glu-OH, CO— N-Me-Lys-OH, CO— N-Me-Arg-OH, CO— N-Me-His- OH, CO— N-Me-Gly-Gly-OH, CO— N-Me-Gly-Gly-Gly-OH, CO— N-Me-Gly-Phe- OH, CO— N-Me-Gly-Glu-OH, CO— N-Me-Gly-Glu-Glu-OH, CO— N-Me-Glu-Glu- OH, CO— N-Me-Gly-Lys-OH, CO— N-Me-Gly-Lys-Lys-OH, CO-Pro-Glu-OH, CO- Pro-Glu-Glu-OH, CO-Pro-Gly-OH, CO-Pro-Lys-OH, CO-Pro-Lys-Lys-OH, CO-Pro- Gly-Lys-OH, and CO-Pro-Lys-Lys-OH; and

R7, R8, R9, and RIO are each independently chosen from the group consisting of Cl, Br, F, CH3, CH2CH3, CH2Ph, CH=CH2, C=CH, C=N, OCH3, OCF3, Ph, OPh, and NO2.

Formula 265 [001159] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 265. Such compounds are described in WO 2010/063487, published June 10, 2010, corresponding to PCT/EP2009/008695, filed December 4, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 265, this reference incorporated by reference herein controls.

[001160] In an embodiment, the glutamate modulator is a compound according to Formula 265:

, wherein

Rl, R2, and R3, which may be the same or different, each independently represent hydrogen, Cl-6alkyl, trifluoromethyl, Cl-6alkoxy, cyano, halogen, or -NR4R5, wherein

R4 and R5, which may be the same or different, each independently represent hydrogen, Cl-6alkyl, or cycloC3-12alkyl, or R4 and R5, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Cl-6alkyl, halogen, trifluoromethyl, Cl - 6alkoxy, and cyano;

R® represents - === — Cy , — L — — Cy , or - . L—Cy , wherein L represents Cl-6alkylene, arylene, heteroarylene, -X-Cl-6alkylene, or Cl- 3alkylene-X-, wherein X represents oxygen or sulfur, and

Cy represents aryl, heteroaryl, cycloCi -6alkyl, cycloC3-12alkenyl, or heterocyclyl; and R7 represents hydrogen, Cl-6alkyl, Cl-6alkoxy, -C(O)NR8R9, carboxy, or aryl, wherein

R8 and R9, which may be the same or different, each independently represent hydrogen, d-Palkyl, or cycloC3-12alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, represent a 5- or 6- membered ring which may be saturated or unsaturated, and wherein the ring in addition to the nitrogen atom may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and may be substituted by one or more groups selected from Cl-6alkyl, halogen, trifluoromethyl, Cl-6alkoxy, and cyano; wherein the term "aryl" means phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, hydroxyCl-6alkyl, C2-6alkenyl, Cl-6alkoxy,

C-l-6alkoxyC-l-6alkyl, amino, hydroxy, nitro, cyano, formyl, cyanomethyl, Cl- 6alkoxy carbonyl, Cl-6alkylcarbonyloxy, Cl-6alkylcarbonyloxyCl-6alkyl, Cl- 6alkylamino, di-(Cl-6alkyl)amino, Cl-6alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N-C 1 -6alkylaminocarbonyl, di-N,N-C 1 -6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloC3-12alkyl, pyridinyl, and optionally Cl-6alkenedioxy the term "arylene" means a divalent aryl radical as defined above; the term "heteroaryl" means an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, hydroxyC-l-6alkyl, C2- 6alkenyl, Cl-6alkoxy, amino, hydroxy, nitro, cyano, Cl - 6alkoxy carbonyl, Cl- 6alkoxy carbonyloxy, Cl-6alkylamino, and di-(Cl-6alkyl)amino, d- Palkylcarbonylamino, aminocarbonyl, N-Cl-6alkylaminocarbonyl, di-N, N-Ci- Palkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC3.i2alkyl, Ci- 6alkylenedioxy, aryl, and pyridinyl; and the term "heteroarylene" means a divalent heteroaryl radical as defined above; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

Formula 266 [001161] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 266. Such compounds are described in WO 2010/049366, published May 6, 2010, corresponding to PCT/EP2009/064015, filed October 23, 2009, and US 2011/0263588, published October 27, 2011 which are each incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 266, this reference incorporated by reference herein controls.

[001162] In an embodiment, the glutamate modulator is a compound according to Formula 266: or a pharmaceutically acceptable salt or N-oxide thereof, wherein: each W is independently N or CR1;

V is N or CR2;

X is selected from the group consisting of: O, S, SO2, N, NR4, CR5, CR5R6, and CO; each T is independently selected from the group consisting of: CO, CR7R8, and NR9; U is selected from the group consisting of: C, CR10, and N;

Y is selected from the group consisting of: N, NR11, O, and CR12;

Z is selected from the group consisting of: N, NR13, and O;

A is selected from the group consisting of: — CONR16 — , — NR. I 6CO — , — O — , —

CONR16— CR14R15— , — NR16CONR16— , — CR14R15— NR16CO— , — CR14R15— O— , — CR14R15— NR16— , — O— CR14R15— , — NR16— CR14R15— , — NR16— ,

B is selected from the group consisting of: aryl, heteroaryl, and heterocyclyl; wherein B is optionally substituted by one, two, or three substituents each independently represented by R3; n is 0, 1 or 2; m is 0, 1 or 2;

Rl, R2, and R3 are each independently selected from the group consisting of: alkoxy, alkyl, alkenyl, alkynyl, alkanoyl, amino, aryl, carboxamido, cycloalkyl, cyano, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, nitro, sulfonamido, sulfonyl, and thio;

R4, R9, Rl 1, R13, and R16 are each independently selected from the group consisting of: alkyl, alkylsulfonyl, alkanoyl, cycloalkyl, haloalkyl, and hydrogen;

R5, R6, R12, R14, and R15 are each independently selected from the group consisting of: alkoxy, alkyl, alkanoyl, amino, aryl, cycloalkyl, cyano, halogen, haloalkyl, hydrogen, and hydroxyl;

R7 and R8 are each independently selected from the group consisting of: alkoxy, alkyl, halogen, haloalkyl, hydrogen, and hydroxyl, or R7 and R8 taken together are oxo; or R7 and R8 taken together form a carbocycle or a heterocycle; and RIO is selected from the group consisting of: methyl, oxide, or hydrogen.

Formula 267

[001163] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 267. Such compounds are described in WO 2010/011570, published January 28, 2010, corresponding to PCT/US2009/050934, filed July 17, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 267, this reference incorporated by reference herein controls.

[001164] In an embodiment, the glutamate modulator is a compound according to formula 267: wherein Rl and R2 are each independently alkyl, cycloalkyl, ketocycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each is optionally mono-, di-, or tri -substituted independently with alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-R3, — NHR3, — N(alkyl)R3, — C(O)NHR3, — C(O)N(alkyl)R3, — NHC(O)R3, — N(alkyl)C(O)R3, —OH or — OR3, wherein:

R3is Cl-C6alkyl or Cl-C6cycloalkyl, which is optionally substituted with halogen, Cl- C3 alkoxy, OH, — CN, — NH2, — NH(C1-C3 alkyl), — N(Cl-C3alkyl)2, Cl- C3alkylheterocyclyl, C1-C3 alkylcarbamate, — C(O)NH(C1-C3 alkyl), — C(O)N(C1- C3alkyl)2, — NHC(O)— Cl -C3 alkyl, — N(Cl-C3alkyl)-C(O)— Cl -C3 alkyl, OH, or — O— Cl-C6alkyl, including pharmaceutically acceptable salts thereof.

Formula 268

[001165] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 268. Such compounds are described in WO 2010/001185, published January 7, 2010, corresponding to PCT/HU2009/000052, filed June 25, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 268, this reference incorporated by reference herein controls.

[001166] In an embodiment, the glutamate modulator is a compound according to Formula 268:

, wherein X is Cl or F, or hydrates, solvates, or salts thereof, optionally wherein the compound is substituted in one or two or three additional positions while retaining glutamate modulatory activity.

Formula 269

[001167] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 269. Such compounds are described in WO 2009/143404, published November 26, 2009, corresponding to PCT/US2009/044938, filed May 22, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 269, this reference incorporated by reference herein controls. [001168] In an embodiment, the glutamate modulator is a compound according to formula 269: wherein:

R1 is each independently selected from H, Cl -6 alkyl, halogen, OH, and OC1-6 alkyl; R2 is selected from -(Ll)a-(Y)c-(L2)b-Q3, -L3-Q4 and -L4-Q5;

L3 is C2-12 alkynyl optionally substituted with 1-3 substituents selected from OH and halogen;

LI and L2 are each independently Cl -3 alkyl;

L4 is C2-12 alkenyl optionally substituted with 1-3 substituents selected from OH and halogen; n is 1 or 2

R4, R4a, R5, and R5a are each independently selected from H, and Cl -6 alkyl or R4 and one of R5a together can form a bridging methylene; or R5 can be together with the carbon to which it is attached — C(=O);

R6 is selected from H, CH3, -(L5)-(3- to 14-membered heterocycle), -(L5)-(5 to 14 membered heteroaromatic), (L5)-(3- to 10-membered cycloalkyl), (L5)-(C6-14 aryl) and -(L5)-Cl-6 alkyl each of which except H can be optionally substituted with 1 to 3 substituents independently selected from H, Cl -6 alkyl, halogen, OH, OC1-6 alkyl, — C(=O)O— (C 1-6 alkyl), NO2, Cl-3 haloalkyl, — S— Cl-6 alkyl, CN, (5- to 14- membered heteroaromatic), NR1R1, SO2C1-6 alkyl, SO2, S02NR1R1, Cl-6 alkylaryl, COC1-6 alkyl, and (3- to 14-membered heterocycle) optionally substituted with NO2.

L5 is selected from a bond, Cl-3 alkyl, — C(=O) — , SO2, (3- to 6-membered heterocycle) and (5- to 14-membered heteroaromatic);

XI, X2 are independently CR3 or N; each R3 is independently selected from H, Cl-6 alkyl, halogen, OH, OC1-6 alkyl, SO2, (3- to 14-membered heterocyclic) and (5- to 14-membered heteroaromatic), wherein each of Cl-6 alkyl or OC1-6 alkyl can be optionally substituted with 1 to 3 substituents independently selected from halogen, OH, OC1-6 alkyl, — C(=O)O — (Cl -6 alkyl), NO2, Cl -3 haloalkyl, — S— Cl -6 alkyl — NH2, — NH— (Cl -6 alkyl), — N(Cl-6 alkyl)(Cl-6 alkyl), cycloalkyl, NR1R1, and CN;

Z is CO;

Y is CR7R8, NR9, O, or S;

R7, R8, R9 are independently H, Cl -6 alkyl, halogen, OH, or OC1-6 alkyl a, b and c are independently 0 or 1 ;

Q3 is selected from C6-14 aryl, (5- to 14-membered heterocyclic), (5- to 14- membered heteroaromatic), and (4- to 9-membered carbocyclic); each of which can be optionally substituted with 1 to 3 substituents independently selected from Cl -6 alkyl, halogen, OH, OC1-6 alkyl, — C(=O)O — (Cl -6 alkyl), NO2, Cl -3 haloalkyl, — S— Cl -6 alkyl — NH2, — NH— (Cl -6 alkyl), — N(Cl-6 alkyl)(Cl-6 alkyl), OC1-3 haloalkyl, OC1-6 alkylaryl and CN;

Q4 is selected from H, C6-14 aryl, (5- to 14-membered heterocyclic), (5- to 14- membered heteroaromatic), and (4- to 9-membered carbocyclic); each of which except H can be optionally substituted with 1 to 3 substituents independently selected from Cl -6 alkyl, halogen, OH, OC1-6 alkyl, — C(=O)O— (Cl -6 alkyl), — C(=O)C1- 6 alkyl, NO2, Cl -3 haloalkyl, — S— Cl -6 alkyl — NH2, — NH— (Cl -6 alkyl), — N(Cl-6 alkyl)(Cl-6 alkyl), OC1-3 haloalkyl, OC1-6 alkylaryl and CN; and

Q5 is selected from C6-14 aryl, (5- to 14-membered heterocyclic), (5- to 14-membered heteroaromatic), and (4- to 9-membered carbocyclic); each of which can be optionally substituted with 1 to 3 substituents independently selected from Cl -6 alkyl, halogen, OH, OC1-6 alkyl, — C(=O)O— (Cl -6 alkyl), NO2, Cl -3 haloalkyl, — S— Cl-16 alkyl — NH2, — NH — (Cl -6 alkyl), — N(Cl-6 alkyl)(Cl-6 alkyl), OC1-3 haloalkyl, OC1-6 alkylaryl and CN. [001169] In an embodiment, the glutamate modulator is a compound according to: wherein:

R1 is H, Cl -6 alkyl, halogen, OH, or OC1-6 alkyl; R2 is -(Ll)a-(Y)c-(L2)b-Q3, -L3-Q4 or -L4-Q5;

L3 is C2-12 alkynyl optionally substituted with 1-3 substituents selected from OH and halogen;

LI and L2 are each independently Cl -3 alkyl;

L4 is C2-12 alkenyl optionally substituted with 1-3 substituents selected from OH and halogen;

R4, R4a, R5, and R5a are each independently H or Cl -6 alkyl;

R6 is selected from H, CH3, -(L5)-2-pyridyl, -(L5)-4-pyridyl, -(L5)-pyrazinyl, -(L5)- phenyl, -(L5)-(3-14 membered heterocyclic), -(L5)-(5 to 14 membered heteroaromatic), and (L5)-(C6-14 aryl) each of which except H can be optionally substituted with 1 to 3 substituents independently selected from H, Cl-6 alkyl, halogen, OH, OC1-6 alkyl, — C(=O)O — (Cl-6 alkyl), NO2, Cl -3 haloalkyl, — S — Cl-6 alkyl, COC1-6 alkyl and CN;

XI, X2 are independently CR3 or N;

L5 is selected from a bond, Cl-3 alkyl, — C(=O) — , SO2, (3- to 6-membered heterocycle) and (5- to 14-membered heteroaromatic). each R3 is independently selected from H, Cl-6 alkyl, halogen, OH, OC1-6 alkyl, SO2, (3- to 14-membered heterocyclic) and (5- to 14-membered heteroaromatic), wherein each of Cl-6 alkyl or OC1-6 alkyl can be optionally substituted with 1 to 3 substituents independently selected from halogen, OH, OC1-6 alkyl, — C(=O)O — (Cl-6 alkyl), NO2, Cl-3 haloalkyl, — S— Cl-16 alkyl — NH2, — NH— (Cl-6 alkyl), — N(Cl-6 alkyl)(Cl-6 alkyl), cycloalkyl, NR1R1, and CN;

Z is CO;

Y is selected from CR7R8, NR9, O, or S;

R7, R8, R9 are independently selected from H, Cl-6 alkyl, halogen, OH, and OC1-6 alkyl; a, b and c are independently 0 or 1 ; and

Q3 is selected from C6-14 aryl, (5- to 14-membered heterocyclic), (5- to 14- membered heteroaromatic), or (4- to 9-membered carbocyclic); each of which can be optionally substituted with 1 to 3 substituents independently selected from Cl-6 alkyl, halogen, OH, OC1-6 alkyl, — C(=O)O — (Cl-6 alkyl), NO2, Cl-3 haloalkyl, — S — Cl-16 alkyl — NH2, — NH— (Cl-6 alkyl), — N(Cl-6 alkyl)(Cl-6 alkyl), OC1-3 haloalkyl, OC1-6 alkylaryl and CN; Q4 is selected from H, C6-14 aryl, 5 to 14 membered heterocyclic, 5 to 14 membered heteroaromatic, or 4 to 9 membered carbocyclic; each of which except H can be optionally substituted with 1 to 3 substituents independently selected from Cl -6 alkyl, halogen, OH, OC1-6 alkyl, — C(=O)O— (Cl -6 alkyl), — C(=O)C1-16 alkyl, NO2, Cl -3 haloalkyl, — S— Cl -6 alkyl — NH2, — NH— (Cl -6 alkyl), — N(Cl-6 alkyl)(Cl- 6 alkyl), OCl-3haloalkyl, OCl-6alkylaryl and CN;

Q5 is selected from C6-14 aryl, (5 to 14 membered heterocyclic), (5 to 14 membered heteroaromatic), and (4 to 9 membered carbocyclic); each of which can be optionally substituted with 1 to 3 substituents independently selected from Cl -6 alkyl, halogen, OH, OC1-6 alkyl, — C(=O)O— (Cl -6 alkyl), NO2, Cl -3 haloalkyl, — S— Cl-16 alkyl — NH2, — NH — (Cl -6 alkyl), — N(Cl-6 alkyl)(Cl-6 alkyl), OC 1-3 haloalkyl, OCl-6alkylaryl and CN.

Formula 270

[001170] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 270. Such compounds are described in WO 2009/095253, published August 6, 2009, corresponding to PCT/EP2009/000615, filed January 30, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 270, this reference incorporated by reference herein controls.

[001171] In an embodiment, the glutamate modulator is a compound according to Formula 270: wherein

R1 represents chloro or bromo;

R2 represents hydrogen, Cl-6alkyl, amino, hydroxy, halogen, trifluoromethyl, formyl, Cl-6alkoxy, nitro, cyano, trifluoromethoxy, aminocarbonyl, Cl- 6alkylaminocarbonyl, di-Cl-6alkylaminocarbonyl, hydroxyCl-6alkyl, C2-6alkenyl, Cl-6alkoxy carbonyl, Cl-6alkylcarbonyloxy, Cl-6alkylamino, aryl, heteroaryl, heterocyclyl, or cycloC3-12alkyl; and

A represents -NR3R4, wherein

R3 represents hydrogen, Cl-6alkyl, cycloC3-12alkyl, aryl, heteroaryl, arylCl-6alkyl, and heteroarylCl-6alkyl and R4 represents Cl-6alkyl, cycloC3-12alkyl, aryl, heteroaryl, arylCl-6alkyl, and heteroarylCl-6alkyl; or

R3 and R4, together with the nitrogen to which they are attached, combine to form a partially unsaturated bicyclic or tricyclic ring system having 9 to 14 members comprising 1 to 8 heteroatoms selected from oxygen, sulfur, and nitrogen, wherein the ring system is optionally substituted with a group selected from halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, Cl-6alkyl, cycloC3- 12alkyl, C2-6alkenyl, C2-6alkynyl, Cl-6alkoxy, cycloC3-12alkyloxy, C2- 6alkenyloxy, C2-6alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, hetcrocyclyloxy, Cl-6alkylamino, di-Cl- 6alkylamino, CycloC3- 12alkylamino, di- cycloC3-12alkylamino, N-Cl-6alkyl-N- cycloC3-12alkylamino, C2-6alkenylamino, C2-6alkynylamino, di-C2-6alkenylamino, di-C2-6alkynylamino, N-Cl-6alkyl-N-C2- 6alkenylamino, N-Cl- 6alkyl-N-C2-6alkynylamino, N-C2-6alkenyl-N-cycloC3- 12alkylamino, N-C2- 6alkynyl-N-cycloC3-12alkylamino, N-C2-6alkenyl-N-C2- 6alkynylamino arylamino, diarylamino, aryl-Cl-6alkylamino, aryl-C2-6alkenylamino, aryl-C2-6alkynyl amino, N-aryl-N-cycloC3-12alkylamino, heteroarylamino, diheteroarylamino, heteroaryl-C 1 -6alkylamino, heteroaryl-C2-6alkenylamino, heteroaryl-C2-6alkynylamino, N-heteroaryl-N-cycloC3-12alkylamino, N- heteroaryl- N-arylamino, heterocyclylamino, diheterocyclylamino, heterocyclyl-C3- 12alkylamino, heterocyclyl-C2-6alkenylamino, heterocyclyl- C2-6alkynylamino, N- heterocyclyl-N-cycloC3-12alkylamino, N-heterocyclyl- N-arylamino, N-heterocyclyl- N-heteroarylamino, acyl, acyloxy, acylamino, Cl-6alkoxy carbonyl, cycloC3- 12alkoxy carbonyl, C2-6alkenyloxy carbonyl, C2-6alkynyloxy carbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, aminocarbonyl, Cl-6alkylaminocarbonyl, di-Cl -6alkylaminocarbonyl, cycloC3- 12alkylaminocarbonyl, di-cycloC3- 12alkylaminocarbonyl, N-Cl-6alkyl -N-CycloC3- 12alkylaminocarbonyl, C2- 6alkenylaminocarbonyl, C2-6alkynylaminocarbonyl, di- C2- 6alkenylaminocarbonyl, di-C2-6alkynylaminocarbonyl, N-Cl-6alkyl -N-C2- 6alkenylaminocarbonyl, N-Cl-6alkyl-N-C2-6alkynylaminocarbonyl, N-C2- 6alkenyl- N-cycloC3-12alkylaminocarbonyl, N-C2-6alkynyl-N-cycloC3-12alkylaminocarbonyl, N-C2-6alkenyl-N-C2-6alkynylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryl-Cl-6alkylaminocarbonyl, aryl- C2-6alkenylaminocarbonyl, aryl-C2-6alkynylaminocarbonyl, N-aryl-N-cyclo C3-12alkylaminocarbonyl, heteroarylaminocarbonyl, dihetero- arylaminocarbonyl, heteroarylCl- 6alkylaminocarbonyl, heteroaryl-C2- 6alkenylaminocarbonyl, heteroaryl-C2- 6alkynylaminocarbonyl, N-heteroaryl- N-cycloC3-12alkylaminocarbonyl, N- heteroaryl-N-arylaminocarbonyl, heterocyclylaminocarbonyl, diheterocyclylaminocarbonyl, heterocyclyl-C 1 -6alkylaminocarbonyl, heterocyclyl- C2-6alkenylaminocarbonyl, heterocyclyl- C2-6alkynylaminocarbonyl, N- heterocyclyl-N-cycloC3-12alkylaminocarbonyl, N-heterocyclyl-N- arylaminocarbonyl, N-heterocyclyl-N- heteroarylaminocarbonyl, Cl-6alkylsulfinyl, cycloC3-12alkylsulfinyl, C2- 6alkenylsulfinyl, C2-6alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, Cl-6alkylsulfonyl, cycloC3-12alkylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynyl sulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclyl sulfonyl, Cl-6alkylsulfonylamino, arylsulfonylamino, and oxo; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.

Formula 271

[001172] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 271. Such compounds are described in WO 2009/095254, published August 6, 2009, corresponding to PCT/EP2009/000616, filed January 30, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 271, this reference incorporated by reference herein controls.

[001173] In an embodiment, the glutamate modulator is a compound according to Formula 271 : wherein

R1 represents chloro or bromo;

A represents:

, wherein

W represents NR2 or CR3R4

R2 represents hydrogen, Cl-6alkyl, trifluoromethyl or cycloC3-12alkyl;

R3, R4, R5, R6, which may be the same or different, each independently represent hydrogen, Cl-6alkyl, cycloC3-12alkyl, or trifluoromethyl;

R7, and R8, which may be the same or different, each independently represent hydrogen, Cl- 6alkyl, cycloC3-12alkyl, amino, hydroxy, halogen, or trifluoromethyl;

XI represents CR9R10, NR11, S, or O; and X2, X3, and X4, which may be the same or different each independently represent CR9 or N, wherein

R9 and RIO, which may be the same or different, each independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, Cl-6alkyl, cycloC3-12alkyl, C2-6alkenyl, C2-6alkynyl, Cl-6alkoxy, cycloC3-12alkyloxy, C2- 6alkenyloxy, C2-6alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, heterocyclyloxy, C2-6alkylamino, di-Cl-6alkylamino, cycloC3-12alkylamino, di-cycloC3- 12alkylamino, N — Cl-6alkyl-N-cycloC3-12alkylamino, C2-6alkenylamino, C2- 6alkynylamino, di-C2-6alkenylamino, di-C2-6alkynylamino, N — Cl-6alkyl-N — C2- 6alkenylamino, N — C 1 -6alkyl-N — C2-6alkynylamino, N — C2-6alkenyl-N-cycloC3 - 12alkylamino, N — C2-6alkynyl-N-cycloC3-12alkylamino, N — C2-6alkenyl-N — C2- 6alkynylamino arylamino, diarylamino, aryl-Cl-6alkylamino, aryl-C2-6alkenylamino, aryl- C2-6alkynylamino, N-aryl-N-cycloC3-12alkylamino, heteroarylamino, diheteroarylamino, heteroaryl-Cl-6alkylamino, heteroaryl-C2-6alkenylamino, heteroaryl-C2-6alkynylamino, N- heteroaryl-N-cycloC3-12alkylamino, N-heteroaryl-N-arylamino, heterocyclylamino, diheterocyclylamino, heterocyclyl-C 1 -6alkylamino, heterocyclyl-C2-6alkenylamino, heterocyclyl-C2-6alkynylamino, N-heterocyclyl-N-cycloC3-12alkylamino, N-heterocyclyl- N-arylamino, N-heterocyclyl-N-heteroarylamino, acyl, acyloxy, acylamino, Cl- 6alkoxy carbonyl, cycloC3-12alkoxy carbonyl, C2-6alkenyloxy carbonyl, C2- 6alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, aminocarbonyl, Cl-6alkylaminocarbonyl, di-Cl-6alkylaminocarbonyl, cycloC3- 12alkylaminocarbonyl, di-cycloC3-12alkylaminocarbonyl, N — Cl-6alkyl-N-cycloC3- 12alkylaminocarbonyl, C2-6alkenylaminocarbonyl, C2-6alkynylaminocarbonyl, di-C2- 6alkenylaminocarbonyl, di-C2-6alkynylaminocarbonyl, N — C 1 -6alkyl-N — C2- 6alkenylaminocarbonyl, N — C 1 -6alkyl-N — C2-6alkynylaminocarbonyl, N — C2-6alkenyl-N- cycloC3-12alkylaminocarbonyl, N — C2-6alkynyl-N-cycloC3-12alkylaminocarbonyl, N — C2-6alkenyl-N — C2-6alkynylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryl- Cl-6 alkylaminoc arbonyl, aryl-C2-6alkenylaminocarbonyl, aryl-C2-6alkynylaminocarbonyl, N-aryl-N-cyclo C3-7alkylaminocarbonyl, heteroarylaminocarbonyl, diheteroarylaminocarbonyl, heteroaryl-C 1 -6alkylaminocarbonyl, heteroaryl-C2- 6alkenylaminocarbonyl, heteroaryl-C2-6alkynylaminocarbonyl, N-heteroaryl-N-cycloC3- 12alkylaminocarbonyl, N-heteroaryl-N-arylaminocarbonyl, heterocyclylaminocarbonyl, diheterocyclylaminocarbonyl, heterocyclyl-C2-6alkylaminocarbonyl, heterocyclyl-C2- 6alkenylaminocarbonyl, heterocyclyl-C2-6alkynylaminocarbonyl, N-heterocyclyl-N-cyclo C3-12alkylaminocarbonyl, N-heterocyclyl-N-arylaminocarbonyl, N-heterocyclyl- Nheteroarylaminocarbonyl, Cl-6alkylsulfinyl, cycloC3-12alkylsulfinyl, C2-6allonylsulfinyl, C2-6alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, Cl-6alkylsulfonyl, cycloC3-12alkylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, Cl-6alkylsulfonylamino, or arylsulfonylamino and Rl l represents hydrogen, Cl-6alkyl, cycloC3-12alkyl, C2-6alkenyl, C2-6alkynyl, acyl, aryl, heteroaryl, heterocyclyl, Cl-6alkylaminocarbonyl, di-Cl-6alkylaminocarbonyl, Cl- 6alkylsulfonyl, arylsulfonyl or heteroaryl sulfonyl;

Yl, Y3, and Y4 represent C orN, wherein at least two of Yl, Y2, Y3, and Y4 represent C; R12 and R13, which may be the same or different, each independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, Cl-6alkyl, cycloC3-12alkyl, C2-6alkenyl, C2-6alkynyl, Cl-6alkoxy, cycloC3-12alkyloxy, C2- 6alkenyloxy, C2-6alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, heterocyclyloxy, Cl-6alkylamino, di-Cl-6alkylamino, cycloC3-12alkylamino, di-cycloC3- 12alkylamino, N — Cl-6alkyl-N-cycloC3-12alkylamino, C2-6alkenylamino, C2- 6alkynylamino, di-C2-6alkenylamino, di-C2-6alkynylamino, N — Cl-6alkyl-N — C2- 6alkenylamino, N — C 1 -6alkyl-N — C2-6alkynylamino, N — C2-6alkenyl-N-cycloC3 - 12alkylamino, N — C2-6alkynyl-N-cycloC3-12alkylamino, N — C2-6alkenyl-N — C2- 6alkynylamino arylamino, diarylamino, aryl-Cl-6alkylamino, aryl-C2-6alkenylamino, aryl- C2-6alkynylamino, N-aryl-N-cycloC3-12alkylamino, heteroarylamino, diheteroarylamino, heteroaryl-Cl-6alkylamino, heteroaryl-C2-6alkenylamino, heteroaryl-C2-6alkynylamino, N- heteroaryl-N-cycloC3-12alkylamino, N-heteroaryl-N-arylamino, heterocyclylamino, diheterocyclylamino, heterocyclyl-C 1 -6alkylamino, heterocyclyl-C2-6alkenylamino, heterocyclyl-C2-6alkynylamino, N-heterocyclyl-N-cycloC3-12alkylamino, N-heterocyclyl- N-arylamino, N-heterocyclyl-N-heteroarylamino, acyl, acyloxy, acylamino, Cl- 6alkoxy carbonyl, cycloC3-12alkoxy carbonyl, C2-6alkenyloxy carbonyl, C2- 6alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, aminocarbonyl, Cl-6alkylaminocarbonyl, di-Cl-6alkylaminocarbonyl, cycloC3- 12alkylaminocarbonyl, di-cycloC3-12 alkylaminocarbonyl, N — C2-6 alkyl-N-cycloC3- 12alkylaminocarbonyl, C2-6alkenylaminocarbonyl, C2-6alkynylaminocarbonyl, di-C2- 6alkenylaminocarbonyl, di-C2-6alkynylaminocarbonyl, N — C 1 -6alkyl-N — C2- 6alkenylaminocarbonyl, N — C 1 -6alkyl-N — C2-6alkynylaminocarbonyl, N — C2-6alkenyl-N- cyclo C3-12alkylaminocarbonyl, N — C2-6alkynyl-N-cycloC3-12alkylaminocarbonyl, N — C2-6alkenyl-N — C2-6alkynylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryl- C 1 -6alkylaminocarbonyl, aryl-C2-6alkenylaminocarbonyl, aryl-C2-6alkynylaminocarbonyl, N-aryl-N-cyclo C3-7alkylaminocarbonyl, heteroarylaminocarbonyl, diheteroarylaminocarbonyl, heteroaryl-C 1 -6alkylaminocarbonyl, heteroaryl-C2- 6alkenylaminocarbonyl, heteroaryl-C2-6alkynylaminocarbonyl, N-heteroaryl-N-cycloC3- 12alkyl-aminocarbonyl, N-heteroaryl-N-arylaminocarbonyl, heterocyclylaminocarbonyl, diheterocyclylaminocarbonyl, heterocyclyl-C 1 -6alkylaminocarbonyl, heterocyclyl-C2- 6alkenylaminocarbonyl, heterocyclyl-C2-6alkynylaminocarbonyl, N-heterocyclyl-N- cycloC3-12alkylaminocarbonyl, N-heterocyclyl-N-arylaminocarbonyl, N-heterocyclyl-N- heteroarylaminocarbonyl, Cl-6alkylsulfinyl, cyclo C3-12alkyl sulfinyl, C2-6alkenyl sulfinyl, C2-6alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, Cl-6alkylsulfonyl, cycloC3-12alkylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, Cl-6alkylsulfonylamino, or arylsulfonylamino; or R12 and R13 together with the two carbon atoms carying them represent an aryl group which may be optionally substituted by a group selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, and Cl-6alkoxy; a heteroaryl group having 5 or 6 ring members which may be optionally substituted by a group selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, and Cl-6alkoxy; or a heterocyclyl group having 5 or 6 ring members, which may be optionally substituted by a group selected from oxo, halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, and Cl-6alkoxy; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

Formula 272

[001174] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 272. Such compounds are described in WO 2009/051556, published April 23, 2009, corresponding to PCT/SE2008/051170, filed October 17, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 272, this reference incorporated by reference herein controls.

[001175] In an embodiment, the glutamate modulator is a compound according to formula 272: pharmaceutically acceptable salt thereof.

[001176] In an embodiment, the glutamate modulator is a compound selected from: 2-(4-methyl-5-{(lR)-l-[2-(3-methylphenyl)-2H-tetrazol-5-yl]e thoxy}-4H-l,2,4- triazol-3 - yl)pyrimidine;

5-(4-methyl-5-{(lR)-l-[2-(3-methylphenyl)-2H-tetrazol-5-y l]ethoxy}-4H-l,2,4- triazol-3 - yl)pyrimidine;

2-methyl-5-(4-methyl-5-{(lR)-l-[2-(3-methylphenyl)-2H-tet razol-5-yl]ethoxy}- 4H- 1 ,2,4- triazol-3-yl)pyrazine;

2-methyl-4-(4-methyl-5-{(lR)-l-[2-(3-methylphenyl)-2H-tet razol-5-yl]ethoxy}- 4H- 1 ,2,4- triazol-3-yl)pyridine; and 3-{4-Methyl-5-[(lR)-l-(2-(3-methylphenyl-2H-tetrazol-5-yl)- ethoxy]-4H- [ 1 ,2,4]triazol-3-yl} -pyridine; as well as pharmaceutically acceptable salts, hydrates and isoforms thereof, and substituted variants retaining glutamate modulatory activity.

[001177] In an embodiment, the glutamate modulator is the compound: 3-{4-Methyl-5-[(lR)-l-(2-(3-methylphenyl-2H-tetrazol-5-yl)-e thoxy]-4H-[l,2,4]triazol-3- yl}-pyridine, or a pharmaceutically acceptable salt thereof or a substituted variant retaining glutamate modulatory activity.

Formula 273

[001178] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 273. Such compounds are described in, WO 2008/128968, published October 30, 2008, corresponding to PCT/EP2008/054682, filed April 17, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 273, this reference incorporated by reference herein controls.

[001179] In an embodiment, the glutamate modulator is a compound according to formula 273 :

XI, X2, X3, X4 each independently represent CR2 or N, provided that at least two of XI, X2, X3 and X4 are CR2; each R2 independently is hydrogen, halogen, hydroxyl, nitro, cyano, formyl, carboxy, carboxamido, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl- 6alkyl)(C3-12cycloalkyl)amino, di(C3-12cycloalkyl)amino, (Cl-6alkoxycarbonyl)amino, Cl-6alkoxy, Cl-6alkoxy carbonyl, sulphonate, sulphate, phosphate, quartenary ammonium, phosphonate, guanidimium, Cl-6alkyl, Cl-6halogenalkyl, Cl-6hydroxyalkyl, Cl- 6alkylcarbonyl(Cl-6alkyl), Cl-6alkoxy(Cl-6alkyl), Cl-6alkoxycarbonyl(Cl-6alkyl), Cl- 6aminoalkyl, Cl-6alkylamino(Cl-6alkyl), di-(Cl-6alkyl)amino(Cl-6alkyl), C3-12cycloalkyl, C3-12halogencycloalkyl, Cl-6alkyl(C3-12cycloalkyl), C3-12cycloalkyl(Cl-6alkyl), C3- 12cycloalkyloxy, C2-6alkenyl, C2-6halogenalkenyl, C2-6alkynyl or C2-6halogenalkynyl; R1 is Cl-6alkyl, Cl-6halogenalkyl, C3-12cycloalkyl, C3-12halogencycloalkyl, Cl- 6alkyl(C3-12cycloalkyl) or C3-12cycloalkyl(Cl-6alkyl); or, when X4 is CR2, Rl, R2 and the nitrogen and two carbon atoms, to which R1 and R2 are bound, may form together a 5- to 8-membered heterocyclic ring system, which may be aromatic or partially saturated and which may contain from 1 to 2 further hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the heterocyclic ring system itself may be substituted once or more than once by Ra; each Ra independently is halogen, nitro, cyano, formyl, carboxy, carboxamido, hydroxyl, amino, (Cl-6alkyl)amino, di-(Cl-6alkyl)amino, (Cl-6alkoxycarbonyl)amino, Cl-6alkoxy, Cl-6alkoxy carbonyl, Cl-6alkyl, Cl-6halogenalkyl, Cl-6hydroxyalkyl, Cl- 6alkylcarbonyl(Cl-6alkyl), Cl-6alkoxy(Cl-6alkyl), Cl-6alkoxycarbonyl(Cl-6alkyl), Cl- 6aminoalkyl, Cl-6alkylamino(Cl-6alkyl), di-(Cl-6alkyl)amino(Cl-6alkyl), C2-6alkenyl, C2- 6halogenalkenyl, C2-6alkynyl or C2-6halogenalkynyl;

B is wherein the bond marked with the asterisk is attached to the group — NH — C;

Yl, Y2, Y3 and Y4 each independently represent CR3 or N, provided that at least one of Yl, Y2, Y3 and Y4 is CR3;

Y5 and Y6 each independently represent CR3 or N, provided that at least one of Y5 and Y6 is CR3;

Y7 is O, S or N(R3a); each R3 independently is hydrogen, halogen, hydroxyl, nitro, cyano, formyl, carboxy, carboxamido, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl- 6alkyl)(C3-12cycloalkyl)amino, di(C3-12cycloalkyl)amino, (Cl-6alkoxycarbonyl)amino, Cl-6alkoxy, Cl-6alkoxy carbonyl, sulphonate, sulphate, phosphate, quartenary ammonium, phosphonate, guanidimium, Cl-6alkyl, Cl-6halogenalkyl, Cl-6hydroxyalkyl, Cl- 6alkylcarbonyl(Cl-6alkyl), Cl-6alkoxy(Cl-6alkyl), Cl-6alkoxycarbonyl(Cl-6alkyl), Cl- 6aminoalkyl, Cl-6alkylamino(Cl-6alkyl), di-(Cl-6alkyl)amino(Cl-6alkyl), C3-12cycloalkyl, C3-12halogencycloalkyl, Cl-6alkyl(C3-12cycloalkyl), C3-12cycloalkyl(Cl-6alkyl), C3- 12cycloalkyloxy, C2-6alkenyl, C2-6halogenalkenyl, C2-6alkynyl or C2-6halogenalkynyl; R3a is hydrogen, Cl-6alkyl, Cl-6halogenalkyl, C3-12cycloalkyl, C3-12halogencycloalkyl, Cl-6alkyl(C3-12cycloalkyl) or C3-12cycloalkyl(Cl-6alkyl);

C is a 5- to 12-membered aromatic ring system, which may be monocyclic or fused polycyclic, which may contain from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system itself may be substituted once or more than once by Rb; each Rb independently is halogen, hydroxyl, nitro, cyano, formyl, carboxy, carboxamido, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl-6alkyl)(C3- 12cycloalkyl)amino, di(C3-12cycloalkyl)amino, (Cl-6alkoxycarbonyl)amino, (Cl- 6alkylcarbonyl)amino, Cl-6alkoxy, Cl-6alkoxy carbonyl, sulphonate, sulphate, phosphate, quartenary ammonium, phosphonate, guanidimium, Cl-6alkyl, Cl-6halogenalkyl, Cl- 6hydroxyalkyl, Cl-6alkylcarbonyl(Cl-6alkyl), Cl-6alkoxy(Cl-6alkyl), Cl- 6alkoxycarbonyl(Cl-6alkyl), Cl-6aminoalkyl, Cl-6alkylamino(Cl-6alkyl), di-(Cl- 6alkyl)amino(Cl-6alkyl), C3-12cycloalkyl, C3-12halogencycloalkyl, Cl-6alkyl(C3- 12cycloalkyl), C3-12cycloalkyl(Cl-6alkyl), C3-12cycloalkyloxy, C2-6alkenyl, C2- 6halogenalkenyl, C2-6alkynyl or C2-6halogenalkynyl; or two groups Rb bound to adjacent carbon atoms of the ring system together are a C3- 6alkandiyl group, wherein a carbon atom may be substituted by — O — , — S — , — N(Rc) — , — C(=O) — , — C(=S) — , — C(=NRd) — , — S(=O) — or — SO2 — , and wherein the group may be substituted once or more than once by Re; each Rc, Rd or Re independently is halogen or Cl-6alkyl; or two groups Rb bound to adjacent carbon atoms of the ring system together are a group — O— (C(Rf)2), — O— ; each Rf independently is hydrogen, halogen or Cl-6alkyl; n is 1 or 2; and salts, solvates, hydrates and N-oxides thereof.

[001180] In an embodiment, the glutamate modulator is a compound according to: wherein

XI, X2 each independently represent CR2 or N; R2a, R2b each independently represent a group chosen from hydrogen, halogen, hydroxy, Cl-6alkyl, Cl-6halogenalkyl, C3-12cycloalkyl, amino, Cl-6alkoxy, C3-12cycloalkyloxy, sulphonate, sulphate, phosphate, quartenary ammonium, phosphonate and guanidimium;

R1 is Cl-6alkyl or C3-12cycloalkyl;

Y 1 and Y2 each independently represent CR3 or N;

R3 represents hydrogen, halogen, hydroxy, Cl-6alkyl, C3-12cycloalkyl, Cl-6alkoxy, C3- 12cycloalkyloxy, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl- 6alkyl)(C3-12cycloalkyl)amino, di(C3-12cycloalkyl)amino or cyano;

Zl, Z2, Z3, Z4 each independently represent CR4 or N, provided that at least one is CR4; and R4 represents hydrogen, halogen, hydroxy, Cl-6alkyl, C3-12cycloalkyl, Cl-6alkoxy, C3- 12cycloalkyloxy, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl- 6alkyl)(C3-12cycloalkyl)amino or di(C3-12cycloalkyl)amino, cyano, Cl-6hydroxyalkyl, Cl- 6alkoxy carbonyl or Cl-6alkylcarbonylamino.

[001181] In an embodiment, the glutamate modulator is a compound according to: wherein

R2a, R2b each independently represent a group chosen from hydrogen, halogen, hydroxy, Cl-6alkyl, Cl-6halogenalkyl, C3-12cycloalkyl, amino, Cl-6alkoxy, C3-12cycloalkyloxy, sulphonate, sulphate, phosphate, quartenary ammonium, phosphonate and guanidimiumcyano;

R1 is Cl-6alkyl or C3-12cycloalkyl;

Y 1 and Y2 each independently represent CR3 or N;

R3 represents hydrogen, halogen, hydroxy, Cl-6alkyl, C3-12cycloalkyl, Cl-6alkoxy, C3- 12cycloalkyloxy, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl- 6alkyl)(C3-12cycloalkyl)amino, di(C3-12cycloalkyl)amino or cyano;

Z2 represents CR4 or N; and R4 represents hydrogen, halogen, hydroxy, Cl-6alkyl, C3-12cycloalkyl, Cl-6alkoxy, C3- 12cycloalkyloxy, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl- 6alkyl)(C3-12cycloalkyl)amino or di(C3-12cycloalkyl)amino; and

R6 is selected from hydrogen, hydroxy, halogen, Cl-6alkyl, C3-12cycloalkyl, Cl-6alkoxy, C3-12cycloalkyloxy, cyano, Cl-6hydroxyalkyl, Cl-6alkoxy carbonyl and Cl- 6alkylcarbonylamino.

Formula 274

[001182] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 274. Such compounds are described in WO 2008/155588, published December 24, 2008, corresponding to PCT/HU2008/000068, filed June 17, 2008, and US 2009/0042934, published February 12, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 274, this reference incorporated by reference herein controls.

[001183] In an embodiment, the glutamate modulator is a compound according to: wherein

Ari represents an optionally substituted phenyl or heteroaryl group;

Ar2 represents a substituted phenyl or an optionally substituted heteroaryl group;

Rl, R2, R3 and R4 represent independently a substituent selected from hydrogen, halogen, cyano, alkyl, alkoxy, hydroxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, and dialkylaminomethyl; or salts, hydrates, solvates, or polymorphs thereof.

[001184] In further embodiments, the glutamate modulator is a compound selected from:

3-(3-cyano-benzenesulfonyl)-7-fluoro-4-(4-fluoro-phenyl)- quinoline;

3-(3-chloro-4-fluoro-benzenesulfonyl)-4-(4-chloro-phenyl) -7-fluoro-quinoline;

3-(3-chloro-4-fluoro-benzenesulfonyl)-7-fluoro-4-(4-fluor o-phenyl)-quinoline;

7-chloro-3-(3-cyano-5-fluoro-benzenesulfonyl)-4-(3-fluoro -phenyl)-quinoline;

3-(3-chloro-4-fluoro-benzenesulfonyl)-7-fluoro-4-(2-fluor o-phenyl)-quinoline; 4-(4-chloro-phenyl)-3-(3-cyano-benzenesulfonyl)-7-fluoro-qui noline;

3 -(3 -cy ano-5 -fluoro-benzenesulfonyl)-7-fluoro-4-(3 -fluoro-phenyl)-quinoline;

7-chl oro-3 -(3 -cyano-benzenesulfonyl)-4-(3 -fluoro-phenyl)-quinoline;

4-(3-chloro-phenyl)-3-(3-cyano-4-fluoro-benzenesulfonyl)- 7-fluoro-quinoline; 7-chloro-3-(3-cyano-benzenesulfonyl)-4-(4-fluoro-phenyl)-qui noline;

4-(4-chloro-phenyl)-3-(3,4-difluoro-benzenesulfonyl)-7-fl uoro-quinoline;

4-(4-chloro-phenyl)-3-(3-cyano-5-fluoro-benzenesulfonyl)- 7-fluoro-quinoline, 3-(3-cyano-benzenesulfonyl)-7-fluoro-4-(4-fluoro-phenyl)-qui noline;

3-(3-chloro-4-fluoro-benzenesulfonyl)-4-(4-chloro-phenyl) -7-fluoro-quinoline; 3-(3-chloro-4-fluoro-benzenesulfonyl)-7-fluoro-4-(4-fluoro-p henyl)-quinoline; 7-chloro-3-(3-cyano-5-fluoro-benzenesulfonyl)-4-(3-fluoro-ph enyl)-quinoline;

3-(3-chloro-4-fluoro-benzenesulfonyl)-7-fluoro-4-(2-fluor o-phenyl)-quinoline;

4-(4-chloro-phenyl)-3-(3-cyano-benzenesulfonyl)-7-fluoro- quinoline;

3 -(3 -cy ano-5 -fluoro-benzenesulfonyl)-7-fluoro-4-(3 -fluoro-phenyl)-quinoline; and 7-chl oro-3 -(3 -cyano-benzenesulfonyl)-4-(3 -fluoro-phenyl)-quinoline;

4-(3-chloro-phenyl)-3-(3-cyano-4-fluoro-benzenesulfonyl)- 7-fluoro-quinoline; 7-chloro-3-(3-cyano-benzenesulfonyl)-4-(4-fluoro-phenyl)-qui noline;

4-(4-chloro-phenyl)-3-(3,4-difluoro-benzenesulfonyl)-7-fl uoro-quinoline; and 4-(4-chloro-phenyl)-3-(3-cyano-5-fluoro-benzenesulfonyl)-7-f luoro-quinoline, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 275

[001185] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 275. Such compounds are described in 2008/152090, published December 18, 2008, corresponding to PCT/EP2008/057374, filed June 12, 2008 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 275, this reference incorporated by reference herein controls.

[001186] In an embodiment, the glutamate modulator is a compound according to Formula 275:

, wherein

R1 is phenyl optionally substituted by one or more halogens;

L is a three atom linker selected from the group consisting of

— OC(Ra)2C(Rb)2 — , and — C(=O)C(Ra)2C(Rb)2 — , wherein the left hand atom of the linker is attached to Rl; wherein each Ra which may be the same or different, is hydrogen or Cl-3alkyl; or the two Ra groups together with the carbon atom to which they are attached form a 3-6-membered cycloalkane ring; each Rb which may be the same or different, is hydrogen or Cl-3alkyl; or the two Rb groups together with the carbon atom to which they are attached form a 3-6- membered cycloalkane ring; and wherein either the two Ra groups or the two Rb groups may form a cycloalkane ring; n is 0, 1 or 2; when n is 1 or 2, R2 is independently Cl-3alkyl or haloC 1-3 alkyl; and

R3 is phenyl optionally substituted by one or more groups independently selected from the group consisting of halogen, Cl-3alkyl, haloC 1-3 alkyl, cyano, — CH(=NOH) and hydroxyC 1-3 alkyl; wherein one of the groups is attached to the ortho position on the phenyl. [001187] In an embodiment, the glutamate modulator is a compound selected from: 2-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-piperazinyl)-6-(tr ifluoromethyl) benzonitrile; 2,3-dichloro-6-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-piper azinyl)benzonitrile;

2-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-piperazinyl)-5- (trifluoromethyl)benzonitrile, 3 -chloro-6-(4- { 3 - [(4-fluorophenyl)oxy ]propanoyl } - 1 -piperazinyl)-2- (trifluoromethyl)benzonitrile;

1 -(2,3 -dichloro-4-fluorophenyl)-4- { 3 -[(4-fluorophenyl)oxy]propanoyl (piperazine; 2-chl oro-3 -fluoro-6-(4- { 3 -[(4-fluorophenyl)oxy]propanoyl ( - 1 -piperazinyl)benzonitrile; 2-(4-{3-[(4-fluorophenyl)oxy]propanoyl(-l-piperazinyl)-6-(tr ifluoromethyl)benzaldehyde; 2-fluoro-6-(4-{3-[(4-fluorophenyl)oxy]propanoyl(-l-piperazin yl)benzonitrile; 3,5-dichloro-2-(4-{3-[(4-fluorophenyl)oxy]propanoyl(-l-piper azinyl)benzonitrile;

1-[2-chloro-3-(trifluoromethyl)phenyl]-4-{3-[(4-fluorophe nyl)oxy]propanoyl(piperazine;

2-{4-[3-(phenyloxy)propanoyl]-l-piperazinyl(-6-(trifluoro methyl)benzonitrile; 1-(2,3-dichlorophenyl)-4-{3-[(4-fluorophenyl)oxy]propanoyl}p iperazine,

5-fluoro-2-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-pipera zinyl)benzonitrile;

2-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-piperazinyl)-6- (trifluoromethyl)benzaldehyde oxime;

2-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-piperazinyl)-6- (trifluoromethyl)benzaldehyde O- methyloxime;

[2 - (4 - { 3 - [(4-fluorophenyl)oxy ]propanoyl } - 1 -piperazinyl)-6-

(trifluoromethyl)phenyl]methanol;

1-(2,3-dichlorophenyl)-4-[3-(phenyloxy)propanoyl]piperazi ne;

2-(4-{3-[(3-bromophenyl)oxy]propanoyl}-l-piperazinyl)-6-( trifluoromethyl)benzonitrile;

5-chloro-2-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-pipera zinyl)benzonitrile;

2-chloro-6-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-pipera zinyl)benzonitrile;

5-fluoro-2-{-4-[3-(phenyloxy)propanoyl]-l-piperazinyl}ben zonitrile;

1 - { 3 - [(4-bromophenyl)oxy ]propanoyl } -4-(2,3 -dichlorophenyl)piperazine;

1-(2,3-dichlorophenyl)-4-{3-[(3-fluorophenyl)oxy]propanoy l}piperazine;

2-[4-(4-oxo-4-phenylbutanoyl)-l-piperazinyl]-6-(trifluoro methyl)benzonitrile;

2-(4-{3-[(4-fluorophenyl)oxy]propanoyl}-l-piperazinyl)ben zonitrile;

1 - { 3 - [(4-fluorophenyl)oxy ]propanoyl } -4-[4-(trifluoromethyl)phenyl]piperazine;

2-{4-[3-(phenyloxy)propanoyl]-l-piperazinyl}benzonitrile; l-(2-chlorophenyl)-4-[3-(phenyloxy)propanoyl]piperazine; l-(2,6-dimethylphenyl)-4-[3-(phenyloxy)propanoyl]piperazine;

4-[4-(2, 3 -dichlorophenyl)- 1 -piperazinyl]- 1 -(4-fluorophenyl)-4-oxo- 1 -butanone; l-(2,3-dimethylphenyl)-4-[3-(phenyloxy)propanoyl]piperazine;

1-(2,3-dichlorophenyl)-4-{3-[(3,4-difluorophenyl)oxy]prop anoyl}piperazine; and

2-(4-{3-[(3-fluorophenyl)oxy]propanoyl}-l-piperazinyl)-6- (trifluoromethyl)benzonitrile; or a pharmaceutically acceptable salt thereof, or a substituted variant retaining glutamate modulatory activity.

[001188] In further embodiments, the glutamate modulator is the compound:

5-Fluoro-2-[4-({[(4-fluorophenyl)methyl]oxy}acetyl)-l-pip erazinyl]benzonitrile;

, or a pharmaceutically acceptable salt thereof or substituted variant thereof retaining glutamate modulatory activity.

Formula 276

[001189] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 276. Such compounds are described in WO 2008/151184, published December 11, 2008, corresponding to PCT/US2008/065647, filed June 3, 2008, and US 2009/0042855, published February 12, 2009, which are incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 276, this reference incorporated by reference herein controls.

[001190] In an embodiment, the glutamate modulator is a compound according to Formula 276: wherein R1 and R2 are independently optionally substituted organic radicals comprising from 1 to 12 carbon atoms; wherein each — is an optional covalent bond; wherein Y1 and Y2 are independently selected from N and C — R; wherein R comprises two to four substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, or an organic radical comprising 1 to 12 carbon atoms; wherein Zl, Z2, and Z3 are independently selected from N and C — R4, with the proviso that no more than two of Zl, Z2, and Z3 are nitrogen; and wherein R4 comprises up to five substituents independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, thiol, optionally substituted alkyl or alkenyl or alkynyl, optionally substituted heteroalkyl or heteroalkenyl or heteroalkynyl, optionally substituted cycloalkyl or cycloalkenyl or cycloalkynyl, optionally substituted heterocycloalkyl or heterocycloalkenyl or heterocycloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxyl, optionally substituted thioalkyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted amino, thioamido, amidosulfonyl, alkoxycarbonyl, carboxamide, amino-carbonyl, and alkylaminecarbonyl; or a pharmaceutically acceptable salt or N-oxide thereof.

Formula 277

[001191] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 277. Such compounds are described in WO 2008/128968, published October 30, 2008, corresponding to PCT/EP2008/054682, filed April 17, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 277, this reference incorporated by reference herein controls.

[001192] In an embodiment, the glutamate modulator is a compound according to Formula 277: wherein:

XI, X2, X3, X4 each independently represent CR2 or N, provided that at least two of XI, X2, X3 and X4 are CR2; each R2 independently is hydrogen, halogen, hydroxyl, nitro, cyano, formyl, carboxy, carboxamido, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl- 6alkyl)(C3-12cycloalkyl)amino, di(C3-12cycloalkyl)amino, (Cl-6alkoxycarbonyl)amino, Cl-6alkoxy, Cl-6alkoxy carbonyl, sulphonate, sulphate, phosphate, quartenary ammonium, phosphonate, guanidimium, Cl-6alkyl, Cl-6halogenalkyl, Cl-6hydroxyalkyl, Cl- 6alkylcarbonyl(Cl-6alkyl), Cl-6alkoxy(Cl-6alkyl), Cl-6alkoxycarbonyl(Cl-6alkyl), Cl- 6aminoalkyl, Cl-6alkylamino(Cl-6alkyl), di-(Cl-6alkyl)amino(Cl-6alkyl), C3-12cycloalkyl, C3-12halogencycloalkyl, Cl-6alkyl(C3-12cycloalkyl), C3-12cycloalkyl(Cl-6alkyl), C3- 12cycloalkyloxy, C2-6alkenyl, C2-6halogenalkenyl, C2-6alkynyl or C2-6halogenalkynyl; R1 is Cl-6alkyl, Cl-6halogenalkyl, C3-12cycloalkyl, C3-12halogencycloalkyl, Cl- 6alkyl(C3-12cycloalkyl) or C3-12cycloalkyl(Cl-6alkyl); or, when X4 is CR2, Rl, R2 and the nitrogen and two carbon atoms, to which R1 and R2 are bound, may form together a 5- to 8-membered heterocyclic ring system, which may be aromatic or partially saturated and which may contain from 1 to 2 further hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the heterocyclic ring system itself may be substituted once or more than once by Ra; each Ra independently is halogen, nitro, cyano, formyl, carboxy, carboxamido, hydroxyl, amino, (Cl-6alkyl)amino, di-(Cl-6alkyl)amino, (Cl-6alkoxycarbonyl)amino, Cl-6alkoxy, Cl-6alkoxy carbonyl, Cl-6alkyl, Cl-6halogenalkyl, Cl-6hydroxyalkyl, Cl- 6alkylcarbonyl(Cl-6alkyl), Cl-6alkoxy(Cl-6alkyl), Cl-6alkoxycarbonyl(Cl-6alkyl), Cl- 6aminoalkyl, Cl-6alkylamino(Cl-6alkyl), di-(Cl-6alkyl)amino(Cl-6alkyl), C2-6alkenyl, C2- 6halogenalkenyl, C2-6alkynyl or C2-6halogenalkynyl;

B is

Bl wherein the bond marked with the asterisk is attached to the group — NH — C;

Yl, Y2, Y3 and Y4 each independently represent CR3 or N, provided that at least one of Yl, Y2, Y3 and Y4 is CR3; Y5 and Y6 each independently represent CR3 or N, provided that at least one of Y5 and Y6 is CR3;

Y7 is O, S or N(R3a); each R3 independently is hydrogen, halogen, hydroxyl, nitro, cyano, formyl, carboxy, carboxamido, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl- 6alkyl)(C3-12cycloalkyl)amino, di(C3-12cycloalkyl)amino, (Cl-6alkoxycarbonyl)amino, Cl-6alkoxy, Cl-6alkoxy carbonyl, sulphonate, sulphate, phosphate, quartenary ammonium, phosphonate, guanidimium, Cl-6alkyl, Cl-6halogenalkyl, Cl-6hydroxyalkyl, Cl- 6alkylcarbonyl(Cl-6alkyl), Cl-6alkoxy(Cl-6alkyl), Cl-6alkoxycarbonyl(Cl-6alkyl), Cl- 6aminoalkyl, Cl-6alkylamino(Cl-6alkyl), di-(Cl-6alkyl)amino(Cl-6alkyl), C3-12cycloalkyl, C3-12halogencycloalkyl, Cl-6alkyl(C3-12cycloalkyl), C3-12cycloalkyl(Cl-6alkyl), C3- 12cycloalkyloxy, C2-6alkenyl, C2-6halogenalkenyl, C2-6alkynyl or C2-6halogenalkynyl; R3a is hydrogen, Cl-6alkyl, Cl-6halogenalkyl, C3-12cycloalkyl, C3-12halogencycloalkyl, Cl-6alkyl(C3-12cycloalkyl) or C3-12cycloalkyl(Cl-6alkyl);

C is a 5- to 12-membered aromatic ring system, which may be monocyclic or fused polycyclic, which may contain from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system itself may be substituted once or more than once by Rb; each Rb independently is halogen, hydroxyl, nitro, cyano, formyl, carboxy, carboxamido, amino, Cl-6alkylamino, C3-12cycloalkylamino, di(Cl-6alkyl)amino, (Cl-6alkyl)(C3- 12cycloalkyl)amino, di(C3-12cycloalkyl)amino, (Cl-6alkoxycarbonyl)amino, (Cl- 6alkylcarbonyl)amino, Cl-6alkoxy, Cl-6alkoxy carbonyl, sulphonate, sulphate, phosphate, quartenary ammonium, phosphonate, guanidimium, Cl-6alkyl, Cl-6halogenalkyl, Cl- 6hydroxyalkyl, Cl-6alkylcarbonyl(Cl-6alkyl), Cl-6alkoxy(Cl-6alkyl), Cl- 6alkoxycarbonyl(Cl-6alkyl), Cl-6aminoalkyl, Cl-6alkylamino(Cl-6alkyl), di-(Cl- 6alkyl)amino(Cl-6alkyl), C3-12cycloalkyl, C3-12halogencycloalkyl, Cl-6alkyl(C3- 12cycloalkyl), C3-12cycloalkyl(Cl-6alkyl), C3-12cycloalkyloxy, C2-6alkenyl, C2- 6halogenalkenyl, C2-6alkynyl or C2-6halogenalkynyl; or two groups Rb bound to adjacent carbon atoms of the ring system together are a C3- 6alkandiyl group, wherein a carbon atom may be substituted by — O — , — S — , — N(Rc) — , — C(=O) — , — C(=S) — , — C(=NRd) — , — S(=O) — or — SO2 — , and wherein the group may be substituted once or more than once by Re; each Rc, Rd or Re independently is halogen or Cl-6alkyl; or two groups Rb bound to adjacent carbon atoms of the ring system together are a group — O— (C(Rf)2), — O— ; each Rf independently is hydrogen, halogen or Cl-6alkyl; n is 1 or 2; and salts, solvates, hydrates and N-oxides thereof.

Formula 278

[001193] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 278. Such compounds are described in WO 2008/107418, published September 12, 2008, corresponding to PCT/EP2008/052564, filed March 3, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 278, this reference incorporated by reference herein controls.

[001194] In an embodiment, the glutamate modulator is a compound according to Formula 278: wherein

U represents C or N;

V represents CH, N, or O;

W represents C, N, or O;

R1 represents an optionally substituted aryl or an optionally substituted heteroaryl group;

R2 if present is selected from the group consisting of H, alkyl, aryl, hydroxy or alkoxy;

R3 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or 3-Cl-phenyl; in free base or acid addition salt form, including other pharmaceutically acceptable salts thereof or substituted variants retaining glutamate modulatory activity.

Formula 279

[001195] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 279. Such compounds are described in WO 2008/092072, published July 31, 2008, corresponding to PCT/US2008/052032, filed January 25, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 279, this reference incorporated by reference herein controls. [001196] In an embodiment, the glutamate modulator is a compound according to formula 279:

(I), wherein X is N or CH; and R4 is Ci -CO alkyl; Y is C or N and when Y is N, R3 is nonexistent; when X is CH, R1 is cyano, halo, aryl, substituted aryl, or heteroaryl; R2 is hydrogen, aryl, 2-pyridyl, or haloaryl;

R3 is hydrogen or halo; with the proviso that when R1 is cyano or halo and X is CH, both R2 and R3 are not hydrogen simultaneously; and when X is N, R1 is haloaryl, dihaloaryl, or trihaloaryl, and R2 and R3 are hydrogen; or a compound of formula 279b: wherein X is N or CH; R6 is Ci-C6 alkyl; and R5 is hydrogen, cyano, or halo; or a pharmaceutically acceptable salt thereof

[001197] In further embodiments, the glutamate modulator is a compound selected from: , including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 280 [001198] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 280. Such compounds are described in WO 2008/056259, published May 15, 2008, corresponding to PCT/IB2007/004160, filed November 7, 2007, and US 2010/0081690, published April 1, 2010, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 280, this reference incorporated by reference herein controls.

[001199] In an embodiment, the glutamate modulator is a compound according to Formula 280:

, Wherein

W represents (C5-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkyl- (Cl-C3)alkyl or (C3-C7)heterocycloalkenyl ring;

R1 and R2 represent independently hydrogen, — (Cl-C6)alkyl, — (C2-C6)alkenyl, — (C2-C6)alkynyl, arylalkyl, heteroarylalkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, — (Cl-C6)alkoxy or R1 and R2 together can form a (C3-C7)cycloalkyl ring, a carbonyl bond C=O or a carbon double bond;

P and Q are each independently selected and denote a cycloalkyl, a heterocycloalkyl, an aryl or heteroaryl group of formula R3, R4, R5, R6, and R7 independently are hydrogen, halogen, — NO2, — (Cl-C6)alkyl, — (C3-C6)cycloalkyl, — (C3- C7)cycloalkylalkyl, — (C2-C6)alkenyl, — (C2-C6)alkynyl, halo-(Cl-C6)alkyl, heteroaryl, heteroarylalkyl, arylalkyl, aryl, — OR8, — NR8R9, — C(=NR10)NR8R9, — NR8COR9, NR8CO2R9, NR8SO2R9, — NR10CONR8R9, — SR8, — S(=O)R8, — S(=O)2R8, — S(=O)2NR8R9, — C(=0)R8, — C(=O)NR8R9, C(=NR8)R9, or C(=NOR8)R9 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, — CN, — (Cl-C6)alkyl, — O— (C0-C6)alkyl, — O— (C3-C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — O — (Cl-C3)alkylheteroaryl, — N(( — C0-C6)alkyl)((C0- C3)alkylaryl) or — N((C0-C6)alkyl)((C0-C3-)alkylheteroaryl) groups;

R8, R9, RIO each independently is hydrogen, (Cl-C6)alkyl, (C3-C6)cycloalkyl, (C3- C7)cycloalkylalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, halo-(Cl-C6)alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — O — (C0-C6)alkyl, — O — (C3-C7)cycloalkylalkyl, — O(aryl), — O(hetero aryl), — N(C0-C6-alkyl)2, — N((C0-C6)alkyl)((C3-C7-)cycloalkyl) or — N((C0-C6)alkyl)(aryl) substituents;

D, E, F, G and H represent independently — C(R3)=, — C(R3)=C(R4) — , — C(=O) — , — C(=S)— , — O— , — N=, — N(R3)— or — S— ;

A is hydrogen, (Cl-C6)alkyl, (C3-C6)cycloalkyl, (C3-C7)cycloalkylalkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, halo-(Cl-C6)alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — O — (C0-C6)alkyl, — O — (C3-C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — N(C0-C6-alkyl)2, — N((C0-C6)alkyl)((C3-C7- )cycloalkyl) or — N((C0-C6)alkyl)(aryl) substituents;

B represents a single bond, — C(=O) — (C0-C2)alkyl-, — C(=O) — (C2-C6)alkenyl-, — C(=O)— (C2-C6)alkynyl-, — C(=O)— O— , — C(=0)NR8— (C0-C2)alkyl-, — C(=NR8)NR9— S(=O)— (C0-C2)alkyl-, — S(=O)2— (C0-C2)alkyl-, — S(=O)2NR8— (C0-C2)alkyl-, C(=NR8)— (C0-C2)alkyl-, — C(=N0R8)— (C0- C2)alkyl- or — C(=NOR8)NR9— (C0-C2)alkyl-;

R8 and R9, independently are as defined above;

Any N may be an N-oxide; or pharmaceutically acceptable salts, hydrates or solvates of such compounds.

[001200] In an embodiment, the glutamate modulator is a compound selected from: (4-Fluoro-phenyl)- { (S)-3 -[4-(4-fluoro- lH-pyrrol-2-yl)-oxazol-2-yl]-piperidin- 1 -y 1 } - methanone

(6-Fluoro-pyri din-3 -yl)- { (S)-3 - [4-(4-fluoro- 1 H-pyrrol-2-yl)-oxazol-2-yl] -piperidin- 1 -y 1 } - methanone (4-Fluoro-phenyl)-{(S)-3-[4-(4-fluorophenyl)-oxazol-2-yl]-pi peridin-l-yl}-methanone (6-Fluoro-pyri din-3 -yl)- { (S)-3 -[4-(4-fluoro-phenyl)-oxazol-2-yl]-piperidin- 1 -yl } -methanone (2-Fluoro-pyridin-4-yl)- { (S)-3 -[4-(4-fluoro-phenyl)-oxazol-2-yl]-piperidin- 1 -yl } -methanone (3 -Fluoro-pyridin-4-yl)- { (S)-3 -[4-(4-fluoro-phenyl)-oxazol-2-yl]-piperidin- 1 -yl } -methanone (S)-(3-(4-(4-Fluoro-phenyl)-oxazol-2-yl)-piperidin-l-yl)(5-m ethyl-isoxazol-4-yl)-methanone (S)-(4-Fluoro-phenyl)(3-(4-(pyridin-2-yl)-oxazol -2 -yl)-piperi din- l-yl)-m ethanone (S)-(3,4-Difluoro-phenyl)(3-(4-(pyridin-2-yl)-oxazol-2-yl)-p iperidin-l-yl)-methanone (S)-(4-Fluoro-phenyl)(3-(4-(5-fluoro-pyridin-2-yl)-oxazol-2- yl)-piperidin-l-yl)-methanone (S)-(4-Fluoro-phenyl)(3-(4-(2-fluoro-phenyl)-oxazol -2 -yl)-piperi din- l-yl)-m ethanone (S)-(3-(4-(2-Fluoro-phenyl)-oxazol-2-yl)-piperidin-l-yl)(6-f luoro-pyridin-3-yl)-methanone (S)-(3-(4-(2-Fluoro-phenyl)-oxazol-2-yl)-piperidin-l-yl)(2-f luoro-pyridin-4-yl)-methanone (S)-(3-(4-(2,4-Difluoro-phenyl)-oxazol-2-yl)-piperi din- l-yl)(4-fluoro-phenyl)-m ethanone (S)-(3-(4-(2,4-Difluoro-phenyl)-oxazol-2-yl)-piperi din- l-yl)(6-fluoro-pyri din-3 -yl)- methanone

(S)-(3-(4-(2,4-Difluoro-phenyl)-oxazol-2-yl)-piperidin-l- yl)(2-fluoro-pyridin-4-yl)- methanone, and pharmaceutically acceptable salts thereof, and substituted variants retaining glutamate modulatory activity.

Formula 281

[001201] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 281. Such compounds are described in WO 2008/035049, published March 27, 2008, corresponding to PCT/GB2007/003518, filed September 17, 2007 , which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 281, this reference incorporated by reference herein controls.

[001202] In an embodiment, the glutamate modulator is a compound according to:

R1 represents aryl, biaryl, heteroaryl, aryl -heteroaryl, heteroaryl-aryl, or heteroarylheteroaryl; R2 represents hydrogen or C-l-6alkyl;

R3 represents hydrogen, cyano, nitro, d-Palkyl or Cl-6alkoxyCl-6alkyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; wherein the term "aryl" represents phenyl or naphthyl, wherein the aryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Ci-6alkyl, Ca-Palkenyl, Ci-6alkoxy, Cl-6alkoxy-Cl-6alkyl, amino, hydroxy, nitro, cyano, Cl-6alkoxy carbonyl, Cl-6alkylamino, Cl-6alkylamino-Cl-6alkyl, di-Cl-6alkylamino, cycloC3-12alkoxy, aryloxy, cycloC3-12alkylamino, cyc!oC3-12alkyl-Cl-6alkylamino, di- Cl-6alkylaminoCl-6alkyl, arylamino, arylCl-6alkylamino, arylCl-6alkoxy, heteroarylC-1- 6alkoxy, heteroarylamino, heteroarylCl-6alkylamino, pyrrolidine, piperidino, morpholino, hexamethyleneimino, -N(R5)-C(=O)-R4, -N(R5)-SO2-R4, -N(R5)-C(=O)OR4, C(=0)-R4, C(=O)N(R5)2, and a bivalent radical selected from -(CH2)3-, -(CH2)4-, -CH=CH-CH=CH-, -(CH2)3O-, -0CH20-, -0(CH2)2O-, and -O(CH2)3-; the term "biaryl" represents biphenylene, wherein one or both phenyl rings may be optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, Cl-6alkyl, C2-6alkenyl, Cl-6alkoxy, Cl-6alkoxyCl-6alkyl, amino, hydroxy, nitro, cyano, Cl-6alkoxy carbonyl, Cl-6alkylamino, Cl-6alkylamino-Cl-6alkyl, di-Cl-6alkylamino, cycloC3-12alkoxy, aryloxy, cycloC3-12alkylamino, cycloC3-12alkyl-C-l-6alkylamino, di- Cl-6alkylaminoCl-6alkyl, arylamino, arylCl-6alkylamino, heteroarylCl-6alkoxy, heteroarylamino, heteroarylCl-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R5)-C(=O)-R4, -N(R5)-SO2-R4, -N(R5)- C(=0)0R4, C(=0)-R4, C(=0)N(R5) 2, and a bivalent radical selected from -(CH2)3-, -(CH2)4-, -CH=CH-CH=CH-, -(CH2)3O-, -0CH20-, -Q(CH2)2O-, and -O(CH2)3-; and the term "heteroaryl" represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Cl-6alkyl, Cl-6alkenyl, Cl-6alkoxy, Cl-6alkoxyCl-6alkyl, amino, hydroxy, nitro, cyano, Cl-6alkoxy carbonyl, Cl- 6alkylamino, Cl-6alkylamino-Cl-6alkyl, di-Cl-6alkylamino, cycloC3-12alkoxy, aryloxy, cycloC3 - 12alkylamino, cycloC3 - 12alkyl- Cl-6alkylamino, di-Cl-6alkylaminoCl-6alkyl, arylamino, arylCl-6alkylamino, heteroarylCl-6alkoxy, heteroarylamino, heteroarylC-l-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R5)-C(=O)-R4, -N(R5)-SO2-R4, -N(R5)-C(=O)OR4, C(=0)-R4, C(=O)N(R5)2, and a bivalent radical selected from -(CH2)3-, -(CH2)4-, -CH=CH-CH=CH-, -(CH2)3O-, -0CH20-, -O(CH2)2O-, and -O(CH2)3-; wherein

R4 represents hydrogen, Cl-6alkyl which may be optionally substituted with one or more halogen atoms, cycloC3-12alkyl, aryl, heteroaryl, adamantyl, carboxyCl-6alkyl or CF3; and R5 represents hydrogen, Cl-6alkyl, cycloC3-12alkyl, aryl, heteroaryl, adamantyl, carboxyCl-6alkyl, alkylcarbonyl or CF3.

Formula 282

[001203] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 282. Such compounds are described in WO 2008/031550, published March 20, 2008, corresponding to PCT/EP2007/007873, filed September 10, 2007 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 282, this reference incorporated by reference herein controls.

[001204] In an embodiment, the glutamate modulator is a compound according to: wherein

R1 represents optionally substituted alkyl or optionally substituted benzyl; and

R2 represents hydrogen (H), optionally substituted alkyl or optionally substituted benzyl; or

R1 and R2 form together with the nitrogen atom to which they are attached an optionally substituted heterocycle with less than 14 ring atoms;

R3 represents halogen, alkyl, alkoxy, alkylamino or dialkylamino;

R4 represents hydroxy (OH), halogen, alkyl or alkoxy;

Q represents CH, CR4 or N;

V represents CH, CR4 or N; w represents CH, CR4 or N;

X represents CH or N; Y represents CH, CR3 or N;

Z represents CH2, NH or O; and provided that Q, V and W are not N at the same time; in free base or acid addition salt form.

[001205] In further embodiments, the glutamate modulator is a compound according to:

, wherein m is 0 or 1, n is 0 or 1 and

A is hydroxy

X is hydrogen and

Y is hydrogen, or

A forms a single bond with X or with Y;

RO is hydrogen, (Cl-4)alkyl, (Cl-4)alkoxy, trifluoromethyl, halogen, cyano, nitro, — COOR1, wherein R1 is (Cl-4)alkyl or — COR2 wherein R2 is hydrogen or (Cl- 4)alkyl, and R is — COR3, — COOR3, — CONR4R5 or — SO2R6, wherein R3 is (C 1 - 4)alkyl, (C3-7)cycloalkyl or optionally substituted phenyl, 2-pyridyl or 2-thienyl; R4 and R5, independently, are hydrogen or (Cl-4)alkyl; and R6 is (Cl-4)alkyl, (C3- 7)cycloalkyl or optionally substituted phenyl,

R' is hydrogen or (Cl-4)alkyl and

R" is hydrogen or (Cl-4)alkyl, or

R' and R" together form a group — CH2 — (CH2)m wherein m is 0, 1 or 2, in which case one of n and m is different from 0, with the proviso that R0 is different from hydrogen, trifluoromethyl and methoxy when n is 0,

A is hydroxy, X and Y are both hydrogen, R is COOEt and R' and R" together form a group — (CH2)2— .

[001206] In further embodiments, the glutamate modulator is a compound according to: wherein

R1 represents hydrogen or alkyl;

R2 represents an unsubstituted or substituted heterocycle or R2 represents an unsubstituted or substituted aryl;

R3 represents alkyl or halogen;

X represents a single bond or an alkandiyl-group, optionally interrupted by one or more oxygen atoms or carbonyl groups or carbonyloxy groups; in free base or acid addition salt forms.

[001207] In further embodiments, the glutamate modulator is the compound (-)- (3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-l-c arboxylic acid methyl ester in free base or acid addition salt form, or a substituted variant thereof retaining glutamate modulatory activity.

Formula 283

[001208] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 283. Such compounds are described in WO 2008/015271, published February 7, 2008 and corresponding to PCT/EP2007/058062, filed August 3, 2007, and WO 2008/015270, published February 7, 2008, corresponding to PCT/EP2007/058061, filed August 3, 2007, and WO 2008/015269, published February 7, 2008, corresponding to PCT/EP2007/058060, filed August 3, 2007, which are incorporated by reference in their entireties herein. In the case of any conflict of terminology in the context of Formula 283, these references incorporated by reference herein control.

[001209] In an embodiment, the glutamate modulator is a compound according to:

wherein,

Y 1 represents N or C — ,

Y2 represents N or C — ,

Y3 represents N or C — ,

Y4 represents N or C — , whereby at least two of the groups Y1 to Y4 represent a carbon atom, R1 represents chloro or bromo;

R2 and R3 each independently represent hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl; or

R2 and R3 both together with the carbon atom of the ring represent a carbonyl group; R4 and R5 each independently represent hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl; or

R4 and R5 both together with the carbon atom of the ring represent a carbonyl group; R6 and R7 independently represent hydrogen, Cl-6-alkyl, C3-7cycloalkyl or trifluoromethyl; or

R6 and R7 both together with the carbon atom of the ring represent a carbonyl group; R2 or R3 together with R6 and R7 may also form a bivalent radical selected from the group CH2— CH2 and CH2— O;

RIO and R11 independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, Cl-6alkyl, C3-7cycloalkyl, C2- 6alkenyl, C2-6alkynyl, Cl-6alkoxy, C3-7-cycloalkyloxy, C2-6alkenyloxy, C2- 6alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, heterocyclyloxy, Cl- 6alkylamino, di-Cl-6alkylamino, C3-7-cycloalkylamino, di-C3-7-cycloalkylamino, Cl-6alkyl-C3-7-cycloalkylamino, C2-6alkenylamino, C2-6alkynylamino, di-C2- 6alkenylamino, di-C2-6alkynylamino, Cl-6alkyl-C2-6-alkenylamino, Cl-6alkyl-C2- 6-alkynylamino, C2-6alkenyl-C3-7-cycloalkylamino, C2-6alkynyl-C3-7- cycloalkylamino, C2-6alkenyl-C2-6-alkynylamino arylamino, diarylamino, aryl-Cl- 6alkylamino, aryl-C2-6alkenylamino, aryl-C2-6alkynylamino, aryl-C3-7- cycloalkylamino, heteroarylamino, diheteroarylamino, heteroaryl-Cl-6alkylamino, heteroaryl-C2-6alkenylamino, hetero-aryl-C2-6alkynylamino, heteroaryl-C3-7- cycloalkylamino, heteroarylarylamino, heterocyclylamino, diheterocyclylamino, heterocyclyl-C 1 -6alkylamino, heterocyclyl-C2-6alkenylamino, heterocyclyl-C2- 6alkynylamino, heterocyclyl-C3-7-cycloalkylamino, heterocyclylarylamino, heterocyclylhetero-arylamino, acyl, acyloxy, acylamino, Cl-6alkoxy carbonyl, C3-7- cycloalkoxy-carbonyl, C2-6alkenyloxy carbonyl, C2-6alkynyloxy carbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, aminocarbonyl, Cl-6alkylamino-carbonyl, di-Cl-6alkyl-aminocarbonyl, C3-7- cycloalkylaminocarbonyl, di-C3-7-cycloalkylaminocarbonyl, Cl-6alkyl-C3-7- cycloalkylaminocarbonyl, C2-6alkenyl-aminocarbonyl, C2-6alkynyl-aminocarbonyl, di-C2-6alkenylaminocarbonyl, di-C2-6alkynylaminocarbonyl, C 1 -6alkyl-C2-6- alkenylaminocarbonyl, Cl-6alkyl-C2-6-alkynyl-aminocarbonyl, C2-6alkenyl-C3-7- cycloalkylaminocarbonyl, C2-6alkynyl-C3-7-cycloalkylaminocarbonyl, C2-6alkenyl- C2-6-alkynylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryl-Cl- 6alkylaminocarbonyl, aryl-C2-6alkenylaminocarbonyl, aryl-C2- 6alkynylaminocarbonyl, aryl-C3-7-cycloalkylaminocarbonyl heteroarylaminocarbonyl, dihetero-arylaminocarbonyl, heteroaryl- C6alkylaminocarbonyl, heteroaryl-C2-6alkenyl-aminocarbonyl, heteroaryl-C2- 6alkynylaminocarbonyl, heteroaryl-C3-7-cycloalkyl-aminocarbonyl, heteroarylarylaminocarbonyl, heterocyclylaminocarbonyl, diheterocyclylamino- carbonyl, heterocyclyl-C 1 -6alkylaminocarbonyl, heterocyclyl-C2-6alkenylamino- carbonyl, heterocyclyl-C2-6alkynylaminocarbonyl, heterocyclyl-C3-7-cycloalkyl- aminocarbonyl, heterocyclylarylaminocarbonyl, heterocyclyl-heteroarylamino- carbonyl, Cl-6alkylsulfinyl, C3-7-cycloalkylsulfinyl, C2-6alkenyl-sulfinyl, C2- 6alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, Cl- 6alkylsulfonyl, C3-7-cycloalkylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, Cl-6alkyl sulfonylamino, or arylsulfonylamino; or RIO and R11 together with the two carbon atoms carrying them represent a heteroaryl having 5 or 6 ring members or a heterocyclyl group having 5 or 6 ring members, which can be substituted by one of the following groups: halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cl-6alkyl and Cl-6alkoxy; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof, with the proviso that the compound of formula (I) does not represent the compound (6-Bromo-pyrazolo[l,5-a]pyrimidin-2-yl)-(3,4-dihydro-lH-isoq uinolin-2-yl)-methanone.

[001210] In an embodiment, the glutamate modulator is a compound according to:

Yl, Y2 and Y3 independently represent CR10, CR11, CR10R11, NR12, S or O, whereby at least one of Yl, Y2 and Y3 represents CR10; or Yl and Y2 together represent a group R10C=N; R10C=CRl 1; R10R11C — C(=O) or R12N— (C=O); or Y2 and Y3 together represent a group R10C=N; R10C=CRl 1; R10R11C — C(=O) or R12N— (C=O);

R1 represents chloro or bromo;

R2 represents hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl;

R3 represents hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl; or

R2 and R3 together with the carbon atom of the ring represent a carbonyl group;

R4 represents hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl;

R5 represents hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl; or

R4 and R5 together with the carbon atom of the ring represent a carbonyl group;

R6 represents hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl;

R7 represents hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl;

R6 and R7 together with the carbon atom of the ring represent a carbonyl group;

R2 or R3 together with R6 or R7 may form a bivalent radical of type CH2 — CH2 or CH2— O;

RIO and R11 independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, Cl-6alkyl, C3-7-cycloalkyl, C2- 6alkenyl, C2-6alkynyl, Cl-6alkoxy, C3-7-cycloalkyloxy, C2-6alkenyloxy, C2- 6alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, heterocyclyloxy, Cl- 6alkylamino, di-Cl-6alkylamino, C3-7-cycloalkylamino, di-C3-7-cycloalkylamino, Cl-6alkyl-C3-7-cycloalkylamino, C2-6alkenylamino, C2-6alkynylamino, di-C2- 6alkenylamino, di-C2-6alkynylamino, Cl-6alkyl-C2-6-alkenylamino, Cl-6alkyl-C2- 6-alkynylamino, C2-6alkenyl-C3-7-cycloalkylamino, C2-6alkynyl-C3-7- cycloalkylamino, C2-6alkenyl-C2-6-alkynylamino arylamino, diarylamino, aryl-Cl- 6alkylamino, aryl-C2-6alkenylamino, aryl-C2-6alkynylamino, aryl-C3-7- cycloalkylamino, heteroarylamino, diheteroarylamino, heteroaryl-Cl-6alkylamino, heteroaryl-C2-6alkenylamino, heteroaryl-C2-6alkynylamino, heteroaryl-C3-7- cycloalkylamino, heteroarylarylamino, heterocyclylamino, diheterocyclylamino, heterocyclyl-C 1 -6alkylamino, heterocyclyl-C2-6alkenylamino, heterocyclyl-C2- 6alkynylamino, heterocyclyl-C3-7-cycloalkylamino, heterocyclylarylamino, heterocyclylhetero-arylamino, acyl, acyloxy, acylamino, Cl-6alkoxy carbonyl, C3-7- cycloalkoxy-carbonyl, C2-6alkenyloxy carbonyl, C2-6alkynyloxy carbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, aminocarbonyl, Cl-6alkylamino-carbonyl, di-Cl-6alkylaminocarbonyl, C3-7- cycloalkylaminocarbonyl, di-C3-7-cycloalkylaminocarbonyl, Cl-6alkyl-C3-7- cycloalkylaminocarbonyl, C2-6alkenyl-aminocarbonyl, C2-6alkynylaminocarbonyl, di-C2-6alkenylaminocarbonyl, di-C2-6alkynylaminocarbonyl, C 1 -6alkyl-C2-6- alkenylaminocarbonyl, Cl-6alkyl-C2-6-alkynyl-aminocarbonyl, C2-6alkenyl-C3-7- cycloalkylaminocarbonyl, C2-6alkynyl-C3-7-cycloalkylaminocarbonyl, C2-6alkenyl- C2-6-alkynylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryl-Cl- 6alkylaminocarbonyl, aryl-C2-6alkenylaminocarbonyl, aryl-C2- 6alkynylaminocarbonyl, aryl-C3-7-cycloalkylaminocarbonyl heteroarylaminocarbonyl, diheteroarylaminocarbonyl, heteroaryl-Cl- 6alkylaminocarbonyl, heteroaryl-C2-6alkenylaminocarbonyl, heteroaryl-C2- 6alkynylaminocarbonyl, heteroaryl-C3-7-cycloalkylaminocarbonyl, heteroarylarylaminocarbonyl, heterocyclylaminocarbonyl, diheterocyclylamino- carbonyl, heterocyclyl-C 1 -6alkylaminocarbonyl, heterocyclyl-C2-6alkenylamino- carbonyl, heterocyclyl-C2-6alkynylaminocarbonyl, heterocyclyl-C3-7-cycloalkyl- aminocarbonyl, heterocyclylarylaminocarbonyl, heterocyclylheteroarylamino- carbonyl, Cl-6alkylsulfinyl, C3-7-cycloalkylsulfinyl, C2-6alkenylsulfinyl, C2- 6alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, Cl- 6alkylsulfonyl, C3-7-cycloalkylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, Cl-C6alkylsulfonylamino or arylsulfonylamino; and

R12 represents hydrogen, Cl-6alkyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl, acyl, aryl, heteroaryl, heterocyclyl, Cl-6alkylamino-carbonyl, di-Cl-6alkylaminocarbonyl, Cl-6alkylsulfonyl, arylsulfonyl or heteroaryl sulfonyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.

[001211] In further embodiments, the glutamate modulator is a compound according to: wherein

R1 represents chloro or bromo;

R2 and R3 each independently represent hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl; or

R2 and R3 both together with the carbon atom of the ring represent a carbonyl group;

R4 and R5 each independently represent hydrogen, Cl-6alkyl, C3-7cycloalkyl or trifluoromethyl; or

R4 and R5 both together with the carbon atom of the ring represent a carbonyl group;

R6 and R7 independently represent hydrogen, Cl-6-alkyl, C3-7cycloalkyl or trifluoromethyl; or

R6 and R7 both together with the carbon atom of the ring represent a carbonyl group; R2 or R3 together with R6 and R7 may also form a bivalent radical selected from the group CH2— CH2 and CH2— O;

R8 represents a radical R9 or a radical RIO, whereby one of the two radicals R8 represents R9 and the other radical R8 represents RIO;

R9 represents a cyclic group selected from aryl, heteroaryl or heterocyclyl, wherein the ring system may be optionally substituted by one or two substituents, which may be the same or different and selected independently from halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cl-6alkyl, hydroxyCl-6alkyl and Cl- 6alkoxy;

RIO represents hydrogen or Cl-6alkyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

Formula 284

[001212] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 284. Such compounds are described in WO 2007/148113, published December 27, 2007, corresponding to PCT/GB2007/002344, filed June 22, 2007 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 284, this reference incorporated by reference herein controls.

[001213] In an embodiment, the glutamate modulator is a compound according to: wherein

Y represents a single bond, CR3R4, C(=O), NR5, NHC(=O), C(=O)NH, OC(=O), C(=O)O, O, S, SO, or SO2;

R1 represents aryl, heteroaryl, arylCl-6alkyl, arylC2-6alkenyl, heteroarylCl-6alkyl, heteroarylC2-6alkenyl, Cl-6alkyl, or cycloC3-12alkyl;

R2 represents Cl-6alkyl, cycloC3-12alkyl, Z-R6a, C(=O) — R6b or C(R7)(R8) — NR10R11;

R3 and R4, which may be the same or different, each independently represent hydrogen, Cl-6alkyl, OH, Cl-6alkoxy, or halogen;

R5 represents hydrogen or Cl-6alkyl;

Z represents CR7R8, NR9, O, S, SO, or SO2;

R6a represents hydrogen, Cl-6alkyl, cycloC3-12alkyl, aryl, heteroaryl, or heterocyclyl;

R6b represents hydrogen, Cl-6alkyl, cycloC3-12alkyl, or aryl;

R7 and R8, which may be the same or different, each independently represent hydrogen, Cl-6alkyl, Cl-6alkoxy, or halogen;

R9 represents hydrogen, Cl-6alkyl, cycloC3-12alkyl, aryl, heteroaryl, heterocyclyl, or arylCl-6alkyl or R6a and R9 together with the nitrogen atom to which they are attached may form a saturated mono-, bi-, spiro- or tricyclic ring system having from 3 to 12 carbon atoms, one or two of which may optionally be replaced by O, S, NH, or N — Cl-6alkyl, wherein the ring system is optionally substituted by one or more substituents, which may be the same or different, selected independently from Cl-6alkyl, Cl-6alkoxy, and halogen;

RIO represents hydrogen, Cl-6alkyl, cycloC3-12alkyl, aryl, heteroaryl, or heterocyclyl;

Rl l represents hydrogen, Cl-6alkyl, cycloC3-12alkyl, aryl, heteroaryl, heterocyclyl, or arylCl-6alkyl or

RIO and R11 together with the nitrogen atom to which they are attached may form a saturated mono-, bi-, spiro- or tricyclic ring system having from 3 to 12 carbon atoms, one or two of which may optionally be replaced by O, S, NH, or N — Cl-6alkyl, wherein the ring system is optionally substituted by one or more substituents, which may be the same or different, selected independently from Cl-6alkyl, Cl-6alkoxy, and halogen; and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.

Formula 285

[001214] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 285. Such compounds are described in WO 2007/113276, published October 11, 2007, corresponding to PCT/EP2007/053155, filed April 2, 2007, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 285, this reference incorporated by reference herein controls.

[001215] In an embodiment, the glutamate modulator is a compound according to: wherein XI, X2, X3, and X4 are independently selected from the group consisting of CR1, CO, N, NR2, O and S,

R1 and R2 are independently selected from the group consisting of H, alkyl, substituted alkyl, benzyl, substituted benzyl, phenyl and substituted phenyl, or R1 and R2 form together with the atoms to which they are attached a hydrocarboncycle, a substituted hydrocarboncycle, a heterocycle or a substituted heterocycle,

Y represents CH or CR3 or N

V represents CH, CR4 or N

Q represents CH, CR5 or N

W represents CH, CR6 or N, and

R3, R4, R5, and R6 are independently selected from the group consisting of OH, halogen, alkyl, trifluoralkyl, alkoxy, trifluoralkoxy, and CN; and pharmaceutically acceptable prodrugs, salts, solvates, hydrates, and N-oxides thereof.

Formula 286

[001216] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 286. Such compounds are described in WO 2007/104485, September 20, 2007, corresponding to PCT/EP2007/002067, filed March 9, 2007, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 286, this reference incorporated by reference herein controls.

[001217] In an embodiment, the glutamate modulator is a compound according to: wherein

R1 and R2 each independently denote hydrogen; a halogen; — NO2; — CN; — NH2; — NHR5; — NR6R7; — NH— C(=O)— R8; — C(=O)— R9, — C(=O)— NH2; — C(=O)— NHR10; — C(=O)— NR11R12; — C(=O)— OR13; — (CH2)m— C(=O)— OR14 with m=l, 2, 3, 4 or 5; — O— C(=O)— R15; — (CH2)n— O— C(=O)— R16 with n=l, 2, 3, 4 or 5; — OR17; — (CH2)o— O— R18 with o=l, 2, 3; 4 or 5; — SR19; — (CH2)p— S(=O)t— R20 with p=l, 2, 3, 4 or 5 and t=0, 1 or 2; — NH— S(=O)2— NR27R28; — S(=O)2— NR29R30; — SF5; — (CH2)u— O— S(=O)2— R31 with u=l, 2, 3, 4 or 5; — (CH2)v— O— S(=O)2— O— R32 with v=l, 2, 3, 4 or 5; — (CH2)w— O — P(=O)(OR33)(OR34) with w=l, 2, 3, 4 or 5; a linear or branched, saturated or unsaturated, unsubstituted or mono- or poly-substituted aliphatic group; a saturated or unsaturated, unsubstituted or mono- or poly-substituted cycloaliphatic group optionally having at least one heteroatom as a ring member, which cycloaliphatic group is bound via a linear or branched, unsubstituted or mono- or poly-substituted alkylene group and/or optionally may be condensed with an unsubstituted or mono- or poly-substituted mono- or polycyclic ring system; or an unsubstituted or mono- or poly-substituted aryl or heteroaryl group, which optionally may be bound via a linear or branched, unsubstituted or mono- or poly-substituted alkylene group and/or optionally may be condensed with an unsubstituted or mono- or poly-substituted mono- or polycyclic ring system;

R3 and R4 each independently denote hydrogen; — C(=O) — R21; — (CH2)q — C(=O)— R22 with q=l, 2, 3, 4 or 5; — C(=O)— O— R23; — (CH2)r— C(=O)— O— R24 with r=l, 2, 3, 4 or 5; — C(=O)— NHR25; — (CH2)s— C(=O)— NHR26 with s=l, 2, 3, 4 or 5; a linear or branched, saturated or unsaturated, unsubstituted or mono- or poly-substituted aliphatic group; a saturated or unsaturated, unsubstituted or mono- or poly-substituted cycloaliphatic group optionally having at least one heteroatom as a ring member, which cycloaliphatic group optionally may be bound via a linear or branched, unsubstituted or mono- or poly-substituted alkylene group and/or optionally may be condensed with an unsubstituted or mono- or polysubstituted mono- or polycyclic ring system; or an unsubstituted or mono- or polysubstituted aryl or heteroaryl group, which optionally may be bound via a linear or branched, unsubstituted or mono- or poly-substituted alkylene group and/or optionally may be condensed with an unsubstituted or mono- or poly-substituted mono- or polycyclic ring system, or

R3 and R4 together with the nitrogen atom to which they are bound form a saturated or unsaturated, unsubstituted or mono- or poly-substituted heterocycloaliphatic group optionally having at least one further heteroatom as a ring member, which heterocycloaliphatic group optionally may be condensed with an unsubstituted or mono- or poly-substituted mono- or polycyclic ring system;

R5, R6, R7, R8, RIO, R11, R12, R15 and R16 each independently denote a linear or branched, saturated or unsaturated, unsubstituted or mono- or poly-substituted aliphatic group or an unsubstituted or mono- or poly-substituted aryl or heteroaryl group, which optionally may be bound via a linear or branched, unsubstituted or mono- or poly-substituted alkylene group and/or optionally may be condensed with an unsubstituted or mono- or poly-substituted mono- or polycyclic ring system;

R9, R13, R14, R17, R13, R19, R20, R21, R22, R23, R24, R25, R26, R27, R23, R29, R30, R31, R32, R33 and R34 each independently denote hydrogen; a linear or branched, saturated or unsaturated, unsubstituted or mono- or poly-substituted aliphatic group or an unsubstituted or mono- or poly-substituted aryl or heteroaryl group, which optionally may be bound via a linear or branched, unsubstituted or mono- or poly-substituted alkylene group and/or optionally may be condensed with an unsubstituted or mono- or poly-substituted mono- or polycyclic ring system;

Ml denotes an aryl or heteroaryl group, which optionally may be substituted with at least one further substituent and/or optionally may be condensed with an unsubstituted or mono- or poly-substituted mono- or polycyclic ring system; and M2 denotes an aryl or heteroaryl group, which may be unsubstituted or mono- or poly-substituted and optionally may be condensed with an unsubstituted or mono- or poly-substituted mono- or polycyclic ring system; or a salt thereof.

Formula 287

[001218] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 287. Such compounds are described in WO 2007/071358, published June 28, 2007 and corresponding to PCT/EP2006/012181, filed December 18, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 287, this reference incorporated by reference herein controls.

[001219] In an embodiment, the glutamate modulator is a compound according to: wherein

R1 represents optionally substituted Alkyl or optionally substituted Benzyl and

R2 represents Hydrogen (H), optionally substituted Alkyl or optionally substituted Benzyl; or

R1 and R2 form together with the Nitrogen atom to which they are attached an optionally substituted heterocycle with less than 14 ring atoms; R3 represents Halogen, Hydroxy (OH), Alkyl, Alkoxy, Amino, Alkylamino, Dialkylamino;

R4 represents Hydroxy (OH), Halogen, Amino, Alkylamino, Dialkylamino Alkyl, Alkoxy;

Q represents CH, CR4, N;

V represents CH, CR4, N; W represents CH, CR4, N; X represents CH, N;

Y represents CH, CR3, N; Z represents CR6aR6b, NR5, O;

R5 represents Hydrogen, Hydroxy (OH);

R6a and R6b are each independently selected from Hydrogen, Halogen, Hydroxy (OH), Amino, Alkyl, Alkoxy, Haloalkyl; and provided that QI V, W are not N at the same time, in free base or acid addition salt form.

Formula 288

[001220] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 288. Such compounds are described in WO 2007/072090, published June 28, 2007, corresponding to PCT/HU2006/000118, filed December 19, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 288, this reference incorporated by reference herein controls.

[001221] In an embodiment, the glutamate modulator is a compound according to:

X is selected from (CH2)n, CH=CH, NH, N(CH3), O, OCH2, CH2COO, and NHCH2OOO; n is an integer ranging from 0 to 2;

Y is selected from H, CH3, F, Cl, and Br;

Z is H or CH3; and,

R is an optionally substituted alkyl, cycloalkyl, phenyl, or heteroaryl; or geometric isomers, salts, hydrates, or solvates thereof.

[001222] In further embodiments, the glutamate modulator is a compound selected from: l-[3-(4-chloro-phenyl)-thieno[2,3-b]pyridin-2-yl]-2-(4-fluor o-phenyl)-ethanone,

1-[3-(4-chloro-phenyl)-thieno[2,3-b]pyridin-2-yl]-2-(3,4- difluoro-phenyl)-ethanone,

2-(4-fluoro-phenyl)-l-[3-(4-fluoro-phenyl)-thieno[2,3-b]p yridin-2-yl]-ethanone,

3-(3-fluoro-phenyl)-l-[3-(4-fluoro-phenyl)-thieno[2,3-b]p yridin-2-yl]-propan-l-one, 3-(4-fluoro-phenyl)-l-[3-(4-fluoro-phenyl)-thieno[2,3-b]pyri din-2-yl]-propan-l-one, 3-(4-fluoro-phenyl)-l-(3-phenyl-thieno[2,3-b]pyridin-2-yl)-p ropan-l-one, l-[3-(4-fluoro-phenyl)-thieno[2,3-b]pyridin-2-yl]-3-thiophen -3-yl-propan-l-one, 3-(4-chloro-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid 4-fluoro-benzyl ester, 3-oxo-3-(3-p-tolyl-thieno[2,3-b]pyridin-2-yl)-propionic acid ethyl ester, 3-[3-(4-chloro-phenyl)-thieno[2,3-b]pyridin-2-yl]-3-oxo-prop ionic acid ethyl ester, 3-[3-(4-fluoro-phenyl)-thieno[2,3-b]pyridin-2-yl]-3-oxo-prop ionic acid ethyl ester, 3-oxo-3-(3-phenyl-thieno[2,3-b]pyridin-2-yl)-propionic acid ethyl ester, 3-[3-(4-chloro-phenyl)-6-methyl-thieno[2,3-b]pyridin-2-yl]-3 -oxo-propionic acid ethyl ester, 3-(4-fluoro-phenyl)-thieno[2,3-b]pyridine-2-carboxylic acid 4-fluoro-benzylamide, including pharmaceutically acceptable salts thereof and substitute variants having glutamate modulatory activity.

Formula 289

[001223] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 289. Such compounds are described in WO 2007/023242, published March 1, 2007, corresponding to PCT/GB2005/003285, filed August 24, 2005, and WO 2007/023290, published March 1, 2007, corresponding to PCT/GB2006/003170, filed August 24, 2006 which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 289, this reference incorporated by reference herein controls.

[001224] In an embodiment, the glutamate modulator is a compound according to:

R1 represents aryl or heteroaryl;

R2 and R3, which may be the same or different, represent hydrogen or Cl-6alkyl;

R4 and R5, which may be the same or different, represent hydrogen or Cl-6alkyl; it being understood that: aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1 , 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of Cl-6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Cl-6alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC3-12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Cl-6alkylamino, N-cycloC3-12alkyl-N- Cl- 6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-C1-6 alkyl- piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1 , 2 or 3 substituents, that may be the same or different, which substituents are selected from the group consisting of Ci-6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Ci- Palkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC3-12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Cl-6alkylamino, N-cycloC3- 12alkyl-N-Cl-6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Cl-6alkyl- piperazinyl, tetrazolyl, oxazolyl, furyl, pyrrolyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl.

Formula 290

[001225] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 290. Such compounds are described in WO 2007/072095, published June 28, 2007, corresponding to PCT/HU2006/000123, filed December 19, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 290, this reference incorporated by reference herein controls.

[001226] In an embodiment, the glutamate modulator is a compound according to Formula 290: , wherein X is selected from SO and SO2;

Y is selected from (CH2)n, NH and NHCH2; n is 0 or 1;

Z is H or monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, or alkyl sulfonylamino;

R1 is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, or heterocyclyl;

R2 is an optionally substituted phenyl, heterocyclyl, or NR3R4 group, wherein R3 and R4 are independently selected from hydrogen and an optionally substituted alkyl, or R3 and R4 together with the N atom to which they are attached form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom(s), or NH — CO — NR5R6 group, wherein R5 and R6 are independently selected from hydrogen and an optionally substituted alkyl, or R5 and R6 together with the N atom to which they are attached form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom(s); or hydrates or solvates or pharmaceutically acceptable salts thereof.

[001227] In further embodiments, the glutamate modulator is a compound according to: wherein

X is selected from SO and SO2;

Y is selected from (CH2)n, NH and NHCH2; n is an integer ranging from 0 to 1;

Z is H or monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, or alkyl sulfonylamino;

R1 is alkyl, or a C3-10 cycloalkyl group optionally substituted with one or more substituent(s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylamino, dialkylamino, aminomethyl, dialkylaminomethyl, acylamino, cyano, and halogen, phenyl or biphenyl optionally substituted with one or more substituent(s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino cyano, halogen, and a saturated or an unsaturated monocyclic or a bicyclic heterocyclyl containing 1-4 heteroatom(s) selected from O, N, and S;

R2 is phenyl optionally substituted with one or more subsituent(s) selected from alkyl, methoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, alkylsulfonyl, alkylsulfonylamino, cyano and halogen, and a saturated or unsaturated monocyclic or bicyclic C5-7 heterocyclyl group containing 1-4 heteroatom(s) selected from O, N and S, or

NR3R4, wherein R3 and R4 are independently selected from hydrogen and alkyls optionally substituted with one or more substitutent(s) selected from alkoxy, trifluormethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, and halogen, or R3 and R4 together with the N atom to which they are attached form a C5-7 heterocyclyl group containing one or more heteroatom(s) selected from O, N and S, and which heterocyclyl group is optionally substituted with one ore more hydroxy, alkylhydroxy, alkyl, alkoxy, trifluormethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethly, dialkyaminomethyl, acylamino, cyano, halogen, or oxo group, or

NH — CO — NR5R6, wherein R5 and R6 are independently selected from hydrogen and alkyls optionally substituted with one or more substituent(s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, and halogen, or R5 and R6 together with the N atom to which they are attached form a C5-7 heterocyclyl group containing one or more heteroatom(s), selected from O, N and S, and which heterocyclyl group is optionally substituted with one or more hydroxy, alkylhydroxy, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo group; or hydrates, solvates, or pharmaceutically acceptable salts thereof.

Formula 291

[001228] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 291. Such compounds are described in WO 2006/129199, published December 7, 2006, corresponding to PCT/IB2006/001882, filed May 17, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 291, this reference incorporated by reference herein controls.

[001229] In an embodiment, the glutamate modulator is a compound according to Formula 291 : Wherein

W represents (C5-C7)cycloalkyl, (C5-C7)heterocycloalkyl or (C5- C7)heterocycloalkenyl ring;

R1 and R2 represent independently hydrogen, — (Cl-C6)alkyl, — (C2-C6)alkenyl, — (C2-C6)alkynyl, arylalkyl, heteroarylalkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, — (Cl-C6)alkoxy or R1 and R2 together can form a (C3-C7)cycloalkyl ring, a carbonyl bond C=O or a carbon double bond;

P and Q are each independently selected and denote a cycloalkyl, a heterocycloalkyl, an aryl or heteroaryl group of formula

, R3, R4, R5, R6, and R7 independently are hydrogen, halogen, — CN, — NO2, — (Cl-C6)alkyl, — (C3-C6)cycloalkyl, — (C3- C7)cycloalkylalkyl, — (C2-C6)alkenyl, — (C2-C6)alkynyl, halo-(Cl-C6)alkyl, heteroaryl, heteroarylalkyl, arylalkyl, aryl, — OR8, — NR8R9, — C(=NR10)NR8R9, N(=NR10)NR8R9, — NR8COR9, NR8CO2R9, NR8SO2R9, — NR10CONR8R9, — SR8, — S(=O)R8, — S(=O)2R8, — S(=O)2NR8R9, — C(=0)R8, — C00R8, — C(=O)NR8R9, — C(=NR8)R9, or C(=NOR8)R9 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, — CN, — (Cl-C6)alkyl, — O — (C0- C6)alkyl, — O — (C3-C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — O — (Cl- C3)alkylaryl, — O — (Cl-C3)alkylheteroaryl, — N(( — C0-C6)alkyl)((C0-C3)alkylaryl) or — N((C0-C6)alkyl)((C0-C3-)alkylheteroaryl) groups;

R8, R9, RIO each independently is hydrogen, (Cl-C6)alkyl, (C3-C6)cycloalkyl, (C3- C7)cycloalkylalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, halo-(Cl-C6)alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — (Cl-C6)alkyl, — O — (C0-C6)alkyl, — O — (C3-C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — N(C0- C6-alkyl)2, — N((C0-C6)alkyl)((C3-C7-)cycloalkyl) or — N((C0-C6)alkyl)(aryl) substituents;

D, E, F, G and H in P and Q represent independently — C(R3)=, — C(R3)=C(R4) — , — C(=O)— , — C(=S)— , — O— , — N=, — N(R3)— or — S— ;

A is azo — N=N — , ethyl, ethenyl, ethynyl, — NR8C(=O) — , — NR8S(=O)2 — , — C(=0)NR8— , — S— , — S(=O)— , — S(=O)2— , — S(=O)2NR8— , — C(=O)— O— , — O— C(=O)— , — C(=NR8)NR9— , — C(=NOR8)NR9— , — NR8C(=NOR9)— , =N— O— , — O — N=CH — or a group aryl or heteroaryl of formula

R3, R4, R5 and R6 independently are as defined above;

D, E, F, G and H in A independently represent a carbon group, oxygen, nitrogen, sulphur or a double bond;

B represents a single bond, — C(=O) — (C0-C2)alkyl-, — C(=O) — (C2-C6)alkenyl-, — C(=O)— (C2-C6)alkynyl-, — C(=O)— O— , — C(=0)NR8— (C0-C2)alkyl-, — C(=NR8)NR9— S(=O)— (C0-C2)alkyl-, — S(=O)2— (C0-C2)alkyl-, — S(=O)2NR8— (C0-C2)alkyl-, C(=NR8)— (C0-C2)alkyl-, — C(=N0R8)— (C0- C2)alkyl- or — C(=NOR8)NR9— (C0-C2)alkyl-;

R8 and R9, independently are as defined above; X and Y are each independently selected from a bond, — NR11C(=O)O — , an optionally substituted — (Cl-C6)alkyl-, — (C2-C6)alkynyl-, — (C2-C6)alkenyl-, — (C3-C7)cycloalkyl-, — (C3-C8)cycloalkenyl-, — (Cl-C6)alkylhalo-, — (Cl- C6)alkylcyano-, — (C0-C6)alkyl-O— (C0-C6)alkyl-, — (C0-C6)alkyl-O— (C2- C6)alkynyl-, — (C0-C6)alkyl-O— (C2-C6)alkenyl-, — (C0-C6)alkyl-O— (C3- C7)cycloalkyl-, — (C0-C6)alkyl-O — (C4-C 10)alkylcycloalkyl-, — (C0-C6)alkyl- C(=O)— (C0-C6)alkyl-, — (C0-C6)alkyl-C(=O)— (C2-C6)alkynyl-, — (C0-C6)alkyl- C(=O)— (C2-C6)alkenyl-, — (C0-C6)alkyl-C(=O)— (C3-C7)alkylcycloalkyl-, — (C0- C6)alkyl-C(=O)— (C4-C 10)cycloalkyl-, — (C0-C6)alkyl-C(=O)O— (C0-C6)alkyl-, — (C0-C6)alkyl-C(=O)O— (C2-C6)alkynyl-, — (C0-C6)alkyl-C(=O)O— (C2- C6)alkenyl-, — (C0-C6)alkyl-C(=O)O— (C3-C7)cycloalkyl-, — (C0-C6)alkyl- C(=O)O— (C4-C10)alkylcycloalkyl-, — (C0-C6)alkyl-C(=O)NRl 1— (C0-C6)alkyl-, — (C0-C6)alkyl-C(=O)NRl 1— (C2-C6)alkynyl-, — (C0-C6)alkyl-C(=O)NRl 1— (C2-C6)alkenyl-, — (C0-C6)alkyl-C(=O)NRl 1— (C3-C7)cycloalkyl-, — (C0- C6)alkyl-C(=O)NR11— (C4-C10)alkylcycloalkyl-, — (C0-C6)alkyl-S— (C0- C6)alkyl-, — (C0-C6)alkyl-S— (C2-C6)alkynyl-, — (C0-C6)alkyl-S— (C2-C6)alkenyl- , — (C0-C6)alkyl-S— (C3-C7)cycloalkyl-, — (C0-C6)alkyl-S— (C4- C10)alkylcycloalkyl-, — (C0-C6)alkyl-S(O)— (C0-C6)alkyl-, — (C0-C6)alkyl-O— (C2-C6)alkynyl-, — (C0-C6)alkyl-S(O)— (C2-C6)alkenyl-, — (C0-C6)alkyl-S(O)— (C3 -C7)cycloalkyl-, — (C0-C6)alkyl-S(O)— (C4-C 10)alkylcycloalkyl-, — (C0- C6)alkyl-S(O)2— (C0-C6)alkyl-, — (C0-C6)alkyl-S(O)2— (C2-C6)alkynyl-, — (C0- C6)alkyl-S(O)2— (C2-C6)alkenyl-, — (C0-C6)alkyl-S(O)2— (C3-C7)cycloalkyl-, — (C0-C6)alkyl-S(O)2— (C4-C10)alkylcycloalkyl-, — (C0-C6)alkyl-S(O)2NRl 1— (C0- C6)alkyl-, — (C0-C6)alkyl-S(O)2NRl 1— (C2-C6)alkynyl-, — (C0-C6)alkyl- S(O)2NR11— (C2-C6)alkenyl-, — (C0-C6)alkyl-S(O)2NRl 1— (C3-C7)cycloalkyl-, — (C0-C6)alkyl-S(O)2NRl 1— (C4-C10)alkylcycloalkyl-, — (C0-C6)alkyl-NRl 1— (C0-C6)alkyl-, — (C0-C6)alkyl-NRl 1— (C2-C6)alkynyl-, — (C0-C6)alkyl-NRl 1— (C2-C6)alkenyl-, — (C0-C6)alkyl-NRl— (C3-C7)cycloalkyl-, — (C0-C6)alkyl- NR11— (C4-C10)alkylcycloalkyl-, — (C0-C6)alkyl-NRl 1C(=O)— (C0-C6)alkyl-, — (C0-C6)alkyl-NRl 1C(=O)— (C2-C6)alkynyl-, — (C0-C6)alkyl-NRl 1C(=O)— (C2- C6)alkenyl-, — (C0-C6)alkyl-NRl 1C(=O)— (C3-C7)cycloalkyl-, — (C0-C6)alkyl- NR11C(=O)— (C4-C10)alkylcycloalkyl-, — (C0-C6)alkyl-NR12C(=O)NRl 1— (C0- C6)alkyl-, — (C0-C6)alkyl-NR12C(=O)NRl 1— (C2-C6)alkynyl-, — (C0-C6)alkyl- NR12C(=O)NR11— (C2-C6)alkenyl-, — (C0-C6)alkyl-NR12C(=O)NRl, — (C3- C7)cycloalkyl-, — (C0-C6)alkyl-NR12C(=O)NRl 1 — (C4-C10)alkylcycloalkyl-, — (C0-C6)alkyl-NRl 1 S(0)2— (C0-C6)alkyl-, — (C0-C6)alkyl-NRl 1 S(0)2— (C2- C6)alkynyl-, — (C0-C6)alkyl-NRl 1S(O)2— (C2-C6)alkenyl-, — (C0-C6)alkyl- NR11 S(0)2— (C3-C7)cycloalkyl-, — (C0-C6)alkyl-NRl 1 S(0)2— (C4- C10)alkylcycloalkyl-, — (C0-C6)alkyl-NR12C(=S)NRl 1— (C0-C6)alkyl-, — (CO- C6)alkyl-NR12C(=S)NR11— (C2-C6)alkynyl-, — (C0-C6)alkyl-NR12C(=S)NRl 1— (C2-C6)alkenyl-, — (C0-C6)alkyl-NR12C(=S)NRl 1— (C3-C7)cycloalkyl-, — (C0- C6)alkyl-NR12C(=S)NR11— (C4-C10)alkylcycloalkyl-, — (C0-C6)alkyl-OC(=O)— (C0-C6)alkyl-, — (C0-C6)alkyl-OC(=O)— (C2-C6)alkynyl-, — (C0-C6)alkyl- OC(=O)— (C2-C6)alkenyl-, — (C0-C6)alkyl-OC(=O)— (C4-C 1 O)alkylcycloalkyl-, — (C0-C6)alkyl-OC(=O)— (C3-C7)cycloalkyl-, — (C0-C6)alkyl-OC(=O)NRl 1— (C0- C6)alkyl-, — (C0-C6)alkyl-OC(=O)NRl 1— (C2-C6)alkynyl-, — (C0-C6)alkyl- OC(=O)NR11— (C2-C6)alkenyl-, — (C0-C6)alkyl-OC(=O)NRl 1— (C4- C10)alkylcycloalkyl-, — (C0-C6)alkyl-OC(=O)NRl 1— (C3-C7)cycloalkyl-, — (C0- C6)alkyl-NR11C(=O)O— (C0-C6)alkyl-, — (C0-C6)alkyl-NRl 1C(=O)O— (C2- C6)alkynyl-, — (C0-C6)alkyl-NRl 1C(=O)O— (C2-C6)alkenyl-, — (C0-C6)alkyl- NR11C(=O)O— (C3-C7)cycloalkyl- or — (C0-C6)alkyl-NRl 1C(=O)O— (C4- C10)alkylcycloalkyl;

X and Y together cannot be a bond;

Rl l and R12 each independently is hydrogen, Cl-C6-alkyl, C3-C6-cycloalkyl, C3- C7-cycloalkylalkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo-Cl-C6-alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, Cl-C6-alkyl, — O(C0- C6-alkyl), — O(C3-C7-cycloalkylalkyl), — O(aryl), — O(heteroaryl), — N(C0-C6- alkyl)(C0-C6-alkyl), — N(C0-C6-alkyl)(C3-C7-cycloalkyl) or — N(C0-C6- alkyl)(aryl) substituents;

Any N may be an N-oxide; or pharmaceutically acceptable salts, hydrates or solvates of such compounds.

Formula 292

[001230] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 292. Such compounds are described in WO 2006/131296, published December 14, 2006, corresponding to PCT/EP2006/005356, filed June 6, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 292, this reference incorporated by reference herein controls.

[001231] In further embodiments, the glutamate modulator is a compound according to: wherein

R ¹ , R ² , R ³ and R ⁴ are each independently H, F, Cl, Br, I, — CN, — NC, — NO2, — SO3H, — S(=O ₂ )NH ₂ , — NH ₂ , —OH, — SH, linear or branched C1-10 alkyl, —OR ⁶ , — O— (CH ₂ )— R ⁷ , —SR ⁸ , — S— (CH ₂ )— R ⁹ , — NR ¹⁰ R ⁿ , — NR ¹³ — C(=O)— R ¹² , — C(=O)— NH ₂ , — C(=O)— R ¹⁴ , — C(=O)— OH or — C(=O)— OR ¹⁵ ;

R ⁵ is a linear or branched, optionally substituted C1-10 alkyl group; a linear or branched, optionally substituted C2-10 alkenyl group; an unsaturated or saturated, optionally substituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic group which optionally may be bridged by 1 or 2 linear or branched C1-5- alkylene groups; an imidazolidinonyl group which optionally may be substituted by 1 or 2 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl and tert-butyl; an optionally substituted 6- to 10-membered aryl group which optionally may be fused to a saturated or unsaturated, optionally substituted mono- or polycyclic ring system; a group selected from the group consisting of 4-nitrophenyl, 3 -nitrophenyl, 2-nitrophenyl, 4- chl oro-3 -nitrophenyl, 4-fluoro-3 -nitrophenyl, 4-bromo-3 -nitrophenyl, (3,5)-dinitrophenyl, 4- methyl-3 -nitrophenyl and 5 -nitrofuranyl; an optionally substituted 5- to 14-membered heteroaryl group; — (CH ₂ ) _n — C(=O) — OR ¹⁶ wherein n is 0, 1, 2, 3, 4 or 5;

— CR ¹⁷ R ¹⁸ — O— C(=O)— R ¹⁹ ;

— (CHR ²⁰ ) — (CH ₂ ) _P — R ²¹ with p=0 or 1; or

— (CH=CH)— R ²² ;

R ⁶ , R ⁸ , R ¹⁴ and R ¹⁵ are each independently a linear or branched, optionally substituted Ci- 10 alkyl group; a linear or branched, optionally substituted C2-10 alkenyl group; or an optionally substituted 5- to 14-membered aryl or heteroaryl group;

R ⁷ and R ⁹ are each independently an optionally substituted 5- to 14-membered aryl or heteroaryl group;

R ¹⁰ and R ¹¹ are each independently hydrogen or are a linear or branched Ci-io alkyl group; R ¹² , R ¹³ , R ¹⁶ and R ¹⁹ are each independently a linear or branched Ci-io alkyl group;

R ¹⁷ is a linear or branched Ci-io alkyl group or an optionally substituted 6- to 10-membered aryl group;

R ¹⁸ and R ²⁰ are each independently hydrogen, are a linear or branched Ci-io alkyl group, or an optionally substituted 6- to 10-membered aryl group;

R ²¹ is an unsaturated or saturated, optionally substituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted heteroaryl group selected from the group consisting of thiophenyl, furanyl, benzo[b]furanyl and benzo[b]thiophenyl; and R ²² is an optionally substituted 6- to 10-membered aryl group; wherein the aforementioned, optionally substituted Ci-io alkyl groups may be unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of F, Cl, Br, I, — OH, — SH, — CN and — NO2; the aforementioned, optionally substituted C2-10 alkenyl groups may be unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of F, Cl, Br, I, — OH, — SH, — CN and — NO2; the aforementioned, optionally substituted cycloaliphatic groups may be unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of oxo (=0), thioxo (=S), F, Cl, Br, I, — CN, — CF ₃ , — SF ₅ , —OH, — O— Ci-5-alkyl, — NH ₂ , — N0 ₂ , — O— CF ₃ , — S— CF ₃ , — SH, — S— Ci-5-alkyl, — Ci- ₅ -alkyl, — C(=0)— H, — C(=0)— Ci-5-alkyl, — C(=0)— O— Ci- ₅ -alkyl, — (CH ₂ )— C(=0)— O— Ci- ₅ -alkyl, — NH— Cl s-alkyl, — N(Ci-5-alkyl)2, — (CH2)-benzo[b] furanyl, — O-phenyl, — O-benzyl, phenyl, benzyl, naphthyl and — (CH ₂ )-naphthyl; wherein the cyclic part of the groups — O-phenyl, — O-benzyl, phenyl, — (CH ₂ )- benzofb] furanyl, benzyl, naphthyl and — (CH ₂ )-naphthyl optionally may be substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, — OH, — CF ₃ , — SF ₅ , — CN, — N0 ₂ , — O— Ci-5-alkyl, — Ci- ₅ -alkyl, — O— CF ₃ , — S— CF ₃ , phenyl and — O-benzyl; the aforementioned optionally substituted aryl or heteroaryl groups may be unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, I, — CN, — CF ₃ , — SF ₅ , —OH, — O— Ci- ₅ -alkyl, — O— C _2.5 -alkenyl, — O— CF ₃ , — O— CHF ₂ , — O— CH ₂ F, — S— CF ₃ , — S— CHF ₂ , — S— CH ₂ F, — SH, — S— Ci-5-alkyl, — Ci-5-alkyl, — C(=O)— O— Ci- ₅ -alkyl, — O— C(=O)— Ci- ₅ -alkyl, — NH— Ci-5-alkyl, — N(Cn ₅ -alkyl) ₂ , — C(=O)— H, — C(=O)— Ci- ₅ -alkyl, — C(=O)— NH ₂ , — C(=O)— NH— Ci-5-alkyl, — C(=O)— N— (Ci-5-alkyl) ₂ , — S(=O) ₂ — NH ₂ , — S(=O) ₂ — NH— Ci- ₅ -alkyl, — S(=O) ₂ — N(Ci-5-alkyl) ₂ , — S(=O) ₂ -phenyl, — S(=O) ₂ — Ci-5-alkyl, — (CH ₂ )-benzo[b]furanyl, dihydrobenzo[b]furanyl, — O-phenyl, — O-benzyl, — S-phenyl, — S-benzyl, phenyl, pyridinyl and benzyl; wherein the cyclic part of the groups — S(=O) ₂ -phenyl, — O-phenyl, — O-benzyl, — S- phenyl, — S-benzyl, phenyl, — (CH ₂ )-benzo[b]furanyl, dihydro[b]benzofuranyl, pyridinyl and benzyl optionally may be substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, — OH, — CF ₃ , — SFs, — CN, — NO ₂ , — O — C1-5- alkyl, — Ci-5-alkyl, — O — CF ₃ , — S — CF ₃ , phenyl and — O-benzyl, and the aforementioned heteroaryl groups each may optionally contain 1, 2, 3, 4 or 5 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur as ring member(s); the rings of the aforementioned optionally substituted mono- or polycyclic ring systems may be unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of oxo (=0), thioxo (=S), F, Cl, Br, I, — CN, — CF ₃ , — SF5, — OH, — O — Ci-5-alkyl, — O— C _2.5 -alkenyl, — NH ₂ , — N0 ₂ , — O— CF ₃ , — O— CHF ₂ , — O— CH ₂ F, — S— CF ₃ , — S— CHF ₂ , — S— CH ₂ F, — SH, — S— Ci-5-alkyl, — Ci- ₅ -alkyl, — C(=0)— O— C1-5- alkyl, — O— C(=0)— Ci- ₅ -alkyl, — NH— Ci-5-alkyl, — N(Ci- ₅ -alkyl) ₂ , — C(=0)— H, — C(=0)— Ci-5-alkyl, — C(=0)— NH ₂ , — C(=0)— NH— Ci-5-alkyl, — C(=0)— N— (C1-5- alkyl) ₂ , — S(=0) ₂ — NH ₂ , — S(=0) ₂ — NH— Ci- ₅ -alkyl, — S(=0) ₂ — N(Ci- ₅ -alkyl) ₂ , — S(=O) ₂ -phenyl and — S(=0) ₂ — Ci-5-alkyl; and the rings of the aforementioned mono- or polycyclic ring systems each have 5, 6 or 7 members and may each contain 1, 2 or 3 heteroatom(s) as ring member(s), which are independently selected from the group consisting of oxygen, nitrogen and sulfur; or a salt or solvate thereof.

Formula 293 [001232] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 293. Such compounds are described in WO 2006/123249, published November 23, 2006, corresponding to PCT/IB2006/001674, filed May 17, 2006, and WO 2006/123255, published November 23, 2006, corresponding to PCT/IB2006/001881, filed May 17, 2006 which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 293, this reference incorporated by reference herein controls.

[001233] In an embodiment, the glutamate modulator is a compound according to:

Wherein

W represents (C5-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkyl- (Cl-C3)alkyl or (C3-C7)heterocycloalkenyl ring;

R1 and R2 represent independently hydrogen, — (Cl-C6)alkyl, — (C2-C6)alkenyl, — (C2-C6)alkynyl, arylalkyl, heteroarylalkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, — (Cl-C6)alkoxy or R1 and R2 together can form a (C3-C7)cycloalkyl ring, a carbonyl bond C=O or a carbon double bond;

P and Q are each independently selected and denote a cycloalkyl, a heterocycloalkyl, an aryl or heteroaryl group of formula R3, R4, R5, R6, and R7 independently are hydrogen, halogen, — NO2, — (Cl-C6)alkyl, — (C3-C6)cycloalkyl, — (C3-C7)cycloalkylalkyl, — (C2-C6)alkenyl, — (C2-C6)alkynyl, halo-(Cl-C6)alkyl, heteroaryl, heteroarylalkyl, arylalkyl, aryl, — OR8, — NR8R9, — C(=NR10)NR8R9, — NR8COR9, NR8CO2R9, NR8SO2R9, — NRIOCO NR8R9, — SR8, — S(=O)R8, — S(=O)2R8, — S(=O)2NR8R9, — C(=O)R8, — C(=O)— O— R8, — C(=O)NR8R9, — C(=NR8)R9, or — C(=NOR8)R9 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, — CN, — (Cl-C6)alkyl, — O — (C0-C6)alkyl, — O — (C3- C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — O — ( — Cl-C3)alkylaryl, — O — (Cl-C3)alkylheteroaryl, — N(( — C0-C6)alkyl)((C0-C3)alkylaryl) or — N((C0- C6)alkyl)((C0-C3-)alkylheteroaryl) groups;

R8, R9, RIO each independently is hydrogen, (Cl-C6)alkyl, (C3-C6)cycloalkyl, (C3- C7)cycloalkylalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, halo-(Cl-C6)alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — (Cl-C6)alkyl, — O — (C0-C6)alkyl, — O — (C3-C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — N(C0- C6-alkyl)2, — N((C0-C6)alkyl)((C3-C7-)cycloalkyl) or — N((C0-C6)alkyl)(aryl) substituents;

D, E, F, G and H represent independently — C(R3)=, — C(R3)=C(R4) — , — C(=O) — , — C(=S)— , — O— , — N=, — N(R3)— or — S— ;

B represents a single bond, — C(=O) — (C0-C2)alkyl-, — C(=O) — (C2-C6)alkenyl-, — C(=O)— (C2-C6)alkynyl-, — C(=O)— O— , — C(=0)NR8— (C0-C2)alkyl-, — C(=NR8)NR9— S(=O)— (C0-C2)alkyl-, — S(=O)2— (C0-C2)alkyl-, — S(=O)2NR8— (C0-C2)alkyl-, C(=NR8)— (C0-C2)alkyl-, — C(=N0R8)— (C0- C2)alkyl- or — C(=NOR8)NR9— (C0-C2)alkyl-;

R8 and R9, independently are as defined above;

Any N may be an N-oxide; or pharmaceutically acceptable salts, hydrates or solvates of such compounds.

Formula 294

[001234] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 294. Such compounds are described in WO 2006/123257, published November 23, 2006, corresponding to PCT/IB2006/002047, filed May 17, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 294, this reference incorporated by reference herein controls.

[001235] In an embodiment, the glutamate modulator is a compound according to:

Wherein

W represents (C4-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (C3-C7)heterocycloalkyl-(Ci- C3)alkyl or (C3-C7)heterocycloalkenyl ring;

Ri and R2 represent independently hydrogen, — (Ci-Ce)alkyl, — (C2-Ce)alkenyl, — (C2- Ce)alkynyl, arylalkyl, heteroarylalkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, — (Ci- Ce)alkoxy or Ri and R2 together can form a (C3-C7)cycloalkyl ring, a carbonyl bond C=O or a carbon double bond;

P represents a (C5-C7)heterocycloalkyl, (C5-C7)heterocycloalkenyl ring or a heteroaryl group of formula

R3, R4, Rs, Re, and R7 independently are hydrogen, halogen, — NO2, — (Ci-Ce)alkyl, — (C3- Ce)cycloalkyl, — (C3-C7)cycloalkylalkyl, — (C2-Ce)alkenyl, — (C2-Ce)alkynyl, halo-(Ci- Ce)alkyl, heteroaryl, heteroarylalkyl, arylalkyl, aryl, — ORx, — NRxRy, — C(=NRIO)NRXR9, — NRXCOR ₉ , NR ₈ CO ₂ R9, NR ₈ SO ₂ R ₉ , — NR10CO NR ₈ R ₉ , — SR ₈ , — S(=O)R ₈ , — S(=O) ₂ R ₈ , — S(=O) ₂ NR ₈ R ₉ , — C(=O)R ₈ , — C(0)— O— R ₈ , — C(=O)NR ₈ R ₉ , — C(=NR ₈ )R ₉ , or C(=NOR ₈ )R ₉ substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, — CN, — (Ci-Ce)alkyl, — O — (Co-Ce)alkyl, — O — (C3-C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — O — ( — Ci- C3)alkylaryl, — O — (Ci-C3)alkylheteroaryl, — N(( — Co-Ce)alkyl)((Co-C3)alkylaryl) or — N((Co-Ce)alkyl)((Co-C3 — )alkylheteroaryl) groups;

R ₈ , R ₉ , RIO each independently is hydrogen, (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, (C3- C7)cycloalkylalkyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, halo-(Ci-Ce)alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — (Ci-Ce)alkyl, — O — (Co-Ce)alkyl, — O — (C3- C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — N(Co-Ce-alkyl) ₂ , — N((Co-Ce)alkyl)((C3- C7 — )cycloalkyl) or — N((Co-Ce)alkyl)(aryl) substituents;

D, E, F, G, K and L in P independently represent — C(R3)=, — C(R3)=C(R4) — , — C(=O) — , — C(=S)— , — O— , — N=, — N(R ₃ )— or — S— ;

Q denotes a cycloalkyl, an aryl or heteroaryl group of formula

R3, R4, Rs, Re, and R7 independently are as defined above;

D, E, F, G and H in Q independently represent — C(R3)=, — C(R3)=C(R4) — , — C(=O) — , — C(=S)— , — O— , — N=, — N(R ₃ )— or — S— ;

A is azo — N=N — , ethyl, ethenyl, ethynyl, — NRxC(=O) — , — NRxC(=O) — O — , — NR ₈ C(=O)— NR ₉ , NR ₈ S(=O) ₂ — , — C(=O)NR ₈ — , — O— C(=O)NR ₈ — , — S— , — S(=O)— , — S(=O) ₂ — , — S(=O) ₂ NR ₈ — , — C(=O)— O— , — O— C(=O)— , — C(=NR ₈ )NR ₉ — , C(=NOR ₈ )NR ₉ — , — NR ₈ C(=NOR ₉ )— , =N— O— , — O— N=CH— or a group aryl or heteroaryl of formula

R3, R4, Rs and Rs independently are as defined above;

D, E, F, G and H in A independently represent — C(Rs)= — C(R3)=C(R4) — , — C(=O) — , — C(=S)— , — O— , — N=, — N(R ₃ )— or — S— ;

R3, R4, Rs and Rs independently are as defined above;

B represents a single bond, — C(=O) — (Co-C2)alkyl-, — C(=O) — (C2-Ce)alkenyl-, — C(=O)— (C ₂ -C ₆ )alkynyl-, — C(=O)— 0— — C(=0)NR ₈ — (Co-C ₂ )alkyl-, — C(=NR ₈ )NR ₉ , — S(=0)— (Co-C ₂ )alkyl-, — S(=0) ₂ — (Co-C ₂ )alkyl-, — S(=O) ₂ NR ₈ — (Co-C ₂ )alkyl-, C(=NR ₈ )— (Co-C ₂ )alkyl-, — C(=N0R ₈ )— (Co-C ₂ )alkyl- or — C(=NOR ₈ )NR ₉ — (Co-C ₂ )alkyl-; R ₈ and R ₉ , independently are as defined above;

Any N may be an N-oxide; or pharmaceutically acceptable salts, hydrates or solvates of such compounds.

Formula 295

[001236] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 295. Such compounds are described in WO 2006/123244, published November 23, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 295, this reference incorporated by reference herein controls.

[001237] In an embodiment, the glutamate modulator is a compound according to: wherein

W represents (C5-C7)cycloalkyl, (C5-C7)heterocycloalkyl, (C5-C7)heterocycloalkyl-(Ci- Cs)alkyl or (C5-C7)heterocycloalkenyl ring;

Ri and R2 represent independently hydrogen, — (Ci-Ce)alkyl, — (C2-Ce)alkenyl, — (C2- Ce)alkynyl, arylalkyl, heteroarylalkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, — (Ci- Ce)alkoxy or Ri and R2 together can form a (C3-C7)cycloalkyl ring, a carbonyl bond C=O or a carbon double bond;

P and Q are each independently selected and denote a cycloalkyl, a heterocycloalkyl, an aryl or heteroaryl group of formula

R3, R4, Rs, Re, and R7 independently are hydrogen, halogen, — CN, — NO2, — (Ci-Ce)alkyl, — (C3-Ce)cycloalkyl, — (C3-C7)cycloalkylalkyl, — (C2-Ce)alkenyl, — (C2-Ce)alkynyl, halo- (Ci-Ce)alkyl, heteroaryl, heteroarylalkyl, arylalkyl, aryl, — ORs, — NR.sR.9, — C(=NRIO)NRSR9, N(=NRIO)NRSR9, — NRgCORg, NR8CO2R9, NR8SO2R9, — NR10CO NR ₈ R ₉ , — SR ₈ , — S(=O)R ₈ , — S(=O) ₂ R ₈ , — S(=O) ₂ NR ₈ R9, — C(=O)R ₈ , —COORS, — C(=0)NRSR9, — C(=NRS)R9, or C(=N0Rs)R9 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, — CN, — (Ci-Ce)alkyl, — O — (Co-Ce)alkyl, — O — (C3-C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — O — ( — Ci-C3)alkylaryl, — O — (Ci-C3)alkylheteroaryl, — N(( — CO-Ce)alkyl)((Co-C3)alkylaryl) or — N((Co-C6)alkyl)((Co-C3-)alkylheteroaryl) groups; Rs, R9, Rio each independently is hydrogen, (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, (C3- C7)cycloalkylalkyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, halo-(Ci-Ce)alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — (Ci-Ce)alkyl, — O — (Co-Ce)alkyl, — O — (C3- C7)cycloalkylalkyl, — O(aryl), — O(heteroaryl), — N(Co-Ce-alkyl)2, — N((Co-C6)alkyl)((C3- C ₇ -)cycloalkyl) or — N((Co-Ce)alkyl)(aryl) substituents;

D, E, F, G and H represent independently — C(R3)=, — C(R3)=C(R4) — , — C(=O) — , — C(=S)— , — O— , — N=, — N(R ₃ )— or — S— ;

B represents a single bond, — C(=O) — (Co-C2)alkyl-, — C(=O) — (C2-Ce)alkenyl-, — C(=O)— (C ₂ -C ₆ )alkynyl-, — C(=O)— O— , — C(=O)NR ₈ — (Co-C ₂ )alkyl-, — C(=NR ₈ )NR ₉ — S(=O)— (Co-C ₂ )alkyl-, — S(=O) ₂ — (Co-C ₂ )alkyl-, — S(=O) ₂ NR ₈ — (Co-C ₂ )alkyl-, C(=NR ₈ )— (Co-C ₂ )alkyl-, — C(=NOR ₈ )— (Co-C ₂ )alkyl- or — C(=NOR ₈ )NR ₉ — (Co-C ₂ )alkyl-;

R ₈ and R ₉ , independently are as defined above;

X represents — (Co-C6)alkyl-NRnC(=0)0 — (Co-Ce)alkyl-, — (Co-C6)alkyl-NRnC(=0)0 — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NRi iC(=O)O— (C ₂ -C ₆ )alkenyl-, — (Co-C ₆ )alkyl- NRi iC(=O)O— (C ₃ -C ₆ )cycloalkyl-, — (Co-C ₆ )alkyl-NRi ₂ C(=0)NRi i— (Co-C ₆ )alkyl-, — (Co- C ₆ )alkyl-NRi ₂ C(=O)NRi i— (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NRi ₂ C(=0)NRi i— (C ₂ - C ₆ )alkenyl-, — (Co-C ₆ )alkyl-NRi2C(=0)NRn— (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl- NRI ₂ C(=O)NRH— (C ₄ -Cio)alkylcycloalkyl, — (Co-C ₆ )alkyl-NRi2C(=S)NRn— (Co-C ₆ )alkyl-, — (Co-C ₆ )alkyl-NRi ₂ C(=S)NRi i— (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NRi ₂ C(=S)NRi i— (C ₂ - C ₆ )alkenyl-, — (Co-C ₆ )alkyl-NRi2C(=S)NRn— (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl- NRI ₂ C(=S)NRH— (C ₄ -Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-OC(=0)NRn— (Co-C ₆ )alkyl-, — (Co-C ₆ )alkyl-OC(=0)NRii— (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-OC(=0)NRn— (C ₂ - C ₆ )alkenyl-, — (Co-C ₆ )alkyl-OC(=0)NRn— (C ₄ -Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl- OC(=O)NRn— (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-NRnC(=0)0— (Co-C ₆ )alkyl-, — (Co- C ₆ )alkyl-NRnC(=O)O— (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NRnC(=0)0— (C ₂ -C ₆ )alkenyl-, — (Co-C ₆ )alkyl-NRiiC(=0)0— (C ₃ -C ₇ )cycloalkyl- or — (Co-C ₆ )alkyl-NRiiC(=0)0— (C ₄ - Cio)alkylcycloalkyl;

Rn and R12 each independently is hydrogen, — (Ci-Ce)alkyl, — (C3-Ce)cycloalkyl, — (C3- C ₇ )cycloalkylalkyl, — (C2-Ce)alkenyl, — (C2-Ce)alkynyl, halo-(Ci-Ce)alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — (Ci-Ce)alkyl, — O — (Co-Ce-alkyl), — O — (C3-C/7- cycloalkylalkyl), — O(aryl), — O(heteroaryl), — N(Co-C6-alkyl)(Co-C6-alkyl), — N(Co-Ce- alkyl)(C3-C ₇ -cycloalkyl) or — N(Co-C6-alkyl)(aryl) substituents;

Any N may be an N-oxide; or pharmaceutically acceptable salts, hydrates or solvates of such compounds.

Formula 296 [001238] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 296. Such compounds are described in WO 2006048771, published May 11, 2006, corresponding to PCT/IB2005/003498, filed November 2, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 296, this reference incorporated by reference herein controls.

[001239] In an embodiment, the glutamate modulator is a compound according to: Wherein

P is an aryl or heteroaryl group of formula

Q is an aryl or heteroaryl group of formula

R3, R4, Rs, Re, and R7 independently are hydrogen, halogen, -(Ci- Ce)alkyl, -(C3- Ce)cycloalkyl, -(C3-C7)cycloalkylalkyl, halo-(Ci-Ce)alkyl, -ORs;

Rs is hydrogen, (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, (C3-C7)cycloalkylalkyl, substituents;

D, E, F, G and H represent independently -C(R3)=, -C(R3)=C(R4)-, -C(=O)-,-C(=S)-, -O-, - N=, -N(R ₃ )- or -S-;

Any N may be an N-oxide; or a pharmaceutically acceptable salt, hydrate or solvate of such a compound;

Formula 297

[001240] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 297. Such compounds are described inWO 2006/029980, published March 23, 2006, corresponding to PCT/EP2005/054436, filed September 8, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 297, this reference incorporated by reference herein controls.

[001241] In an embodiment, the glutamate modulator is a compound according to: wherein

Al represents a nitrogen atom or a C — Ria group, A2 represents a nitrogen atom or a C — Rib group, A3 represents a nitrogen atom or a C — Rlc group, A4 represents a nitrogen atom or a C — Rid group, Ria, Rib, Rlc, Rid, mutually independently, in each case represent a hydrogen; a halogen; — NO2; — CN; — NH2; — NHR4; — NR5R6; — NH— C(=O)— R7; — C(=O)— R8, — C(=O)— NH2; — C(=O)— NHR9; — C(=O)— NR10R11; — C(=O)— OR12; — (CH2)m— C(=O)— OR13 with m=l, 2, 3, 4 or 5; — O— C(=O)— R14; — (CH2)n— O— C(=O)— R15 with n=l, 2, 3, 4 or 5; — OR16; — (CH2)o— O— R17 with o=l, 2, 3; 4 or 5; — SR18; — (CH2)p— S(=0) t— R19 with p=l, 2, 3, 4 or 5 and t=0, 1 or 2; — NH— S(=0)2— R26R27; — S(=0)2— NR28R29, — SF5; a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic group; a saturated or unsaturated, unsubstituted or at least monosubstituted cycloaliphatic group optionally comprising at least one heteroatom as a ring member, which cycloaliphatic group may be attached via a linear or branched alkylene group and/or may be fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system; or represent an unsubstituted or at least monosubstituted aryl or heteroaryl group, which may be attached via a linear or branched alkylene group and/or may be fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system, or Ria and Rib form an unsubstituted or at least monosubstituted anellated phenyl group with the C — C bridge joining them together, or Rib and Rlc form an unsubstituted or at least monosubstituted anellated phenyl group with the C — C bridge joining them together, or Rlc and Rid form an unsubstituted or at least monosubstituted anellated phenyl group with the C — C bridge joining them together,

R2 and R3, mutually independently, in each case represent hydrogen; — C(=0) — R20; — (CH2)q— C(=0)— R21 with q=l, 2, 3, 4 or 5; — C(=0)— O— R22; — (CH2)r— C(=0)— O— R23 with r=l, 2, 3, 4 or 5; — C(=0)— NHR24; — (CH2)s— C(=0) — NHR25 with s=l, 2, 3, 4 or 5; a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic group; a saturated or unsaturated, unsubstituted or at least monosubstituted cycloaliphatic group optionally comprising at least one heteroatom as a ring member, which cycloaliphatic group may be attached via a linear or branched alkylene group and/or may be fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system; or represent an unsubstituted or at least monosubstituted aryl or heteroaryl group, which may be attached via a linear or branched alkylene group and/or may be fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system, or R2 and R3, together with the nitrogen atom joining them together as a ring member, form a saturated or unsaturated heterocycloaliphatic group optionally comprising at least one further heteroatom as a ring member, which heterocycloaliphatic group may be fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system,

R4, R5, R6, R7, R9, RIO, R11, R14 and R15, in each case mutually independently, represent a linear or branched, saturated or unsaturated aliphatic group or an unsubstituted or at least monosubstituted aryl or heteroaryl group, which may be attached via a linear or branched alkylene group and/or may be fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system,

R8, R12, R13, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28 and R29, in each case mutually independently, represent hydrogen; a linear or branched, saturated or unsaturated aliphatic group or an unsubstituted or at least monosubstituted aryl or heteroaryl group, which may be attached via a linear or branched alkylene group and/or may be fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system,

Ml represents an aryl or heteroaryl group, which may be substituted with at least one further substituent and/or fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system,

M2 represents an aryl or heteroaryl group, which is unsubstituted or at least monosubstituted and optionally fused with an unsubstituted or at least monosubstituted mono- or polycyclic ring system, or a salt or solvate thereof.

Formula 298 [001242] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 298. Such compounds are described in WO 2006/002981, published January 12, 2006, corresponding to PCT/EP2005/007248, filed July 5, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 298, this reference incorporated by reference herein controls.

[001243] In an embodiment, the glutamate modulator is a compound according to wherein

X denotes N or C — R ² ;

R ¹ and R ² each independently denote a hydrogen, a halogen radical, or a nitro group, a cyano group, or an amino group, a hydroxyl group, a thiol group, or a carboxyl group, or a formyl group, an — NH — C(=O) — H group, an — NH — R ⁵ group, an — NR/’R. ⁷ group, or a — C(=O) — R ⁸ group, or a — C(=O) — O — R ⁹ group, an — O — C(=O) — R ¹⁰ group, an — NH — C(=O) — R ¹¹ group, or an — NR ¹² — C(=O) — R ¹³ group, or a — C(=O) — NH2 group, a — C(=O) — NH — R ¹⁴ group, a — C(=O) — NR ¹⁵ R ¹⁶ group, or an — O — R ¹⁷ group, or an — S — R ¹⁸ group, an — S(=O) — R ¹⁹ group, an — S(=O)2 — R ²⁰ group, or an — NH — C(=O) — NH — R ²¹ group, or an — NH — C(=S) — NH — R ²² group, an — NH — S(=O)2 — R ²³ group, an — NR ²⁴ — S(=O)2 — R ²⁵ group, or a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic radical which optionally contains at least one hetero atom as link, or an unsubstituted or at least monosubstituted, unsaturated or saturated cycloaliphatic radical which optionally contains at least one hetero atom as ring member, and which can be bonded via a linear or branched, unsubstituted or at least monosubstituted alkylene group, alkenylene group or alkynylene group optionally containing at least one hetero atom as link and/or optionally condensed with an unsubstituted or at least monosubstituted monocyclic or polycyclic ring system, or an unsubstituted or at least monosubstituted aryl radical or an unsubstituted or at least monosubstituted heteroaryl radical, and which can be bonded via a linear or branched, unsubstituted or at least monosubstituted alkylene group, alkenylene group or alkynylene group optionally containing at least one hetero atom as link and/or optionally condensed with an unsubstituted or at least monosubstituted monocyclic or polycyclic ring system;

R ³ denotes a halogen radical, or a nitro group, a cyano group, or an amino group, a hydroxyl group, a thiol group, or a carboxyl group, or a formyl group, an — NH — C(=O) — H group, an oxo group (=0), an — NH — R ⁵ group, an — NR R ⁷ group, or a — C(=0) — R ⁸ group, or a — C(=0) — O — R ⁹ group, an — O — C(=0) — R ¹⁰ group, an — NH — C(=0) — R ¹¹ group, or an — NR ¹² — C(=0) — R ¹³ group, or a — C(=0) — NH2 group, a — C(=0) — NH — R ¹⁴ group, a — C(=0) — NR ¹⁵ R ¹⁶ group, or an — O — R ¹⁷ group, or an — S — R ¹⁸ group, an — S(=0) — R ¹⁹ group, an — S(=0)2 — R ²⁰ group, or an — NH — C(=0) — NH — R ²¹ group, or an — NH — C(=S) — NH — R ²² group, an — NH — S(=0)2 — R ²³ group, an — NR ²⁴ — S(=0)2 — R ²⁵ group, a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic radical which optionally contains at least one hetero atom as link, an unsubstituted or at least monosubstituted, unsaturated or saturated cycloaliphatic radical which optionally contains at least one hetero atom as ring member, and which can be bonded via a linear or branched, unsubstituted or at least monosubstituted alkylene group, alkenylene group or alkynylene group optionally containing at least one hetero atom as link and/or optionally condensed with an unsubstituted or at least monosubstituted monocyclic or polycyclic ring system, or an unsubstituted or at least monosubstituted aryl radical or an unsubstituted or at least monosubstituted heteroaryl radical, and which can be bonded via a linear or branched, unsubstituted or at least monosubstituted alkylene group, alkenylene group or alkynylene group optionally containing at least one hetero atom as link and/or optionally condensed with an unsubstituted or at least monosubstituted monocyclic or polycyclic ring system;

R ⁴ denotes a hydrogen, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, a cyano group, or an amino group, or a hydroxyl group, a thiol group, a carboxyl group, or a formyl group, or an — NH — C(=0) — H group, an — NH — R ⁵ group, an — NR ⁶ R ⁷ group, or a — C(=0) — R ⁸ group, or a — C(=0) — O — R ⁹ group, an — O — C(=0) — R ¹⁰ group, an — NH — C(=0) — R ¹¹ group, or an — NR ¹² — C(=0) — R ¹³ group, or a — C(=0) — NH2 group, a — C(=0) — NH — R ¹⁴ group, a — C(=0) — NR ¹⁵ R ¹⁶ group, or an — O — R ¹⁷ group, or an — S — R ¹⁸ group, an — S(=0) — R ¹⁹ group, an — S(=0)2 — R ²⁰ group, or an — NH — C(=0) — NH — R ²¹ group, or an — NH — C(=S) — NH — R ²² group, an — NH — S(=0)2 — R ²³ group, an — NR ²⁴ — S(=0)2 — R ²⁵ group, a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic radical which optionally contains at least one hetero atom as link, an unsubstituted or at least monosubstituted, unsaturated or saturated cycloaliphatic radical which optionally contains at least one hetero atom as ring member, and which can be bonded via a linear or branched, unsubstituted or at least monosubstituted alkylene group, alkenylene group or alkynylene group optionally containing at least one hetero atom as link and/or optionally condensed with an unsubstituted or at least monosubstituted monocyclic or polycyclic ring system, or an unsubstituted or at least monosubstituted aryl radical or an unsubstituted or at least monosubstituted heteroaryl radical, and which can be bonded via a linear or branched, unsubstituted or at least monosubstituted alkylene group, alkenylene group or alkynylene group optionally containing at least one hetero atom as link and/or optionally condensed with an unsubstituted or at least monosubstituted monocyclic or polycyclic ring system;

R ⁵ to R ²⁵ each independently denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic radical which optionally contains at least one hetero atom as link, an unsubstituted or at least monosubstituted, unsaturated or saturated cycloaliphatic radical which optionally contains at least one hetero atom as ring member, and which can be bonded via a linear or branched, unsubstituted or at least monosubstituted alkylene group, alkenylene group or alkynylene group optionally containing at least one hetero atom as link and/or optionally condensed with an unsubstituted or at least monosubstituted monocyclic or polycyclic ring system, or an unsubstituted or at least monosubstituted aryl radical or an unsubstituted or at least monosubstituted heteroaryl radical, and which can be bonded via a linear or branched, unsubstituted or at least monosubstituted alkylene group, alkenylene group or alkynylene group optionally containing at least one hetero atom as link, and n is O, 1, 2, 3, 4, 5, 6, 7 or 8; in the form of a pure stereoisomer or a mixture of stereoisomers in any mixing ratio; or a salt or solvate thereof.

Formula 299

[001244] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 299. Such compounds are described in US 2006/0004001, published January 5, 2006 corresponding to 11/211,829, filed August 25, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 299, this reference incorporated by reference herein controls.

[001245] In an embodiment, the glutamate modulator is a compound according to: wherein

A represents heteroaryl;

R1 represents aryl or heteroaryl;

R2 and R3, which may be the same or different, represent hydrogen or Cl-6alkyl; R4 and R5, which may be the same or different, represent hydrogen or Cl-6alkyl; it being understood that: aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1, 2, 3, 4 or 5 substituents, that may be the same or different, which substituents are selected from Cl-6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Cl-6alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC3-12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, amino, di-Cl-6alkylamino, N-cycloC3-12alkyl-N-Cl-6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Cl-6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl; heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms, said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1, 2 or 3 substituents, that may be the same or different, which substituents are selected from Cl-6alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Cl-6alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC3-12alkyl, hydroxyl, F, Cl, Br, I, CN, nitro, amino, di-Cl- 6alkylamino, N-cycloC3-12alkyl-N-Cl-6alkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Cl-6alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

Formula 300 [001246] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 300. Such compounds are described in US 2005/0288284, published December 29, 2005, corresponding to US 11/210,569, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 300, this reference incorporated by reference herein controls.

[001247] In an embodiment, the glutamate modulator is a compound according to:

R ¹ represents aryl or heteroaryl;

R ² and R ³ , which may be the same or different, represent hydrogen or Cnealkyl; R ⁴ and R ⁵ , which may be the same or different, represent hydrogen or Cnealkyl; it being understood that: aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1, 2, 3, 4 or 5 substituents, that may be the same or different, which substituents are selected from Cn ealkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Cnealkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloCnnalkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Cnealkylamino, N-cycloCs- nalkyl-N-Cnealkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Ci-ealkyl- piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl; heteroaryl represents a (hetero)aromatic 5-, 6- or 7-membered ring having from 1 to 4 heteroatoms, said heteroatoms being independently selected from oxygen, nitrogen and sulfur, wherein said ring is unsubstituted or substituted with 1, 2 or 3 substituents, that may be the same or different, which substituents are selected from Cnealkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Cnealkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloCs-nalkyl, hydroxyl, F, Cl, Br, I, CN, nitro, di-Cnealkylamino, N-cycloCs-nalkyl-N- Cnealkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-Cnealkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, pyrrolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

Formula 301

[001248] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 301. Such compounds are described in WO 2005/123703, published December 29, 2005, corresponding to PCT/IB2005/002390, filed June 17, 2005, US 8,101,637, issued January 24, 2012, US 8,883,826, issued November 11, 2014, and US 8,674,106, issued March 18, 2014 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 301, this reference incorporated by reference herein controls.

[001249] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt or hydrate thereof; wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci-Ce-alkyl, Ci-Ce-alkylhalo and Co-Ce-alkyl- NR ⁵ R ⁶ substituents;

R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, optionally substituted Ci-Ce-alkyl, Ci-Ce-alkylhalo, C3-C?-cycloalkyl, Cs-Cv-cycloalkyl-Ci-Ce-alkyl, heteroaryl, Ci-Ce-alkyl-heteroaryl, and aryl;

G ^q groups are each independently selected from the group consisting of hydrogen, halogen, CN, an optionally substituted Ci-Ce-alkyl, Ci-Ce-alkylhalo, O — Co-Ce-alkyl, O — Co-Ce- alkylaryl, heteroaryl and aryl; q is an integer from 1 to 5; and any N may be an N-oxide.

[001250] In further embodiments, the glutamate modulator is the compound 6-fluoro-2- (4-(pyri din-2 -yl)but-3-ynyl)-imidazo[l,2-a]pyri dine, or a pharmaceutically acceptable salt thereof or a substituted variant retaining glutamate modulatory activity.

[001251] In further embodiments, the glutamate modulator is a compound selected from:

2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[l,2-a]pyridine;

8-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[l,2-a]pyr idine; 5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[l,2-a]pyridi ne;

5-Phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[l,2-a]pyr idine; 2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)imidazo[l,2-a]pyridine ;

6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[l,2-a]pyr idine; 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)-imidazo[l,2-a]pyridin e;

8-Chloro-2-(4-(6-(fluoromethyl)pyri din-2 -yl)but-3-ynyl)-imidazo[l,2-a]pyri dine; 8-Chloro-2-(4-(pyri din-2 -yl)but-3-ynyl)-imidazo[l,2-a]pyri dine;

6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H- imidazo[l,2-a]pyridine; 6-fluoro-2-(4-(2-(fluoromethyl)thi azol -4-yl)but-3-ynyl)-imidazo[l,2-a]pyri dine; 8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imida zo[l,2-a]pyridine;

8-(benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn yl)-imidazo[l,2-a]pyridine; 2-(4-(6-(fluoromethyl)pyri din-2 -yl)but-3-ynyl)-8-phenyl-imidazo[l,2-a]pyri dine;

6.8-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[l,2-a ]pyridine; and

6.8-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-yny l)H-imidazo[l,2-a]pyridine; or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate modulatory activity.

Formula 302

[001252] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 302. Such compounds are described in WO 2005/066155, published July 21, 2005, corresponding to PCT/US2004/041401, filed December 13, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 302, this reference incorporated by reference herein controls.

[001253] In an embodiment, the glutamate modulator is a compound according to: wherein:

Xi is N and X2 is C or Xi is C and X2 is N;

Z is fluoro, chloro or cyano; R ¹ and R ² are independently selected from the group consisting of hydrogen, hydroxy, halo, Ci- ₆ alkylhalo, OCi- ₆ alkylhalo, Ci- ₆ alkyl, OCo- ₆ allyl, Ci- ₆ alkylOR ⁴ , OC _2-6 alkylOR ⁴ , Co- ealkylcyano, Co-ealkylNR ⁴ R ⁵ and OC2-ealkylNR ⁴ R ⁵ ;

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, hydroxy and Ci- 3 alkyl; or salts, solvates or solvated salts thereof.

[001254] In further embodiments, the glutamate modulator is a compound selected from:

3-fluoro-5-[5-(5-fluoropyri din-2 -yl)-2H-tetrazol-2-yl]benzonitrile, 6-[2-(3-cyano-5-fluorophenyl)-2H-tetrazol-S-yl]nicotinonitri le, 3-[5-(5-chloropyridin-2-yl)-2H-tetrazol-2-yl]-5-fluorobenzon itrile, 3-[5-(5-fluoro-pyridin-2-yl)-tetrazol-2-yl]-5-methoxymethyl- benzonitrile, 3-fluoro-5-[2-(5-fluoropyri din-2 -yl)-2H-tetrazol-5-yl]benzonitrile, 6-[5-(3-cyano-5-fluorophenyl)-2H-tetrazol-2-yl]nicotinonitri le,

3-[2-(5-chloropyridin-2-yl)-2H-tetrazol-5-yl]-5-fluoroben zonitrile, 3-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]-5-(methoxymeth yl)benzonitrile, 5-fluoro-2-[2-(3-fluoro-5-methoxyphenyl)-2H-tetrazol-5-yl]py ridine, 3-[5-(5-fluoro-pyridin-2-yl)-2H-tetrazol-2-yl]-5-methoxybenz onitrile, 3-[5-(5-fluoropyridin-2-yl)-2H-tetrazol -2 -yl]-S-(tri fluoromethoxy )benzonitrile, 3-(difluoromethoxy)-5-[5-(5-fluoropyridin-2-yl]-2H-tetrazol- 2-yllbenzonitrile,

3-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl] -5-(2 -methoxy ethoxy )benzonitrile, 3-(ethylamino)-5-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl] benzonitrile, 3-amino-5-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]benzoni trile, 3-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl]-5-iodobenzonit rile, and or salts, solvates or solvated salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 303

[001255] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 303. Such compounds are described in WO 2005/044797, published May 19, 2005, corresponding to PCT/IB2004/003822, filed November 4, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 303, this reference incorporated by reference herein controls.

[001256] In an embodiment, the glutamate modulator is a compound according to:

Wherein

Ri and R2 represent independently hydrogen, Ci-Ce-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, arylalkyl, heteroarylalkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, Ci-Ce-alkoxy or Ri and R2 together can form a C3-C?-cycloalkyl ring, a carbonyl bond C=O or a carbon double bond ;

P and Q are each independently selected and denote a cycloalkyl, an aryl or heteroaryl group of formula

R3, R4, Rs, Re, and R7 independently are hydrogen, halogen, -CN, nitro, Ci-Ce-alkyl, C3-C6- cycloalkyl, C3-C7-cycloalkylalkyl, Ci-Ce-alkenyl, Ci-Ce-alkynyl, halo-Ci-Ce-alkyl, - heteroaryl, heteroarylalkyl, arylalkyl, aryl, -ORx, -NR8R9,-C(=NRIO)NR8R9, N(=NRIO)NR8R9, -NR8COR9, NR8CO2R9, NR ₈ S0 ₂ R9,-NRIOCO NR ₈ R ₉ , -SR ₈ , -S(=O)R ₈ , -S(=O) ₂ R ₈ , - S(=O) ₂ NR ₈ R9, -C(=O)R ₈ ,-C(=O)NR ₈ R9, -C(=NR ₈ )R ₉ , or C(=NOR8)R9 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, -CN, Ci-C6-alkyl,-0(Co-Ce-alkyl), -O(C3-C7 cycloalkylalkyl), -O(aryl), - O(heteroaryl). -O(Ci-C3-alkylaryl), -O(Ci-C3 -alkylheteroaryl), -N(Co-Ce-alkyl)(Co-C3- alkylaryl) or -N(Co-C6-alkyl)(Co-C3-alkylheteroaryl) groups;

Rs, R9, Rio each independently is hydrogen, Ci-Cs-alkyl, C3-Ce-cycloalkyl, C3- C7cycloalkylalkyl. C2-Ce-alkenyl, C2-Ce-alkynyl, halo-Ci-Ce-alkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, Ci-C6-alkyl-0(Co-Ce-alkyl), -O(C3-C7-cycloalkylalkyl), -O(aryl), - O(heteroaryl), -N(Co-C6-alkyl)(Co-C6-alkyl),-N(Co-C ₆ -alkyl)(C3-C7-cycloalkyl) or -N(Co-C ₆ - alkyl)(aryl) substituents; D, E. F. G and H represent independently-C(R3)=, -C(R3)=C(R4)-,-C(=O)-,-C(=S)-, -O-, -N=, -N(R ₃ )- or -S-;

A is azo -N=N-, ethyl, ethenyl, ethynyl, -NR ₈ C(=O)-, NR ₈ S(=O)2, -C(=O)NR ₈ -, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ NR ₈ -, -C(=O)-O-, -O-C(=O)-, -C(=NR ₈ )NR ₉ -, C(=NOR ₈ )NR ₉ -, - NR ₈ C(=NOR9)-, =N-O-, -O-N=CH- or a group aryl or heteroaryl of formula

Rs, R4, Rs and Rs independently are as defined above;

D, E, F, G and H independently represent a carbon group, oxygen, nitrogen, sulphur or a double bond;

B represents a single bond, -C(=0)-Co-C2-alkyl-, -C(=O)-C2-Ce-alkenyl-, -C(=O)-C2-Ce- alkynyl-, -C(=O)-O-, -C(=O)NR ₈ -C ₀ -C ₂ -alkyl-, -C(=NR ₈ )NR9-S(=0)-Co-C ₂ -alkyl-, -S(=O) ₂ - Co-C ₂ -alkyl, -S(=O) ₂ NR ₈ -C ₀ -C2-alkyl-, C(=NR ₈ )-Co-C2-alkyl-,-C(=NOR ₈ )-Co-C ₂ -alkyl- or- C(=NOR ₈ )NR9-Co-C2-alkyl-; R ₈ and R9, independently are as defined above;

J represents -C(Rn, R12), -O-, -N(Rn)- or -S-;

R11, R12 independently are hydrogen, Ci-Ce-alkyl, Cs-Ce-cycloalkyl, Cs-Cv-cycloalkylalkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, halo-Ci-Ce-alkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1-5 independent halogen, -CN, Ci-Ce-alkyl, - O(Co-Ce-alkyl), -O(C3-C7-cycloalkylalkyl), -O(aryl), -O(heteroaryl), -N(Co-C6-alkyl)(Co-Ce- alkyl),-N(Co-C6-alkyl)(C3-C7-cycloalkyl) or -N(Co-C6-alkyl)(aryl) substituents;

Any N may be an N-oxide; or pharmaceutically acceptable salts, hydrates or solvates of such compounds, but excluding the following compounds 4-(3-phenyl-oxadiazol-5-yl)-N-(4-bromophenyl)aminocarbonylpi peridine N-benzoyl-3-(3,4-dimethoxyphenylaminocarbonyl)-piperidin-4-o ne N-(3-cyanophenytlmethylcarbonyl)-4-(3-(2,3-dichlorophenyl)-p yrazo-5-yl)piperidine.

Formula 304 [001257] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 304. Such compounds are described in WO 2005/030128, published April 7, 2005, corresponding to PCT/US2004/030482, filed September 17, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 304, this reference incorporated by reference herein controls.

[001258] In an embodiment, the glutamate modulator is a compound according to:

, wherein R ¹ is selected from the group consisting of:

(1) hydrogen,

(2) Ci-ealkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(3) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and

(4) phenyl, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) trifluoromethyl,

(f) — OCF ₃ ,

(g) — CO2R ⁹ , wherein R ⁹ is independently selected from:

(i) hydrogen,

(ii) — Ci-ealkyl, which is unsubstituted or substituted with 1-6 fluoro,

(iii) benzyl, and

(iv) phenyl,

(h) — NR ¹⁰ R ⁿ , wherein R ¹⁰ and R ¹¹ are independently selected from:

(i) hydrogen, (ii) — Ci-ealkyl, which is unsubstituted or substituted with 1-6 fluoro,

(iii) — Cs-ecycloalkyl,

(iv) benzyl,

(v) phenyl,

(vi) — S(O) ₂ — Ci- ₆ alkyl,

(vii) — S(O)2-benzyl, and

(viii) — S(O) ₂ -phenyl,

(i) — CONR ¹⁰ R ⁿ , and

(j) — NO ₂ ;

(5) heterocycle, wherein heterocycle is selected from: benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) phenyl,

(f) trifluoromethyl,

(g) -OCF ₃ ,

(h) — CO ₂ R ⁹ , (i) — NR ¹⁰ R ⁿ , and

(j) — CONR ¹⁰ R ⁿ ;

R ² and R ⁵ are independently selected from the group consisting of:

(1) hydrogen,

(2) Ci-ealkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(3) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and

(4) phenyl, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl, which is unsubstituted or substituted with

— NR ¹⁰ R ⁿ ,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) trifluoromethyl,

(f) — OCF ₃ ;

(g) — CO2R ⁹ ,

(h) — NR ¹⁰ R ⁿ ,

(i) — C(O)NR ¹⁰ R ⁿ , and

(j) — NO2,

(5) heterocycle, wherein heterocycle is selected from: benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) phenyl,

(f) trifluoromethyl,

(g) - OCF ₃ ;

(h) — CO2R ⁹ ,

(i) — NR ¹⁰ R ⁿ , and

(j) — CONR ¹⁰ R ⁿ ;

R ³ is independently selected from the group consisting of:

(1) hydrogen, and

(2) Ci- ₆ alkyl;

R ⁴ is selected from the group consisting of:

(1) Ci-ealkyl, which is unsubstituted or substituted with halogen, hydroxyl, phenyl or heterocycle,

(2) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and

(3) phenyl, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) trifluoromethyl,

(f) — OCF3,

(g) — CO2R ⁹ ,

(h) — CN,

(i) — NR ¹⁰ R ⁿ ,

(j) — CONR ¹⁰ R ⁿ , and

(k) — NO ₂ ; (4) heterocycle, wherein heterocycle is selected from: benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) phenyl,

(f) trifluoromethyl,

(g) — OCF ₃ ,

(h) — CO2R ⁹ ,

(i) — NR ¹⁰ R ⁿ , and

(j) — CONR ¹⁰ R ⁿ ; and pharmaceutically acceptable salts thereof and individual diastereomers thereof. Formula 305

[001259] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 305. Such compounds are described in WO 2005/021529, published March 10, 2005, corresponding to PCT/US2004/027916, filed August 27, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 305, this reference incorporated by reference herein controls.

[001260] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof wherein:

R1 is selected from:

1) hydrogen,

2) Cl-lOalkyl,

3) C2-10alkenyl,

4) C2-10alkynyl

5) cycloalkyl,

6) heterocyclyl,

7) aryl,

8) heteroaryl,

NRdRe,

— CO2Rd,

— ORd,

— CN, and halogen, where alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are optionally substituted with one to four substituents selected from Ra, and where aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; R2 is selected from:

1) hydrogen,

2) Cl-lOalkyl,

3) C2-10alkenyl,

C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl and alkynyl, cycloalkyl and heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; R3 is selected from:

1) Rb,

2) hydrogen, -Z-aryl

-Z -heteroaryl where aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb, and wherein Z is a bond, C, O, S or NRd;

Ra is selected from:

1) hydrogen,

2) — ORd,

3) — NO2,

4) halogen,

5) — S(O)mRd,

6) — SRd,

7) — S(O)mNRdRe,

8) — NRdRe,

9) — C(O)Rd,

10) — CO2Rd,

11) — OC(O)Rd,

12) — CN,

13) — C(O)NRdRe,

14) — NRdC(O)Re,

15) — OC(O)NRdRe,

16) — NRdC(O)ORe,

17) — NRdC(O)NRdRe,

18) — CRd(N— ORd),

19) CF3, and

20) — OCF3;

Rb is selected from:

1) a group selected from Ra,

2) Cl-10 alkyl, 3) C2-10 alkenyl,

4) C2-10 alkynyl,

5) cycloalkyl,

6) heterocyclyl,

7) aryl, and

8) heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one to four substituents selected from a group independently selected from Rc;

Rc is selected from:

1) halogen,

2) amino,

3) carboxy,

4) cyano,

5) Cl-4alkyl,

6) Cl-4alkoxy,

7) aryl,

8) aryl Cl-4alkyl,

9) heteroaryl,

10) hydroxy,

11) CF3, and

12) aryl oxy;

Rd and Re are independently selected from hydrogen, Cl-lOalkyl, C2-10alkenyl, C2- lOalkynyl and Cy, where alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or Rd and Re together with the atoms to which they are attached form a ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;

Cy is independently selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is 1 or 2;

X is — NRd— , — O— , or — S— ;

Y is a bond, — O — , — NRa — or — S — .

Formula 306 [001261] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 306. Such compounds are described in WO 2004/089308, published October 21, 2004, corresponding to PCT/US2004/009845, filed March 31, 2004 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 306, this reference incorporated by reference herein controls.

[001262] In an embodiment, the glutamate modulator is a compound according to:

X is phenyl; wherein X is unsubstituted or substituted with 1-7 independent halogen, — CN, NO2, — Cn ₆ alkyl, — Ci- ₆ alkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR'R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR ³ COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO ₂ R ⁴ , — SChNR^ ² , —COR ¹ , — CChR ¹ , — CONR'R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each is further unsubstituted or substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-ealkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) substituents; R ¹ , R ² , and R ³ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is which is unsubstituted or substituted with 1-5 independent halogen, — CN, — Ci- ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co- 6alkyl)(C3-7cycloalkyl), — N(Co-6alkyl)(aryl) substituents;

R ⁴ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; which is unsubstituted or substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), — N(Co-6alkyl)(aryl) substituents;

A is — Co-4alkyl;

W is — Co-ealkyl-pyridyl which is unsubstituted or substituted with 1-7 independent halogen, — CN, NO ₂ , — Ci-ealkyl, — Ci- ₆ alkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR'R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR^OiR ² , — NR^OiR ² , — NR^ChR ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO2R ⁴ , — SO ₂ NR ¹ R ² , —COR ¹ , — CO2R ¹ , — CONR’R ² , — C(=NR ¹ )R ² , or — C(NOR')R ² substituents;

Y is pyridyl, wherein the N of the pyridyl is adjacent to the position of attachment to B; and wherein Y is which is unsubstituted or substituted with 1-7 independent halogen, — CN, NO ₂ , — Ci- ₆ alkyl, — Ci- ₆ alkenyl, — Ci- ₆ alkynyl, —OR ⁵ , — NR ⁵ R ⁶ , — C(=NR ⁵ )NR ⁶ R ⁷ , — N(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁵ COR ⁶ , — NR ⁵ CO ₂ R ⁶ , — NR ⁵ SO ₂ R ⁸ , — NR ⁵ CONR ⁶ R ⁷ , —SR ⁸ , — SOR ⁸ , — SO2R ⁸ , — SO ₂ NR ⁵ R ⁶ , —COR ⁵ , — CO2R ⁵ , — CONR ⁵ R ⁶ , — C(=NR ⁵ )R ⁶ , or — C(=NOR ⁵ )R ⁶ substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each is unsubstituted or further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-ealkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) substituents; R ⁵ , R ⁶ , and R ⁷ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is which is unsubstituted or substituted with 1-5 independent halogen, — CN, — Ci- ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co- 6alkyl)(C3-7cycloalkyl), — N(Co-6alkyl)(aryl) substituents;

R ⁸ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; which is unsubstituted or substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), — N(Co-6alkyl)(aryl) substituents;

B is — Co-4alkyl;

R ⁹ and R ¹⁰ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is which is unsubstituted or substituted with 1-5 independent halogen, — CN, — Ci- ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ¹¹ , R ¹² and R ¹³ is each independently halogen, — Co-ealkyl, — Co-ealkoxyl, =0, =N(Co- 4alkyl), or — N(Co-4alkyl)(Co-4alkyl), wherein optionally two of R ¹¹ , R ¹² and R ¹³ are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3- 7cycloalkyl), or — N(Co-ealkyl)(aryl) substituents;

Z is absent; and any N may be an N-oxide; or a pharmaceutically acceptable salt thereof.

Formula 307

[001263] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 307. Such compounds are described in WO 2004/089306, published October 21, 2004, corresponding to PCT/US2004/009750, filed March 31, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 307, this reference incorporated by reference herein controls.

[001264] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein: Y is phenyl and X is pyridyl with the N in said pyridyl adjacent to the position of attachment to A; three adjacent members of the group consisting of A ¹ , A ² , A ³ , A ⁴ , and A ⁵ are N, the remaining members of the group consisting of A ¹ , A ² , A ³ , A ⁴ , and A ⁵ are C wherein one but not both of A ¹ and A ⁴ must be N;

W is — C3-7cycloalkyl, -heteroCs-vcycloalkyl, — Co-ealkylaryl, or — Co-ealkylheteroaryl optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Ci-ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR'R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR'COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO ₂ R ⁴ , — SOiNR^ ² , — COR ¹ , — CO2R ¹ , — CONR'R ² , — (=NR')R ² , or — C(=NOR ¹ )R ² substituents;

X is optionally substituted with 1-7 independent halogen, — CN, NO ₂ , — Ci-ealkyl, — C ₂ . ealkenyl, — C _2.6 alkynyl, —OR ¹ , — NR'R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR ^X COR ² , — NR ¹ CO ₂ R ² , — NR^OiR ⁴ , — NR'CONR ² R\ —SR ⁴ , —SOR ⁴ , — SO ₂ R ⁴ , — SOiNR^ ² , —COR ¹ , — CO2R ¹ , — CONR'R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — (C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups; R ¹ , R ² , and R ³ each independently is — Co-ealkyl, — C3-?cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — (heteroaryl), — N(Co-6alkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), or — N(Co-ealkyl)(aryl) substituents;

R ⁴ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — (Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), or — N(Co- ealkyl)(aryl) substituents;

A is — Coalkyl;

Y is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — C2- ealkenyl, — C _2-6 alkynyl, —OR ⁵ , — NR ⁵ R ⁶ , — C(=NR ⁵ )NR ⁶ R ⁷ , — N(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁵ COR ⁶ , — NR ⁵ CO ₂ R ⁶ , — NR ⁵ SO ₂ R ⁸ , — NR ⁵ CONR ⁶ R ⁷ , —SR ⁸ , — SOR ⁸ , — SO2R ⁸ , — SO ₂ NR ⁵ R ⁶ , —COR ⁵ , — CO2R ⁵ , — CONR ⁵ R ⁶ , — C(=NR ⁵ )R ⁶ , or — C(=NOR ⁵ )R ⁶ substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — (heteroaryl), — N(Co-6alkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), or — N(Co-ealkyl)(aryl) groups;

R ⁵ , R ⁶ , and R ⁷ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), or — N(Co-ealkyl)(aryl) substituents;

R ⁸ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), or — N(Co- ealkyl)(aryl) substituents;

B is — Coalkyl;

R ⁹ and R ¹⁰ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

Z is pyridyl optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Ci- ₆ alkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR’COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , —SOR ⁴ , — SO2R ⁴ , — SChNR^ ² , —COR ¹ , — C02R ¹ , — CONR'R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² ; R ¹¹ is halogen, — Co-ealkyl, — Co-ealkoxyl, =0, =N(Co-4alkyl), or — N(Co-4alkyl)(Co-4alkyl); any alkyl optionally substituted with 1-5 independent halogen substitutents; any N optionally is an N-oxide; and W is optionally absent.

Formula 308

[001265] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 308. Such compounds are described in WO 2004/089303, published October 21, 2004, corresponding to PCT/US2004/011651, filed March 30, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 308, this reference incorporated by reference herein controls.

[001266] In an embodiment, the glutamate modulator is a compound according to: pharmaceutically acceptable salt thereof, wherein:

X and Y each independently is aryl or heteroaryl wherein at least one of X and Y is a heteroaryl with N adjacent to the position of attachment to A or B respectively;

X is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Cn ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR ³ COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO ₂ R ² , — COR ¹ , — C02R ¹ , — CONR’R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co- 6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ¹ , R ² , and R ³ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents; R ⁴ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, — CN, Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), — N(Co-6alkyl)(aryl) substituents;

A is — Co- ₄ alkyl, — Co- ₂ alkyl-SO— Co- ₂ alkyl-, — Co-2alkyl-S0 ₂ — Co- ₂ alkyl-, — Co- ₂ alkyl- CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ⁹ CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ⁹ S0 ₂ — Co- ₂ alkyl- or - heteroCo-4alkyl;

W is — C3-7cycloalkyl, -heteroC3-7cycloalkyl, — Co-ealkylaryl, or — Co-ealkylheteroaryl optionally substituted with 1-7 independent halogen, — CN, NO ₂ , — Ci-ealkyl, — Ci-ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR'COR ² , — NR ³ CO ₂ R ² , — NR'SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO ₂ R ⁴ , — SO ₂ NR ³ R ² , — COR ¹ , — CO ₂ R — CONR’R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents;

Y is optionally substituted with 1-7 independent halogen, — CN, NO ₂ , — Ci-ealkyl, — Cn ealkenyl, — Ci- ₆ alkynyl, —OR ⁵ , — NR ⁵ R ⁶ , — C(=NR ⁵ )NR ⁶ R ⁷ , — N(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁵ COR ⁶ , — NR ⁵ CO ₂ R ⁶ , — NR ⁵ SO ₂ R ⁸ , — NR ⁵ CONR ⁶ R ⁷ , —SR ⁸ , —SOR ⁸ , — SO ₂ R ⁸ , — SO ₂ NR ⁵ R ⁶ , —COR ⁵ , — CO ₂ R ⁵ , — CONR ⁵ R ⁶ , — C(=NR ⁵ )R ⁶ , or — C(=NOR ⁵ )R ⁶ substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), -(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ⁵ , R ⁶ , and R ⁷ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁸ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — (C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

B is — Co-4alkyl, — Co- ₂ alkyl-SO — Co- ₂ alkyl-, — Co- ₂ alkyl-S0 ₂ — Co- ₂ alkyl-, — Co- ₂ alkyl- heteroCo-4alkyl;

R ⁹ and R ¹⁰ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, Ci-ealkyl, — 0(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-ealkyl), — N(Co- 6alkyl)(C3-7cycloalkyl), — N(Co-6alkyl)(aryl) substituents; one of A ¹ and A ² is N, the other is CR ¹² ;

R ¹¹ and R ¹² is each independently halogen, — Co-ealkyl, — Co-ealkoxyl, or — N(Co-4alkyl)(Co- 4alkyl), wherein optionally R ¹¹ and R ¹² are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co- ealkyl)(aryl) groups; and wherein optionally R ¹¹ and R ¹² each independently forms =0, =N(Co-4alkyl) using a bond from the adjoining double bond; wherein any of the alkyl optionally is substituted with 1-9 independent halogens;

Z is — C3-7cycloalkyl, -heteroC3-7cycloalkyl, — Co-ealkylaryl, or — Co-ealkylheteroaryl optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Ci-ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR'COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\-SR ⁴ , — SOR ⁴ , — SO ₂ R ⁴ , — SChNR^ ² , — COR ¹ , — C02R ¹ , — CONR’R ² , — C(=NR ¹ )R ² , or — C(=N0R ¹ )R ² substituents; one of W and Z is optionally absent; and any N may be an N-oxide.

Formula 309

[001267] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 309. Such compounds are described in WO 2004/087048, published October 14, 2004, corresponding to PCT/US2004/008627, filed March 22, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 309, this reference incorporated by reference herein controls.

[001268] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ is selected from the group consisting of: (1) hydrogen,

(2) halogen,

(3) Ci-ealkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(4) — OCi- ₆ alkyl,

(5) -S(O) m Ci-ealkyl, wherein m is selected from 0, 1 and 2,

(6) — CO2R ⁹ , wherein R ⁹ is independently selected from:

(a) hydrogen,

(b) — Ci-ealkyl, which is unsubstituted or substituted with 1-6 fluoro,

(c) benzyl, and

(d) phenyl,

(7) — NR ¹⁰ R ⁿ , wherein R ¹⁰ and R ¹¹ are independently selected from:

(a) hydrogen,

(b) — Ci-ealkyl, which is unsubstituted or substituted with 1-6 fluoro,

(c) — Cs-ecycloalkyl,

(d) benzyl,

(e) phenyl,

(f) — S(O) ₂ — Ci- ₆ alkyl,

(g) — S(O) ₂ -benzyl, and

(h) — S(O) ₂ -phenyl,

(8) — S(O) ₂ — NR ¹⁰ R ⁿ ,

(9) phenyl, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) trifluoromethyl, and

(f) — OCF3;

R ³ is selected from the group consisting of:

(1) Ci-ealkyl, which is substituted with halogen, hydroxyl or phenyl,

(2) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and

(3) phenyl, which is unsubstituted or substituted with one or more substituents independently selected from: (a) — Ci-ealkyl, which is unsubstituted or substituted with — NR ¹⁰ R ⁿ ,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) trifluoromethyl,

(f) — OCF ₃ ;

(g) — CO2R ⁹ ,

(h) — NR ¹⁰ R ⁿ ,

(i) — C(O)NR ¹⁰ R ⁿ , and

(j) — NO2,

(4) heterocycle, wherein heterocycle is selected from: benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) phenyl,

(f) trifluoromethyl,

(g) - OCF3; (h) — CO2R ⁹ ,

(i) — NR ¹⁰ R ⁿ , and

(j) — CONR ¹⁰ R ⁿ ;

R ⁴ is selected from the group consisting of:

(1) Ci-ealkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(2) C3-7cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and

(3) phenyl, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) trifluoromethyl,

(f) — OCF3,

(g) — CO2R ⁹ ,

(h) — NR ¹⁰ R ⁿ ,

(i) — CONR ¹⁰ R ⁿ , and

(j) — NO ₂ ;

(4) heterocycle, wherein heterocycle is selected from: benzoimidazolyl, benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof, which is unsubstituted or substituted with one or more substituents independently selected from:

(a) — Ci-ealkyl,

(b) — O — Ci-ealkyl,

(c) halo,

(d) hydroxy,

(e) phenyl,

(f) trifluoromethyl,

(g) — OCF ₃ ,

(h) — CO2R ⁹ ,

(i) — NR ¹⁰ R ⁿ , and

(j) — CONR ¹⁰ R ⁿ ; or wherein R ⁴ and R ⁵ are joined together to form a phthalimidyl, succinimidyl or glutamidyl ring, which is unsubstituted or substituted with one or more substituents independently selected from the definitions of R ² ;

R ² is selected from the group consisting of:

(1) hydrogen,

(2) — Ci-ealkyl,

(3) — O— Ci-ealkyl,

(4) halo,

(5) hydroxyl,

(6) — NO2, and

(7) phenyl;

R ⁵ and R ⁶ are independently selected from the group consisting of:

(1) hydrogen, and

(2) Ci-ealkyl; n is an integer selected from 1, 2 and 3; or a pharmaceutically acceptable salt thereof.

Formula 310

[001269] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 310. Such compounds are described in WO 2004/087653, published October 14, 2004, corresponding to PCT/US2004/009658, filed March 30, 2004 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 310, this reference incorporated by reference herein controls. [001270] In an embodiment, the glutamate modulator is a compound according to: pharmaceutically acceptable salt thereof, wherein:

X and Y each independently is aryl or heteroaryl wherein at least one of X and Y is a heteroaryl with N adjacent to the position of attachment to A or B respectively;

X is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Cn ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR'R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR ³ COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO ₂ R ⁴ , — SOiNR^ ² , —COR ¹ , — C02R ¹ , — CONR'R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-ealkyl)(C3- 7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ¹ , R ² , and R ³ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-ealkyl), — N(Co-ealkyl)(C3- 7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁴ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

A is — Co- ₄ alkyl, — Co- ₂ alkyl-SO— Co- ₂ alkyl-, — Co- ₂ alkyl-S0 ₂ — C _0.2 alkyl-, — Co- ₂ alkyl- CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ⁹ CO— C _0.2 alkyl-, — Co- ₂ alkyl-NR ⁹ S0 ₂ — Co- ₂ alkyl- or — heteroCo-4alkyl;

W is — C3-7cycloalkyl, -heteroC3-7cycloalkyl, — Co-ealkylaryl, or — Co-ealkylheteroaryl optionally substituted with 1-7 independent halogen, — CN, NO ₂ , — Ci-ealkyl, — Ci-ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR'R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR'COR ² , — NR^OiR ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , —SOR ⁴ , — SO ₂ R ⁴ , — SOiNR^ ² , — COR ¹ , — C02R ¹ , — CONR'R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents; Y is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Cn ealkenyl, — C ₆ alkynyl, —OR ⁵ , — NR ⁵ R ⁶ , — C(=NR ⁵ )NR ⁶ R ⁷ , — N(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁵ COR ⁶ , — NR ⁵ CO ₂ R ⁶ , — NR ⁵ SO ₂ R ⁸ , — NR ⁵ CONR ⁶ R ⁷ , —SR ⁸ , — SOR ⁸ , — SO ₂ R ⁸ , — SO ₂ NR ⁵ R ⁶ , —COR ⁵ , — CO ₂ R ⁵ , — CONR ⁵ R ⁶ , — C(=NR ⁵ )R ⁶ , or — C(=NOR ⁵ )R ⁶ substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-ealkyl)(C3- 7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ⁵ , R ⁶ , and R ⁷ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-ealkyl), — N(Co-ealkyl)(C3- 7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁸ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

B is — Co-4alkyl, — Co- ₂ alkyl-SO — Co- ₂ alkyl-, — Co- ₂ alkyl-S0 ₂ — Co- ₂ alkyl-, — Co- ₂ alkyl- CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ¹⁰ CO— C _0.2 alkyl-, — C _0-2 alkyl-NR ¹⁰ SO ₂ — Co- ₂ alkyl- or - heteroCo-4alkyl;

R ⁹ and R ¹⁰ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3- 7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

Z is — C3-7cycloalkyl, -heteroC3-7cycloalkyl, — Co-ealkylaryl, or — Co-ealkylheteroaryl optionally substituted with 1-7 independent halogen, — CN, NO ₂ , — Ci-ealkyl, — Ciealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR'COR ² , — NR^OiR ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , —SOR ⁴ , — SO ₂ R ⁴ , — SOiNR^ ² , — COR ¹ , — CO2R ¹ , — CONR’R ² , — C(=NR')R ² , or — C(=NOR')R ² substituents; one of W and Z is optionally absent;

R ¹¹ and R ¹² is each independently halogen, — Co-ealkyl, — Co-ealkoxyl, =0, =N(Co-4alkyl),or — N(Co-4alkyl)(Co-4alkyl); and any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide. Formula 311

[001271] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 311. Such compounds are described in WO 2004/024074, published March 25, 2004 corresponding to PCT/US2003/028344, filed September 9, 2003 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 311, this reference incorporated by reference herein controls.

[001272] In an embodiment, the glutamate modulator is a compound according to: (I) or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , X ⁴ , and X ⁶ are independently C, N, S or O; X ³ and X ⁵ are independently C or N; wherein at least one of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , and X ⁶ is N; at most one of X ¹ , X ² , X ⁴ , and

X ⁶ is S or O; Y is C0-4alkyl, aryl, or heteroaryl; R ¹ and R ² are independently halogen, C0- 4alkyl, or pyridyl; and n ¹ and n ² are independently 0 or 1.

[001273] In an embodiment, the glutamate modulator is a compound selected from:

, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 312

[001274] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 312. Such compounds are described in WO 2003/059904, published July 24, 2003 corresponding to PCT/US2002/040486, filed December 17, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 312, this reference incorporated by reference herein controls.

[001275] In an embodiment, the glutamate modulator is a compound according to: wherein:

X and Y each independently is aryl or heteroaryl wherein at least one of X and Y is a heteroaryl with N adjacent to the position of attachment to A or B respectively;

X is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Cn ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR ³ COR ² , — NR ³ CO ² R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO2R ⁴ , — SO ₂ NR ¹ R ² , —COR ¹ , — CO2R ¹ , — CONR’R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ¹ , R ² , and R ³ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, - □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁴ is Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

A is — Co- ₄ alkyl, — Co- ₂ alkyl-SO— C _0.2 alkyl-, — Co-2alkyl-S0 ₂ — Co- ₂ alkyl-, — Co- ₂ alkyl- CO — Co-2alkyl-, — Co-2alkyl-NR ⁹ CO — Co-2alkyl-, — Co-2alkyl-NR ⁹ S02-Co-2alkyl or heteroCo- ₄ alkyl;

Y is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Cn ealkenyl, — Ci- ₆ alkynyl, —OR ⁵ , — NR ⁵ R ⁶ , — C(=NR ⁵ )NR ⁶ R ⁷ , — N(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁵ COR ⁶ , — NR ⁵ CO ₂ R ⁶ , — NR ⁵ SO ₂ R ⁸ , — NR ⁵ CONR ⁶ R ⁷ , —SR ⁸ , —SOR ⁸ , — SO2R ⁸ , — SO ₂ NR ⁵ R ⁶ , —COR ⁵ , — CO2R ⁵ , — CONR ⁵ R ⁶ , — C(=NR ⁵ )R ⁶ , or — C(=NOR ⁵ )R ⁶ substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ⁵ , R ⁶ , and R ⁷ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁸ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

B is — Co- ₄ alkyl, — Co- ₂ alkyl-SO— C _0.2 alkyl-, — Co- ₂ alkyl-S0 ₂ — C _0.2 alkyl-, — CO ₂ alkyl- CO— Co- ₂ alkyl-, Co- ₂ alkyl-NR ¹⁰ CO— C _0.2 alkyl-, — C _0-2 alkyl-NR ¹⁰ SO ₂ C _0-2 alkyl or heteroCo- ₄ alkyl;

R ⁹ and R ¹⁰ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ¹¹ , R ¹² and R ¹³ is each independently halogen, — Co-ealkyl, — Co-ealkoxyl, =0, =N(Co- ₄ alkyl),or — N(Co- ₄ alkyl)(Co- ₄ alkyl), wherein optionally two of R ¹¹ , R ¹² and R ¹³ are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrrole moiety; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3- 7cycloalkyl), or — N(Co-ealkyl)(aryl) groups; any N may be an N-oxide; and wherein any of the alkyl optionally is substituted with 1-9 independent halogens; or a pharmaceutically acceptable salt thereof.

Formula 313

[001276] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 313. Such compounds are described in WO 2003/053922, published July 3, 2003, corresponding to PCT/US2002/040237, filed December 16, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 313, this reference incorporated by reference herein controls.

[001277] In an embodiment, the glutamate modulator is a compound according to: pharmaceutically acceptable salt thereof, wherein

X and Y each independently is aryl or heteroaryl wherein at least one of X and Y is a heteroaryl with N adjacent to the position of attachment to A or B respectively;

X is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — C2- ealkenyl, — C ₂ -6alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR ³ COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO2R ⁴ , — SO ₂ NR ¹ R ² , —COR ¹ , — CO2R ¹ , — CONR’R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ¹ , R ² , and R ³ each independently is — Co-ealkyl, C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), or — N(Co-6 alkyl)(aryl) substituents;

R ⁴ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), or — N(Co- ealkyl)(aryl) substituents;

A is — Co- ₄ alkyl, — Co- ₂ alkyl-SO— C _0.2 alkyl-, — Co-2alkyl-S0 ₂ — Co- ₂ alkyl-, — Co- ₂ alkyl- CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ⁹ CO— C _0.2 alkyl-, — Co-2alkyl-NR ⁹ S0 ₂ — Co- ₂ alkyl- or - heteroCo-4alkyl;

Y is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — C2- ealkenyl, — C _2-6 alkynyl, —OR ⁵ , — NR ⁵ R ⁶ , — C(=NR ⁵ )NR ⁶ R ⁷ , — N(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁵ COR ⁶ , — NR ⁵ CO ₂ R ⁶ , — NR ⁵ SO ₂ R ⁸ , — NR ⁵ CONR ⁶ R ⁷ , —SR ⁸ , — SOR ⁸ , — SO ₂ R ⁸ , SO ₂ NR ⁵ R ⁶ , —COR ⁵ , — CO ₂ R ⁵ , — CONR ⁵ R ⁶ , — C(=NR ⁵ )R ⁶ , or — C(=NOR ⁵ )R ⁶ substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ⁵ , R ⁶ , and R ⁷ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), or — N(Co-ealkyl)(aryl) substituents;

R ⁸ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), or — N(Co- ealkyl)(aryl) substituents;

B is — Co-4alkyl, — Co- ₂ alkyl-SO — Co- ₂ alkyl-, — Co- ₂ alkyl-S0 ₂ — Co- ₂ alkyl-, — Co- ₂ alkyl- CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ¹⁰ CO— C _0.2 alkyl-, — C _0-2 alkyl-NR ¹⁰ SO ₂ — C _0.2 alkyl-, or - heteroCo-4alkyl;

R ⁹ and R ¹⁰ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-e alkyl)(aryl) substituents;

R ¹¹ and R ¹² is each independently halogen, — Co-ealkyl, — Co-6 alkoxyl, =0, =N(Co-4alkyl), or — N(Co-4alkyl)(Co- ₄ alkyl); any alkyl optionally substituted with 1-5 independent halogen substituents, and any N may be an N-oxide.

Formula 314

[001278] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 314. Such compounds are described in WO 2003/051833, published June 26, 2003, corresponding to PCT/US2002/040147, filed December 13, 2002 and US 7,569,592, issued August 4, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 314, this reference incorporated by reference herein controls.

[001279] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein

X and Y each independently is aryl or heteroaryl wherein at least one of X and Y is a heteroaryl with N adjacent to the position of attachment to A or B respectively;

X is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Cn ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR ³ COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO ₂ R ⁴ , — SOiNR^ ² , —COR ¹ , — C02R ¹ , — CONR’R ² , — C(=NR ¹ )R ² , or — C(=NOR ¹ )R ² substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ¹ , R ² , and R ³ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁴ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, (Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

A is — Co- ₄ alkyl, — Co- ₂ alkyl-SO— Co- ₂ alkyl-, — Co- ₂ alkyl-S0 ₂ — Co- ₂ alkyl-, — Co- ₂ alkyl- CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ⁹ CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ⁹ S0 ₂ — Co- ₂ alkyl- or - heteroCo-4alkyl;

Y is optionally substituted with 1-7 independent halogen, — CN, NO ₂ , — Ci-ealkyl, — Ci- ealkenyl, — Ci- ₆ alkynyl, —OR ⁵ , — NR ⁵ R ⁶ , — C(=NR ⁵ )NR ⁶ R ⁷ , — N(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁵ COR ⁶ , — NR ⁵ CO ₂ R ⁶ , — NR ⁵ SO ₂ R ⁸ , — NR ⁵ CONR ⁶ R ⁷ , —SR ⁸ , —SOR ⁸ , — SO ₂ R ⁸ , — SO ₂ NR ⁵ R ⁶ , —COR ⁵ , — CO ₂ R ⁵ , — CONR ⁵ R ⁶ , — C(=NR ⁵ )R ⁶ , or — C(=NOR ⁵ )R ⁶ substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ⁵ , R ⁶ , and R ⁷ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁸ is — Ci-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

B is — Co-4alkyl, — Co-2alkyl-SO — Co-2alkyl-, — Co-2alkyl-S02 — Co-2alkyl-, — Co-2alkyl- CO— Co- ₂ alkyl-, — Co- ₂ alkyl-NR ¹⁰ CO— C _0.2 alkyl-, — C ₀ -2alkyl-NR ¹⁰ SO ₂ — Co- ₂ alkyl- or - heteroCo-4alkyl;

R ⁹ and R ¹⁰ each independently is — Co-ealkyl, — C3-7cycloalkyl, heteroaryl or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — □(Co- ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co- ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents; one of A ¹ and A ² is N, the other is CR ¹² ;

R ¹¹ and R ¹² is each independently halogen, — Co-ealkyl, — Co-ealkoxyl, or — N(Co-4alkyl)(Co- 4alkyl), wherein optionally R ¹¹ and R ¹² are combined to form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring fused to the pyrazole moiety; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), or — N(Co- ealkyl)(aryl) groups; and wherein optionally R ¹¹ and R ¹² each independently forms =0, =N(Co-4alkyl) using a bond from the adjoining double bond; any N may be an N-oxide; wherein any of the alkyl optionally is substituted with 1-9 independent halogens; optionally provided that when X=2-pyridyl, A ¹⁼ N, A ² =CH, R ¹¹⁼ R ¹² =H and A=B=Coalkyl, then Y is not 4-methoxyphenyl or 2,5-dimethoxyphenyl.

[001280] In some embodiments, the glutamate modulator is a compound selected from: 3 -(4-pyri din-2 -yl- IH-pyrazol- 1 -yl)benzonitrile;

2-[ 1 -(3 -fluorophenyl)- lH-pyrazol-4-yl]pyri dine; -(l -pyri din-2 -yl-lH-pyrazol-4-yl)benzonitrile; -[4-(3-methoxyphenyl)-lH-pyrazol-l-yl]pyridine; -(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile; -(l -pyri din-2 -yl-lH-pyrazol-3-yl)benzonitrile; -[ 1 -(3 -bromophenyl)- lH-pyrazol-4-yl]pyri dine; -fluoro-5-(3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile; -fluoro-5-(5-methyl-3-pyridin-2-yl-lH-pyrazol-l-yl)benzonitr ile; -[l-(2,5-difluorophenyl)-lH-pyrazol-3-yl]pyridine; -(3,5-dimethyl-4-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile; - [ 1 -(2, 3 , 5 , 6-tetrafluoro-phenyl)- 1 H-pyrazol-3 -yl]pyridine; - [ 1 -(3 , 5 -difluoro-phenyl)- 1 H-pyrazol-3 -yl] -pyridine; -(l-pentafluorophenyl-lH-pyrazol-3-yl)-pyridine; -[l-(4-methoxy -phenyl)- lH-pyrazol-3-yl]-pyridine; - [ 1 -(2, 3 , 5 , 6-tetrafluoro-4-methyl-phenyl)- 1 H-pyrazol-3 -yl] -pyridine; - [ 1 -(3 -nitro-phenyl)- 1 H-pyrazol-3 -yl] -pyridine; -fluoro-5-(4-pyridin-2-yl-lH-pyrazol-l-yl)benzonitrile; -{l-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-4-yl}pyr idine; -(4-pyri din-2 -yl- IH-pyrazol- 1 -yl)pyridine-2-carbonitrile; -[l-(4-nitro-phenyl)-lH-pyrazol-3-yl]-pyridine; -(l -pyri din-2 -yl-lH-pyrazol-3-yl)benzonitrile; -[4-(3-methylphenyl)-lH-pyrazol-l-yl]pyridine; -[l-(3-fluoro-phenyl)-lH-pyrazol-4-yl]-pyridine; -[l-(3,4-dimethyl-phenyl)-lH-pyrazol-4-yl]-pyridine; -[l-(4-phenoxy-phenyl)-lH-pyrazol-4-yl]-pyridine; -[l-(3-methoxy-phenyl)-lH-pyrazol-4-yl]-pyridine; -[l-(2-benzyl-phenyl)-lH-pyrazol-4-yl]-pyridine; -[l-(4-isopropoxy -phenyl)- lH-pyrazol-4-yl]-pyridine; -[l-(3-ethyl-phenyl)-lH-pyrazol-4-yl]-pyridine; -[l-(3-trifluoromethoxy-phenyl)-lH-pyrazol-4-yl]-pyridine; -[l-(2-fluoro-5-trifluoromethyl-phenyl)-lH-pyrazol-4-yl]-pyr idine; -[l-(3-tert-butyl-phenyl)-lH-pyrazol-4-yl]-pyridine; - [ 1 -(2, 3 , 5 -trifluorophenyl)- 1 H-pyrazol-3 -yl]pyridine; -(3-pyridin-2-yl-lH-pyrazol-l-yl)-5-(trifluoromethyl)benzoni trile; -[(5-chloropyri din-3-yl)oxy]-5-(3-pyri din-2 -yl-lH-pyrazol-l-yl)benzonitrile; 2-(3-pyridin-2-yl-lH-pyrazol-l-yl)isonicotinonitrile;

2-[ 1 -(3 , 5 -dibromophenyl)- lH-pyrazol-3 -yl]pyridine;

3-bromo-5-(3-pyri din-2 -yl-lH-pyrazol-l-yl)benzonitrile;

2-{4-[3-fluoro-5-(pyridin-3-yloxy)phenyl]-lH-pyrazol-l-yl }pyridine;

2-[l-(3-bromo-5-fluorophenyl)-lH-pyrazol-3-yl]pyridine;

3-[(3-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;

2-[l-(2,4-difluorophenyl)-lH-pyrazol-3-yl]pyridine;

4-[(4-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;

3-[(4-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;

6-(4-pyri din-2 -yl- IH-pyrazol- 1 -yl)nicotinonitrile;

2-[(4-pyridin-2-yl-lH-pyrazol-l-yl)methyl]benzonitrile;

2-[l-(3,5-bis-trifluoromethyl-phenyl)-lH-pyrazol-3-yl]-py ridine;

2-[4-(4-fluorophenyl)-lH-pyrazol-l-yl]pyridine;

4-(l -pyri din-2 -yl-lH-pyrazol-4-yl)benzonitrile;

2-{4-[3-(trifluoromethyl)phenyl]-lH-pyrazol-l-yl}pyridine ;

2-{4-[4-(trifluoromethyl)phenyl]-lH-pyrazol-l-yl}pyridine ;

2- [4-(3 -fluorophenyl)- IH-pyrazol- 1 -yl]pyridine;

2-[l-(3-bromo-4-methylphenyl)-lH-pyrazol-4-yl]pyridine;

2-[l-(4-bromo-3-methyl-phenyl)-lH-pyrazol-4-yl]-pyridine;

2-[l-(4-sec-butyl -phenyl)- IH-pyrazol -4-yl]-pyri dine;

2-[l-(4-propyl-phenyl)-lH-pyrazol-4-yl]-pyridine;

2-[ 1 -(4-cy cl ohexyl-phenyl)- IH-pyrazol -4-yl]-pyri dine;

2,2-dimethyl-propionic acid 4-(4-pyridin-2-yl-pyrazol-l-yl)-phenyl ester;

2,2-dimethyl-propionic acid 4-(4-pyrimidin-4-yl-pyrazol-l-yl)-phenyl ester;

2-[l-(2-propyl-phenyl)-lH-pyrazol-4-yl]-pyridine; dimethyl-carbamic acid 4-(4-pyridin-2-yl-pyrazol-l-yl)-phenyl ester;

2-[ 1 -(2, 6-dimethyl-phenyl)- IH-pyrazol -4-yl]-pyri dine;

2-[l-(2-fluoro-4-methyl-phenyl)- IH-pyrazol -4-yl]-pyri dine;

2-[l-(3-bromo-2-methyl-phenyl)-lH-pyrazol-4-yl]-pyridine;

4-(3 -pyri din-2 -yl- IH-pyrazol- 1 -yl)benzoic acid;

2-{l-[3-(pyridin-4-yloxy)phenyl]-lH-pyrazol-3-yl}pyridine ;

2-(3 -pyri din-2 -yl- IH-pyrazol- l-yl)-5-(trifluoromethyl)pyri dine;

2-( 1 -phenyl- lH-pyrazol-3 -yl)pyridine;

3 -(3 -pyri din-2 -yl- IH-pyrazol- 1 -yl)benzoic acid; 2-{ l-[3-fluoro-5-(pyridin-4-ylthio)phenyl]-lH-pyrazol-3-yl}pyri dine; and 2-{ l-[(4-methylphenyl)sulfonyl]-lH-pyrazol-3-yl}pyridine; or a pharmaceutically acceptable salt thereof, or a substituted variant thereof retaining glutamate modulatory activity.

Formula 315

[001281] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 315. Such compounds are described in WO 2003/051315, published June 26, 2003, corresponding to PCT/US2002/041720, filed December 13, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 315, this reference incorporated by reference herein controls.

[001282] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein

X is aryl and Y is pyridyl;

X is optionally substituted with 1-7 independent halogen, — CN, NO2, — Cl-6alkyl, — C2- 6alkenyl, — C2-6alkynyl, — OR1, — NR1R2, — C(=NR1)NR2R3, — N(=NR1)NR2R3, — NR1COR2, — NRICO2R2, — NRISO2R4, — NR1CONR2R3, — SR4, — SOR4, — SO ₂ R4, — SO2NRIR2, —CORI, — CO2RI, — CONR1R2, — C(=NR1)R2, or — C(=NOR1)R2 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fined to X; wherein the — Cl-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Cl-6alkyl, — O(C0-6alkyl), — O(C3-7 cycloalkyl), — O(aryl), — O(heteroaryl), — N(C0-6alkyl)(C0-6alkyl), — N(C0-6alkyl)(C3-7 cycloalkyl), or — N(C0-6alkyl)(aryl) groups;

Rl, R2, and R3 each independently is — C0-6alkyl, — C3-7 cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Cl-6alkyl, — O(C0-6alkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(C0-6alkyl)(C0- 6alkyl), — N(C0-6alkyl)(C3-7 cycloalkyl), or — N(C0-6alkyl)(aryl) substituents; R4 is — Cl-6alkyl, — C3-7 cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Cl-6alkyl, — O(C0-6alkyl), — O(C3-7 cycloalkyl), — O(aryl), — O(heteroaryl), — N(C0-6alkyl)(C0-6alkyl), — N(C0-6alkyl)(C3-7cycloalkyl), or — N(C0-6alkyl)(aryl) substitutents;

A is a bond

Y is optionally substituted wit 1-7 independent halogen, — CN, NO2, — Cl-6alkyl, C2- 6alkenyl, — C2-6alkynyl, — OR5, — NR5R6, — C(=NR5)NR6R7, — N(=NR5)NR6R7 — NR5OCR6, — NR5CO ₂ R6, — NR5SO ₂ R8, — NR5CONR6R7, — SR8, — SOR8, — SO ₂ R8, — SO ₂ NR5R6, — C0R5, — CO ₂ R5, — CONR5R6, — C(=NR5)R6, or — C(=NOR5)R6 substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the Cl-6alkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Cl-6alkyl, — O(C0-6alkyl), — O(C3-7 cycloalkyl), — O(aryl), — O(heteroaryl), — N(C0-6alkyl)(C0-6alkyl), — N(C0-6alkyl)(C3-7 cycloalkyl), or — N(C0-6alkyl)(aryl) groups;

R5, R6, and R7 each independently is — C0-6alkyl, — C3-7 cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Cl-6alkyl, — O(CO0-6alkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(C0-6alkyl)(C0- 6alkyl), — N(C0-6alkyl)(C3-7 cycloalkyl), or — N(C0-6alkyl)(aryl) substituents;

R8 is — Cl-6alkyl, — C3-7 cycloalkyl, heteroaryl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Cl-6alkyl, — O(C0-6alkyl), — O(C3-7 cycloalkyl), — O(aryl), — O(heteroaryl), — N(C0-6alkyl)(C0-6alkyl), — N(C0-6alkyl)(C3-7cycloalkyl), or N(C0-6alkyl)(aryl) substituents;

B is a bond

R9 and RIO each independently is — C0-6alkyl, C3-7 cycloalkyl, heteroaryl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Cl-6alkyl, — O(C0- 6alkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(C0-6alkyl)(C0-6alkyl), — N(C0-6alkyl)(C3-7cycloalkyl), — N(C0-6alkyl)(aryl) substituents;

R11 is halogen, — C0-6alkyl, — C0-6alkoxyl, =0, =N(C0-4alkyl),or — N(C0-4alkyl)(C0- 4alkyl); any alkyl optionally substituted with 1-5 independent halogen substitutents, and any N may be an N-oxide

Formula 316 [001283] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 316. Such compounds are described in WO 2003/048137, published June 12, 2003, corresponding to international patent application number PCT/US2002/038201, filed November 26, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 316, this reference incorporated by reference herein controls.

[001284] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein

X is N or NR ⁴ when Y is O, and X is O when Y is N or NR ⁴ ;

Y is O when X is N or NR ⁴ , and Y is N or NR ⁴ when X is O; one of Z ¹ , Z ² , Z ³ or Z ⁴ is N, or NH;

R ¹ is optionally substituted with 1-5 substituents; wherein each substituent is independently halogen, — OH, — CN, — Ci-ealkyl, — Ci-4alkoxyl, — N(Co-4alkyl)(Co-4alkyl), — Co-4alkyl- C(O) — O — Co-4alkyl, — Co-4alkyl-morpholinyl, or — Co-4alkyl-benzoxazolyl;

R ² is hydrogen, halogen, — OH, — CN, — N(Co-4alkyl)(Co-4alkyl), — NO2; or — Ci-ealkyl, — Ci-4alkoxyl, — Co-4alkyl-phenyl, or — Ci-4alkoxy -phenyl group, wherein any of the groups is optionally substituted with 1-3 independently halogen, — OH, — CN, or — Ci-4alkoxyl substituents;

R ³ is hydrogen or — Ci-4alkoxyl;

R ⁴ is — Co-4alkyl; and

R ⁵ is H, halogen, or — Ci-4alkyl.

[001285] In an embodiment, the glutamate modulator is a compound selected from: and , including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 317

[001286] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 317. Such compounds are described in WO 2003/029210, published April 10, 2003, corresponding to PCT/US2002/031294, filed October 1, 2002, and US 7,253,190, issued August 7, 2007 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 317, this reference incorporated by reference herein controls.

[001287] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein

X is phenyl and Y is 2-pyridyl

X is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Cn ealkenyl, — Ci- ₆ alkynyl, —OR ¹ , — NR’R ² , — C(=NR ¹ )NR ² R ³ , — N(=NR ¹ )NR ² R ³ , — NR ³ COR ² , — NR ¹ CO ₂ R ² , — NR ¹ SO ₂ R ⁴ , — NR'CONR ² R\ —SR ⁴ , — SOR ⁴ , — SO ₂ R ⁴ , — SOiNR^R ² , —COR ¹ , — CO2R ¹ , — CONR’R ² , — C(=NR ¹ )R ² , or —

C(=NOR ¹ )R ² substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to X; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-?cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co- ealkyl)(aryl) groups; R ¹ , R ² , and R ³ each independently is — Co-ealkyl, — C3-?cycloalkyl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁴ is — Ci-ealkyl, — C3-7cycloalkyl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co- 6alkyl)(Co-ealkyl), — N(Co-6alkyl)(C3-7cycloalkyl), — N(Co-6alkyl)(aryl) substituents;

A is a bond;

Y is optionally substituted with 1-7 independent halogen, — CN, NO2, — Ci-ealkyl, — Cn ealkenyl, — Ci- ₆ alkynyl, —OR ⁵ , — NR ⁵ R ⁶ , — C(=NR ⁵ )NR ⁶ R ⁷ , — N(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁵ COR ⁶ , — NR ⁵ CO ₂ R ⁶ , — NR ⁵ SO ₂ R ⁸ , — NR ⁵ CONR ⁶ R ⁷ , —SR ⁸ , — SOR ⁸ , — SO ₂ R ⁸ , — SO ₂ NR ⁵ R ⁶ , —COR ⁵ , — CO ₂ R ⁵ , — CONR ⁵ R ⁶ , — C(=NR ⁵ )R ⁶ , or — C(=NOR ⁵ )R ⁶ substituents, wherein optionally two substituents are combined to form a cycloalkyl or heterocycloalkyl ring fused to Y; wherein the — Ci-ealkyl substituent, cycloalkyl ring, or heterocycloalkyl ring each optionally is further substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(COo-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — O(heteroaryl), — N(Co-6alkyl)(Co-6alkyl), — N(Co-6alkyl)(C3-7cycloalkyl), or — N(Co-6alkyl)(aryl) groups;

R ⁵ , R ⁶ , and R ⁷ each independently is Co-ealkyl, — C3-7cycloalkyl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-6alkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

R ⁸ is — Ci-ealkyl, — C3-7cycloalkyl, or aryl; optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co- ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents;

B is a bond;

R ⁹ and R ¹⁰ each independently is — Co-ealkyl, C3-7cycloalkyl, or aryl; any of which is optionally substituted with 1-5 independent halogen, — CN, — Ci-ealkyl, — O(Co-ealkyl), — O(C3-7cycloalkyl), — O(aryl), — N(Co-ealkyl)(Co-ealkyl), — N(Co-ealkyl)(C3-7cycloalkyl), — N(Co-ealkyl)(aryl) substituents; and any N is optionally an N-oxide.

Formula 318

[001288] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 318. Such compounds are described inWO 2002/058691, published August 1, 2002, corresponding to PCT/DK02/00046, filed January 23, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 318, this reference incorporated by reference herein controls.

[001289] In an embodiment, the glutamate modulator is a compound selected from: 5-carboxyl-2,4-di-benzamido-benzoic acid;

5-carboxyl-3,4-di-benzamido-2-furoic acid;

4-carboxyl-2,5-di-benzamido-3-furoic acid;

5-carboxyl-3,4-di-benzamido-2 -thiophene carboxylic acid; 4-carboxyl-2,5-di-benzamido-3-thiophene carboxylic acid; 2,4-dibenzenesulfonamido-5-carboxyl-benzoic acid; l,3-dibenzamido-4,6-di-(5,5'-tetrazolyl)-benzene;

2.6-dibenzamido-3,5-dicarboxyl-pyrazine; or

2.6-dicarboxyl-3,5-dibenzamido-pyridine; or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate modulatory activity.

[001290] In an embodiment, the glutamate modulator is 5-carboxyl-2,4-di-benzamido- benzoic acid, or a pharmaceutically-acceptable addition salt thereof, or substituted variant retaining glutamate modulatory activity.

Formula 319

[001291] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 319. Such compounds are described in WO 2021/155196, published August 5, 2021 corresponding to PCT/US2021/015774, filed January 29, 2021, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 319, this reference incorporated by reference herein controls.

[001292] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein: ring B is selected from formula (i), formula (ii), formula (v), and formula (vi):

wherein b indicates a point of attachment of ring B to L ¹ ;

L ¹ is Ci-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from oxo, halo, C1-3 haloalkyl, OH, C1-3 alkoxy, C1-3 haloalkoxy, amino, Cn 6 alkylamino, di(Ci-6 alkyl)amino, thio, and C1-6 alkylthio; ring A is selected from formula (iii) and formula (iv):

wherein ai indicates a point of attachment of ring A to L ¹ , and a2 indicates a point of attachment of ring A to L ² ; each L ² is independently selected from C1-3 alkylene, O, N(R ^N ), and S(=O)2, wherein said Ci- 3 alkylene is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 haloalkyl, OH, C 1-3 alkoxy, C1-3 haloalkoxy, amino, C 1-6 alkylamino, di(Ci-6 alkyl)amino, thio, and C1-6 alkylthio; each R ^N is selected from H and C1-3 alkyl; n is 0, 1, 2, or 3;

X ¹ is selected from N and CR ⁵ ;

X ² is selected from N and CR ¹⁴ ; and

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , and R ¹⁸ are each independently selected from H, OH, SH, NO2, CN, halo, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 haloalkyl, C1-3 haloalkoxy, cyano-Ci-3 alkyl, HO — C1-3 alkyl, C3-10 cycloalkyl-Ci-3 alkyl, amino, C 1-6 alkylamino, di(Ci-6 alkyl)amino, thio, and C 1-6 alkylthio; or R ⁶ and R ⁷ , together with the carbon atom to which R ⁷ is attached and the N atom to which R ⁶ is attached form a 5-7-membered heterocycloalkyl ring, which is optionally substituted with 1 or 2 substituents independently selected from OH, SH, NO2, CN, halo, C1-3 alkyl, Ci- 3 alkoxy, C1-3 alkylthio, C1-3 haloalkyl, C1-3 haloalkoxy, cyano-Ci-3 alkyl, HO — C1-3 alkyl, C3- 10 cycloalkyl-Ci-3 alkyl, amino, C1-6 alkylamino, di(Ci-6 alkyl)amino, thio, and C1-6 alkylthio; optionally further provided that the compound of Formula (I) comprises at least one radioisotope selected from ⁿ C and ¹⁸ F.

Formula 320 [001293] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 320. Such compounds are described in WO 2019/098211, published May 23, 2019, corresponding to PCT/JP2018/042053, filed November 14, 2018, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 320, this reference incorporated by reference herein controls.

[001294] In an embodiment, the glutamate modulator is a compound according to: R 1 and R 2 each independently represent a hydrogen atom, halogen, cyano, C 1-4 alkyl or C 3-6 saturated carbocyclic group (wherein the alkyl and the saturated carbocyclic group are each independently a halogen , Hydroxy, and C 1-4 alkoxy, optionally substituted with the same or different 1 to 5 substituents);

Wherein R 1 and R 2 together with the carbon atom to which they are attached are selected from the group consisting of C 3-6 saturated carbocycles (wherein the saturated carbocycles are halogen, hydroxy and C 1-4 alkoxy And may be substituted with the same or different 1 to 5 substituents); n is 1 or 2;

Ring A is a C 3-10 saturated carbocyclic ring, a 3 to 10 membered saturated heterocycle, a C 6-10 aromatic carbocyclic ring or a 5 to 10 membered aromatic heterocycle;

R 3 , R 4 and R 5 each independently represent a hydrogen atom, halogen, cyano, hydroxy, -C (O) -R c , -C (O) -OR d , -C (O) -NR a R b , C 1-6 alkyl, C 3-6 saturated carbocyclic group, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkylthio, C 2-4 alkenyl, 3- to 6-membered saturated complex The cyclic group or the 5- or 6-membered aromatic heterocyclic group (the alkyl, the saturated carbocyclic group, the alkoxy, the cycloalkoxy, the alkylthio, the saturated heterocyclic group and the aromatic heterocyclic group are each independently And the same or different 1 to 5 halogens may be substituted); Ring B is a C 6-10 aromatic carbocyclic ring or a 5- to 10-membered aromatic heterocyclic ring;

R 6 , R 7 and R 8 are each independently a hydrogen atom, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 saturated carbocyclic group , 3- to 6- membered saturated heterocyclic group, -CH 2 -C (O) -NR a R b , -C (O) -R c , -C (O) -OR d , -C (O) -NR a R b, -NR a R b , -NR d -C (O) -R c, -NR d -C (O) -NR a R b, -NR d -S (O) 2 -R c, - NR d -S (O) 2 -NR a R b , -S (O) -R c , -S (O) 2 -R c , -S (O) 2 -OH, -S (O) 2 -NR a R b or -S (O) (= NR d ) -R c (wherein the alkyl, the alkoxy, the alkylthio, the saturated carbocyclic group and the saturated heterocyclic group each independently represent The same or different 1 to 5 substitutions selected from the group consisting of: halogen, cyano, -NR a R b , hydroxy and C 1-4 alkoxy optionally substituted with the same or different 1 to 5 halogens A group which may be substituted),

R a and R b are each independently, and each of R a or R b when there is a plurality of NR a R b is independently a hydrogen atom, C 1-4 alkyl, C 3-6 saturated carbocyclic ring Or 3- to 6-membered saturated heterocyclic group (wherein the alkyl, the saturated carbocyclic group and the saturated heterocyclic group each independently represent halogen, hydroxy, C 1-4 alkyl and C 1-4 alkoxy) And R 1) is optionally selected from the group consisting of the same or different 1 to 5 substituents;

Here, R a and R b together with the nitrogen atom to which they are attached, are a 3- to 6-membered saturated heterocyclic group (the saturated heterocyclic group is a halogen, hydroxy, C 1-4 alkyl and C 1 -4 alkoxy, which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of

In the case where there are a plurality of R c s , each of R c s independently is a C 1-4 alkyl, a C 3-6 saturated carbocyclic group or a 3 to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and the saturated heterocycle) The ring groups each independently represent, optionally selected from the group consisting of halogen, hydroxy and C 1-4 alkoxy, which may be substituted with the same or different 1 to 5 substituents.

In the case where there are a plurality of R d 's each independently, a hydrogen atom, C 1-4 alkyl, a C 3-6 saturated carbocyclic group or a 3 to 6 membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and The saturated heterocyclic group is each independently selected from the group consisting of halogen, hydroxy and C 1-4 alkoxy, which may be substituted with the same or different 1 to 5 substituents.

Formula 321

[001295] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 321. Such compounds are described in JP 7266010, published December 10, 2020, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 321, this reference incorporated by reference herein controls.

[001296] In an embodiment, the glutamate modulator is a compound according to: each independently represent a hydrogen atom, a halogen atom, a cyano, a C 1-4 alkyl or a C 3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are each independently optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atoms, hydroxy and C 1-4 alkoxy);

Alternatively, R 1 and R 2 together with the carbon atom to which they are attached are a C 3-4 saturated carbocyclic group, which saturated carbocyclic group is selected from the group consisting of halogen atoms, hydroxy and C 1-4 alkoxy, optionally substituted with the same or different 1 to 5 substituents selected);

Ring A is benzene, naphthalene, pyridine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indolizine, imidazopyridine, 1,3 -benzodi oxole, representing chroman, 2,3- dihydrobenzofuran, or 1,3-dihydroisobenzofuran ;

R 3 and R 4 are each independently

(1) a hydrogen atom,

(2) a halogen atom,

(3) cyano,

(4) hydroxy,

(5) C 1-4 alkyl optionally substituted by the same or different 1 to 5 halogen atoms , (6) C 1-4 alkoxy optionally substituted by 1 to 5 halogen atoms which are the same or different ,

(7) C 3-6 cycloalkoxy (wherein said cycloalkoxy is optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of C 1-4 alkyl and halogen atoms) , or

(8) C 1-4 alkylthio optionally substituted with the same or different 1 to 5 halogen atoms represents;

R 5 and R 6 are each independently

(1) a hydrogen atom,

(2) a halogen atom,

(3) cyano,

(4) hydroxy,

(5) C 1-4 alkyl (wherein the same alkyl is selected from the group consisting of a halogen atom, hydroxy, and C 1-4 alkoxy optionally substituted with 1 to 5 of the same or different halogen atoms; or may be substituted with 1 to 5 different substituents),

(6) C 1-4 alkoxy (wherein the same or may be substituted with 1 to 5 different substituents),

(7) azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl (said azetidinyl, said pyrrolidinyl, said piperidinyl, said piperazinyl, said morpholinyl, said oxetanyl, said tetrahydrofuranyl, and said tetrahydropyranyl is substituted with 1 to 5 identical or different substituents selected from the group consisting of halogen atoms, hydroxy, and C 1-4 alkoxy optionally substituted by 1 to 5 identical or different halogen atoms may have been), or

(8) —NR a R b , —NR d — C(O)— R c , —NR d — C(O)— OR c , —NR d — C(O)— NR a R b , —NR d —SO 2 — R c , —CH 2 — C(O)— NR a R b , — C(O)— R d , — C(O)— OR d , or — C(O) — NR a R b R a and R b are each independently, and each of R a or R b when there are a plurality of NR a R b is independently a hydrogen atom, C 1-4 alkyl (the alkyl is each independently optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atoms, hydroxy and C 1-4 alkoxy), C 3-6 saturated carbocyclic group , azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl (the saturated carbocyclic group , the azetidinyl, the pyrrolidinyl, the piperidinyl, the piperazinyl, the morpholinyl, the oxetanyl, the tetrahydrofuranyl, and said tetrahydropyranyl is each independently substituted with 1 to 5 substituents, the same or different, selected from the group consisting of halogen atoms, hydroxy, C 1-4 alkyl and C 1-4 alkoxy; ) represents; Alternatively, R a and R b together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (the azetidinyl, the pyrrolidinyl, the piperidinyl, the piperazinyl, and the morpholinyl are halogen atoms, optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of hydroxy, C 1-4 alkyl and C 1-4 alkoxy);

When there are multiple R c , each independently C 1-4 alkyl, C 3-6 saturated carbocyclic group , azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl (the alkyl , the saturated carbocyclic group , the azetidinyl, the pyrrolidinyl, the piperidinyl, the piperazinyl, the morpholinyl, the oxetanyl, the tetrahydrofuranyl, and the tetrahydropyranyl group are each independently a halogen atom, hydroxy and C l - optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of 4 alkoxy);

R d is each independently hydrogen atom, C 1-4 alkyl, C 3-6 saturated carbocyclic group , azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl when there are more than one (the alkyl, the saturated carbocyclic group , the azetidinyl, the pyrrolidinyl, the piperidinyl, the piperazinyl, the morpholinyl, the oxetanyl, the tetrahydrofuranyl, and the tetrahydropyranyl are each independently a halogen atom, hydroxy and C optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of 1-4 alkoxy);

X represents a nitrogen atom or -CR e -;

R e is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl or C 1-6 alkoxy (the alkyl and the alkoxy may be substituted with the same or different 1 to 5 halogen atoms); ] R 1 and R 2 are each independently a hydrogen atom or C 1-4 alkyl (wherein the alkyl is selected from the group consisting of halogen atoms, hydroxy and C 1-4 alkoxy, 1 to 5 identical or different or R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropane or cyclobutane ring, including pharmaceutically acceptable salts thereof

Formula 322

[001297] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 322. Such compounds are described in JP 2020- 193176, published December 3, 2020, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 322, this reference incorporated by reference herein controls.

[001298] In an embodiment, the glutamate modulator is a compound according to: , wherein R 1 and R 2 are independently hydrogen atom, halogen atom, cyano, C 1-4 alkyl or C 3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are each independently, respectively. Represents (may be substituted with the same or different 1-5 substituents, selected from the group consisting of halogen atoms, hydroxy and C 1-4 alkoxy);

Alternatively, R 1 and R 2 may be combined with the carbon atom to which they are attached to form a C 3-4 saturated carbocyclic group (the saturated carbocyclic group comprises a group consisting of halogen atoms, hydroxy and C 1-4 alkoxy. It may be substituted with the same or different 1 to 5 substituents of choice);

Ring A represents a C 6-10 aromatic carbocyclic group, a 4-10 member saturated heterocyclic group or a 5-10 member aromatic heterocyclic group;

R 3 and R 4 are independently hydrogen atom, halogen atom, cyano, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkyl thio, C 2-4 alkenyl, 4 to 6 members. Saturated heterocyclic groups or 5- or 6-membered aromatic heterocyclic groups (the alkyl, the alkoxy, the alkylthio, the saturated heterocyclic group and the aromatic heterocyclic group are independently the same or different 1- It may be substituted with 5 halogen atoms), a C 3-6 saturated carbocyclic group, or a C 3-6 cycloalkoxy (the saturated carbocyclic group and the cycloalkoxy are independently each of the halogen atom and the halogen atom and the cycloalkoxy. C (may be substituted with the same or different 1-5 substituents selected from the group consisting of 1-4 alkyl);

Ring B represents a C 6-10 aromatic carbocyclic group, a 4-10 member saturated heterocyclic group or a 5-10 member aromatic heterocyclic group;

R 5 and R 6 are independently hydrogen atom, halogen atom, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, 4- to 6-membered saturated heterocyclic group ( The alkyl, the alkoxy, the alkylthio and the saturated heterocyclic group are each independently from C 1-4 alkoxy which may be substituted with halogen atom, hydroxy and 1 to 5 halogen atoms which are the same or different. C 3-6 cycloalkoxy, C 3-6 saturated carbocyclic group (the cycloalkoxy and the saturated carbocyclic ring), which may be substituted with the same or different 1 to 5 substituents selected from the group Each group is independently selected from the group consisting of halogen atoms, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy optionally substituted with the same or different 1-5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents), -NR a R b , -NR d- C (O) -R c , -NR d- C (O) - OR c ,- NR d- C (O) -NR a R b , -NR d -SO 2- R c , -CH 2- C (O) -NR a R b , -C (O) -R d , - C (O) ) -OR d , or -C (O) -NR a R b ;

R a and R b are independent of each other, and when there are a plurality of NR a R b , each of R a or R b is independent of a hydrogen atom and C 1-4 alkyl (the alkyl is independent of each other). It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atoms, hydroxy and C 1-4 alkoxy), C 3-6 saturated carbocyclic groups or 4 to 4 to A 6-membered saturated heterocyclic group (the saturated carbocyclic group and the saturated heterocyclic group are each independently selected from the group consisting of halogen atom, hydroxy, C 1-4 alkyl and C 1-4 alkoxy. It may be substituted with the same or different 1 to 5 substituents);

Alternatively, Ra and R b may be a 4- to 6-membered nitrogen-containing saturated heterocyclic group together with the nitrogen atom to which they are bonded (the nitrogencontaining saturated heterocyclic group is a halogen atom, hydroxy, C 1-4. It may be substituted with the same or different 1-5 substituents selected from the group consisting of alkyl and C 1-4 alkoxy);

If there are a plurality of Rc , each of them is independently C 1-4 alkyl, C 3-6 saturated carbocyclic group or 4- to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and the saturated heterocyclic group). The ring groups each independently represent (may be optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of halogen atoms, hydroxy and C 1-4 alkoxy);

R d may be a hydrogen atom, a C 1-4 alkyl, a C 3-6 saturated carbocyclic group or a 4- to 6- membered saturated heterocyclic group (the alkyl, the saturated carbon ring group and Each of the saturated heterocyclic groups independently represents the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C 1-4 alkoxy). ; X represents a nitrogen atom or CR e ;

Re is a hydrogen atom, a halogen atom, a cyano, a hydroxy, a C 1-4 alkyl, a C 1-4 alkoxy or - C (O) -NR a R b (the alkyl and the alkoxy are the same or different 1 to 5). May be replaced with a halogen atom or hydroxy);

However, when X is a nitrogen atom, ring B is not azetidine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, pyridine, isoxazole, imidazole, or oxadiazole] R 1 and R 2 are independently selected from the group consisting of hydrogen atom or C 1-4 alkyl (the alkyl is a halogen atom, hydroxy and C 1-4 alkoxy, 1 to 5 identical or different). , Or R 1 and R 2 together with the carbon atoms to which they are attached to form a cyclopropane or cyclobutane ring.

Formula 323

[001299] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 323. Such compounds are described in JP 2019- 182805, published October 24, 2019, which is incorporated by reference in its entirety herein.

In the case of any conflict of terminology in the context of Formula 323, this reference incorporated by reference herein controls.

[001300] In an embodiment, the glutamate modulator is a compound according to: n represents 1 or 2,

L Ais a combination or -CH ₂ ^_ and ring A is C ₃ -i o Saturated carbon ring, 3 to 10 membered saturated heterocycles, C ₆ -i o Represents an aromatic carbon ring or a 5 to 10 member aromatic heterocycle, or

L ABut-CH ₂ ^_ , then R instead of ring A ^A may be replaced by

R ^A C i-e Alkyl, C 2-6 Alkenes, or C ₂ -e Alkynes (the C i- ₆ Alkyl, C ₂ -e Alkenes and C ₂ -e Alkynes, halogens, hydroxys and C i - ₄ It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy),

L BIS the following structural formulas LI, L2, L3, L4, L5, L6, L7, L8, L9 or L10:

(In each structural formula, the connection 1 represents the position bonded to the pyrazole ring of formula (1), the connection 2 represents the position connected to the ring B, y and z represent 0 or 1 (However, if the ring contains a double bond, y is not 0)), ring B is C ₃ -i o Saturated carbon ring, 3 to 10 membered saturated heterocycles, C ₆ -i o Represents an aromatic carbon ring or a 5 to 10 member aromatic heterocycle, or L BWhen is the structural formula L9 or LIO, R instead of ring B ^B may be replaced by

R ^B is a hydrogen atom, C i- ₆ Alkyl, -C (O) -OR ^c or -S (O) ₂ ^_ R ^c and

R ^x & R ² Each is independently a hydrogen atom, halogen, cyano, C _x - ₄ Alkyl or C _{3 - 6} The saturated carbon ring group (the alkyl and the saturated carbon ring group are each independently halogen, hydroxy and C i- ₄ Selected from the group consisting of alkoxy, may be substituted with the same or different 1 to 5 substituents), wherein, R ¹ & R ² is the carbon atom to which they bond C _{3 -6} Saturated carbon ring (the saturated carbon ring is halogen, hydroxy and C _{x -4} Selected from the group consisting of alkoxy, may be substituted with the same or different 1 to 5 substituents),

R R ⁴ & R ⁵ Each is independently hydrogen atom, halogen, cyano, hydroxy, C _{x - 6} Alkyl, C 3-6 Saturated carbon ring group, C _{x -4} Alkoxy, C _{3- 6} Cycloalkoxy, C _{x -4} Alkylthio, C 2-4 Alkenyl, 3 to 6 membered saturated heterocyclic groups or 5 or 6 aromatic heterocyclic groups (the alkyl, the saturated carbon group, the alkoxy, the cycloalkoxy, the alkylthio, the saturated heterocyclic group and the aromatic heterocyclic group may each independently be substituted with one to five halogens of the same or different),

R R ⁷ & R ⁸ Each is independently hydrogen atom, halogen, cyano, hydroxy, C _{x - 6} Alkyl, C _x - ₆ Alkoxy, C _{x - 6} Alkylthio, C _{3- 6} Saturated carbon ring group, 3 to 6 membered saturated heterocyclic group, -CH 2 -C(O)-NR ^a R -C(O)-R ~C (O) -O R - S (O) 2-O H, - S (O) 2-NR ^a R ^h -S(O)(=NR ^d ) — R ^c (The alkyl, the alkoxy, the alkylthio, the saturated carbon ring group, and the saturated heterocyclic group are each independently halogen, cyano, -NR ^a R ^b C may be substituted with hydroxy and 1 to 5 halogens _{x -4} It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy),

R ^a & R ^b Each is independent and R ^a or R ^b If there are multiple hydrogen atoms, C _x - ₄ Alkyl, C 3-6 Saturated carbon ring groups or 3 to 6 membered saturated heterocyclic groups (the alkyl, the saturated carbon ring group, and the saturated heterocyclic group are each independently halogen, hydroxy, C _{x -4} Alkyl & C _{x -4} Selected from the group consisting of alkoxy, may be substituted with the same or different 1 to 5 substituents), wherein, R ^a & R ^b Together with the nitrogen atoms to which they are attached, there are 3 to

6 membered saturated heterocyclic groups (the saturated heterocyclic groups are halogens, hydroxys, C _{x -4} Alkyl & C _{x -4} Selected from the group consisting of alkoxy, may be substituted with the same or different 1 to 5 substituents),

R ^c If there are more than one, each one independently, C _{x -4} Alkyl, C _{3- 6} Saturated carbocyclic groups or 3 to 6 membered saturated heterocyclic groups (the alkyl, the saturated carbon ring group and the saturated heterocyclic group are each independently halogen, hydroxy and C _{x -4} It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy),

R ^d If there are more than one, each one independently, hydrogen atom, C _x - ₄ Alkyl, C ₃ -e Saturated carbocyclic groups or 3 to 6 membered saturated heterocyclic groups (the alkyl, the saturated carbon ring group and the saturated heterocyclic group are each independently halogen, hydroxy and C i - ₄ Selected from the group consisting of alkoxy, may be substituted with the same or different 1 to 5 substituents)] or a pharmaceutically acceptable salt thereof.

Formula 324

[001301] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 324. Such compounds are described in JP 2019182784, published October 24, 2019, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 324, this reference incorporated by reference herein controls.

[001302] In an embodiment, the glutamate modulator is a compound according to:

, wherein 1 & R 2 Each is independently composed of hydrogen atoms, halogen atoms, cyanos, and C 1 - 4 Alkyl (the alkyl may be independently substituted with a halogen atom, a hydroxy and 1 to 5 halogen atoms C 1 - 4 It may be substituted with 1 to 5 substituents of the same or different, selected from the group consisting of alkoxy) or C 3 - 6 Saturated carbon ring groups (the saturated carbon ring groups may be independently replaced with 1 to 5 halogen atoms, respectively C. 1 - 4 C may be substituted with alkyl, halogen atom, hydroxy and 1 to 5 halogen atoms 1 - 4 It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy), or R 1 & R 2 is the carbon atom to which they bond C 3 - 4 Saturated carbon ring group (the saturated carbon ring group may be substituted with 1 to 5 halogen atoms C 1 - 4 C may be substituted with alkyl, halogen atom, hydroxy and 1 to 5 halogen atoms 1 - 4 Selected from the group consisting of alkoxy, may be substituted with the same or different 1 to 5 substituents),

Ring A is C 6 - 1 0 Represents an aromatic carbocycle, a 4-10 membered saturated heterocycle or a 5-10 membered aromatic heterocycle; 3 & R 4 Each is independently composed of hydrogen atoms, halogen atoms, cyano, hydroxys, C 1 - 6 Alkyl, C 1 - 4 Alkoxy, C 1 - 4 Alkylthio (the alkyl, the alkoxy, the alkylthio may be independently substituted with 1 to 5 halogen atoms and 1 to 5 halogen atoms, each of which is the same or different. 1 - 4 It may be substituted with 1 to 5 substituents of the same or different, selected from the group consisting of alkoxy), C 2 - 4 Alkenyl (the alkenyl may be substituted with 1 to 5 halogen atoms and 1 to 5 halogen atoms that are identical or different, C 1 - 4 It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkyl), 4 to 6 membered saturated heterocyclic groups, 5 or 6 aromatic heterocyclic groups, C 3 - 6 Saturated carbon ring group or C 3 - 6 Cycloalkoxy (the saturated heterocyclic group, the aromatic heterocyclic group, the saturated carbon ring group, and the cycloalkoxy are each independently substituted with 1 to 5 halogen atoms, 1 to 5 halogen atoms, the same or different, C 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 Selected from the group consisting of alkoxy, may be substituted with the same or different 1 to 5 substituents, Ring B has the following formulas (2a), (2b) or (2c):

R 5 Hydrogen atoms, halogen atoms, cyano, hydroxy, C 1 - 6 Alkyl, C 1 - 6 Alkoxy, C 1 - 6 Alkylthio, (the alkyl, the alkoxy and the alkylthio may be substituted with a halogen atom, a hydroxy and 1 to 5 halogen atoms C 1 - 4 It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy), 4 to 6 membered saturated heterocyclic groups, C 3 - 6 Cycloalkoxy, C 3 - 6 Saturated carbon ring group (the saturated heterocyclic group, the cycloalkoxy and the saturated carbon ring group may be substituted with a halogen atom, a hydroxy, 1 to 5 halogen atoms C 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy), -NR a R b , -NR d-C(O)-R c , -NR d-C (O) -OR c , -NR d-C(0)-NR a R b , -NR d-P (O) (OR f ) (OR g), -NR d-C (R h) (R i ) -O P (O)

(OR f ) (OR g\ -NR d- [CH 2 O] n C(O)-O[C(R h ) (R i ) ] m NO a R b _N -NR d- [CH 2 O] nC(0)-[C(R h) (R i ) ] mNO a R b , -NR d - [C H 2 O] n C(0)-NR d [ C ( R h ) ( R i ) ] mNO a R b or-NR d- [CH 20] n C(O)-O[C(R h ) (R i ) ] mOP (O) (OR f ) (OR g) and

R 6 & R 7 is a hydrogen atom, C 1 - 6 Alkyl (the alkyl may be independently substituted with a halogen atom, a hydroxy and 1 to 5 halogen atoms C 1 - 4 It may be substituted with 1 to 5 substituents of the same or different, selected from the group consisting of alkoxy), C 6-1 0 Aromatic carbon ring group, C 3 - 6 Saturated carbon ring group, 4 to 6 member saturated heterocyclic group, 5 or 6 membered aromatic heterocyclic group (the aromatic carbon ring group, the saturated carbon ring group, the saturated heterocyclic group, and the aromatic heterocyclic group may each be independently substituted with a halogen atom, a hydroxy, 1 to 5 halogen atoms C 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1-4 May be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy), -C (O) -R c -C (O) -OR c , -C(0)-NR a R b, -P (O) (OR f ) (OR g) _N -C (R h) (R i ) -OP (O) (OR f ) (OR g) . - [CH 20] n C(0)-0[C(R h ) (R i ) ] mNO a R b or-

[CH 2O] nC(0)-0[C(R h) (R i ) ] mOP (O) (OR f ) (OR gX REPRESENTS A NITROGEN ATOM OR -CR and- and

R a & R b Each independently or R a & R b If there are multiple hydrogen atoms, C 1 - 4 Alkyl (the alkyl may be independently substituted with a halogen atom, a hydroxy and 1 to 5 halogen atoms C 1 - 4 It may be substituted with 1 to 5 substituents of the same or different, selected from the group consisting of alkoxy), C 3 - 6 A saturated carbocyclic group or a 4-6 membered saturated heterocyclic group (the saturated carbon ring group and the saturated heterocyclic group may each be independently substituted with a halogen atom, a hydroxy, 1 to 5 halogen atoms, 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy), or R a & R b is a nitrogen- saturated heterocyclic group with 4 to 6 membered nitrogen- saturated heterocyclic groups (the nitrogen-saturated heterocyclic groups may be independently substituted with halogen atoms, hydroxys, 1 to 5 halogen atoms together with the nitrogen atoms to which they are attached. 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy),

R c If there are more than one, each one independently, C 1 - 4 Alkyl (the alkyl may be independently substituted with a halogen atom, a hydroxy and 1 to 5 halogen atoms C 1 - 4 It may be substituted with 1 to 5 substituents of the same or different, selected from the group consisting of alkoxy), C 3 - 6 A saturated carbocyclic group or a 4-6 membered saturated heterocyclic group (the saturated carbon ring group and the saturated heterocyclic group may each be independently substituted with a halogen atom, a hydroxy, 1 to 5 halogen atoms, 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 Selected from the group consisting of alkoxy, may be substituted with 1 to 5 substituents of the same or different, R d If there are more than one, each one independently, hydrogen atom, C 1 - 4 Alkyl (the alkyl may be independently substituted with a halogen atom, a hydroxy and 1 to 5 halogen atoms C 1 - 4 It may be substituted with 1 to 5 substituents of the same or different, selected from the group consisting of alkoxy), C 3 - 6 A saturated carbocyclic group or a 4-6 membered saturated heterocyclic group (the saturated carbon ring group and the saturated heterocyclic group may each be independently substituted with a halogen atom, a hydroxy, 1 to 5 halogen atoms, 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 Selected from the group consisting of alkoxy, may be substituted with 1 to 5 substituents of the same or different,

R andHydrogen atoms, halogen atoms, cyano, C 1 - 6 Alkyl or C 1 - 6 Represents an alkoxy (the alkyl and the alkoxy may be substituted with 1 to 5 halogen atoms that are the same or different); f & R g Each independently or R f & R g If there are multiple hydrogen atoms, C 1 - 4 Alkyl (the alkyl is independently a halogen atom, a hydroxy, C 6 - 1 0 Aromatic carbon ring group, 1-3 C 1 - 4 C may be substituted with aminos that may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 It may be substituted with 1 to 5 substituents of the same or different, selected from the group consisting of alkoxy), C 6 - 1 0 Aromatic carbon ring group or C 3 - 6 Saturated carbon ring group (the aromatic carbon ring group and the saturated carbon ring group may be independently substituted with a halogen atom and 1 to 5 halogen atoms, respectively C 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy), or R f & R g is a 5 to 7 membered cyclic phosphate ester together with the oxygen atoms to which they bond (the cyclic phosphate ester may be substituted with a halogen atom, a hydroxy, 1 to 5 halogen atoms C 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy),

R h & R i Each independently, hydrogen atom, C 1 - 4 Alkyl (the alkyl may be independently substituted with a halogen atom, a hydroxy and 1 to 5 halogen atoms C 1 - 4 It may be substituted with 1 to 5 substituents of the same or different, selected from the group consisting of alkoxy), C 6 - 1 0 Aromatic carbon ring group or C 3 - 6 Saturated carbon ring group (the aromatic carbon ring group and the saturated carbon ring group may be independently substituted with 1 to 5 halogen atoms, 1 to 5 halogen atoms, each of which is the same or different, C 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 It may be substituted with 1 to 5 substituents of the same or different selected from the group consisting of alkoxy), or R h & R i is a 3 to 6 membered saturated carbon ring group (the saturated carbon ring group may be substituted with a halogen atom, a hydroxy, 1 to 5 halogen atoms together with the carbon atoms to which they are attached, C 1 - 4 C may be substituted with alkyl and 1 to 5 halogen atoms 1 - 4 It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of alkoxy), where n represents 0 or 1 and m represents 1 to 4)] compounds represented by or pharmaceutically acceptable salts thereof.

Formula 325

[001303] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 325. Such compounds are described in WO 2019/103070, published May 31, 2019, corresponding to PCT/JP2018/043094, filed November 22, 2018, and US 11,633,395, issued April 25, 2023 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 325, this reference incorporated by reference herein controls.

[001304] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein Ring A is a saturated 4- to 10-membered heterocyclyl, Ce-io aromatic carbocyclyl, or 5- to 10-membered aromatic heterocyclyl;

X is CR ^e or N;

R ¹ is H, halogen, CN, Ci-4 alkyl, or a saturated C3-6 carbocyclyl; wherein the C1-4 alkyl or saturated C3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or

5 substituents independently selected from the group consisting of halogen, OH, and Cn

4 alkoxy;

R ² is H, halogen, CN, C1-4 alkyl, or a saturated C3-6 carbocyclyl; wherein the C1-4 alkyl or saturated C3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or

5 substituents independently selected from the group consisting of halogen, OH, and Cn

4 alkoxy; or

R ¹ and R ² , taken together with the carbon atom to which they are attached, form a saturated C3-4 carbocyclyl; wherein the saturated C3-4 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and Ci-

4 alkoxy;

R ³ is H, halogen, CN, C1-6 alkyl, C2-4 alkenyl, OH, C1-4 alkoxy, C1-4 alkylthio, a saturated C3-

6 carbocyclyl, C3-6 cycloalkoxy, a saturated 4- to 6-membered heterocyclyl, or a 5- or 6- membered aromatic heterocyclyl; wherein the Ci-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, saturated 4- to 6-membered heterocyclyl, or 5- or 6-membered aromatic heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and wherein the saturated C3-6 carbocyclyl or C3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and Ci- 4 alkyl;

R ⁴ is H, halogen, CN, C1-6 alkyl, C2-4 alkenyl, OH, C1-4 alkoxy, C1-4 alkylthio, a saturated C3- 6 carbocyclyl, C3-6 cycloalkoxy, a saturated 4- to 6-membered heterocyclyl, or a 5- or 6- membered aromatic heterocyclyl; wherein the C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, saturated 4- to 6-membered heterocyclyl, or 5- or 6-membered aromatic heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; and wherein the saturated C3-6 carbocyclyl or C3-6 cycloalkoxy is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen and Ci- 4 alkyl;

R ⁵ is H, halogen, CN, CH ₂ C(O)NR ^a R ^b , C1-6 alkyl, C(O)R ^d , C(O)NR ^a R ^b , C(O)OR ^d , NR ^a R ^b , NR ^d C(O)R ^c , NR ^d C(O)NR ^a R ^b , NR ^d C(O)OR ^c , NR ^d S(O) ₂ R ^c , OH, C1-6 alkoxy, C1-6 alkylthio, a saturated C3-6 carbocyclyl, C3-6 cycloalkoxy, or a saturated 4- to 6-membered heterocyclyl; wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, or saturated 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy; wherein the C3-6 cycloalkoxy or saturated C3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy; and wherein each C1-4 alkoxy substituent of the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, saturated C3- 6 carbocyclyl, C3-6 cycloalkoxy, or saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; R ⁶ is H, halogen, CN, CH ₂ C(O)NR ^a R ^b , C1-6 alkyl, C(O)R ^d , C(O)NR ^a R ^b , C(O)OR ^d , NR ^a R ^b , NR ^d C(O)R ^c , NR ^d C(O)NR ^a R ^b , NR ^d C(O)OR ^c , NR ^d S(O) ₂ R ^c , OH, C1-6 alkoxy, C1-6 alkylthio, a saturated C3-6 carbocyclyl, C3-6 cycloalkoxy, or a saturated 4- to 6-membered heterocyclyl; wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, or saturated 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy; wherein the C3-6 cycloalkoxy or saturated C3-6 carbocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy; and wherein each C1-4 alkoxy substituent of the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, saturated C3- 6 carbocyclyl, C3-6 cycloalkoxy, or saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents; each R ^a is independently H, C1-4 alkyl, a saturated C3-6 carbocyclyl, or a saturated 4- to 6- membered heterocyclyl; wherein each C1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and Ci- 4 alkoxy; and wherein each saturated C3-6 carbocyclyl and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy; each R ^b is independently H, C1-4 alkyl, a saturated C3-6 carbocyclyl, or a saturated 4- to 6- membered heterocyclyl; wherein each C1-4 alkyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and Ci- 4 alkoxy; and wherein each saturated C3-6 carbocyclyl and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy; or each R ^a and R ^b , taken together with the nitrogen atom to which they are attached, independently forms a saturated 4- to 6-membered heterocyclyl; wherein each saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-4 alkyl, OH, and C1-4 alkoxy; each R ^c is independently C1-4 alkyl, a saturated C3-6 carbocyclyl, or a saturated 4- to 6- membered heterocyclyl; wherein each C1-4 alkyl, saturated C3-6 carbocyclyl, and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy; each R ^d is independently H, C1-4 alkyl, a saturated C3-6 carbocyclyl, or a saturated 4- to 6- membered heterocyclyl; wherein each Ci-4 alkyl, saturated C3-6 carbocyclyl, and saturated 4- to 6-membered heterocyclyl is optionally and independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, OH, and C1-4 alkoxy; and R ^e is H, halogen, CN, C1-6 alkyl, or C1-6 alkoxy; wherein the C1-6 alkyl or C1-6 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents.

[001305] In an embodiment, the glutamate modulator is a compound selected from: (7S)-3-(imidazo[l,2-a]pyridin-6-yl)-7-methyl-5-[4-(trifluoro methyl)phenyl]-6,7- dihydropyrazolo[l,5-a]pyrazin-4(5H)-one;

(7S)-3-(imidazo[l,2-a]pyridin-6-yl)-7-methyl-5-[3-chloro- 4-fluorophenyl]-6,7- dihydropyrazolo[l,5-a]pyrazin-4(5H)-one;

(7S)-3-(3-fluoroimidazo[l,2-a]pyridin-6-yl)-7-methyl-5-[4 -(trifluoromethyl)phenyl]-

6.7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one; and (7S)-7-methyl-3-(3-methylimidazo[l,2-a]pyridin-6-yl)-5-[4-(t rifluoromethyl)phenyl]-

6.7-dihy dropyrazolof 1 , 5 -a]pyrazin-4(5H)-one, or a pharmaceutically acceptable salt thereof, or substituted variants retaining glutamate modulatory activity.

[001306] In further embodiments, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R3 is H, halogen, Cl -6 alkyl, or Cl -4 alkoxy; wherein the Cl -6 alkyl or Cl -4 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;

R4 is H, halogen, Cl -6 alkyl, or Cl -4 alkoxy; wherein the Cl -6 alkyl or Cl -4 alkoxy is optionally substituted with 1, 2, 3, 4, or 5 independently selected halogen substituents;

R5 is H, halogen, Cl-6 alkyl, or NH2; and

R6 is H, halogen, Cl-6 alkyl, or NH2;

Formula 326

[001307] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 326. Such compounds are described in WO 2018/206820, published November 15, 2018, corresponding to PCT/EP2018/062409, filed May 14, 2018, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 326, this reference incorporated by reference herein controls.

[001308] In an embodiment, the glutamate modulator is a compound according to:

A is phenyl;

B is a heteroaryl group;

X and Y are each C;

Z is O, S or N(— R ^z ); each is independently a single bond or a double bond;

R ^z is selected from hydrogen, Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, Ci-Cio haloalkyl, — CN, —OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — NH2, — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), cycloalkyl, and heterocycloalkyl, and further wherein, if R ^z is C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, Ci-Cio haloalkyl, — CN, — OH, — 0(Ci-Cio alkyl), — NH2, — NH(Ci- C10 alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), cycloalkyl, and heterocycloalkyl; each R ¹ is independently a group -I -R ¹¹ ; each L ¹ is independently selected from a bond, C1-C10 alkylene, C2-C10 alkenylene, and C2- C10 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from halogen, Ci- C10 haloalkyl, — CN, —OR ¹² , — NR ¹² R ¹² , —COR ¹² , — COOR ¹² , — OCOR ¹² , — CONR ¹² R ¹² , — NR ¹² COR ¹² , —SR ¹² , — SOR ¹² , — SO2R ¹² , — SO ₂ NR ¹² R ¹² , and — NR ¹² SO ₂ R ¹² , and further wherein one or more — CH2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from — O — , — NR ¹² —, —CO—, — S— , —SO—, and — SO ₂ — ; each R ¹¹ is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C1-C1 haloalkyl, — CN, C1-C10 alkyl, C2- C10 alkenyl, C ₂ -C 10 alkynyl, — NR ¹² R ¹² , —OR ¹² , —SR ¹² , —SOR ¹² , — SO2R ¹² , —COR ¹² , — COOR ¹² , —OCOR ¹² , — CONR ¹² R ¹² , — NR ¹² COR ¹² , — SO ₂ NR ¹² R ¹² , — NR ¹² SO ₂ R ¹² , and — SO3R ¹² , wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C1-C10 haloalkyl, — CN, C1-C10 alkyl, C2- C10 alkenyl, C2-C 10 alkynyl, — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (Ci-

C10 alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), — CHO, — CO(Ci-Cio alkyl), — COOH, tetrazolyl, — COO(Ci-Cio alkyl), — OCO(Ci-

C10 alkyl), — CO— NH ₂ , — CO— NH(Ci-Cio alkyl), — CO— N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— CO— (C1-C10 alkyl), — N(Ci-Cio alkyl)-CO— (C1-C10 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(Ci-Cio alkyl), — SO ₂ — N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— SO ₂ — (C1-C10 alkyl), — N(Ci-Cio alkyl)-S02 — (C1-C10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L ¹¹ - R ¹³ , and further wherein, if R ¹¹ is C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, Ci-C 10 haloalkyl, — CN, — OH, — 0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), —CHO, — CO(Ci-Cio alkyl), — COOH, tetrazolyl, — COO(Ci-Cio alkyl), — OCO(Ci-Cio alkyl), — CO— NH ₂ , — CO— NH(Ci-Cio alkyl), — CO— N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— CO— (C1-C10 alkyl), — N(Ci-Cio alkyl)-CO— (C1-C10 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(Ci-Cio alkyl), — SO ₂ — N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— SO ₂ — (C1-C10 alkyl), — N(Ci-Cio alkyl)-SO ₂ — (Ci- Cio alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L ⁿ -R ¹³ ; each R ¹² is independently selected from hydrogen, C1-C10 alkyl, C ₂ -Cio alkenyl, C ₂ - Cio alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C1-C10 alkyl, C ₂ -Cio alkenyl, C ₂ -Cio alkynyl, halogen, Ci-Cio haloalkyl, — CN, — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (Ci- Cio alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), cycloalkyl, and heterocycloalkyl, wherein if R ¹² is C1-C10 alkyl, C ₂ -Cio alkenyl or C ₂ - Cio alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, Ci-Cio haloalkyl, — CN, — OH, — O(Ci- Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R ¹² are attached to the same nitrogen atom, then these two groups R ¹² may also together form a C ₂ -Cs alkylene; each L ¹¹ is independently selected from a bond, C1-C10 alkylene, C ₂ -Cio alkenylene, and C ₂ - Cio alkynylene, wherein one or more — CH ₂ — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from — O— , — NH— , — N(Ci-Cio alkyl)-, —CO—, — S— , —SO—, and — SO ₂ — ; each R ¹³ is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C ₂ - Cio alkenyl, C ₂ -Cio alkynyl, — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — SH, and — S(Ci-Cio alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C ₂ -Cio alkenyl, C ₂ -Cio alkynyl, —OH, — 0(Ci-Cio alkyl), — (Ci- Cio alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci- Cio alkyl)(Ci-C 10 alkyl), cycloalkyl, and heterocycloalkyl; n is an integer of 0 to 4;

R ² and R ³ are mutually linked to form, together with the carbon atom that they are attached to, a cycloalkyl or a heterocycloalkyl;

R ⁴ is selected from Ci-Cio alkyl, C ₂ -Cio alkenyl, C ₂ -Cio alkynyl, cycloalkyl, and heterocycloalkyl, wherein said alkyl, said alkenyl and said alkynyl are each optionally substituted with one or more groups independently selected from halogen, Ci-Cio haloalkyl, — O — (Ci-Cio haloalkyl), — CN, — OH, — 0(Ci-Cio alkyl), and cycloalkyl, and further wherein, if R ⁴ is cycloalkyl or heterocycloalkyl, then said cycloalkyl or said heterocycloalkyl is optionally substituted with one or more groups independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halogen, Ci-Cio haloalkyl, — CN, — OH, — 0(Ci-Cio alkyl), and cycloalkyl; each R ⁵ is independently a group -L ⁵ -R ⁵¹ ; each L ⁵ is independently selected from a bond, C1-C10 alkylene, C2-C10 alkenylene, and C2- Cio alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from halogen, Ci- Ciohaloalkyl, — CN, —OR ⁵² , — NR ⁵² R ⁵² , —COR ⁵² , — COOR ⁵² , — OCOR ⁵² , — CONR ⁵² R ⁵² , — NR ⁵² COR ⁵² , —SR ⁵² , — SOR ⁵² , — SO2R ⁵² , — SO ₂ NR ⁵² R ⁵² , and — NR ⁵² SO ₂ R ⁵² , and further wherein one or more — CH2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from — O — , — NR ⁵² —, —CO—, — S— , —SO—, and — SO ₂ — ; each R ⁵¹ is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C2- C10 alkenyl, C ₂ -C 10 alkynyl, — NR ⁵² R ⁵² , —OR ⁵² , —SR ⁵² , —SOR ⁵² , — SO2R ⁵² , —COR ⁵² , — COOR ⁵² , —OCOR ⁵² , — CONR ⁵² R ⁵² , — NR ⁵² COR ⁵² , — SO ₂ NR ⁵² R ⁵² , — NR ⁵² SO ₂ R ⁵² , and — SO3R ⁵² , wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C2- C10 alkenyl, C2-C 10 alkynyl, — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (Ci- C10 alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), — CHO, — CO(Ci-Cio alkyl), — COOH, tetrazolyl, — COO(Ci-Cio alkyl), — OCO(Ci-

C10 alkyl), — CO— NH ₂ , — CO— NH(Ci-Cio alkyl), — CO— N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— CO— (C1-C10 alkyl), — N(Ci-Cio alkyl)-CO— (C1-C10 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(Ci-Cio alkyl), — SO ₂ — N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— SO ₂ — (C1-C10 alkyl), — N(Ci-Cio alkyl)-S02 — (C1-C10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L ⁵¹ - R ⁵³ , and further wherein, if R ⁵¹ is C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, Ci-Cio haloalkyl, — CN, — OH, — 0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), —CHO, — CO(Ci-Cio alkyl), — COOH, tetrazolyl, — COO(Ci-Cio alkyl), — OCO(Ci-Cio alkyl), — CO— NH ₂ , — CO— NH(Ci-Cio alkyl), — CO— N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— CO— (C1-C10 alkyl), — N(Ci-Cio alkyl)-CO— (Ci-Cio alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(Ci-Cio alkyl), — SO ₂ — N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— SO ₂ — (Ci-Cio alkyl), — N(Ci-Cio alkyl)-SO ₂ — (Ci- Cio alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L ⁵¹ -R ⁵³ ; each R ⁵² is independently selected from hydrogen, Ci-Cio alkyl, C ₂ -Cio alkenyl, C ₂ - Cio alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from Ci-Cio alkyl, C ₂ -Cio alkenyl, C ₂ -Cio alkynyl, halogen, Ci-Cio haloalkyl, — CN, — OH, — 0(Ci-Cio alkyl), — (Ci-Cio alkylene)-OH, — (Ci- Cio alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), cycloalkyl, and heterocycloalkyl, wherein if R ⁵² is Ci-Cio alkyl, C ₂ -Cio alkenyl or C ₂ - Cio alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, Ci-Cio haloalkyl, — CN, — OH, — O(Ci- Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R ⁵² are attached to the same nitrogen atom, then these two groups R ⁵² may also together form a C ₂ -Cs alkylene; each L ⁵¹ is independently selected from a bond, Ci-Cio alkylene, C ₂ -Cio alkenylene, and C ₂ - Cio alkynylene, wherein one or more — CH ₂ — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from — O— , — NH— , — N(Ci-Cio alkyl)-, —CO—, — S— , —SO—, and — SO ₂ — ; each R ⁵³ is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, Ci-Cio haloalkyl, — CN, Ci-Cio alkyl, C ₂ - Cio alkenyl, C ₂ -Cio alkynyl, — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), — OH, — 0(Ci-Cio alkyl), -(Ci-Cio alkylene)-OH, -(Ci-Cio alkylene)-0(Ci-Cio alkyl), — SH, and — S(Ci-Cio alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, Ci-Cio haloalkyl, — CN, Ci-Cio alkyl, C ₂ -Cio alkenyl, C ₂ -Cio alkynyl, —OH, — 0(Ci-Cio alkyl), — (Ci- Cio alkylene)-OH, — (Ci-Cio alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci- Cio alkyl)(Ci-C 10 alkyl), cycloalkyl, and heterocycloalkyl; and m is an integer of 0 to 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[001309] In an embodiment, the glutamate modulator is a compound selected from: 10-chloro-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,l'-cy clopropan]-5(6H)-one; 10-(6-Fluoro-pyridin-3-yl)-6-methylspiro[benzo[c]pyrido[3,2- e]azepine-7,r-cyclopropan]- 5(6H)-one;

10-(5-Fluoro-pyridin-2-yl)-6-methylspiro[benzo[c]pyrido[3 ,2-e]azepine-7,r-cyclopropan]- 5(6H)-one;

10-chloro-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]az epine-7,l'-cyclopropan]-5(6H)- one;

10-(6-Fluoro-pyridin-3-yl)-3-methoxy-6-methylspiro[benzo[ c]pyrido[3,2-e]azepine-7,r- cyclopropan]-5(6H)-one;

9-Chloro-2-(methoxymethyl)-5-methyl-2H-spiro[benzo[c]pyra zolo[4,3-e]azepine-6,l'- cyclopropan]-4(5H)-one;

2-(Methoxymethyl)-5-methyl-9-(6-fluoro-pyridin-3-yl)-2H-s piro[benzo[c]pyrazolo[4,3- e]azepine-6, 1 '-cyclopropan]-4(5H)-one;

2-(Methoxymethyl)-5-methyl-9-(5-fluoro-pyridin-2-yl)-2H-s piro[benzo[c]pyrazolo[4,3- e]azepine-6, 1 '-cyclopropan]-4(5H)-one; and pharmaceutically acceptable salts, solvates and prodrugs thereof, including substituted variants retaining glutamate modulatory activity.

Formula 327

[001310] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 327. Such compounds are described in WO 2017/198180, published November 23, 2017, corresponding to PCT/CN2017/084750, filed May 17, 2017, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 327, this reference incorporated by reference herein controls.

[001311] In an embodiment, the glutamate modulator is a compound according to: wherein:

Ri is selected from the group consisting of a hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl and cyano;

R-2 is select from the group consisting of a hydrogen, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-7 membered heterocyclic group, substituted or unsubstituted 5-7 membered aryl-methylene and 3-7 membered heterocycle-methylene, wherein each of the heterocyclic groups independently contains 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen; or the R2 is selected from the group consisting of: wherein R3, R4, Rs, Rs, R7 and Rs each independently represents 0-4 substituents on any position of the ring, and each substituent is selected from the group consisting of a halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, C1-C6 alkoxycarbonyl, cyano and hydroxy;

R9 is selected from the group consisting of a hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 9- membered heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

Rio and Rn respectively represents 0-4 substituents on any position of the ring, and each Rio and Rn is independently selected from the group consisting of a halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, cyano and hydroxy;

X, Y are each independently selected from CH2, O, NH or S; Z is selected from CH or N; and a, b, c, d, e, f, g, h and i are each independently selected from the group consisting of 0 and 1; wherein the X, Y and Z can be substituted by R3, R4, Rs, Re, R7, Rs, R9, Rio and Rn; and the “substituted” means one or more hydrogen atoms of the group are substituted by substituents selected from the group consisting of a halogen, C1-C6 alkyl, halogensubstituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy carbonyl, halogen-substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, cyano-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, carboxy, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group; wherein the heterocyclic group each independently contain 1-4 heteroatoms selected from oxygen, sulfur or nitrogen.

[001312] In an embodiment, the glutamate modulator is the compound:

, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 328

[001313] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 328. Such compounds are described in WO 2017/081483, published May 18, 2017, corresponding to PCT/GB2016/053550, filed November 11, 2016, and US 11,008,323, issued May 18, 2021, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 328, this reference incorporated by reference herein controls.

[001314] In an embodiment, the glutamate modulator is a compound according to:

wherein:

Xi, X2 and X3 are each independently C or N; each is independently a single bond or a double bond, wherein at least one of any two adjacent bonds is a single bond; each R ¹ is independently a group -I -R ¹¹ ; each L ¹ is a bond; each R ¹¹ is independently selected from the group consisting of: phenyl, imidazo[l,2- a]pyridinyl, and heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; wherein said phenyl, said imidazo[l,2- a]pyridinyl and said heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, Ci-Cio haloalkyl, — CN, Ci- C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci- C10 alkyl), — CHO, — CO(Ci-Cio alkyl), — COOH, tetrazolyl, — COO(Ci-Cio alkyl), — OCO(Ci-Cw alkyl), — CO— NH ₂ , —CO— NH(Ci-Cio alkyl), — CO— N(Ci-Cio alkyl)(Ci- C10 alkyl), — NH— CO— (C1-C10 alkyl), — N(Ci-Cio alkyl)-CO— (C1-C10 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(CI-CW alkyl), — SO ₂ — N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— SO ₂ — (Ci- C10 alkyl), — N(Ci-Cio alkyl)-SO2 — (C1-C10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms, and -L ⁿ -R ¹³ ; each L ¹¹ is independently selected from the group consisting of a bond, C1-C10 alkylene, C2- C10 alkenylene, and C2-C10 alkynylene, wherein one or more — CH2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from the group consisting of — O — , — NH — , — N(Ci-Cio alkyl)-, — CO—, — S— , —SO—, and — SO ₂ — ; each R ¹³ is independently selected from the group consisting of aryl, heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C2- C10 alkenyl, C2-C10 alkynyl, — NH2, — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — SH, and — S(Ci-Cio alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C2-C 10 alkenyl, C2-C10 alkynyl, — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), cycloalkyl, and heterocycloalkyl; n is an integer of 1 to 4;

R ² and R ³ are mutually linked to form, together with the carbon atom that they are attached to, a C3-C5 cycloalkyl; or R ² and R ³ are each independently selected from the group consisting of hydrogen and C1-C4 alkyl;

R ⁴ is C1-C4 alkyl, wherein said alkyl is optionally substituted with one or more groups independently selected from the group consisting of — OH and — O(Ci-C4 alkyl); each R ⁵ is independently a group -L ⁵ -R ⁵¹ ; each L ⁵ is independently selected from the group consisting of a bond and methylene; each R ⁵¹ is independently selected from the group consisting of: phenyl; heteroaryl having 5 or 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C3-C7 cycloalkyl; heterocycloalkyl having 5, 6 or 7 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; — CN; C1-C4 alkyl; — NR ⁵² R ⁵² ; — COOR ⁵² ; and — CONR ⁵² R ⁵² ; wherein said phenyl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), — CHO, — CO(Ci-Cio alkyl), — COOH, tetrazolyl, — COO(Ci-Cio alkyl), — OCO(Ci-Cio alkyl), — CO— NH ₂ , — CO— NH(Ci- C10 alkyl), — CO— N(Ci-Cio alkyl)(Ci-Cio alkyl), — NH— CO— (C1-C10 alkyl), — N(Ci- C10 alkyl)-CO— (C1-C10 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(Ci-Cio alkyl), — SO ₂ — N(Ci- C10 alkyl)(Ci-Cio alkyl), — NH— SO ₂ — (C1-C10 alkyl), — N(Ci-Cio alkyl)- SO ₂ -(Ci- C10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms, and -L ⁵¹ -R ⁵³ ; each R ⁵² is independently selected from the group consisting of hydrogen and C1-C4 alkyl; each L ⁵¹ is independently selected from the group consisting of a bond, C1-C10 alkylene, C2- C10 alkenylene, and C2-C10 alkynylene, wherein one or more — CH2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from the group consisting of — O — , — NH — , — N(Ci-Cio alkyl)-, — CO—, — S— , —SO—, and — SO ₂ — ; each R ⁵³ is independently selected from the group consisting of aryl, heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C2- C10 alkenyl, C2-C10 alkynyl, — NH2, — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — SH, and — S(Ci-Cio alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, Ci-Cio haloalkyl, — CN, C1-C10 alkyl, C2-C 10 alkenyl, C2-C10 alkynyl, — OH, — 0(Ci-Cio alkyl), — (C1-C10 alkylene)-OH, — (C1-C10 alkylene)-0(Ci-Cio alkyl), — NH ₂ , — NH(Ci-Cio alkyl), — N(Ci-Cio alkyl)(Ci-Cio alkyl), cycloalkyl, and heterocycloalkyl; and m is an integer of 0 to 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Formula 329

[001315] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 329. Such compounds are described in WO 2016/149324, published September 22, 2016, corresponding to PCT/US2016/022580, filed March 16, 2016, and US 10,538,491, issued March 15, 2018 which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 329, this reference incorporated by reference herein controls.

[001316] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein

R ¹ is aryl, heteroaryl, heterocycle, or cycloalkyl;

R ^2a and R ^2b are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci- C4 haloalkyl, or C1-C4 haloalkoxy;

R ³ is — X— (CR ^5a R ^5b ) _p — Z— (CR ^5c R ^5d ) _q — N(R ^6a )(R ^6b ), — X— (CR ^5a R ^5b )— Z— (CR ^5c R ^5d ) _q — Y-A, -A'-X— (CR ^5a R ^5b ) _p — Z— (CR ^5c R ^5d ) _q — N(R ^6a )(R ^6b ), — X— (CR ^5a R ^5b ) _p — Z— (CR ^5c R ^5d ) _q - A'-Y-A, or -A'-X— (CR ^5a R ^5b ) _p —Z—(CR ^5c R ^5d )q— Y-A; p is 0-2; q is 0-2;

X, Y, and Z are each independently selected from a bond, CR ^5e R ^5f , O, S, NR ⁷ , — C(O) — , — O— C(O)— , — C(O)— O— , — O— C(O)— NR ⁷ — , — C(O)— NR ⁷ — , — NR ⁷ — C(O)— , — NR ⁷ — C(O)— O— , — NR ⁷ — C(O)— NR ⁷ — , — NR ⁷ — SO ₂ — , and — SO ₂ — ;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e and R ^5f , at each occurrence, are independently selected from hydrogen, fluorine, C1-C4 alkyl, C1-C4 alkoxy, Ci-C4 haloalkyl, and C1-C4 haloalkoxy;

R ^6a and R ^6b are each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, cycloalkyl, Ci- G> heteroalkyl, and heterocycle, or R ^6a and R ^6b together with the nitrogen atom to which they attach form a heterocycle;

R ⁷ at each occurrence is independently selected from hydrogen, C1-C4 alkyl, and Ci-

C4 haloalkyl;

A is aryl, heteroaryl, cycloalkyl, or heterocycle;

A' is aryl, heteroaryl, cycloalkyl, or heterocycle; and

R ⁴ is — CONH2 or cyano; wherein said aryl, heteroaryl, cycloalkyl, and heterocycle, at each occurrence, are independently substituted or unsubstituted.

[001317] In a further embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein R ¹ is substituted or unsubstituted phenyl;

R ^2a and R ^2b are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci- C4 haloalkyl, or C1-C4 haloalkoxy;

Y is selected from a bond, CR ^5e R ^5f , O and NR ⁷ ;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e and R ^5f , at each occurrence in R ³ , are independently selected from hydrogen and C1-C4 alkyl; R ^6a and R ^6b together with the nitrogen atom to which they attach form a heterocycle optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl;

R ⁷ at each occurrence is independently selected from hydrogen and C1-C4 alkyl; and A is aryl, heteroaryl, or heterocycle; wherein said aryl, heteroaryl or heterocycle in A is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, cyano, alkyl, alkoxy, and haloalkyl;

R ⁴ is — CONH2 or cyano.

Formula 330

[001318] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 330. Such compounds are described in WO 2016/130652, published August 18, 2016, corresponding to PCT/US2016/017318, filed February 10, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 330, this reference incorporated by reference herein controls.

[001319] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein

A is aryl, heteroaryl, heterocycle, or cycloalkyl;

Z is a bond, O, S, NR ² , or CR ^lg R ^{l h} ;

X is — (CR ^le R ^lf )m, O, S, NR ² , — C(O)— , — O— C(O)— , — C(O)— O— , — O— C(O)— NR ² —, — C(O)— NR ² — , — NR ² — C(O)— , — NR ² — C(O)— O— , — NR ² — C(O)— NR ² — , — NR ² — SO ₂ — , —SO—, or — SO ₂ — ;

R ^le , R ^lf , R ^lg and R ^lh are each independently hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy; m is 1-3;

R ² is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; R ^la , R ^lb , R ^lc , and R ^ld are each independently hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy;

Q is N or CR ^3a ;

V is N or CR ^3b ;

W is N or CR ^3c ; wherein no more than one of Q, V and W is N;

R ^3a , R ^3b , and R ^c are hydrogen, cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy; and

Y is aryl, heteroaryl, cycloalkyl, or heterocycle; wherein said aryl, heteroaryl, cycloalkyl, and heterocycle, at each occurrence, are independently substituted or unsubstituted.

Formula 331

[001320] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 331. Such compounds are described in JP2016124810, published July 11, 2016 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 331, this reference incorporated by reference herein controls.

[001321] In an embodiment, the glutamate modulator is a compound according to:

, wherein R

1 and R 2 is identical or different, hydrogen atom, halogen atom, cyano group, C 1

- 4 Alkyl group, C 3 - 4 Cycloalkyl group (wherein the C 1 - 4 Alkyl groups and C 3 - 4 The cycloalkyl group may be replaced with 1 to 5 halogen atoms or 1 or 2 hydroxy groups) or C 1 - 4 Represents an alkoxy group, or R 1 and R 2 C together with carbon atoms to bond 3 - 4 Cycloalkyl group (wherein the C 3 - 4 The cycloalkyl group may be substituted with 1 to 4 halogen atoms or 1 or 2 hydroxy groups), m represents 0 or 1, If m represents 0, n represents 1 or 2, If m indicates 1, n represents

1, X -C(0)- or -CHR A- and

R AHydrogen atom, halogen atom, cyano group, C 1 - 4 Alkyl group, C 3 - 4 Cycloalkyl group (wherein the C 1 - 4 Alkyl groups and C 3 - 4 The cycloalkyl group may be replaced with 1 to 5 halogen atoms or 1 or 2 hydroxy groups) or C 1 - 4 Represents an alkoxy group,

R 3 is a hydrogen atom, halogen atom or C 1 - 4 An alkyl group (where the C 1 - 4 The alkyl group may be substituted with 1 to 5 halogen atoms or 1 or 2 hydroxy groups), ring

A represents a phenyl group or a 5 or 6-membered ring heteroaryl group,

R 4 and R 5 is identical or different, hydrogen atom, halogen atom, cyano group, C 1 - 6 Alkyl group, C 3 - 6 Cycloalkyl group, C 1 - 4 Alkoxy group (where the C 1

- 6 Alkyl group, C 3 - 6 Cycloalkyl group and C 1 - 4 The alkoxy group may be replaced by 1 to 5 halogen atoms), C 2 - 4 represents an alkenyl group or a 4, 5 or 6- membered saturated heterocyclic group, or R 4 and R 5 Together with A, C 5 - 8 Cycloalkyl ring (wherein the C 5 - 8 The cycloalkyl ring may be substituted with 1 to 5 halogen atoms or 1 or 2 hydroxy groups) or 5 or 6 membered saturated heterocycles, ring B represents a phenyl group, a 5 or 6-membered heteroaryl group, or a 4, 5 or 6-membered saturated heterocyclic group,

R 6 , R 7 and R 8 is identical or different, hydrogen atom, halogen atom, cyano group, hydroxy group, amino group, C 1 - 6 Alkyl group, C 3 - 4 Cycloalkyl group (wherein the C 1 - 6 Alkyl groups and C 3 - 4 The cycloalkyl group may be replaced by 1 to 5 halogen atoms or 1 or 2 hydroxy groups), C 1 - 6 Alkoxy group, - C (O) -R a , -C (O) O R a , -C(O)-NR a R b , -C H 2 -C(0)-NR a R b , - S O 2 -O H, - S O 2 -NR a R b , - S O 2 -R a , -NR a - S O 2 -R b , -NR a - S O 2 -NR c R d , -NR a -C(O)-NR c R d or-NR a -C(O)-R b or R 6 , R 7 and R 8 Of these, two adjacent groups together with ring B form a 5- or 6-membered saturated heterocycle (wherein the 5-membered saturated heterocycle and the 6-membered saturated heterocycle are C 1 - 4 An alkyl group, one or two halogen atoms or one or two hydroxy groups may be substituted),

R a and R b Identical or different, hydrogen atoms, C 1 - 4 Alkyl group, C 3 - 6 Cycloalkyl group, 4, 5 or 6-membered saturated heterocyclic group (wherein the C 1

- 4 Alkyl group, 4-, 5- or 6-membered saturated heterocyclic group and C 3 - 6 The cycloalkyl group consists of 1 to 5 halogen atoms, 1 hydroxy group, and 1 C 1 - 4 Alkoxy group or one -NR c R d may be substituted with a group), or R aand R bis the combination of the nitrogen atoms to which they bind C 2 - 5 Cyclic amino group (where the C 2 - 5 The cyclic amino group consists of 1 to 5 halogen atoms, 1 hydroxy group or 1 C 1 - 4 may be substituted with an alkoxy group),

R c and R d Identical or different, hydrogen atoms, C 1 - 4 Alkyl group, C 3 - 6 Cycloalkyl group (wherein the C 1 - 4 Alkyl groups and C 3 - 6 The cycloalkyl group consists of 1 to 5 halogen atoms, 1 hydroxy group or 1 C 1 - 4 may be substituted with an alkoxy group), or R c and R d is the combination of the nitrogen atoms to which they bind C 2 - 5 Cyclic amino (where the cyclic amino group is C 1 - 4 Alkyl group, 1 to 5 halogen atoms, 1 hydroxy group or 1 C 1 - 4 May be substituted with an alkoxy group]] or a pharmaceutically acceptable salt thereof.

Formula 332

[001322] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 332. Such compounds are described in WO 2016/092002, published June 16, 2016, corresponding to PCT/EP2015/079216, filed December 10, 2015, and US 10,138,237, issued November 27, 2018, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 332, this reference incorporated by reference herein controls.

[001323] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R1 is selected from Cl-6alkyl, (C3-8cycloalkyl)C 1-3 alkyl, and (Cl-3alkyloxy)Cl- 3 alkyl; or a pharmaceutically acceptable salt thereof.

[001324] In an embodiment, the glutamate modulator is a compound selected from: 7-[l-(5-chloro-4-ethoxy-pyrimidin-2-yl)pyrrolidin-3-yl]-3-(c yclopropylmethyl)-8- (trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridine;

7-[(3*R)-l-(5-chloro-4-ethoxy-pyrimidin-2-yl)pyrrolidin-3 -yl]-3- (cyclopropylmethyl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- a]pyridine; 7-[(3*S)-l-(5-chloro-4-ethoxy-pyrimidin-2-yl)pyrrolidin-3-yl ]-3- (cyclopropylmethyl)-8-(trifhioromethyl)-[l,2,4]triazolo[4,3- a]pyridine; 7-[l-(5-chloro-4-ethoxy-pyrimidin-2-yl)pyrrolidin-3-yl]-3-(e thoxymethyl)-8- (trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridine;

7-[(3*R)-l-(5-chloro-4-ethoxy-pyrimidin-2-yl)pyrrolidin-3 -yl]-3-(ethoxymethyl)-8- (trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridine; and

7-[(3*S)-l-(5-chloro-4-ethoxy-pyrimidin-2-yl)pyrrolidin-3 -yl]-3-(ethoxymethyl)-8- (trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridine, including substituted variants thereof retaining glutamate modulatory activity.

Formula 333

[001325] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 333. Such compounds are described in WO 2016/087487, published June 9, 2016, corresponding to PCT/EP2015/078285, filed

December 2, 2015, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 333, this reference incorporated by reference herein controls.

[001326] In an embodiment, the glutamate modulator is a compound according to: or a stereoisomeric form or a tautomer thereof, wherein

R ¹ is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-4alkyl, mono-haloCi-4alkyl, poly-halo-Ci-4alkyl, — CN, and C3-7cycloalkyl;

R ² is selected from the group consisting of H; Ci-4alkyl; C3-?cycloalkyl; — CN; — NR ^a R ^b ; — C(O)NR ^c R ^d ; — C(O)Ci-4alkyl; — Ci-4alkyl — OH; — Ci-4alkyl-0 — Ci-4alkyl; Aryl; Het; and Ci-4alkyl substituted with one or more substituents each independently selected from the group consisting of halo and C3-7cycloalkyl; wherein

R ^a , R ^b , R ^c , and R ^d are each independently selected from consisting of H and Ci-4alkyl; Aryl is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-4alkyl, mono-haloCi-4alkyl, and poly-halo-Ci- 4alkyl;

Het is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of pyridinyl, and pyrazinyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-4alkyl, and — NR ^e R ^f ; or (b) a 5-membered aromatic heterocyclyl selected from the group consisting of thiazolyl, oxazolyl, IH-pyrazolyl, and IH-imidazolyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci- 4alkyl, mono-haloCi-4alkyl, and poly-halo-Ci-4alkyl;

R ^e and R ^f are each independently selected from consisting of hydrogen, and Ci-4alkyl;

R ³ is selected from the group consisting of hydrogen, halo, Ci-4alkyl, C3-?cycloalkyl, — CN, and — OCi-4alkyl;

R ⁴ is selected from the group consisting of hydrogen and Ci-4alkyl; and

R ⁵ is selected from the group consisting of hydrogen, Ci-4alkyl, and -Ci-4alkyl-0 — Ci-4alkyl; or an N-oxide, or a pharmaceutically acceptable salt thereof.

Formula 334

[001327] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 334. Such compounds are described in WO 2016/046404, published March 31, 2016, corresponding to PCT/EP2015/072178, filed September 25, 2015, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 334, this reference incorporated by reference herein controls.

[001328] In an embodiment, the glutamate modulator is a compound selected from: wherein:

A is N; R ¹ , R ² and R ⁴ are each independently selected from the group consisting of R ¹⁰ , halogen, — CN, — NR ⁷ R ⁸ , — COOR ⁷ , — SO ₃ H, — B(OH) ₂ , — CONR ⁷ R ⁸ , —COR ⁷ , —SR ⁷ , — SOR ⁷ , — SO2R ⁷ , — SO ₂ NR ⁷ R ⁸ , — NR ⁷ COR ⁸ , — NR ⁷ SO ₂ R ⁸ , — OCOR ⁷ , — NR ⁷ C(O)NR ⁸ R ⁹ , — NR ⁷ C(S)NR ⁸ R ⁹ , and — NR ⁷ COOR ⁸ ;

R ³ is selected from the group consisting of hydrogen, halogen, — CN, — NR ⁷ R ^X , — COOR ⁷ , — SO3H, — B(OH) ₂ , — CONR ⁷ R ⁸ , —COR ⁷ , —SOR ⁷ , — SO ₂ R ⁷ , — SO ₂ NR ⁷ R ⁸ , — NR ⁷ COR ⁸ , — NR ⁷ SO ₂ R ⁸ , —OCOR ⁷ , — NR ⁷ C(O)NR ⁸ R ⁹ , — NR ⁷ C(S)NR ⁸ R ⁹ , — NR ⁷ COOR ⁸ , C1-C4 alkyl, C ₂ -C ₄ alkenyl, cycloalkyl and heterocycloalkyl, wherein said C1-C4 alkyl and said C ₂ - C ₄ alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, — CF3, — CN, — OH, — O(Ci-C4 alkyl), — NH ₂ , — NH(CI-C ₄ alkyl) and — N(Ci-C ₄ alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of: C1-C4 alkyl; halogen; CF3; — CN; — OH; — O(Ci- C ₄ alkyl); C1-C4 alkyl substituted with one or more — OH groups; — NH ₂ ; — NH(CI-C4 alkyl); and — N(CI-C ₄ alkyl)(Ci-C ₄ alkyl);

R ⁵ is heteroaryl which is optionally substituted with one or more groups independently selected from the group consisting of R ⁷ , halogen, — CN, — NR ⁷ R ^S , — CONR ⁷ R ⁸ , — COR ⁷ , —SR ⁷ , —SOR ⁷ , — SO ₂ R ⁷ , — SO ₂ NR ⁷ R ⁸ , — NR ⁷ COR ⁸ , — NR ⁷ SO ₂ R ⁸ , —OCOR ⁷ , and — COOR ⁷ ;

R ⁶ is selected from the group consisting of C1-C4 alkyl, cycloalkyl, and heterocycloalkyl, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from the group consisting of cycloalkyl, halogen, — CF3, — CN, — OH and — O(Ci- C ₄ alkyl), and further wherein, if R ⁶ is cycloalkyl or heterocycloalkyl, then said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of C1-C4 alkyl, cycloalkyl, halogen, — CF3, — CN, — OH and — O(Ci-C4 alkyl); and each R ⁷ , R ⁸ and R ⁹ is independently selected from the group consisting of hydrogen, Ci- C ₄ alkyl, C ₂ -C ₄ alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, wherein said C1-C4 alkyl and said C ₂ -C ₄ alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, — CF3, — CN, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, — OH, — O(Ci-C4 alkyl), — NH ₂ , — NH(CI-C4 alkyl) and — N(Ci-C ₄ alkyl)(Ci- C ₄ alkyl), and further wherein, if R ⁷ , R ⁸ or R ⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of: Ci- C4 alkyl; halogen; — CF3; — CN; — OH; — O(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more — OH groups; — NH2; — NH(CI-C4 alkyl); and — N(CI-C4 alkyl)(Ci-C4 alkyl); each R ¹⁰ is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C2- C4 alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl, wherein said C1-C4 alkyl and said C2-C4 alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, — CF3, — CN, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, — OH, — O(Ci-C4 alkyl), — NH ₂ , — NH(CI-C4 alkyl) and — N(CI-C4 alkyl)(Ci-C4 alkyl), and further wherein, if R ¹⁰ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from the group consisting of: Ci- C4 alkyl; halogen; — CF3; — CN; — OH; — O(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more — OH groups; — NH2; — NH(CI-C4 alkyl); and — N(CI-C4 alkyl)(Ci-C4 alkyl); or a pharmaceutically acceptable salt or solvate thereof.

[001329] In further embodiments, the glutamate modulator is a compound according to: wherein:

A is —CH;

R ¹ , R ² and R ⁴ are each independently selected from the group consisting of R ⁷ , halogen, — CN, —OR ⁷ , — NR ⁷ R ⁸ , — COOR ⁷ , — SO3H, — B(OH) ₂ , — CONR ⁷ R ⁸ , —COR ⁷ , —SR ⁷ , — SOR ⁷ , — SO2R ⁷ , — SO ₂ NR ⁷ R ⁸ , — NR ⁷ COR ⁸ , — NR ⁷ SO ₂ R ⁸ , — OCOR ⁷ , — NR ⁷ C(O)NR ⁸ R ⁹ , — NR ⁷ C(S)NR ⁸ R ⁹ , — NR ⁷ COOR ⁸ , aryl, and heteroaryl, wherein said aryl and said heteroaryl are each substituted with one or more groups independently selected from the group consisting of R ⁷ , halogen, — CN, —OR ⁷ , — NR ⁷ R ⁸ , —COOR ⁷ , — SO3H, — B(OH) ₂ , — CONR ⁷ R ⁸ , —COR ⁷ , —SR ⁷ , —SOR ⁷ , — SO2R ⁷ , — SO ₂ NR ⁷ R ⁸ , — NR ⁷ COR ⁸ , — NR ⁷ SO ₂ R ⁸ , —OCOR ⁷ , — NR ⁷ C(O)NR ⁸ R ⁹ , — NR ⁷ C(S)NR ⁸ R ⁹ , and — NR ⁷ COOR ⁸ ; R ³ is selected from the group consisting of hydrogen, halogen, — CN, — OR ⁷ , — NR ⁷ R ^X , — COOR ⁷ , — SO ₃ H, — B(OH) ₂ , — CONR ⁷ R ⁸ , —COR ⁷ , —SR ⁷ , — SOR ⁷ , — SO2R ⁷ , — SO ₂ NR ⁷ R ⁸ , — NR ⁷ COR ⁸ , — NR ⁷ SO ₂ R ⁸ , — OCOR ⁷ , — NR ⁷ C(O)NR ⁸ R ⁹ , — NR ⁷ C(S)NR ⁸ R ⁹ , — NR ⁷ COOR ⁸ , C1-C4 alkyl, C ₂ -C4 alkenyl, cycloalkyl and heterocycloalkyl, wherein said Ci- C4 alkyl and said C ₂ -C4 alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, — CF3, — CN, — OH, — O(Ci- C4 alkyl), — NH ₂ , — NH(CI-C4 alkyl) and — N(CI-C4 alkyl)(Ci-C4 alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of: C1-C4 alkyl; halogen; — CF3; — CN; — OH; — O(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more — OH groups; — NH ₂ ; — NH(CI-C ₄ alkyl); and — N(CI-C ₄ alkyl)(Ci-C ₄ alkyl);

R ⁵ is heteroaryl which is optionally substituted with one or more groups independently selected from the group consisting of R ⁷ , halogen, — CN, — NR ⁷ R ^S , — CONR ⁷ R ⁸ , — COR ⁷ , —OR ⁷ , —SR ⁷ , —SOR ⁷ , — SO ₂ R ⁷ , — SO ₂ NR ⁷ R ⁸ , — NR ⁷ COR ⁸ , — NR ⁷ SO ₂ R ⁸ , —OCOR ⁷ , and —COOR ⁷ ;

R ⁶ is selected from the group consisting of C1-C4 alkyl, cycloalkyl, and heterocycloalkyl, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from the group consisting of cycloalkyl, halogen, — CF3, — CN, — OH and — O(Ci- C4 alkyl), and further wherein, if R ⁶ is cycloalkyl or heterocycloalkyl, then said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of C1-C4 alkyl, cycloalkyl, halogen, — CF3, — CN, — OH and — O(Ci-C4 alkyl); and each R ⁷ , R ⁸ and R ⁹ is independently selected from the group consisting of hydrogen, Ci- C4 alkyl, C ₂ -C ₄ alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, wherein said C1-C4 alkyl and said C ₂ -C4 alkenyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, — CF3, — CN, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, — OH, — O(Ci-C4 alkyl), — NH ₂ , — NH(CI-C4 alkyl) and — N(CI-C4 alkyl)(Ci- C4 alkyl), and further wherein, if R ⁷ , R ⁸ or R ⁹ is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, then said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, said heterocycloalkenyl, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of: Ci- C4 alkyl; halogen; — CF3; — CN; — OH; — O(Ci-C4 alkyl); C1-C4 alkyl substituted with one or more — OH groups; — NH ₂ ; — NH(CI-C4 alkyl); and — N(CI-C4 alkyl)(Ci-C4 alkyl); or a pharmaceutically acceptable salt, solvate or prodrug thereof,

Formula 335

[001330] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 335. Such compounds are described in WO 2012/062750, published May 18, 2012, corresponding to PCT/EP2011/069640, filed November 8, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 335, this reference incorporated by reference herein controls.

[001331] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is selected from the group consisting of Cnealkyl; (C3-scycloalkyl)Ci-3alkyl;

(Ci-3alkyloxy)Ci-3alkyl; and Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents;

R ² is selected from the group consisting of Cl, CF3, — CN and cyclopropyl;

R ³ is selected from the group consisting of hydrogen, methyl and CF3;

R ⁴ is selected from the group consisting of hydrogen and methyl; or R ³ and R ⁴ together with the carbon to which they are bound form a cyclopropyl ring;

L is selected from the group consisting of (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L- h):

wherein m _a , mb, and m _c are each independently selected from the group consisting of 0 and 1; m _e and m _g are each independently selected from the group consisting of 1 and 2; n _a , nb, n _c , na, n _e , nf, h _g and nhare each independently selected from the group consisting of 0, 1 and 2;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g and R ^5h are each independently selected from the group consisting of fluoro; Ci-3alkyl; Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents; Ci-3alkyloxy; and Ci-3alkyloxy substituted with 1, 2 or 3 fluoro substituents;

R ^6a is selected from the group consisting of hydrogen; halo; Ci-3alkyl; Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents; Ci-3alkyloxy; and Ci-3alkyloxy substituted with 1, 2 or 3 fluoro substituents;

R ^6c is selected from the group consisting of hydrogen; halo; Ci-3alkyl; Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents; Ci-3alkyloxy; Ci-3alkyloxy substituted with 1, 2 or 3 fluoro substituents; and cyclopropyl;

R ^7a , R ^8a , R ^7b and R ^8b are each independently selected from the group consisting of hydrogen; fluoro and methyl; or R ^7a and R ^8a , and R ^7b and R ^8b together with the carbon to which they are attached form a cyclopropyl or a carbonyl group; wherein each halo is selected from the group consisting of fluoro, chloro, bromo and iodo; with the optional proviso that (L-c) is not bound to the triazolopyridine core through a carbon atom that is alpha to the oxygen atom; or a pharmaceutically acceptable salt thereof.

Formula 336

[001332] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 336. Such compounds are described in US 9,676,782, issued June 13, 2017, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 336, this reference incorporated by reference herein controls.

[001333] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, cyano, alkyl, fluoroalkyl, alkyloxy, fluoroalkyloxy, hydroxyalkyl, hydroxyfluoroalkyl, alkoxyalkyl, alkoxyfluoroalkyl, cyanoalkyl, and cyanofluoroalkyl;

R ² is selected from the group consisting of phenyl and pyridinyl, each optionally substituted with one to five substituents independently selected from halogen, cyano, alkyl, fluoroalkyl, alkyloxy, fluoroalkyloxy, hydroxyalkyl, hydroxyfluoroalkyl, alkoxyalkyl, alkoxyfluoroalkyl, cyanoalkyl, and cyanofluoroalkyl, wherein two of the substituents on adjacent carbons can together form a 5 or 6 membered ring;

R ³ is selected from the group consisting of hydrogen, C1-C3 alkyl, and C1-C3 fluoroalkyl;

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen and Ci- C3 alkyl; and

R ⁶ is selected from the group consisting of hydrogen, C1-C3 alkyl, and C1-C3 fluoroalkyl.

Formula 337

[001334] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 337. Such compounds are described in WO 2015/157187, published October 15, 2015, corresponding to PCT/US2015/024554, filed April 6, 2015, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 337, this reference incorporated by reference herein controls.

[001335] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ is —OH, — NHOR ⁵ , — NHSO2R ⁴ , — NR ⁴ R ⁵ or R ⁴ ;

L ¹ is absent;

R ² is hydrogen, halogen, nitro, — CN, — OH, — OR ⁴ , substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted C3- Cecycloalkyl; n is 0, 1, 2, 3, or 4; R ³ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted O-Cecycloalkyl, or substituted or unsubstituted aryl;

X is — OH, — OR ⁴ , halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted O-Cecycloalkyl;

Z is — OH, — OR ⁴ , halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted O-Cecycloalkyl;

R ⁴ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cecycloalkyl substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and

R ⁵ is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Cs-Cecycloalkyl, or substituted or unsubstituted aryl; or R ⁴ and R ⁵ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C8heterocycloalkyl.

[001336] In further embodiments, the glutamate modulator is a compound according to: wherein:

R ¹ is —OH, —OR ⁴ , — NHOR ⁵ , — NHSO2R ⁴ , — NR ⁴ R ⁵ , or R ⁴ ; d bioisostere having the structure

Ring A is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

Ring B is substituted or unsubstituted 6-membered heteroaryl;

L ² is absent or — O — (Ci-Cealkylene);

R ² is hydrogen, halogen, nitro, — CN, — OH, — OR ⁴ , substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted C3- Cecycloalkyl; R ³ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted O-Cecycloalkyl, or substituted or unsubstituted aryl;

Z is — OH, — OR ⁴ , halogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Cefluoroalkyl, or substituted or unsubstituted O-Cecycloalkyl;

R ⁴ is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Cs-Cecycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R ⁵ is hydrogen, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci- Cefluoroalkyl, substituted or unsubstituted Cs-Cecycloalkyl, or substituted or unsubstituted aryl; or R ⁴ and R ⁵ taken together with the nitrogen to which they are attached to form a substituted or unsubstituted C2-C8heterocycloalkyl; n is 0, 1, 2, 3, 4; and p is 0 or 1.

Formula 338

[001337] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 338. Such compounds are described in WO 2009/033704, published March 19, 2009, corresponding to PCT/EP2008/007551, filed September 12, 2008, US 9,114,138, issued August 25, 2015, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 338, these references incorporated by reference herein control.

[001338] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is Ci-ealkyl; or Ci-salkyl substituted with C3-?cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, Ci-3alkyl or cyclopropyl;

R ³ is hydrogen, fluoro, hydroxyl, hydroxyCi-salkyl, hydroxyCi-salkyloxy, fluoroCi-3 alkyl, fluoroCi-3 alkyloxy or cyano; and

Ar is unsubstituted phenyl; or phenyl substituted with n radicals R ⁴ , wherein n is 1, 2 or 3; R ⁴ is selected from the group consisting of hydrogen, halo, Ci-3alkyl, hydroxyCi-3alkyl, polyhaloCi-3alkyl, cyano, hydroxyl, amino, carboxyl, C1-3 alkyloxyCi-3 alkyl, C1-3 alkyloxy, polyhaloCi-3 alkyloxy, C1-3 alkylcarbonyl, mono- and di(Ci-3alkyl)amino, and morpholinyl; or two vicinal R ⁴ radicals taken together form a bivalent radical of formula — N=CH— NH— (a),

— CH=CH— NH— (b), or

— O— CH ₂ — CH ₂ — NH— (c); or

R ³ and a R ⁴ radical in ortho position taken together form a bivalent radical of formula

— CH ₂ — O— (d), or

— O — CH ₂ — (e); or a pharmaceutically acceptable salt or a solvate thereof. [001339] In another embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is Ci-ealkyl; or Ci-3alkyl substituted with C3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, Ci-3alkyl or cyclopropyl;

R ³ is hydrogen, fluoro, hydroxyl, hydroxyCi-3alkyl, hydroxyCi-3alkyloxy, fluoroCi-3alkyl, fluoroCi-3alkyloxy or cyano; and

Ar is unsubstituted phenyl; or a pharmaceutically acceptable salt thereof.

[001340] In another embodiment, the glutamate modulator is the compound: , or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate modulatory activity. [001341] In another embodiment, the glutamate modulator is the compound: substituted variant retaining glutamate modulatory activity.

Formula 339

[001342] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 339. Such compounds are described in WO 2015/042243, published March 26, 2015, corresponding to PCT/US2014/056273, filed September 18, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 339, this reference incorporated by reference herein controls.

[001343] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ is selected from the group consisting of hydrogen, cyano, halo, alkyl, haloalkyl, (cycloalkyl)alkyl, cycloalkyl, alkoxy, and haloalkoxy;

R ² is selected from the group consisting of alkyl, haloalkyl, (cycloalkyl)alkyl, (halocycloalkyl)alkyl, (alkoxy)alkyl, (haloalkoxy)alkyl, cycloalkyl, halocycloalkyl, (alkyl)cycloalkyl, and (dialkyl)cycloalkyl;

R ³ is Ar ¹ or OAr ¹ ;

Ar ¹ is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, cycloalkylalkoxy, and haloalkoxy;

Y is a bond or C3-6 cycloalkyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy; and Z is a bond or C1-3 alkyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy; provided that where Y and Z are bonds, R ³ is Ar ¹ ; or a pharmaceutically acceptable salt thereof

[001344] In an embodiment, the glutamate modulator is a compound selected from: (ls,3s)-3-(3-(cyclopropylmethyl)-8-(trifluoromethyl)-[l,2,4] triazolo[4,3-a]pyridin-7- yloxy)-l-(3,5-(di-3H)-2-methoxyphenyl)cyclobutanecarbonitril e and 3- (cyclopropylmethyl)-7-((ls,4s)-4-(4-fluorophenyl)-4-(methoxy -d3)cyclohexyloxy)-8- (trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridine; or a pharmaceutically acceptable salt thereof, or substituted variant retaining glutamate modulatory activity.

Formula 340

[001345] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 340. Such compounds are described in WO 2015/032790, published March 12, 2015, corresponding to PCT/EP2014/068676, filed September 3, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 340, this reference incorporated by reference herein controls.

[001346] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is selected from the group consisting of Ci-ealkyl, (C3-scycloalkyl)Ci-3alkyl, and (Ci- 3alkyloxy)Ci-3alkyl; each R ² is independently selected from F, Cl, Ci-salkyl, Ci-salkyloxy, mono- or polyhaloCi- salkyl, and mono- or polyhaloCi-salkyloxy; n is an integer selected from 1, 2, and 3; or a pharmaceutically acceptable salt or solvate thereof.

[001347] In an embodiment, the glutamate modulator is a compouns selected from: Formula 341

[001348] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 341. Such compounds are described in WO 2010/130422, published November 18, 2010, corresponding to PCT/EP2010/002908, filed May 11, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 341, this reference incorporated by reference herein controls.

[001349] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein the bond drawn into the ring indicates that the bond may be attached to any carbon ring atom; R ¹ is selected from the group consisting of hydrogen; Ci-ealkyl; (Ci-3alkyloxy)-Ci-3alkyl; [(Cn 3alkyloxy)-Ci-3alkyloxy]Ci-3alkyl; Ci-3alkyl substituted with one or more independently selected halo substituents; unsubstituted benzyl; benzyl substituted with one or more substituents each independently selected from the group consisting of halo, Ci-3alkyl, (Cn 3alkyloxy)Ci-3alkyl, Ci-3alkyloxy, hydroxyCi-3alkyl, cyano, hydroxyl, amino, (C=O)R', (C=O)OR', (C=O)NR'R", mono- or di-(Ci-3alkyl)amino, morpholinyl, (C3-7cycloalkyl)Ci- 3alkyloxy, trifluoromethyl and trifluoromethoxy, wherein R' and R" are independently selected from hydrogen and Ci-ealkyl; (benzyloxy)Ci-3alkyl; unsubstituted C3-?cycloalkyl; C3- 7cycloalkyl substituted with one or more independently selected Ci-3alkyl substituted with one or more independently selected halo substituents; (C3-7cycloalkyl)Ci-3alkyl; 4-(2,3,4,5- tetrahydro-benzo[f][l,4]oxazepine)methyl; Het ¹ ; He^Ci-salkyl; Het ² ; and Het ² Ci-3alkyl;

R ² is selected from the group consisting of cyano; halo; Ci-3alkyl substituted with one or more independently selected halo substituents; Ci-3alkyloxy substituted with one or more independently selected halo substituents; Ci-3alkyl; C3-7cycloalkyl; and (C3-7cycloalkyl)Ci- 3 alkyl; forms a radical selected from (a), (b), (c), (d) and (e): wherein the bond drawn into (a) indicates that R ⁴ may be attached to any of carbon ring atoms 2 and 3; each R ³ is independently selected from the group consisting of hydrogen; unsubstituted Ci- ealkyl; Ci-ealkyl substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, Ci-3alkoxy and trifluoromethyl; unsubstituted C3- 7cycloalkyl; C3-?cycloalkyl substituted with one or more substituents independently selected from the group consisting of halo, Ci-3alkyl, hydroxy, Ci-3alkoxy and trifluoromethyl; C3- 7cycloalkylCi-3alkyl; unsubstituted phenyl; phenyl substituted with one or more substituents independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkoxy and trifluoromethyl; Het ³ ; and Het ³ C 1-3 alkyl; each R ³ is independently selected from a cyclic radical of formula (f) wherein R ⁸ is selected from hydrogen, Ci-3alkyl, Ci-3alkyloxy and hydroxyCi-salkyl; q is 1 or 2; X is selected from O, CH2 and CR ⁹ (OH), wherein R ⁹ is selected from hydrogen, Ci-3alkyl and C3-?cycloalkyl; or

X is a cyclic radical of formula (g) wherein r and s are independently selected from 0, 1 and 2, provided that r+s^2; each R ⁴ , R ⁶ and R ⁷ are each independently selected from Ci-3alkyl and Ci-3alkyl substituted with one or more independently selected halo substituents; each R ⁵ is independently selected from the group consisting of hydrogen, Ci-3alkyl, and Ci- 3alkyl substituted with one or more independently selected halo substituents; n, m and p are each independently selected from 0, 1 and 2; v is 0 or 1; t and u are each independently selected from 1 and 2;

W is selected from N and C ¹⁰ ; wherein R ¹⁰ is selected from hydrogen, halo and trifluoromethyl; each Het ¹ is a saturated heterocyclic radical selected from pyrrolidinyl; piperidinyl; piperazinyl; and morpholinyl; each of which may be optionally substituted with one or more each independently selected from the group consisting of Ci-ealkyl; mono-, di- and tri-haloCi- 3alkyl; unsubstituted phenyl; and phenyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, trifluoromethyl, and trifluoromethoxy; each Het ² is pyridyl or pyrimidinyl; and each Het ³ is a heterocycle selected from the group consisting of tetrahydropyran, pyridyl; and pyrimidinyl; each of them being optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkoxy and trifluoromethyl; and halo is selected from fluoro, chloro, bromo and iodo; or a pharmaceutically acceptable salt thereof.

[001350] In further embodiments, the glutamate modulator is a compound selected from: trans-4-[5-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-l,2,4- triazolo[4,3-a]-pyridine-

7-yl]-lH-indol-l-yl]-cyclohexanol;

8-chloro-7-(7-chloro-lH-indol-5-yl)-3-(cyclopropylmethyl) -l,2,4-triazolo[4,3-a]- pyridine;

8-chloro-3-(cyclopropylmethyl)-7-[l-(3-pyridinyl)-lH-indo l-5-yl]-l,2,4-triazolo[4,3- a]pyridine;

8-chloro-3-(cyclopropylmethyl)-7-[l-(cyclopropylmethyl)-l H-pyrrolo[2,3-b]-pyridin- 5-yl]-l,2,4-triazolo[4,3-a]pyridine; or 7-[8-chloro-3-(cyclopropylmethyl)-l,2,4-triazolo[4,3-a]pyrid in-7-yl]-3,4-dihydro-4- (2-pyrimidinyl)-2H- 1 ,4-benzoxazine; or the pharmaceutically acceptable salt or solvate thereof, or substituted variant retaining glutamate modulatory activity.

Formula 342

[001351] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 342. Such compounds are described in WO 2013/062074, published May 2, 2013, corresponding to PCT/US2010/077688, filed October 26, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 342, this reference incorporated by reference herein controls.

[001352] In an embodiment, the glutamate modulator is a compound according to:

R ¹ is C i-6 alkyl (the C i-6 alkyl is a halogen atom, C 3-8 cycloalkyl, C i-6 alkoxy, and phenyl (the phenyl is a halogen atom, cyano, C i-6 alkyl , C i-6 alkyl, and C i-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group consisting of: 3 may be substituted with three groups), or C 2- 6 alkenyl; R ² represents a hydrogen atom or C 1-6 alkyl;

Any one of R ³ and R ⁴ is a hydrogen atom, a halogen atom, C i-6 alkyl (the C i-6 alkyl may be substituted with one hydroxy), halo C i-6 alkyl, Or C 2-6 alkenyl, the other being aryl or heteroaryl (the aryl and heteroaryl may be substituted with the same or different 1 to 3 groups selected from the following substituent group A '). Show;

Substituent group A ' is a halogen atom, cyano, hydroxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, cyano, hydroxy, oxo, C 1-6 alkoxy, C 2-6 alkanoylamino, C 3 -8 cycloalkyl, C 3- 8 cycloalkyloxy (the C 3-8 cycloalkyl and C 3-8 cycloalkyloxy are the same or different 1 to 3 groups selected from C 1-6 alkyl and a halogen atom) And optionally substituted with 1 to 5 groups selected from the group consisting of aryl, heteroaryl, aryloxy, and saturated heterocyclyl), C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with the same or different 1 to 3 groups selected from the group of halogen atom and aryl.), C 3-8 cycloalkyl, C 3-

8 cycloalkyloxy (the C 3-8 Shikuroa Kill and C 3-8 cycloalkyloxy optionally substituted by the same or different 1 to 3 halogen atoms.), Amino, carbamoyl (said amino and carbamoyl same or different one or two C 1 -6 alkyl may be substituted.), Aryl, heteroaryl, aryloxy, heteroaryloxy, saturated or partially unsaturated heterocyclyl (the saturated and partially unsaturated heterocyclyl may be the same or different 1 or 2 C 1-6 alkyl may be substituted.), C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, cyclic aminocarbonyl, C 2-6 alkenyl, C 1-

6 alkoxycarbonyl, and saturated heterocyclyloxy Indicates;

X represents a nitrogen atom or the formula CH. ] Or an pharmaceutically acceptable salt thereof.

Formula 343

[001353] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 343. Such compounds are described in WO 2013/062079, published May 2, 2013, corresponding to PCT/JP2012/077697, filed October 26, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 343, this reference incorporated by reference herein controls.

[001354] In an embodiment, the glutamate modulator is a compound according to: wherein R ¹ is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is amino (the amino may be substituted with one or two C 1-6 alkyl)), 4-8 membered cyclic amino, hydroxy, and C 1-6 with 1 to 3 groups selected from the group consisting of alkoxy may be substituted.), halo C i- 6 alkyl, C i-6 alkanoyl, C 2-6 alkenyl, amino (wherein the amino is one or two groups selected from the group consisting of C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, and C 1-6 alkanoyl 4) 8-membered cyclic amino, C 1-6 alkylsulfonyl, carbamoyl (wherein the carbamoyl may be substituted with one or two C 1-6 alkyl), aryl, hetero, aryl (the aryl, and heteroaryl C 1-6 alkyl, halo C 1-6 A . Kill, and the C 3-8 may be substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl), or shows the carboxy;

R ² is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is amino (the amino may be substituted with one or two C 1-6 alkyl)), 4- to 8-membered cyclic amino (The 4- to 8- membered cyclic amino may be substituted with 1 to 3 halogen atoms), imino, hydroxy, C 1- 6 alkoxy, aryl, C 3-8 cyclo Alkyl, and optionally substituted with 1 to 3 groups selected from the group consisting of carboxy), halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1-6 alkyl sulfonyl , Carbamoyl (the carbamoyl may be substituted with one or two C 1-6 alkyl), aryl or heteroaryl (the aryl and heteroaryl are each a halogen atom, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 3-8 cycloalkyl Carboxymethyl, aryl C 1-6 alkoxy, C 1-6 alkylsulfonyl, amino (said amino may be substituted by one or two C 1-6 alkyl.), Or 4-8 membered cyclic amino (said 4-8 membered cyclic amino may be substituted by 1 to 3 groups selected from the group consisting of 1 C 1- 6 alkyl)), pyridonyl (the pyridonyl is optionally substituted by one C 1-6 alkyl), tri C 1-6 alkylsilyl, arylcarbonyl, arylsulfonyl, C 3-8 cycloalkyl, C 2-6 alkenyl (the C 2-6 alkenyl (the C 2- 6 alkenyl) Represents C i-6 alkoxy) or C 3-8 cycloalkylcarbonyl;

R ³ is aryl, heteroaryl or C 3-8 cycloalkyl (the aryl, heteroaryl and C 3-8 cycloalkyl are each a halogen atom, C 1-8 alkyl (the C 1-8 alkyl is cyano, And C 1 -C 6 alkyl, which may be substituted with 1 to 3 groups selected from the group consisting of hydroxy and aryl), halo C 1-6 alkyl, C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is a halogen atom, It may be substituted by 1 to 5 groups selected from the group consisting of C 1-6 alkyl, halo C 1-6 alkyl and aryl), C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkyloxy, aryl C 1-6 alkoxy, aryloxy, C 1- 6 alkanoyl, aryl (the aryl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1- 6 alkoxy, C 3-8 Sik With 1 to 3 substituents selected from the group consisting of alkyloxy and C 1-6 alkanoyl which may be substituted.), Heteroaryl (said heteroaryl halogen atom, C 1- 6 alkyl, halo C 1-6 Alkyl, C 1-6 alkoxy, and optionally substituted with 1 to 3 groups selected from the group consisting of halo C 1-6 alkoxy), 4 to 8 membered cyclic amino, pyridonyl (the pyridonyl is 1 may be substituted with pieces of C 1-6 alkyl.), 4 cyclic ethers to 8-membered cyclic ether (the 4-8 membered is optionally substituted with 1 to 3 C 1-6 alkyl. ), C 5- 8 bicycloalkyl (wherein the C 5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms), adamantyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, and 1 to 6 selected from the group consisting of arylcarbonyl In three groups may be substituted.), Kinorinoniru (the Kinorinoniru may be substituted with one C 1-6 alkyl.), Or indanyl (the indanyl 1 to 3 C 1- 6 Optionally substituted with alkyl));

R ⁴ represents a hydrogen atom or C 1-6 alkyl]

The dihydroimidazo oxazole derivative represented by, or its pharmaceutically acceptable salt.

Formula 344

[001355] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 344. Such compounds are described in WO 2014/195311, published December 11, 2014, corresponding to PCT/EP2014/061478, filed June 3, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 344, this reference incorporated by reference herein control.

[001356] In an embodiment, the glutamate modulator is a compound according to: or a stereoisomeric form thereof, wherein:

R ¹ is phenyl or 2-pyridinyl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, — Ci-4alkyl, monohaloCi-4alkyl, polyhaloCi-4alkyl, — O — Ci-4alkyl, — Ci-4alkyl-0 — Ci-4alkyl, monohaloCi-4alkyloxy, polyhaloCi-4alkyloxy, — Ci-4alkyl-OH, — Ci-4alkylthio, monohaloCi-4alkylthio, polyhaloCi- 4alkylthio, cyano, — C3-?cycloalkyl optionally substituted with trifluoromethyl and — SF5; or R ¹ is

R ³ is selected from the group consisting of hydrogen and — Ci-4alkyl;

R ⁴ is selected from the group consisting of hydrogen, — Ci-4alkyl, monohaloCi-4alkyl, polyhaloCi-4alkyl, — Ci-4alkyl-0 — Ci-4alkyl and — Ci-4alkyl-OH;

R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, halo, cyano, — Ci-4alkyl, — Ci-4alkyl-OH, — C3-?cycloalkyl, monohaloCi-4alkyl, polyhaloCi-4alkyl, — Ci-4alkyl-0 — Ci-4alkyl, — O — Ci-4alkyl, monohaloCi-4alkyloxy, polyhaloCi-4alkyloxy, 1- acetylazeti din-3 -yl and — NR'R"; and

R' and R" are each independently selected from the group consisting of hydrogen and — Ci- 4alkyl; or

R' and R", together with the nitrogen atom to which they are attached, form a heterocyclic group selected from the group consisting of 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1- piperazinyl and 4-morpholinyl, wherein 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1- piperazinyl and 4-morpholinyl are optionally substituted with a substituent selected from the group consisting of halo, hydroxy, — Ci-4alkyl, monohaloCi-4alkyl, polyhaloCi-4alkyl and — C(O)— Ci- ₄ alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof.

[001357] In further embodiments, the glutamate modulator is a compound according to: wherein: R ^2a is halo;

R ³ is selected from the group consisting of hydrogen and — Ci-4alkyl; and

R ⁴ is selected from the group consisting of hydrogen, — Ci-4alkyl, monohaloCi-4alkyl, polyhaloCi-4alkyl, — Ci-4alkyl-0 — Ci-4alkyl and — Ci-4alkyl-OH, and alternatively, the glutamate modulator is a compound according to:

[001358] In further embodiments, the glutamate modulator is a compound selected from:

,or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate modulatory activity.

[001359] In further embodiments, the glutamate modulator is a compound selected from: including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

Formula 345

[001360] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 345. Such compounds are described in JP 2014- 214130, published November 17, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 345, this reference incorporated by reference herein controls.

[001361] In an embodiment, the glutamate modulator is a compound according to: halogen atom, cyano, C i-6 alkyl (the C i-6 alkyl is amino (the amino may be substituted with 1 or 2 C i-6 alkyl)), Optionally substituted with 1-3 groups selected from the group consisting of 4- to 8-membered cyclic amino, hydroxy, and C i-6 alkoxy.), Halo C i-6 alkyl, C i-

6 alkanoyl, C 2-6 alkenyl, amino (wherein the amino is one or two groups selected from the group consisting of C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, and C 1-6 alkanoyl) Optionally substituted)) 4-8 membered cyclic amino, C 1-6 alkyl sulfonyl, carbamoyl (the carbamoyl may be substituted with 1 or 2 C 1-6 alkyl), aryl, hetero aryl (the aryl, and heteroaryl C 1-6 alkyl, halo C 1-6 A . Kill, and the C 3-8 optionally substituted with 1 to 3 substituents selected from the group consisting of cycloalkyl), or shows the carboxy;

R ² represents a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl is amino (the amino may be substituted with 1 or 2 C 1-6 alkyl)), 4- to 8-membered cyclic amino (the 4- to 8-membered cyclic amino may be substituted with 1 to 3 halogen atoms), imino, hydroxy, C 1-6 alkoxy, aryl, C 3-8 cyclo Optionally substituted with 1 to 3 groups selected from the group consisting of alkyl and carboxy)), halo C 1-6 alkyl, C 1-6 alkanoyl, C 2-6 alkenyl, C 1- 6 alkylsulfonyl , Carbamoyl (the carbamoyl may be substituted with 1 or 2 C 1-6 alkyl), aryl, or heteroaryl (the aryl and heteroaryl are halogen atoms, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 3-8 cycloalkyl Carboxymethyl, aryl C 1-6 alkoxy, C 1-6 alkylsulfonyl, amino (said amino may be substituted by one or two C 1-6 alkyl.), Or 4-8 membered cyclic amino (said 4- to 8- membered cyclic amino may be substituted with 1 to 3 groups selected from the group consisting of 1 C 1-6 alkyl.), Pyridonyl (the pyridonyl is May be substituted with one C 1-

6 alkyl.), Tri C 1-6 alkylsilyl, arylcarbonyl, arylsulfonyl, C 3-8 cycloalkyl, C 2-6 alkenyl (the C 2- 6 alkenyl). May be substituted with C 1-6 alkoxy), or C 3-8 cycloalkylcarbonyl;

R ³ is aryl, heteroaryl, or C 3-8 cycloalkyl (the aryl, heteroaryl, and C 3-8 cycloalkyl are halogen atoms, C 1-8 alkyl (the C 1-8 alkyl is cyano, Optionally substituted with 1 to 3 groups selected from the group consisting of hydroxy and aryl), halo C 1-6 alkyl, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is a halogen atom, optionally substituted with 1 to 5 groups selected from the group consisting of C 1-6 alkyl, halo C 1-6 alkyl, and aryl.), C 1-6 alkoxy, halo C 1-6 alkoxy, C 3- 8 cycloalkyloxy, aryl C 1-6 alkoxy, aryloxy, C 1-6 alkanoyl, aryl (the aryl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 Sik With 1-3 substituents selected from the group consisting of alkyloxy and C 1-6 alkanoyl which may be substituted.), Heteroaryl (said heteroaryl halogen atom, C 1-6 alkyl, halo C 1-6 Optionally substituted with 1 to 3 groups selected from the group consisting of alkyl, C 1-6 alkoxy, and halo C 1-6 alkoxy.) 4-8 membered cyclic amino, pyridonyl (wherein pyridonyl is 1 may be substituted with pieces of C 1-6 alkyl.), cyclic ethers 4-8 membered cyclic ether (said 4-8 membered is optionally substituted with 1 to 3 C 1-6 alkyl. ), C 5-8 bicycloalkyl (the C 5-8 bicycloalkyl may be substituted with 1 to 3 halogen atoms), adamantyl, C 1-6 alkoxycarbonyl, C 1- 6 alkyl sulfonyl, and 1 to selected from the group consisting of arylcarbonyl May be substituted with 3 groups), quinolinonyl (which may be substituted with 1 C 1-6 alkyl), or indanyl (wherein indanyl is 1-3 C 1-6). Optionally substituted with alkyl);

R ⁴ represents a hydrogen atom or C 1-6 alkyl]

Formula 346

[001362] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 346. Such compounds are described in JP 2014- 214124, published November 17, 2014 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 346, this reference incorporated by reference herein controls.

[001363] In an embodiment, the glutamate modulator is a compound according to:

[001364] wherein R ¹ represents C 1-6 alkyl (the C 1-6 alkyl may be substituted with one C 3- 8 cycloalkyl);

R ² represents a hydrogen atom or C 1-6 alkyl;

Ring A represents benzene or pyridine (wherein the benzene or pyridine may be substituted with one or two identical or different groups selected from a halogen atom and cyano);

Ring B represents benzene or a 6-membered aromatic heterocyclic ring;

R ³ is a halogen atom, cyano, carboxy, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one group selected from hydroxy and C 1-6 alkoxy), C 1. -6 alkoxy, C 3-8 cycloalkyl, halo C 1- 6 alkyl, halo C 1-6 alkoxy, C 2-6 alkanoyl, C 1-6 alkylsulfonyl, or -CO-NR ⁵ R ⁶ ;

R ⁴ represents a hydrogen atom, a halogen atom, or C 1-6 alkyl;

R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or C 1-6 alkyl, Alternatively, R ⁵ and R ⁶ together with the adjacent nitrogen atom represent a 4-6 membered nitrogen-containing saturated heterocyclic ring. ]

Or an pharmaceutically acceptable salt thereof. In the above formula (I),

R ³ is a halogen atom, cyano, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one group selected from hydroxy and C 1-6 alkoxy), C 1-6. Alkoxy, C 3-8 cycloalkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-6 alkanoyl, C 1-6 alkylsulfonyl, or the formula — CO — NR ⁵ R ⁶ .

Formula 347

[001365] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 347. Such compounds are described in WO 2014/117919, published August 7, 2014, corresponding to PCT/EP2014/000160, filed January 22, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 347, this reference incorporated by reference herein controls.

[001366] In an embodiment, the glutamate modulator is a compound selected from: wherein:

Xi, X2 independently from each other denote N or CW;

V denotes an at least one nitrogen atom comprising moiety selected from the group consisting of:

(i) NR4R5;

(ii) CN;

R1 independently denotes H, cycloalkyl, aryl, heteroaryl, heterocyclyl or CN, wherein alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl can optionally be substituted by one or more identical or different substituents T; or R1 and V together with the carbon atoms to which they are attached to form heterocyclyl or heteroaryl comprising at least one nitrogen atom, which can optionally be substituted by one or more identical or different substituents T;

R2, R3 independently from each other denote H, CN, C(O) — N=C — (NYY)2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, C(O)-alkyl, C(O)OH, C(O)O-alkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl moieties can optionally be substituted by one or more identical or different substituents T; or R2 and R3 together with the carbon atoms to which they are attached to form cycloalkyl, heterocyclyl, aryl or heteroaryl, which can optionally be substituted by one or more identical or different substituents T; or, if X2 is CW, X2 and R3 together with the carbon atoms to which they are attached to form cycloalkyl, heterocyclyl, aryl or heteroaryl, which can optionally be substituted by one or more identical or different substituents T;

R4, R5 independently from each other denote H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, which can optionally be substituted by one or more identical or different substituents T; or R4 and R5 together with the nitrogen atom to which they are attached to form heterocyclyl or heteroaryl, which can optionally be substituted by one or more identical or different substituents T;

W independently from each other denotes H, CN, NYY, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, C(O) — C(O)O- alkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl moieties can optionally be substituted by one or more identical or different substituents T;

T denotes independently from each other alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, F, Cl, Br, I, OH, CN, NO2, NYY, CF3, OCF3, alkyl-OH, alkyl-NYY, alkyl-CN, alkyl-C(O)-heterocyclyl, O-alkyl, O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl, O-alkyl-heteroaryl, O- heterocyclyl, O-alkyl-heterocyclyl, O-alkyl-NYY, C(O)OY, C(O)NY-alkyl-NYY, C(O)NYY, C(O)— C(O)— NYY, C(O)-alkyl-NY-alkyl, C(O)-alkyl-NY-alkyl-O-alkyl, C(O)- alkyl, C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl, C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl, C(O)-alkyl-heterocyclyl, C(O)NY-alkyl, C(O)NY- cycloalkyl, C(O)NY-alkyl-cycloalkyl, C(O)NY-aryl, C(O)NY-alkyl-aryl, C(O)NY- heteroaryl, C(O)NY-alkyl-heteroaryl, C(O)NY-heterocyclyl, C(O)NY-alkyl-heterocyclyl, S(O)2-alkyl, S(O)2-cycloalkyl, S(O)2-alkyl-cycloalkyl, S(O)2-aryl, S(O)2-alkyl-aryl, S(O)2- heteroaryl, S(O)2-alkyl-heteroaryl, S(O)2-heterocyclyl, S(O)2-alkyl-heterocyclyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl moieties can optionally be substituted by one or more identical or different substituents Z;

Y denotes independently from each other H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl can optionally be substituted by one or more identical or different substituents Z;

Z denotes independently from each other alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, F, Cl, Br, I, OH, CN, NO ₂ , NH ₂ , NH-alkyl, N(alkyl) ₂ , NH-alkyl-OH, NH-alkyl-O-alkyl, NH-alkyl-aryl, CF ₃ , OCF ₃ , alkyl-OH, alkyl-NH2, alkyl-NH-alkyl, alkyl-N(alkyl)2, alkyl-CN, alkyl-C(O)-heterocyclyl, O- alkyl, O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl, O-alkyl- heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, O-alkyl-NH2, C(O)OH, C(O)NH-alkyl- NH ₂ , C(O)NH ₂ , C(0)— C(0)— NH ₂ , C(O)-alkyl-NH-alkyl, C(O)-alkyl-NH-alkyl-O-alkyl, C(O)-alkyl, C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl, C(0)- heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl, C(O)-alkyl-heterocyclyl, C(O)- heterocyclylalkyl, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH — alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH — heterocyclyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-aryl-halogen, C(O)NH-aryl- O-alkyl, C(O)N(alkyl)-aryl, C(O)N(aryl) ₂ , S(O) ₂ -alkyl, S(O) ₂ -cycloalkyl, S(O) ₂ -alkyl- cycloalkyl, S(O) ₂ -aryl, S(O) ₂ -alkyl-aryl, S(O) ₂ -heteroaryl, S(O) ₂ -alkyl-heteroaryl, S(O) ₂ - heterocyclyl, S(O) ₂ -alkyl-heterocyclyl; and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

[001367] In further embodiments, the glutamate modulator is a compound selected from:

, or a pharmaceutically acceptable salt thereof or a substituted variant retaining glutamate modulatory activity.

Formula 348

[001368] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 348. Such compounds are described in jWO 2010/043396, published April 22, 2010, corresponding to PCT/EP2009/007404, filed October 15, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 348, this reference incorporated by reference herein controls.

[001369] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is Ci-ealkyl; or Ci-3alkyl substituted with C3-?cycloalkyl, halo, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy; R ² is halo, trifluoromethyl, Ci-salkyl or cyclopropyl;

R ³ is hydrogen, halo or trifluoromethyl; n is 1 or 2;

X is — CH2CH2— O— , — CH=CH— , or — CH2CH2— ;

Y is — O— or — CR ⁴ (OH)— ;

R ⁴ is hydrogen or C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.

[001370] In further embodiments, the glutamate modulator is a compound selected from: trans-l-Butyl-3-chloro-4-[l-(4-hydroxy-cyclohexyl)-lH-indol- 5-yl]-lH-pyridin-2-one (E3), or trans-l-Butyl-3-chloro-4-[l-(4-hydroxy-4-methyl-cylohexyl)-l H-indol-5-yl]-lH -pyri din-2 - one (E5), or a pharmaceutically acceptable salt or substituted variant thereof retaining glutamate modulatory activity.

Formula 349

[001371] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 349. Such compounds are described in WO 2010/025890, published March 11, 2010 and corresponding to PCT/EP2009/006326, filed September 1, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 349, this reference incorporated by reference herein controls.

[001372] In an embodiment, the glutamate modulator is a compound according to: stereochemically isomeric form thereof, wherein

R ¹ is Ci-6 alkyl; or C1-3 alkyl substituted with C3-7 cycloalkyl, halo, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;

X is a covalent bond, O, NR ³ , NR ³ — CH2 or O — CH2;

R ³ is hydrogen or C 1-33 alkyl; and Ar is unsubstituted phenyl; or phenyl substituted with n radicals R ⁴ ; wherein n is 1, 2 or 3; wherein each R ⁴ is independently selected from the group consisting of halo, C1-3 alkyl, hydroxyCi-salkyl, polyhaloCi-salkyl, cyano, hydroxyl, amino, carboxyl, C1-3 alkyloxyCi- salkyl, Ci-salkyloxy, polyhaloCi-salkyloxy, Ci-salkylcarbonyl, mono- and di(Ci-3alkyl)amino, and morpholinyl; or wherein two vicinal R ⁴ radicals taken together form a bivalent radical of formula

— N=CH— NH— (a), or

— CH=CH— NH— (b), or

— O— CH ₂ — CH ₂ — NH— (c); or a pharmaceutically acceptable addition salt or a solvate thereof.

Formula 350

[001373] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 350. Such compounds are described in WO 2013/192306, published December 27, 2013, corresponding to PCT/US2013/046572, filed June 19, 2013, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 350, this reference incorporated by reference herein controls.

[001374] In an embodiment, the glutamate modulator is a compound according to: wherein:

A is Ar ¹ — Y— Z;

B is hydrogen or alkyl; or A and B together with the nitrogen to which they are attached form ring A;

R ¹ is selected from the group consisting of hydrogen, cyano, halo, alkyl, haloalkyl, (cycloalkyl)alkyl, cycloalkyl, alkoxy, and haloalkoxy;

R ² is selected from the group consisting of alkyl, haloalkyl, (cycloalkyl)alkyl, benzyl, and cycloalkyl;

R ³ is hydrogen, alkyl, haloalkyl, or cycloalkyl; Ar ¹ is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, and haloalkoxy;

Ar ² is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, hydroxy, alkoxy, (cycloalkyl)alkoxy, haloalkoxy, and alkoxycarbonyl;

XHs CH or N;

X ² is CR ³ or N;

X ³ is CH or N; provided that one of X ² and X ³ is N, thus when X ² is N, X ³ is CH and when X ³ is N, X ² is CR ³ ;

Y is C3-6 cycloalkyl substituted with 0-2 halo or alkyl substituents; and

Z is a bond or C1-3 alkyl; ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 1 Ar ² or (Ar ² )alkyl substituent and is also substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy; or ring A is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

[001375] In an embodiment, the glutamate modulator is a compound selected from: 3-(cyclopropylmethyl)-7-(4-(3,6-difluoro-2-methoxyphenyl)pip eridin-l-yl)-8- (trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazine;

7-(4-(3,6-difluoro-2-methoxyphenyl)piperidin-l-yl)-3-(2,2 ,2-trifluoroethyl)-8- (trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazine;

8-chloro-3-(cyclopropylmethyl)-7-(4-(2-(difluoromethoxy)- 3,6-difluorophenyl)piperidin-l- yl)-[l,2,4]triazolo[4,3-b]pyridazine;

8-chloro-7-(4-(2-fluoro-6-methoxyphenyl)piperidin-l-yl)-3 -(2,2,2-trifluoroethyl)-

[ 1 ,2,4]triazolo[4,3 -b]pyridazine;

3-(cyclopropylmethyl)-7-(4-phenylpiperidin-l-yl)-8-(trifl uoromethyl)-[l,2,4]triazolo[4,3- b]pyridazine;

8-chloro-3-(cyclopropylmethyl)-7-(4-(2-fluorophenyl)piper idin-l-yl)-[l,2,4]triazolo[4,3- c]pyrimidine; and 8-chloro-7-(4-(2-fluorophenyl)piperidin-l-yl)-3-(2,2,2-trifl uoroethyl)-[l,2,4]triazolo[4,3- c]pyrimidine; or a pharmaceutically acceptable salt thereof, including substituted variants retaining glutamate modulatory activity.

Formula 351

[001376] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 351. Such compounds are described in WO 2013/174822, published November 28, 2013, corresponding to PCT/EP2013/060426, filed May 21, 2013, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 351, this reference incorporated by reference herein controls.

[001377] In an embodiment, the glutamate modulator is a compound according to: wherein:

A is N or C(H);

B is aryl or heteroaryl; each R1 is independently selected from R5, halogen, — CF3, — CN, — OR5, — OCF3, — NR5R6 COOR5, tetrazolyl, — SO3H, — B(OH)2, — CONR5R6, — COR5, — SR5, — SOR5, — SO2R5, — SO2NR5R6, — NR5COR6, — NR5SO2R6 or — OCOR5; nl is 1,2 or 3; each R2 is independently selected from R5, halogen, — CF3, — CN, — OR5, — OCF3, — NR5R6, — COOR5, — CONR5R6, — COR5, — SR5, — SOR5, — SO2R5, SO2NR5R6, — NR5COR6, — NR5SO2R6, or — OCOR5; n2 is 1, 2 or 3;

R3 is a -L-R7 group, wherein:

L is a bond or C1-C4 alkylene, wherein one or more — CH2 — units comprised in said alkylene are each optionally replaced by a group independently selected from — O — , — NR5— , —CO—, — S— , —SO—, or — SO2— ; and

R7 is selected from hydrogen, halogen, — CF3, — CN, an optionally substituted C1-C4 alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, wherein said C1-C4 alkyl, said cycloalkyl, said heterocycloalkyl, said aryl or said heteroaryl is optionally substituted with one or more groups independently selected from R5, halogen, — CF3, — CN, — NR5R6, — CONR5R6, — COR5, — OR5, — SR5, — SOR5, — SO2R5, — SO2N R5R6, — NR5COR6, — NR5SO2R6, — OCOR5, — COOR5, tetrazolyl, — SO3H, or — B(OH)2;

R4 is selected from an optionally substituted C1-C4 alkyl, an optionally substituted cycloalkyl, or an optionally substituted heterocycloalkyl, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from cycloalkyl, halogen, — CF3, — CN, — OH or — O(C1-C4 alkyl), and further wherein said cycloalkyl or said heterocycloalkyl is optionally substituted with one or more groups independently selected from C1-C4 alkyl, cycloalkyl, halogen, — CF3, — CN, — OH or — O(C1-C4 alkyl); and each R5 and each R6 is independently selected from hydrogen, an optionally substituted Cl- C4 alkyl, an optionally substituted cycloalkyl, or an optionally substituted heterocycloalkyl, wherein said C1-C4 alkyl is optionally substituted with one or more groups independently selected from halogen, — CF3, — CN, —OH, — O(C1-C4 alkyl), — NH2, — NH(C1-C4 alkyl) or — N(C1-C4 alkyl)(Cl-C4 alkyl), and further wherein said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C1-C4 alkyl, halogen, — CF3, — CN, — OH, — O(C1-C4 alkyl), — NH2, — NH(C1-C4 alkyl) or — N(C1-C4 alkyl)(Cl-C4 alkyl); or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Formula 352

[001378] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 352. Such compounds are described in WO 2013/138687, published September 19, 2013, corresponding to PCT/US2013/031905, filed March 15, 2013, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 352, this reference incorporated by reference herein controls.

[001379] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ is selected from the group consisting of cyano, halo, alkyl, haloalkyl, (cycloalkyl)alkyl, cycloalkyl, alkoxy, and haloalkoxy;

R ² is selected from the group consisting of alkyl, haloalkyl, (cycloalkyl)alkyl, cycloalkyl,

OR ⁴ , and N(R ⁵ )(R ⁶ );

R ³ is hydrogen or alkyl;

R ⁴ is alkyl, haloalkyl, (cycloalkyl)alkyl, or cycloalkyl;

R ⁵ is alkyl, haloalkyl, (cycloalkyl)alkyl, or cycloalkyl;

R ⁶ is hydrogen or alkyl;

Ar ¹ is phenyl or heteroaryl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, and haloalkoxy;

X is CH or N;

Y is C3-6 cycloalkyl substituted with 0-2 halo or alkyl substituents; and

Z is a bond or C1-3 alkyl; or a pharmaceutically acceptable salt thereof.

Formula 353

[001380] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 353. Such compounds are described in WO 2013/066736, published May 10, 2013, corresponding to PCT/US2012/062027, filed October 26, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 353, this reference incorporated by reference herein controls.

[001381] In an embodiment, the glutamate modulator is a compound according to: or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein: ring A is a moiety selected from the group consisting of: phenyl, — (Cs-Ce) cycloalkyl, — (Cs-Ce) cycloalkyenl, -pyridinyl, pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadi azolyl, and -oxazolyl;

R ^Q is selected from the group consisting of — CN and — C(O)NH2;

-L- is a bond or a divalent moiety selected from the group consisting of:

— C(O)— , — S(O)— , and — S(O) ₂ — ; p is 1, 2, or 3; each R ^1L is independently selected from the group consisting of H, — CHa, — CF3, — OH, — C(O) — , halogen, -cyclopropyl, — O — CH3, and — O — CF3;

R ¹ is selected from the group consisting of:

(1) heterocycloalkyl and heterocycloalkenyl, wherein said heterocycloalkyl and said heterocycloalkenyl are monocyclic or multicyclic ring systems comprising from 3 to 10 ring atoms in which 1, 2, or 3 of the atoms of each said ring system is a ring heteroatom independently selected from the group consisting of N, S, S(O), S(O) ₂ , and O, and wherein each said heterocycloalkyl group and each said heterocycloalkenyl group is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, — OH, halogen, — (Ci-Ce) alkyl, hydroxy-substituted — (Ci-Ce) alkyl, — (Ci-Ce) alkynyl, — (Ci-Ce) haloalkyl, hydroxy-substituted — (Ci-Ce) haloalkyl, — O — (Ci- Ce) alkyl, — (Cs-Cs) cycloalkyl, -alkyl-cycloalkyl, — CH(OH)cycloalkyl, phenyl, -alkylphenyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, — (Cs-Cs) spirocycloalkyl, — (C ₃ -C ₈ ) spiroheterocycloalkyl, — C(O)H, — C(O)OH, — C(O)(Ci-C ₆ ) alkyl, — C(O)O(Ci-C ₆ ) alkyl, — N(R ^1A )C(O)— (Ci-C ₆ ) alkyl, — N(R ^1A ) ₂ , — C(O)N(R ^1A ) ₂ , — S(O) ₂ H, — S(O)-phenyl, — S(O) — (Ci-Ce) alkyl-phenyl, — S(O) ₂ -phenyl, — S(O) ₂ — (Ci-Ce) alkyl-phenyl, — S(O) ₂ OH, and — S(O) ₂ — (Ci-C ₆ ) alkyl, wherein each R ^1A group is independently selected from the group consisting of H and — (Ci- Ce alkyl);

(2) heteroaryl, wherein said heteroaryl is a monocyclic or multi cyclic ring system comprising from 5 to 10 ring atoms in which from 1 to 4 of the atoms of said ring system is a ring nitrogen atom, and wherein said heteroaryl is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, — OH, halogen, — (Ci-Ce) alkyl, hydroxysubstituted — (Ci-Ce) alkyl, — (Ci-Ce) alkynyl, — (Ci-Ce) haloalkyl, hydroxy-substituted — (Ci-Ce) haloalkyl, — O — (Ci-Ce) alkyl, — (Cs-Cs) cycloalkyl, -alkyl-cycloalkyl, — CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, -(Cs-Cs) spirocycloalkyl, — C(O)H, — C(O)OH, — C(O)(Ci-C ₆ ) alkyl, — C(O)O(Ci-C ₆ ) alkyl, — N(R ^1B )C(O)— (Ci-C ₆ ) alkyl, — N(R ^1B ) ₂ , — C(O)N(R ^1B ) ₂ , — S(O) ₂ H, — S(O)-phenyl, — S(O) — (Ci-Ce) alkyl-phenyl, — S(O) ₂ -phenyl, — S(O) ₂ — (Ci-Ce) alkyl- phenyl, — S(O) ₂ OH, and — S(O) ₂ — (Ci-C ₆ ) alkyl, wherein each R ^1B group is independently selected from the group consisting of H and — (Ci- Ce alkyl), with the proviso that R ¹ is not unsubstituted or substituted triazolyl, and with the further proviso that when R ¹ is substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl, then -L- is selected from the group consisting of — (C(R ^1L ) ₂ ) _P — , and

(3) phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 5 groups independently selected from the group consisting of oxo, CN, — OH, halogen, — (Ci-Ce) alkyl, — (Ci-Ce) alkynyl, — (Ci-Ce) haloalkyl, — O — (Ci-Ce) alkyl, — (Cs-Cs) cycloalkyl, -alkyl-cycloalkyl, — CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl- monocyclic heteroaryl, — (Cs-Cs) spirocycloalkyl, — C(O)H, — C(O)OH, — C(O)(Ci-C ₆ ) alkyl, — C(O)O(Ci-C ₆ ) alkyl, — N(R ^1C )C(O)— (Ci-C ₆ ) alkyl, — N(R ^1C ) ₂ , — C(O)N(R ^1C ) ₂ , — S(O) ₂ H, — S(O)-phenyl, — S(O)— (C1-C ₆ ) alkyl-phenyl, — S(O) ₂ -phenyl, — S(O) ₂ — (Ci-C ₆ ) alkyl-phenyl, — S(O) ₂ OH, and — S(O) ₂ — (Ci-C ₆ ) alkyl, wherein each R ^1C group is independently selected from the group consisting of H and — (Ci- Ce alkyl);

(4) H and — (Ci-C ₆ ) alkyl;

(5) — CH ₂ N(R ^1D )R ^1E , wherein:

R ^1D is selected from the group consisting of H, — (Ci-Ce) alkyl, and — C(O)OR ^1H ; and R ^1E is selected from the group consisting of — O — (Ci-Ce) alkyl, heteroalkyl, -alkyl- C(O)N(R ^1H ), and — C(O)OR ^1H , wherein each R ^1H is independently selected from the group consisting of H and — (Ci-Ce) alkyl; and

(6) — CH ₂ N(R ^1F )OR ^1G , wherein:

R ^1F is selected from the group consisting of H, — (Ci-Ce) alkyl, and — C(O)OR ^1H , wherein each R ^1H is independently selected from the group consisting of H and — (Ci-Ce) alkyl; and

R ^1G is selected from the group consisting of H and — (Ci-Ce) alkyl; n is 0, 1, 2, or 3; each R ² (when present) is independently selected from the group consisting of halogen, — CN, —OH, — (Ci-C ₆ ) alkyl, — O— (Ci-C ₆ ) alkyl, — (Ci-C ₆ ) haloalkyl, — O— (Ci-C ₆ ) haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, — NH ₂ , — NH(Ci-Ce)alkyl, — N(Ci-Cealkyl) ₂ , — C(O)O(Ci-Ce) alkyl, and phenyl; and

R ³ is selected from the group consisting of hydrogen and fluorine.

[001382] In further embodiments, the glutamate modulator is a compound selected from:

and , including pharmaceutically acceptable salts and substituted variants retaining glutamate modulatory activity.

Formula 354

[001383] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 354. Such compounds are described in WO 2013/033246, published March 7, 2023, corresponding to PCT/US2012/052904, filed August 29, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 354, this reference incorporated by reference herein controls.

[001384] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

R ¹ and R ² are independently H, halogen, Ci-Cs alkyl, — NR ⁿ R ¹² , — SR ¹³ , C3-C6 heteroalkyl containing 1-4 heteroatoms selected from N and S, aryl or a monocyclic heteroaryl; or R ¹ and R ² together with the carbon to which they are attached form a C3-C8 cycloalkyl or heterocycloalkyl containing 1-4 heteroatoms selected from Oxygen Nitrogen and Sulfur; R ⁴ is L ⁴ , wherein: L ⁴ is wherein n is 1 or 2; wherein R ³ is H, halogen, —OR ¹¹ , — NR ⁿ R ¹² , —SR ¹¹ , — S(O)R ⁿ , — S(O) ₂ R ¹² , — S(O) ₂ NR ⁿ R ¹² , CI-CS haloalkyl, Ci-Cs alkyl, Ci-Cs alkoxy, cyano, Ci-Cs alkylamino, Ci- Cs alkoxyamino, aryl, monocyclic heteroaryl containing 1-4 heteroatoms selected from Oxygen Nitrogen and Sulfur or monocyclic heterocycle containing 1-4 heteroatoms selected from Oxygen Nitrogen and Sulfur; and

R ⁶ and R ⁹ each are independently selected from H, hydroxy, halogen, cyano, — SR ¹¹ , — S(O)R ⁿ , — S(O) ₂ R ¹² , — S(O) ₂ NR ^U R ¹² , CI-CS haloalkyl, — C(O)OR ¹² , — C(O)NR ⁿ R ¹² , — C(O)R ¹² , — NR ⁿ C(O)R ¹² , — NR ⁿ S(O) ₂ R ¹² , — NR ⁿ C(O)OR ¹² , — B(OH) ₂ , tetrazole, carboxylic acid biostere, Ci-Cs alkyl, C3-C8 cycloalkyl, C ₂ -C8 alkenyl, Ci-Cs alkoxy, aryl, - alkylC(O)— OR ¹² , -alkylC(O)NR ⁿ R ¹² , -alkenylC(O)OR ¹² , -alkenylC(O)NR ¹¹ R ¹² , - aryl(CH ₂ ) _m C(O)OR ¹² , -aryl(CH ₂ ) _m C(O)NR ¹¹ R ¹² , — NR ⁿ R ¹² , — (CH ₂ ) _m C(O)NR ¹¹ S(O) ₂ R ¹² , - aryl(CH ₂ ) _m — C(O)NR ⁿ S(O) ₂ R ¹² , — (CH ₂ ) _m S(O) ₂ NR ⁿ C(O)R ¹² , - aryl(CH ₂ ) _m S(O) ₂ NR ¹¹ C(O)R ¹² , — XZ, or substituted or unsubstituted monocyclic heterocycle containing 1-4 heteroatoms selected from Oxygen Nitrogen and Sulfur or substituted or unsubstituted monocyclic heteroaryl containing 1-4 heteroatoms selected from Oxygen Nitrogen and Sulfur, optionally substituted with 1 to 2 substituents selected from the group consisting ofH, hydroxyl, halogen, CF3, Ci-Cs alkyl, Ci-Cs alkoxy, cyano, amino, Ci- Cs alkylamino, and Ci-Cs alkoxyCi-Cs alkylamino;

R ⁷ is hydrogen;

R ⁸ is selected from: H, hydroxy, halogen, CF3, cyano, — SR ¹¹ , — S(O)R ⁿ , — (CH2) _m C(O) — OR ¹² , — (CH ₂ )mC(O)NR ¹¹ R ¹² — S(O) ₂ R ¹² , — S(O) ₂ NR ^U R ¹² , — C(O)OR ¹² , — C(O)NR ⁿ R ¹² , — C(O)R ¹² , — NR ⁿ C(O)R ¹² , — NR ⁿ S(O) ₂ R ¹² , — NR ⁿ C(O)OR ¹² , — C(O)(CH ₂ ) _m aryl, — C(=NR ¹¹ )NR ¹¹ R ¹² , NR ¹¹ C(=NR ¹¹ )NR ¹¹ R ¹² , — Ci-C ₈ haloalkyl, — B(OH) ₂ , tetrazole, carboxylic acid biostere, Ci-Cs alkyl, C3-C8 cycloalkyl, C ₂ -C ₈ alkenyl, Ci-Cs alkoxy, aryl, - alkylC(O)OR ¹² , -alkylC(O)NR ⁿ R ¹² , -alkenylC(O)OR ¹² , -alkenylC(O)NR ⁿ R ¹² , - aryl(CH ₂ ) _m C(O)OR ¹² , -aryl(CH ₂ ) _m C(O)NR ¹¹ R ¹² , — NR ⁿ R ¹² , — (CH ₂ ) _m C(O)NR ¹¹ S(O) ₂ R ¹² , - aryl(CH ₂ ) _m C(O)NR ¹¹ S(O) ₂ R ¹² , — (CH ₂ ) _m S(O) ₂ NR ¹¹ C(O)R ¹² , -aryl(CH ₂ ) _m S(O) ₂ NR ¹¹ C(O)R ¹² , — XZ, or alkynyl-phenyl optionally substituted with halogen, or substituted or unsubstituted monocyclic heterocycle or substituted or unsubstituted monocyclic heteroaryl containing 1 to 4 heteroatoms, optionally substituted with 1 to 2 substituents selected from the group consisting ofH, hydroxyl, halogen, CF3, Ci-Cs alkyl, Ci-Cs alkoxy, cyano, amino, Ci- C ₈ alkylamino, and Ci-Cs alkoxyCi-Cs alkylamino, and

X is Ci-C ₈ alkylene, C ₂ -C ₈ alkenylene, C ₂ -C ₈ alkynylene, — C(O) or — S(O) ₂ ;

Z is H, CF3, — Ci-Cs alkyl, C3-C8 cycloalkyl, Ci-Cs alkoxy, amino, Ci-Cs alkylthio, aryl, or C3-C6 heterocycle or monocyclic heteroaryl, optionally substituted with halogen; m is 0, 1, 2, 3, or 4;

R ¹⁰ is H, CF ₃ , CI-C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₅ -Cio aryl, C ₅ - C 10 heterocycle each of which is optionally substituted with halogen, — OR ¹¹ , — NR ⁿ R ¹² , — SR ¹¹ , — S(O)R ⁿ , — S(O) ₂ R ¹² , or — S(O) ₂ NR ⁿ R ¹² ;

R ¹¹ , R ¹² and R ¹³ are each independently H, Ci-C ₈ alkyl, Ci-Cs fluoroalkyl, aryl, benzyl, C ₂ . 8 alkenyl, C ₂ -8 alkynyl, -alkyl-C(O)OR ¹⁴ , -alkenyl-C(O)OR ¹⁴ C(O)R ¹⁴ , monocylic heteroaryl, or monocylic heterocycle; and

R ¹⁴ is H, Ci-C ₈ alkyl, Ci-Cs haloalkyl, aryl, or benzyl.

Formula 355

[001385] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 355. Such compounds are described in WO 2012/174199, published December 20 ,2012, corresponding to PCT/US2012/042387, filed June 14, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 355, this reference incorporated by reference herein controls.

[001386] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein: X ¹ is selected from the group consisting of: Cnsalkyl, C2-salkenyl, C2-salkynyl, Cs-ecycloalkyl and C3-6cycloalkylCi-4alkyl, any of which may bear up to 5 halogen substituents;

R ¹ represents H or Ci-4alkyl which is optionally substituted with OH, CN, CF3, Ci-4alkoxy, amino, Ci-4alkylamino or di(Ci-4alkyl)amino;

R ² is selected from:

(i) Cnsalkyl or C2-salkenyl, either of which optionally bears up to 3 substituents independently selected from halogen, OH, CN, CF3, OR ⁴ , SR ⁵ , SO2R ⁵ , SO2N(R ⁴ )2, COR ⁴ , CO2R ⁴ , CON(R ⁴ ) ₂ , N ₃ , N(R ⁴ ) ₂ , NR ⁴ COR ⁵ , NR ⁴ SO ₂ R ⁵ and phenyl, said phenyl bearing 0 to 5 halogen substituents; and

(ii) C3-iocycloalkyl, C3-iocycloalkylCi-4alkyl, Het, HetCi-4alkyl, aryl or arylCi-4alkyl, any of which optionally bears up to 4 substituents independently selected from halogen, OH, oxo, CN, CF ₃ , R ⁵ , OR ⁴ , SR ⁵ , SO2R ⁵ , SO ₂ N(R ⁴ ) ₂ , COR ⁴ , CO2R ⁴ , CON(R ⁴ ) ₂ , N(R ⁴ ) ₂ , NR ⁴ COR ⁵ , NR ⁴ SO2R ⁵ and — P(O) — (OR ⁴ )2; where “aryl” refers to phenyl or 5- or 6-membered heteroaryl, either of which phenyl or heteroaryl is optionally fused to a 5- or 6-membered carbocycle or heterocycle, each “Het” independently refers to a nonaromatic or partially aromatic mono- or bicyclic heterocyclic system of up to 10 ring atoms and C3-iocycloalkyl and the cyclic portion of C3-iocycloalkylCi-4alkyl may be fused with phenyl or a 5- or 6- membered heteroaryl; or R ¹ and R ² together may complete a non-aromatic monocyclic, bicyclic or tricyclic carbocylic or heterocyclic ring system of up to 12 ring atoms which optionally bears up to 4 substituents independently selected from R ³ ;

R ³ is selected from the group consisting of: halogen, OH, oxo, CN, CF3, R ⁵ , OR ⁴ , SR ⁵ , SO2R ⁵ , COCH2SO2R ⁵ , SO ₂ N(R ⁴ ) ₂ , COR ⁵ , CO2R ⁴ , CON(R ⁴ ) ₂ , N(R ⁴ ) ₂ , NR ⁴ COR ⁵ , NR ⁴ CON(R ⁴ ) ₂ , NR ⁴ CO ₂ R ⁴ , NR ⁴ SO ₂ R ⁵ , — Ci- ₄ alkyl-N(R ⁴ ) ₂ , — Ci- ₄ alkyl-NR ⁴ COR ⁵ and — Cn ₄ alkyl-NR ⁴ CO ₂ R ⁴ ; each R ⁴ independently represents H, Cnealkyl, Cs-iocycloalkyl, C3-iocycloalkylCi-4alkyl, C3- wcycloalkenyl or C3-iocycloalkenylCi-4alkyl, any of which except H optionally bear up to 3 halogen atoms or with OH, CN, CF3, OCF3, Ci-4alkoxy, Ci-4alkyl-C(O) — O — , Ci-4alkyl- C(O) — , amino, Ci-4alkylamino and di(Ci-4alkyl)amino, or R ⁴ represents phenyl, benzyl, phenylethyl, 5- or 6-membered monocyclic heteroaryl optionally bridged with — (CH2) _P — , or a 9- or 10-membered bicyclic heteroaryl optionally bridged with — (CH2) _P — , any of which optionally bear up to 3 substituents independently selected from halogen, OH, CN, CF3, OCF3, Ci-4alkyl, C3-6cycloalkyl, phenyl, Ci-4alkoxy, amino, Ci-4alkylamino, di(Ci- 4alkyl)amino, a 5- or 6-membered monocyclic heteroaryl optionally bridge with methylene and optionally substituted with one or two methyl groups, and Het, optionally substituted with 1 to 3 substituents selected from oxo and methyl, or R ⁴ represents Het, optionally bridged with — (CH2) _P — and said Het optionally bearing up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, OCF3, Ci-4alkyl, C3-ecycloalkyl, phenyl, benzyl, a 5- or 6-membered monocyclic heteroaryl optionally bridged with methylene and substituted with one or two methyl groups, Ci-4alkoxy, Ci-4alkyl-0 — C(O) — , Ci-4alkyl-C(O) — , acetyl, amino, Ci-4alkylamino, di(Ci-4alkyl)amino and Het, optionally substituted with 1 to 3 substituents selected from oxo and methyl; each p is independently 1, 2, 3 or 4; and

R ⁵ has the same definition as R ⁴ except that R ⁵ is optionally not H.

[001387] In an embodiment, the glutamate modulator is a compound according to:

, or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is selected from the group consisting of: C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-

6 cycloalkyl and C3-6cycloalkylCi-4alkyl, any of which may bear up to 5 halogen substituents; R ³ is selected from the group consisting of: halogen, OH, oxo, CN, CF3, R ⁵ , OR ⁴ , SR ⁵ , SO2R ⁵ , COCH2SO2R ⁵ , SO ₂ N(R ⁴ ) ₂ , COR ⁵ , CO2R ⁴ , CON(R ⁴ ) ₂ , N(R ⁴ ) ₂ , NR ⁴ COR ⁵ , NR ⁴ CON(R ⁴ ) ₂ , NR ⁴ CO ₂ R ⁴ , NR ⁴ SO ₂ R ⁵ , — Ci- ₄ alkyl-N(R ⁴ ) ₂ , — Ci- ₄ alkyl-NR ⁴ COR ⁵ and — Cn ₄ alkyl-NR ⁴ CO ² R ⁴ ; each R4 independently represents H, Ci-ealkyl, Cs-iocycloalkyl, C3-iocycloalkylCi-4alkyl, C3- wcycloalkenyl or C3-iocycloalkenylCi-4alkyl, any of which except H optionally bear up to 3 halogen atoms or with OH, CN, CF3, OCF3, Ci-4alkoxy, Ci-4alkyl-C(O) — O — , Ci-4alkyl- C(O) — , amino, Ci-4alkylamino and di(Ci-4alkyl)amino, or R ⁴ represents phenyl, benzyl, phenylethyl, 5- or 6-membered monocyclic heteroaryl optionally bridged with — (CH2) _P — , or a 9- or 10-membered bicyclic heteroaryl optionally bridged with — (CH2) _P — , any of which optionally bear up to 3 substituents independently selected from halogen, OH, CN, CF3, OCF3, Ci-4alkyl, C3-6cycloalkyl, phenyl, Ci-4alkoxy, amino, Ci-4alkylamino, di(Ci- 4alkyl)amino, a 5- or 6-membered monocyclic heteroaryl optionally bridge with methylene and optionally substituted with one or two methyl groups, and Het, optionally substituted with 1 to 3 substituents selected from oxo and methyl, or R ⁴ represents Het, optionally bridged with — (CH2) _P — and said Het optionally bearing up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, OCF3, Ci-4alkyl, C3-ecycloalkyl, phenyl, benzyl, a 5- or 6-membered monocyclic heteroaryl optionally bridged with methylene and substituted with one or two methyl groups, Ci-4alkoxy, Ci-4alkyl-0 — C(O) — , Ci-4alkyl-C(O) — , acetyl, amino, Ci-4alkylamino, di(Ci-4alkyl)amino and Het, optionally substituted with 1 to 3 substituents selected from oxo and methyl; each p is independently 1, 2, 3 or 4; and

R ⁵ has the same definition as R ⁴ except that R ⁵ is not H.

Formula 356

[001388] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 356. Such compounds are described in WO 2008/107480, published September 12, 2008, corresponding to PCT/EP2008/052767, filed March 7, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 356, this reference incorporated by reference herein controls.

[001389] In further embodiments, the glutamate modulator is a compound according to: including any stereochemically isomeric form thereof, wherein

Ri is C4-ealkyl, or Ci-3alkyl substituted with C3-?cycloalkyl; R.2 is hydrogen or halo;

A is pyridinyl substituted with one or two substituents, each substituent independently selected from halo or Ci-4alkyl; n is an integer of value 1 or 2; or a pharmaceutically acceptable salt or a solvate thereof; provided that if R2 is 2-fluoro then A is not 3-pyridinyl substituted with one or two substituents, each substituent independently selected from halo or Ci-4alkyl.

Formula 357

[001390] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 357. Such compounds are described in WO 2009/033702, published March 19, 2009, corresponding to PCT/EP2008/007549, filed September 12, 2008 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 357, this reference incorporated by reference herein controls.

[001391] In an embodiment, the glutamate modulator is a compound according to or a stereochemically isomeric form thereof, wherein

R ¹ is Ci-ealkyl; or Ci-salkyl substituted with C3-?cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, Ci-3alkyl or cyclopropyl;

R ³ is hydrogen or halo;

X is O, S, SO, SO ₂ , or CF ₂ ; and

Ar is unsubstituted phenyl; unsubstituted pyridinyl; or phenyl or pyridinyl substituted with one or two substituents selected from the group consisting of halo, Ci-3alkyl, Ci-3alkoxy, trifluoromethyl, hydroxyCi-salkyl and (CH2) _n — CO2H, wherein n=0, 1, or 2; or a pharmaceutically acceptable salt or a solvate thereof, provided that when R ³ is 2'-fluoro then Ar is not 3-pyridinyl substituted with one or two Ci-3alkyl substituents. [001392] In an embodiment, the glutamate modulator is a compound selected from: l-Butyl-3-chloro-4-[4-(2-methylpyridin-4-yloxy)-phenyl]-lH-p yridin-2-one l-Butyl-3-chloro-4-[2-fluoro-4-(2-methylpyridin-4-yloxy)-phe nyl]-lH-pyridin-2-one

3-Chl oro-1 -cyclopropylmethyl-4-[4-(2,6-dimethylpyri din-3 -yloxy)-3 -fluoro-phenyl]- 1H- pyridin-2-one

4-[4-(l-Butyl-3-chloro-2-oxo-l,2-dihydro-pyridin-4-yl)-ph enoxy]-benzoic acid l-Cyclopropylmethyl-4-[4-(2,6-dimethyl-pyridin-4-yloxy)-3-fl uoro-phenyl]-3- trifluoromethyl- lH-pyridin-2-one, including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

Formula 358

[001393] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 358. Such compounds are described in WO 2012/062750, published May 18, 2012, corresponding to PCT/EP2011/069640, filed November 8, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 358, this reference incorporated by reference herein controls.

[001394] In an embodiment, the glutamate modulator is a compound according to: stereochemically isomeric form thereof, wherein

R ¹ is selected from the group consisting of Ci-ealkyl; (C3-scycloalkyl)Ci-3alkyl; (Ci-3alkyloxy)Ci-3alkyl; and Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents;

R ² is selected from the group consisting of Cl, CF3, — CN and cyclopropyl;

R ³ is selected from the group consisting of hydrogen, methyl and CF3;

R ⁴ is selected from the group consisting of hydrogen and methyl; or R ³ and R ⁴ together with the carbon to which they are bound form a cyclopropyl ring;

L is selected from the group consisting of (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L- h):

wherein m ^a , M ^b , and m ^c are each independently selected from the group consisting of 0 and 1; m ^e and m ^g are each independently selected from the group consisting of 1 and 2; n ^a , n ^b , n ^c , n ^d , n ^e , n ^f , h ^g and n ^h are each independently selected from the group consisting of 0, 1 and 2;

R ^5a , R ^5b , R ^5c , R ^5d , R ^5e , R ^5f , R ^5g and R ^5h are each independently selected from the group consisting of halo; Ci-3alkyl; Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents; Ci-3alkyloxy; and Ci-3alkyloxy substituted with 1, 2 or 3 fluoro substituents;

R ^6a is selected from the group consisting of hydrogen; halo; Ci-3alkyl; Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents; Ci-3alkyloxy; and Ci-3alkyloxy substituted with 1, 2 or 3 fluoro substituents;

R ^6c is selected from the group consisting of hydrogen; halo; Ci-3alkyl; Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents; Ci-3alkyloxy; Ci-3alkyloxy substituted with 1, 2 or 3 fluoro substituents; and cyclopropyl;

R ^7a , R ^8a , R ^7b and R ^8b are each independently selected from the group consisting of hydrogen; fluoro and methyl; or R ^7a and R ^8a , and R ^7b and R ^8b together with the carbon to which they are attached form a cyclopropyl or a carbonyl group; wherein each halo is selected from the group consisting of fluoro, chloro, bromo and iodo; with the proviso that (L-c) is not bound to the triazolopyridine core through a carbon atom that is alpha to the oxygen atom; or a pharmaceutically acceptable salt thereof.

Formula 359

[001395] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 359. Such compounds are described in WO 2012/062751, published May 18, 2012, corresponding to PCT/EP2011/069641, filed November 8, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 359, this reference incorporated by reference herein controls.

[001396] In an embodiment, the glutamate modulator is a compound according to:

or a stereoisomerically isomeric form thereof, wherein

R ¹ is selected from the group consisting of Ci-ealkyl, (C3-scycloalkyl)Ci-3alkyl, (Cn 3alkyloxy)Ci-3alkyl and Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents;

R ² is selected from the group consisting of CI, CF3, — CN and cyclopropyl;

R ³ is selected from the group consisting of hydrogen, methyl and CF3;

R ⁴ is selected from the group consisting of hydrogen and methyl; or R ³ and R ⁴ together with the carbon to which they are bound form a cyclopropyl ring or a carbonyl group;

L is selected from the group consisting of (L-c), (L-a), (L-b), (L-d), (L-e), (L-f) and (L-g):

wherein

R ^5a , R ^5b , R ^5c and R ^5d are each independently selected from the group consisting of phenyl; phenyl substituted with 1 or 2 substituents each independently selected from the group consisting of Ci-3alkyloxy and halo; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of Ci-3alkyl, Ci-3alkyloxy and halo; pyrimidinyl and pyrimidinyl substituted with 1 or 2 substituents each independently selected from the group consisting of Ci-3alkyl, Ci-3alkyloxy and halo;

R ^5e and R ^5f are each independently selected from the group consisting of phenyl and phenyl substituted with 1 or 2 substituents each independently selected from the group consisting of Ci-3alkyloxy and halo;

R ^5g is selected from the group consisting of Ci-3alkyl, phenyl and phenyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of Ci-3alkyloxy and halo;

R ^6a , R ^6b , R ^C , R ^C , R ^6f and R ^6g are each independently selected from the group consisting of hydrogen; fluoro; Ci-3alkyl; Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents; Ci- 3alkyloxy; Ci-3alkyloxy substituted with 1, 2 or 3 fluoro substituents; and C3-ecycloalkyl;

R ^7a , R ^8a , R ^7b , R ^8b , R ^7c , R ^8c , R ^7d , R ^8d , R ^7e , R ^8e , R ^7f and R ^8f are each independently selected from the group consisting of hydrogen, fluoro and methyl;

R ^9b is selected from the group consisting of hydrogen, Ci-3alkyl and C3-ecycloalkyl; wherein each halo is selected from the group consisting of fluoro, chloro, bromo and iodo; or a pharmaceutically acceptable salt thereof.

Formula 360

[001397] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 360. Such compounds are described in WO 2012/062759, published May 18, 2012, corresponding to PCT/EP2011/069654, filed November 8, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 360, this reference incorporated by reference herein controls.

[001398] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is selected from the group consisting of Ci-ealkyl, (C3-scycloalkyl)Ci-3alkyl, (Cn 3alkyloxy)Ci-3alkyl, and Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents;

R ² is selected from the group consisting of Cl, CF3, — CN and cyclopropyl;

R ³ is selected from the group consisting of hydrogen, methyl and CF3;

R ⁴ is selected from the group consisting of hydrogen and methyl; or R ³ and R ⁴ together with the carbon to which they are bound form a cyclopropyl ring or a carbonyl group;

L is selected from the group consisting of (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L- h):

wherein

R ^5a , R ^5b , R ^5c and R ^5d are each independently selected from the group consisting of phenyl; phenyl substituted with 1 or 2 substituents each independently selected from the group consisting of Ci-3alkyloxy and halo; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of Cnsalkyl, Ci-salkyloxy and halo; pyrimidinyl; and pyrimidinyl substituted with 1 or 2 substituents each independently selected from the group consisting of Ci-3alkyl, Cnsalkyloxy and halo;

R ^6e is selected from the group consisting of hydrogen and Cnsalkyl;

R ^5f , R ^5g , and R ^5h are each independently selected from phenyl and phenyl substituted with 1 or 2 fluoro substituents;

R ^6a , R ^6b and R ^6c are each independently selected from the group consisting of hydrogen; fluoro; Cnsalkyl; Ci-3alkyl substituted with 1, 2 or 3 fluoro substituents;

Ci-3alkyloxy; Ci-3alkyloxy substituted with 1, 2 or 3 fluoro substituents; and C3-ecycloalkyl; R ^6h is Ci-3alkyl;

R ^7a , R ^8a , R ^7b , R ^8b , R ^7c , R ^8c , R ^7d and R ^8d are each independently selected from the group consisting of hydrogen, halo and methyl; or each R ^7a and R ^8a , R ^7b and R ^8b , R ^7c and R ^8c , and R ^7d and R ^8d together with the carbon to which they are attached form a cyclopropyl or a carbonyl group;

R ^9b is selected from the group consisting of hydrogen, Ci^alkyl and C3-ecycloalkyl; wherein each halo is selected from the group consisting of fluoro, chloro, bromo and iodo; or a pharmaceutically acceptable salt or a solvate thereof.

Formula 361

[001399] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 361. Such compounds are described in WO 2012/021382, published February 16, 2012, corresponding to PCT/US2011/046677, filed August 5, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 361, this reference incorporated by reference herein controls.

[001400] In an embodiment, the glutamate modulator is a compound according to: wherein:

Z is selected from H, halo, hydroxy, methyl, methoxy or CN; Y is cyano, benzyl, Ci-ealkyl or C2-ealkenyl, said Ci-ealkyl and C2-ealkenyl optionally substituted with cyano;

R ¹ is selected from the group consisting of

(1) C2-salkyl,

(2) C2-salkenyl,

(3) C2-salkynyl,

(4) C3-6cycloalkyl-(CH2) _p — ,

(5) aryl-(CH ₂ ) _p — ,

(6) heteroaryl-(CH2) _p — , and

(7) heterocycle-(CH2) _p — , wherein p is 0, 1, 2, 3 or 4, and groups (1) to (7) above are optionally substituted with 1 to 4 R ² groups; each R ² is independently selected from the group consisting of: halo, OH, oxo, — CN, Ci- 4alkyl, Ci-4alkoxy, CF3, — OCF3, — C(O) — O — Ci-4alkyl, — N(R)i, pyrimidinyl and — CN; ring A is selected from aryl, heteroaryl and heterocycle, wherein said heterocycle is partially aromatic and wherein said aryl, heteroaryl and heterocycle are optionally substituted with one or more R ³ groups up to the maximum number of substitutable positions; each R ³ is independently selected from the group consisting of: halo, — CN, — NO2, X, — C(R ⁴ ) ₂ — N(R)— X, — C(R ⁴ ) ₂ — N(R)C(O)— X, — C(R ⁴ ) ₂ — N(R)S(O) _k — X, — C(R ⁴ ) ₂ — N(R)C(O)— O— X, — C(O)— X, — C(O)— O— X, — C(O)— N(R)— X, — S(O) _k — X, — S(O) _k N(R)— X, — N(R)— X, — O— X, — N(R)C(O)— X, — N(R)S(O) _k — X, — N(R)C(O)— O— X, — N(R)C(O)N(R)— X and — N(R)SO ₂ N(R)— X, each X is independently selected from the group consisting of: H, Ci-salkyl, C2-ealkenyl, C2- ealkynyl, C3-ecycloalkyl, aryl, heterorayl, heterocycle, C3-ecycloalkyl-C(R ⁴ )2 — , aryl-C(O)2 — , heteroaryl-C(R ⁴ )2 — and heterocycle-C(R ⁴ )2 — , wherein each member of the group excluding hydrogen is optionally substituted from one up to the maximum number of substitutable positions with one or more substituents independently selected from the group consisting of: CN, halo, R ⁵ , — O— R ⁵ , — N(R)— R ⁵ , — N(R)C(O)— R ⁵ , — N(R)S(O) ₂ — R ⁵ , — N(R)— C(O)— O— R ⁵ , — C(O)— N(R)— R ⁵ , — C(O)— O— R ⁵ , — C(O)— R ⁵ , — C(O)— C(R ⁴ ) ₂ — R ⁵ , — C(O)— C(R ⁴ ) ₂ — S(O) ₂ — R ⁵ , — C(R ⁴ ) ₂ — N(R)— R ⁵ , — SO ₂ — N(R)— R ⁵ , — Si(CH ₃ ) ₂ (R ⁵ ), — C(R ⁴ ) ₂ — R ⁵ and — SO ₂ — R ⁵ ; each k is independently 0, 1 or 2; each R is independently selected from the group consisting of H and Ci-4alkyl; each R ⁴ is independently selected from the group consisting of: H, OH and Ci-4alkyl; each R ⁵ is independently selected from the group consisting of H, Ci-4alkyl, C2-4alkenyl, C2- 4alkynyl, Cs-ecycloalkyl, phenyl, benzyl, heterocycle and heteroaryl, wherein each member of the group excluding hydrogen is optionally substituted with 1 to 3 substituents independently selected from: halogen, cyano, hydroxy and methyl; aryl at each occurrence is independently selected from the group consisting of: phenyl, naphthyl, anthryl and phenanthryl; heteroaryl at each occurrence independently means a 5- or 6-membered monocyclic aromatic or 9- or 10-membered bicyclic aromatic, wherein at least one atom in the aromatic is selected from N, O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N, O and S, the sulfur optionally oxidized to sulfone or sulfoxide; heterocycle at each occurrence independently means a 4- to 7-membered monocyclic nonaromatic ring, an 8- to 11 -membered bi-cyclic, including spiro-cyclic, non- or partially- aromatic ring or a 12- to 20-memberd tri-cyclic, including spiro-cyclic portions, non- or partially-aromatic ring, each optionally substituted with 1 to 2 oxo groups, wherein at least one atom is selected from N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide; and pharmaceutically acceptable salts thereof.

[001401] In another embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof, wherein

Ei and E2 are independently C or N; ring B is phenyl or heteroaryl,

R ³ is CN, halo or Ci-4alkyl, optionally substituted with 1-5 halo atoms, and each R ⁶ is independently selected from the group consisting of: CN, halo, R ⁵ , — O — R ⁵ , — N(R)— R ⁵ , — N(R)C(O)— R ⁵ , — N(R)S(O) ₂ — R ⁵ , — N(R)— C(O)— O— R ⁵ , — C(O)— N(R)— R ⁵ , — C(O)— O— R ⁵ , — C(O)— R ⁵ , — C(O)— C(R ⁴ ) ₂ — R ⁵ , — C(O)— C(R ⁴ ) ₂ — S(O) ₂ — R ⁵ , — C(R ⁴ ) ₂ — N(R)— R ⁵ , — SO ₂ — N(R)— R ⁵ , — Si(CH ₃ ) ₂ (R ⁵ ), — C(R ⁴ ) ₂ — R ⁵ and — SO ₂ — R ⁵ ; each R is independently selected from the group consisting of: H and Ci-4alkyl; each R ⁴ is independently selected from the group consisting of: H, OH and Ci-4alkyl; each R ⁵ is independently selected from the group consisting of: H, Ci-4alkyl, C2-4alkenyl, C2-4alkynyl, Cs-ecycloalkyl, phenyl, benzyl, heterocycle and heteroaryl, wherein each member of the group excluding hydrogen is optionally substituted with 1 to 3 substituents independently selected from: halogen, cyano, hydroxy and methyl;

Z is selected from H, halo, hydroxy, methyl, methoxy or CN;

R ¹ is selected from the group consisting of:

(1) C2-salkyl,

(2) C2-salkenyl,

(3) C2-salkynyl,

(4) C3-6cycloalkyl-(CH2) _p — ,

(5) aryl-(CH ₂ ) _p — ,

(6) heteroaryl-(CH2) _p — , and

(7) heterocycle-(CH2) _p — , wherein p is 0, 1, 2, 3 or 4, and groups (1) to (7) above are optionally substituted with 1 to 4 R ² groups; and each R ² is independently selected from the group consisting of: halo, OH, — CN, Ci- 4alkyl, Ci-4alkoxy, CF3, — OCF3, — C(O) — O — Ci-4alkyl, — N(R)i, pyrimidinyl and — CN; or a compound according to: or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl or heteroaryl,

R ³ is CN, halo or Ci-4alkyl, optionally substituted with 1-5 halo atoms, and each R ⁷ is independently selected from the group consisting of: CN, halo, R ⁵ , — O — R ⁵ , — N(R)— R ⁵ , — N(R)C(O)— R ⁵ , — N(R)S(O) ₂ — R ⁵ , — N(R)— C(O)— O— R ⁵ , — C(O)— N(R)— R ⁵ , — C(O)— O— R ⁵ , — C(O)— R ⁵ , — C(O)— C(R ⁴ ) ₂ — R ⁵ , — C(O)— C(R ⁴ ) ₂ — S(O) ₂ — R ⁵ , — C(R ⁴ ) ₂ — N(R)— R ⁵ , — SO ₂ — N(R)— R ⁵ , — Si(CH ₃ ) ₂ (R ⁵ ), — C(R ⁴ ) ₂ — R ⁵ and — SO ₂ — R ⁵ ;

R ⁸ is H or methyl; each R is independently selected from the group consisting of: H and Ci-4alkyl; each R ⁴ is independently selected from the group consisting of: H, OH and Ci-4alkyl; each R ⁵ is independently selected from the group consisting of: H, Ci-4alkyl, C2-4alkenyl, C2-4alkynyl, Cs-ecycloalkyl, phenyl, benzyl, heterocycle and heteroaryl, wherein each member of the group excluding hydrogen is optionally substituted with 1 to 3 substituents independently selected from: halogen, cyano, hydroxy and methyl;

Z is selected from H, halo, hydroxy, methyl, methoxy or CN;

Y is cyano, benzyl, Ci-ealkyl or C2-ealkenyl, said Ci-ealkyl and C2-ealkenyl optionally substituted with cyano;

R ¹ is selected from the group consisting of:

(1) C2-salkyl,

(2) C2-salkenyl,

(3) C2-salkynyl,

(4) C3-6cycloalkyl-(CH2) _p — ,

(5) aryl-(CH ₂ ) _p — ,

(6) heteroaryl-(CH2) _p — ,and

(7) heterocycle-(CH2) _p — , wherein wherein p is 0, 1, 2, 3 or 4, and groups (1) to (7) above are optionally substituted with 1 to 4 R ² groups; and each R ² is independently selected from the group consisting of: halo, OH, — CN, Ci- 4alkyl, Ci-4alkoxy, CF3, — OCF3, — C(O) — O — Ci-4alkyl, — N(R)i, pyrimidinyl and — CN.

Formula 362

[001402] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 362. Such compounds are described in WO 2011/156245, published December 15, 2011, corresponding to PCT/US2011/039205, filed June 6, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 362, this reference incorporated by reference herein controls.

[001403] In an embodiment, the glutamate modulator is a compound according to: wherein:

Y is H, Ci-ealkyl or C2-ealkenyl, said Ci-ealkyl and C2-ealkenyl optionally substituted with 1 to 3 groups selected from: halo and Ci-4alkoxy;

R ¹ is selected from the group consisting of:

(1) Ci-salkyl,

(2) C2-salkenyl,

(3) C2-salkynyl,

(4) C3-6cycloalkyl-(CH2) _p — , wherein p is 1, 2, 3 or 4,

(5) benzyl,

(6) biphenyl, and

(7) 1 -phenyl- lH-pyrazol-4-yl, wherein groups (1) to (7) above are optionally substituted with 1 to 3 R ² groups; each R ² is independently selected from the group consisting of: halo, OH, Ci-4alkyl, Ci- 4alkoxy, CF3, — OCF3 and — CN; ring A is selected from aryl, heteroaryl and heterocycle, wherein said heterocycle is fused to an aryl group or a heteroaryl group, and wherein said aryl, heteroaryl and heterocycle are optionally substituted with one or more R ³ groups up to the maximum number of substitutable positions; each R ³ is independently selected from the group consisting of: halo, — CN, — NO2, X, — C(R ⁴ ) ₂ — N(R)— X, — C(R ⁴ ) ₂ — N(R)C(O)— X, — C(R ⁴ ) ₂ — N(R)S(O) _k — X, — C(R ⁴ ) ₂ — N(R)C(O)— O— X, — C(O)— X, — C(O)— O— X, — C(O)— N(R)— X, — S(O) _k — X, — S(O) _k N(R)— X, — N(R)— X, — O— X, — N(R)C(O)— X, — N(R)S(O) _k — X, — N(R)C(O)— O— X, — N(R)C(O)N(R)— X and — N(R)SO ₂ N(R)— X; each X is independently selected from the group consisting of: H, Ci-salkyl, C2-ealkenyl, C2- ealkynyl, C3-ecycloalkyl, aryl, heteroaryl, heterocycle, C3-ecycloalkyl-C(R ⁴ )2 — , aryl-C(R ⁴ )2 — , heteroaryl-C(R ⁴ )2 — and heterocycle-C(R ⁴ )2 — , wherein each member of the group excluding hydrogen is optionally substituted from one up to the maximum number of substitutable positions with one or more substituents independently selected from the group consisting of: CN, halo, R ⁵ , — O— R ⁵ , — N(R)— R ⁵ , — N(R)C(O)— R ⁵ , — N(R)S(O) ₂ — R ⁵ , — N(R)— C(O)— O— R ⁵ , — C(O)— N(R)— R ⁵ , — C(O)— O— R ⁵ , — C(O)— R ⁵ , — C(O)— C(R ⁴ ) ₂ — R ⁵ , — C(O)— C(R ⁴ ) ₂ — S(O) ₂ — R ⁵ , — C(R ⁴ ) ₂ — N(R)— R ⁵ , — SO ₂ — N(R)— R ⁵ , — Si(CH ₃ ) ₂ (R ⁵ ), — C(R ⁴ ) ₂ — R ⁵ and — SO ₂ — R ⁵ ; each k is independently 0, 1 or 2; each R is independently selected from the group consisting of: H and Ci-4alkyl; each R ⁴ is independently selected from the group consisting of: H, OH and Ci-4alkyl; each R ⁵ is independently selected from the group consisting of: H, Ci-4-alkyl, C ₂ -4alkenyl, C ₂ . 4alkynyl, C ₃ -6cycloalkyl, phenyl, heterocycle and heteroaryl, wherein each member of the group excluding hydrogen is optionally substituted with 1 to 3 substituents independently selected from: halogen, cyano, hydroxy and methyl; aryl at each occurrence is independently selected from the group consisting of: phenyl, naphthyl, anthryl and phenanthryl; heteroaryl at each occurrence independently means a 5-membered monocyclic aromatic selected from the group consisting of isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl and thienyl, a 6-membered monocyclic aromatic or 9- or 10-membered bicyclic aromatic, wherein at least one atom in the aromatic is selected from N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide; heterocycle at each occurrence independently means a 4- to 7-membered monocyclic nonaromatic ring, an 8- to 11 -membered bi-cyclic non-aromatic ring or a 12- to 20-membered tricyclic, non-aromatic ring, each optionally substituted with 1 to 2 oxo groups, wherein at least one atom is selected from N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide; or a pharmaceutically acceptable salt thereof.

Formula 363

[001404] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 363. Such compounds are described in WO 2011/137046, published November 3, 2011, corresponding to PCT/US2011/0337167, filed April 25, 2011, and US 8,952,005, issued February 10, 2015, which are incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 363, this reference incorporated by reference herein controls. [001405] In an embodiment, the glutamate modulator is a compound according to: wherein: R ¹ is selected from the group consisting of — (CH2) _p cyclopropyl, — (CH2) _p cyclopentyl, — (CH2) _p cyclohexyl, — (CH2) _p piperidinyl, (CH2) _p phenyl, and Ci-6 alkyl, wherein each said cyclopropyl, cyclopentyl, cyclohexyl and alkyl is optionally substituted with 1-3 halo, Ci-6 alkyl, CF3, — C(O)OCn 6 alkyl, pyrimidinyl, 2,2-dimethylpropyl and 4,4,4-trifluorobutyl;

X represents — CR ^b — , or — N — ; each R ² is independently selected from the group consisting of: hydrogen, halo, OH, Ci- 4alkyl, Ci-4alkoxy, CF3 and — CN;

R ³ is selected from the group consisting of phenyl, pyridyl, — O-phenyl, and — O-pyridyl, wherein each said phenyl, pyridyl, — O-phenyl, and — O-pyridyl are optionally substituted with 1 to 3 R ^a groups; each R ^a is independently selected from the group consisting of:

(1) halo,

(2) Ci- ₈ alkyl,

(3) C2-ealkenyl,

(4) C2-ealkynyl,

(5) C3-6cycloalkyl,

(6) Ci-ealkoxy,

(7) C3-6cycloalkoxy,

(8) — CN,

(9) —OH,

(10) — C(O)— O— R,

(11) — C(O)— Ci- ₆ alkyl,

(12) — N(R) ₂ ,

(13) — C(O)— N(R) ₂ ,

(14) — S(O)k — Ci-ealkyl, wherein k is 0, 1 or 2,

(15) — (CH ₂ )pC6-ioaryl, (16) — (CH ₂ )pC5-ioheterocyclyl,

(17) CF ₃ ,

(18) — C(O)-aryl,

(19) — N(R)-aryl,

(20) benzyl,

(21) benzyloxy,

(22) phenoxy,

(23) — C(CH ₃ ) ₂ OR,

(24) — SH,

(25) — SO ₂ N(R)R,

(26) — (CH ₂ ) _P N(R)C(O)N(R)R,

(27) — (CH ₂ )pN(R)C(O)Ci- ₆ alkyl,

(28) — (CH ₂ )pN(R)SO ₂ N(R)R, and

(29) — B(OH) ₂ ,

(30) —OR,

(31) — (CH ₂ ) _p NHC(O)OCi- ₆ alkyl,

(32) — OCs-ioheterocyclyl, wherein groups (2) to (7), (11), (14) to (16), (18) to (23), and (32) above are optionally substituted with one up to the maximum number of substitutable positions of one or more substituents independently selected from the group consisting of: OH, CN, halo, carboxy, — C(O) — O — Ci-4alkyl, Ci-4alkyl, Ci-4alkoxy, Ci-4alkylamino, phenyl and C5-10 heterocycle, R is selected from the group consisting of: H, (CH ₂ ) _p C6-ioaryl and Ci-ealkyl;

R ^b and R ^k independently represent H or halo; p represents 0-1; and pharmaceutically acceptable salts thereof.

Formula 364

[001406] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 364. Such compounds are described in US 2011/0245232, published March 4, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 364, this reference incorporated by reference herein controls.

[001407] In an embodiment, the glutamate modulator is a compound according to:

, wherein

X ² is N or C— R ²

X ³ is N or C— R ³

X ⁴ is N or C— R ⁴ provided that none or one of X ² , X ³ or X ⁴ is N;

Y ¹ is N, C or C— R ⁵

Y ² is N, C or C— R ⁶

Y ³ is N, C or C— R ⁷

Y ⁴ is N, C or C— R ⁸ provided that only the moiety Y ¹ , Y ² , Y ³ or Y ⁴ to which Z is bound is C and further provided at most one of Y ¹ , Y ² , Y ³ or Y ⁴ is N;

Z is O, S, S(O), S(O) ₂ or NR ^z ;

R ^z is hydrogen, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl, Ci-C4-alkyl, which is unsubstituted or carries one radical selected from Ci-C4-alkoxy and NR ^Z1 R ^Z2 ; where R ^Z1 and R ^Z2 are independently of each other selected from hydrogen, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl, Ci-C4-alkyl and Ci-C4-alkoxy-Ci-C4-alkyl, or

R ^Z1 and R ^Z2 together with the nitrogen to which they are attached form a 5- or 6-membered N- bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 Ci-C4-alkyl radicals; or R ^z is a radical SO ₂ R ^Z3 or a radical S(O) ₂ NR ^Z4 R ^Z5 ; where R ^Z3 is Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl, C3- Ce-cycloalkylmethyl, phenyl or benzyl, wherein the phenyl ring in the last two mentioned radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals selected from halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy, R ^Z4 and R ^Z5 have one of the meanings given for R ^Z1 and R ^Z2 ;

Q is CH ₂ or CH ₂ CH ₂ , where one or two of the hydrogen atoms in CH ₂ or CH ₂ CH ₂ may be replaced by halogen, Ci-C4-alkyl or Ci-C4-haloalkyl;

R4s hydrogen, halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-C4-haloalkoxy, C3- Cs-cycloalkyl, a radical NR ^la R ^lb , C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH2, aryloxy, hetaryl, hetaryloxy or hetaryl-CH2, wherein the heterocyclyl, aryl and hetaryl rings ring in the last seven radicals themselves are unsubstituted or carry 1, 2, 3, 4 or

5 identical or different radicals R ^lc ;

R ^la is hydrogen, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Cs-Cs-cycloalkyl, Ci-Cs-alkylcarbonyl, Ci-Cs-alkoxycarbonyl, benzyl, phenyl or 5- or 6-membered hetaryl, wherein the phenyl and hetaryl rings in the last three radicals itself are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ^lc ;

R ^lb is hydrogen or Ci-C4-alkyl; or

NR ^la R ^lb is a 3- to 10-membered mono- or bicyclic N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 radicals R ^lc ;

R ^lc is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;

R ² , R ³ and R ⁴ are, independently of each other, selected from hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, phenyl, C1-C4- haloalkoxy, a radical (CH2) _n NR'R", where R' and R" have one of the meanings given for R ^Z1 and R ^Z2 and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^6c , where R ^6c has one of the meanings given for R ^lc ;

R ⁵ is hydrogen, halogen, CN, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci- C4-alkyl, Ci-C4-haloalkoxy, (CH2) _n NR'R", where R' and R" have one of the meanings given for R ^Z1 and R ^Z2 and wherein n is 0, 1, 2, 3 or 4 or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^6c , where R ^6c has one of the meanings given for R ^lc ;

R ⁶ , R ⁷ , R ⁸ are, independently of each other, selected from hydrogen, halogen, CN, C1-C4- alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, (CH2)nNR'R", where R' and R" have one of the meanings given for R ^Z1 and R ^Z2 and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^6c , where R ^6c has one of the meanings given for R ^lc ;

R ^a is Cs-Ce-cycloalkyl, Ci-Ce-haloalkyl or Ci-Ce-alkyl, which is unsubstituted or carries one radical selected from Ci-C4-alkoxy, Ci-C4-haloalkoxy and a radical NR ^al R ^a2 , where R ^al and R ^a2 are independently of each other selected from hydrogen, Ci-C4-alkyl, Cs- Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl and Ci-C4-alkoxy-Ci-C4-alkyl, a radical NR ^a3 R ^a4 or a radical N=C(R ^a5 )R ^a6 , where

R ^a3 and R ^a5 are independently of each other selected from hydrogen, Ci-C4-alkyl, C1-C4- haloalkyl, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl and Ci-C4-alkoxy-Ci-C4-alkyl;

R ^a4 and R ^a6 are independently of each other selected from hydrogen, Ci-C4-alkyl, C1-C4- haloalkyl, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl, Ci-C4-alkoxy-Ci-C4-alkyl, C-bound 3- to 10-membered, saturated heterocyclyl, 3- to 10-membered, saturated heterocyclylmethyl, where heterocyclyl in the last two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH2, hetaryl and hetaryl-CH2, wherein the heterocyclyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ^ac , where R ^ac has one of the meanings given for R ^lc ;

R ^b is hydrogen, halogen or Ci-C4-alkyl; and the N-oxides and the pharmaceutically acceptable salts thereof.

Formula 365

[001408] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 365. Such compounds are described in US 2011/0245247, published November 20, 2012, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 365, this reference incorporated by reference herein controls.

[001409] In an embodiment, the glutamate modulator is a compound according to: wherein

X ¹ is N or C-R ¹

X ² is N or C-R ² X ³ is N or C-R ³

X ⁴ is N or C-R ⁴ provided that none or one of X ¹ , X ² , X ³ or X ⁴ is N;

Y ¹ is N, C or C-R ⁵

Y ² is N, C or C-R ⁶

Y ³ is N, C or C-R ⁷

Y ⁴ is N, C or C-R ⁸ provided that only the moiety Y ¹ , Y ² , Y ³ or Y ⁴ to which Z is bound is C and further provided that 0, or 1 of Y ¹ , Y ² , Y ³ or Y ⁴ is N;

Z is CR ^Za R ^zb , O, S, S(O), S(O) ₂ or NR ^Zc ;

R ^Za , R ^zb are independently of each other selected from hydrogen, halogen and Ci-C4-alkyl;

R ^Zc is hydrogen, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl, or Ci-C4-alkyl, which is unsubstituted or carries one radical selected from Ci-C4-alkoxy and NR ^Z1 R ^Z2 ; where R ^Z1 and R ^Z2 are independently of each other selected from hydrogen, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl, Ci-C4-alkyl and Ci-C4-alkoxy-Ci-C4-alkyl, or

R ^Z1 and R ^Z2 together with the nitrogen to which they are attached form a 5- or 6-membered N- bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from O, S and N, as ring member and which is unsubstituted or carries 1, 2, 3 or 4 Ci-C4-alkyl radicals; or R ^Zc is a radical S(O) ₂ R ^Z3 or a radical S(O) ₂ NR ^Z4 R ^Z5 ; where R ^Z3 is Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Ci-C4-haloalkyl, Cs-Ce-cycloalkyl, C3- Ce-cycloalkylmethyl, phenyl or benzyl, wherein the phenyl ring in the last two mentioned radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals selected from halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;

R ^Z4 and R ^Z5 have one of the meanings given for R ^Z3 or R ^Z4 and R ^Z5 together with the nitrogen to which they are attached form a 5- or 6-membered N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 Ci-C4-alkyl radicals;

Q is CH ₂ or CH ₂ CH ₂ , where one or two of the hydrogen atoms in CH ₂ or CH ₂ CH ₂ may be replaced by halogen, Ci-C4-alkyl or Ci-C4-haloalkyl;

R ¹ is selected from hydrogen, halogen, Ci-Ce-alkyl, which is unsubstituted or carries one Ci- C4-alkoxy radical, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-C4-haloalkoxy, Cs-Cs-cycloalkyl, a radical NR ^la R ^lb , a radical CH ₂ NR ^la R ^lb , C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CJHfc, aryloxy, hetaryl, hetaryloxy or hetaryl-CH2, wherein the aryl, heterocyclyl and hetaryl rings ring in the last seven radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ^lc ;

R ^la is hydrogen, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Cs-Cs-cycloalkyl, Ci-Cs-alkylcarbonyl, Ci-Cx-alkoxycarbonyl, benzyl, phenyl or 5- or 6-membered hetaryl, wherein the phenyl and hetaryl rings in the last three radicals itself are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ^lc ;

R ^lb is hydrogen or Ci-C4-alkyl; or

NR ^la R ^lb is a 5- to 10-membered mono- or bicyclic N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 Ci-C4-alkyl radicals;

R ^lc is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;

R ² is selected from hydrogen, halogen, Ci-Ce-alkyl, which is unsubstituted or carries one Ci- C4alkoxy radical, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-C,4-haloalkoxy, Cs-Cs-cycloalkyl, a 5- to 10-membered mono- or bicyclic N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 Ci-C,4-alkyl radicals, a radical CH2NR ^la R ^lb , C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH2 aryloxy, hetaryl, hetaryloxy or hetaryl-CH2 wherein the aryl, heterocyclyl and hetaryl rings ring in the last seven radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ^lc provided that R ² is different from hydrogen, if X ¹ is N or CH, further provided that R ¹ is different from hydrogen, if X ² is N;

R ³ and R ⁴ are independently of each other, selected from hydrogen, halogen, Ci-C4-alkyl, Ci- C4-haloalkyl, Cs-Ce-cycloalkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, phenyl, C1-C4- haloalkoxy, a radical (CH2) _n NR'R", where R' and R" have one of the meanings given for R ^Z1 and R ^Z2 and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^6c , where R ^6c has one of the meanings given for R ^lc ;

R ² and R ³ can form together with the carbon atoms, to which they are bound, a fused 5- to 6- membered ring, which is itself unsubstituted or carries 1, 2, 3 or 4 identical or different radicals R ^23a ; R ^23a is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy;

R ⁵ is hydrogen, halogen, CN, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci- C4-alkyl, Ci-C4-haloalkoxy, (CH2) _n NR'R", where R' and R" have one of the meanings given for R ^Z1 and R ^Z2 and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^5c , where R ^5c has one of the meanings given for R ^lc ;

R ⁶ , R ⁷ , R ⁸ are, independently of each other, selected from hydrogen, halogen, CN, C1-C4- alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkyoxy, Ci-C4-alkoxy-Ci-C4-alkyl, (CH2)nNR'R", where R' and R" have one of the meanings given for R ^Z1 and R ^Z2 and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^6c , where R ^6c has one of the meanings given for R ^lc ;

R ^a is Cs-Ce-cycloalkyl, Ci-Ce-haloalkyl or Ci-Ce-alkyl, which is unsubstituted or carries one radical selected from Ci-C4-alkoxy, Ci-C4-haloalkoxy and a radical NR ^al R ^a2 , where R ^al and R ^a2 are independently of each other selected from hydrogen, Ci-C4-alkyl, C3- Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl and Ci-C4-alkoxy-Ci-C4-alkyl, a radical NR ^a3 R ^a4 or a radical N=C(R ^a5 )R ^a6 , where

R ^a3 and R ^a5 are independently of each other selected from hydrogen, Ci-C4-alkyl, Ci- C4haloalkyl, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl and Ci-C4-alkoxy-Ci-C4-alkyl; R ^a4 and R ^a6 are independently of each other selected from hydrogen, Ci-C4-alkyl, C1-C4- haloalkyl, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkylmethyl, Ci-C4-alkoxy-Ci-C4-alkyl, C-bound 3- to 7-membered, saturated heterocyclyl, 3- to 7-membered, saturated heterocyclylmethyl, where heterocyclyl in the last two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH2, hetaryl and hetaryl-CH2, wherein the heterocycicyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ^ac where R ^ac has one of the meanings given for R ^lc ; the pharmaceutically acceptable salts; or N-oxides thereof.

Formula 366 [001410] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 366. Such compounds are described WO 2011/109277, published September 9, 2011, corresponding to PCT/US2011/026441, filed February 28, 2011 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 366, this reference incorporated by reference herein controls.

[001411] In an embodiment, the glutamate modulator is a compound according to: wherein:

X is selected from the group consisting of C and N;

Y is Ci -ealkyl;

R ¹ is selected from the group consisting of:

(1) Ci-salkyl,

(2) C2-salkenyl,

(3) C2-salkynyl,

(4) C3-6cycloalkyl-(CH2)p — , wherein p is 1, 2, 3 or 4, and

(5) benzyl, wherein groups (1) to (5) above are optionally substituted with 1 to 3 R ² groups; each R ² is independently selected from the group consisting of: halo, OH, Ci-4alkyl, Cn 4alkoxy, CF3, — OCF3 and — CN; ring A is selected from the group consisting of phenyl and pyridyl, wherein said phenyl and pyridyl are optionally substituted with one or more R ³ groups up to the maximum number of substitutable positions; each R ³ is independently selected from the group consisting of:

(1) halo,

(2) Ci- ₈ alkyl,

(3) C2-ealkenyl,

(4) C2-ealkynyl, (5) Cs-ecycloalkyl,

(6) Ci-ealkoxy,

(7) Cs-ecycloalkoxy,

(8) — CN,

(9) —OH,

(10) — C(O)— O— Ci- ₄ alkyl,

(11) — C(O)— Ci- ₄ alkyl,

(12) — N(R) ₂ ,

(13) — C(O)— N(R) ₂ ,

(14) — S(O)k — Ci- ₄ alkyl, wherein k is 0, 1 or 2,

(15) -aryl,

(16) -heteroaryl,

(17) -heterocycle,

(18) — C(O)-aryl,

(19) — N(R)-aryl,

(20) benzyl,

(21) benzyloxy,

(22) aryl-O— ,

(23) heteroaryl-0 — ,

(24) heterocycle-0 —

(23) — CO ₂ H,

(24) — SH,

(25) — SO ₂ N(R)R,

(26) — N(R)C(O)N(R)R,

(27) — N(R)C(O)Ci- ₄ alkyl,

(28) — N(R)SO ₂ N(R)R,

(29) — B(OH) ₂ ,

(30) heteroaryl-CH2 — ,

(31) heterocycle-CH2 — ,

(32) aryl-C(O)— N(R)— CH ₂ — ,

(33) heteroaryl-C(O) — N(R) — CH2 — ,

(34) heteroaryl-CH ₂ — C(O)— N(R)— CH ₂ — ,

(35) heterocycle-CH2 — C(O) — N(R) — CH ₂ — , and

(36) Ci- ₆ alkyl-C(O)— N(R)— CH ₂ — , wherein groups (2) to (7), (10), (11), (14) to (24), (27) and (30) to (36) above are optionally substituted from one up to the maximum number of substitutable positions with one or more substituents independently selected from the group consisting of: OH, CN, halo, — N(R) ₂ , — C(O)— N(R) ₂ , — CH ₂ — N(R) ₂ , — C(O)— CH ₂ — N(R) ₂ , carboxy, — C(O)— O— Ci- ₄ alkyl, — C(O) — C(R) ₂ — C(O) — O — Ci-4alkyl, — CH ₂ — Cs-ecycloalkyl, Ci-4alkoxy, Ci-4alkylamino, acetyl, acetylamino, methylsulfonyl, methylsulfonylamino, phenyl, heterocycle, heteroaryl, heteroaryl-C(O) — , Ci-4alkyl and Ci-4alkyl-C(O) — , said Ci-4alkyl, Ci-4alkyl-C(O) — , heteroaryl and heteroaryl-C(O)-optionally substituted with 1 to 3 halogen atoms and hydroxyl, and heteroaryl and heteroaryl-C(O) — additionally optionally substituted with methyl, and each R is independently selected from the group consisting of: H and Ci-4alkyl; aryl at each occurrence is independently selected from the group consisting of: phenyl, naphthyl, anthryl and phenanthryl; heteroaryl at each occurrence independently means a 5- or 6-membered monocyclic aromatic or 9- or 10-membered bicyclic aromatic, wherein at least one atom in the aromatic is selected from the group consisting of N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from the group consisting of C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide; heterocycle at each occurrence independently means a 5- or 6-membered monocyclic nonaromatic ring or 9- or 10-membered bi- or spiro-cyclic fully or partially unsaturated ring, wherein each said ring is optionally substituted with 1 to 2 oxo groups, wherein at least one atom of said 5- or 6-membered monocyclic non-aromatic ring or said 9- or 10-membered bi- or spiro-cyclic fully or partially unsaturated ring is selected from the group consisting of N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide, and the remaining atoms are selected from the group consisting of C, N(R), O and S, the sulfur optionally oxidized to sulfone or sulfoxide; or a pharmaceutically acceptable salt thereof.

Formula 367

[001412] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 367. Such compounds are described in WO 2011/051490, published May 5, 2011, corresponding to PCT/EP2010/066584, filed November 2, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 367, this reference incorporated by reference herein controls.

[001413] In an embodiment, the glutamate modulator is a compound according to:

wherein

R ¹ is Ci-4alkyl, Co-4alkylC3-8cycloalkyl, or Co^alkylZ ¹ , said Ci-4alkyl and Co-4alkylC3- scycloalkyl being optionally substituted with one or more substituent independently selected from hydroxy, Ci-4alkyl, C alkyloxy, CN and halogen;

Z ¹ is a 4-7 membered saturated ring containing a heteroatom selected from O, S and SO2; n is 1 or 2; each R ² and R ³ is independently H or Ci-4alkyl;

Y is O or NR ⁸ ;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently H or Ci-4alkyl; or when Y is NR ⁸ , either R ⁴ and R ⁵ , or R ⁶ and R ⁷ , may together represent oxo;

R ⁸ is Ci-4alkyl, Co-4alkylC3-scycloalkyl, or Co-4alkylZ ² , said Ci-4alkyl and Co-4alkylC3- scycloalkyl being optionally substituted with one or more substituent independently selected from hydroxy, Ci-4alkyl, C alkyloxy, oxo, CN and halogen;

Z ² is a 4-7 membered saturated ring containing a heteroatom selected from O, S and SO2;

X ³ -X ⁷ are CR ⁹ ; or one of X ^{1 -x 7} may be N; each R ⁹ is independently selected from H, Ci-4alkyl, Ci-4alkyloxy, nitrile and halogen, said Ci-4alkyl and Ci-4alkyloxy being optionally substituted with one or more substituent independently selected from hydroxy and halogen;

R ¹⁰ and R ¹¹ are independently H or Ci-4alkyl; or, when R ¹⁰ is alkyl and X ¹ is CR ⁹ , R ¹⁰ and

R ⁹ together with the atoms to which they are bonded may form a fused ring optionally comprising a heteroatomic moiety selected from O, S and SO2; or a pharmaceutically acceptable salt thereof.

Formula 368

[001414] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 368. Such compounds are described in WO 2011/034830, published March 24, 2011, corresponding to PCT/US2010/048695, filed September 14, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 368, this reference incorporated by reference herein controls.

[001415] In an embodiment, the glutamate modulator is a compound according to: wherein: n is 1, 2 or 3;

Ri is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2- fluoroethyl and propyl;

R2 is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2- fluoroethyl, propyl, 1,1 -difluoropropyl, methoxymethyl and 2-fluoroethoxymethyl;

R3 and R4 are the same or different and independently of each other selected from the group consisting of (Ci-C4)alkyl, phenyl and benzyl; and

Rs and Re are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, (Ci-C4)alkyl and (Ci-C4)alkoxy.

Formula 369

[001416] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 369. Such compounds are described in WO 2011/034832, published March 24, 2011, corresponding to PCT/US2010/048697, filed September 14, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 369, this reference incorporated by reference herein controls.

[001417] In an embodiment, the glutamate modulator is a compound according to: wherein Ri is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, hydroxy ethyl, 2-(tetrahydro- pyran-2-yloxy)-ethyl; R2 is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, methoxymethyl, ethoxymethyl, 2- fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, -COOH, phenyl, benzyl, 2-, 3-, 4-, or 5 -fluorophenyl, 2-, 3-, 4-, or 5-f uorobenzyl, 2,4-dif uorophenyl, 2,4- difluorobenzyl, phenoxy, benzyloxy, 2-, 3-, 4-, or 5 -fluorophenoxy, 2-, 3-, 4-, or 5-fluorobenzyloxy, 2,4- difluorophenoxy, 2,4-difluorobenzyloxy, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, tetrahydrofuranylmethoxymethyl, phenyl, cyclopropyl, cyclopropylmethyl and cyclopentyloxymethyl; and R3, R4 and R5 are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF3, (Cl-C6)alkyl, (Cl-C6)alkoxy, cyclohexyl, 1 -methylcyclohexyl, 4- methoxycyclohexyl, 4,4'-difluorocyclohexyl, cyclohexenyl, 4-fluoro-cyclohexenyl, bicyclo [3 ,3,1 ]nonyl, bicyclo [3,3,1 ]nonylethyl, 1, , 1 ",3,3' ,3 " — hexaf uoro-2- hydroxy -propyl; or two of R3, R4 and R5 are on adjacent carbons and taken together with the carbons to which they are attached form a five or a six-membered ring; or a salt thereof or a diastereoisomer or a tautomer thereof.

Formula 370

[001418] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 370. Such compounds are described in WO 2011/034828, published March 24, 2011, corresponding to PCT/US2010/048687, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 370, this reference incorporated by reference herein controls.

[001419] In an embodiment, the glutamate modulator is a compound according to: wherein: R1 is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2- fluoroethyl and propyl;

R2 is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2- fluoroethyl, propyl, 1,1 -difluoropropyl, methoxymethyl, ethoxymethyl, 2- fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, phenyl, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, tetrahydrofuranylmethoxymethyl, cyclopropyl and cyclopentyloxymethyl; and R3, R4, Rs, R6, R7 and Rs are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF3, (Cl-C4)alkyl, (C3-Ce)cycloalkyl, (Cl- C4)alkoxy; or two of R6, R7 and Rs are on adjacent carbons and taken together with the phenyl ring form a naphthalene ring; or two of R6, R7 and Rs are on adjacent carbons and taken together with the carbons to which they are attached form a five or a six-membered ring; or one of R6, R7 and Rs bonds with the adjacent phenyl ring to form a fluorenyl ring; or a salt thereof.

Formula 371

[001420] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 371. Such compounds are described in WO 2010/130423, published November 18, 2010 corresponding to PCT/EP2010/002909, filed May 11 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 371, this reference incorporated by reference herein controls.

[001421] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

A is CH or N;

R ¹ is selected from the group consisting of hydrogen; Ci-6alkyl; (Cioalkyloxy)Ci..3alkyl; [(Ci. 3alkyloxy)-Ci-3alkyloxy]Ci-3a1ky1; Cnsalkyl substituted with one or more independently selected halo substituents; unsubstituted benzyl; benzyl substituted with one or more substituents each independently selected from the group consisting of halo, C1.3alk.oxy, Ci- 3alkyk CiualkyloxyCioaHcyL hydroxyCmalkyl, cyano, hydroxyl, amino, ClMFjR', C(=O)OR', C(=O)NR'R", mono- or di-(Ci-3alkyl)amino, morpholinyl, (C.i-vcycloalkyljCi- 3alkyloxy, trifluoromethyl and trifluoromethoxy, wherein R' and R" are independently selected from hydrogen and Coealkyl; (benzyloxyjCioalkyl; unsubstituted C3-7Cydoalkyl; C3- -cycloalkyl substituted with trihaloCi-salkyl; (C3-7cycloalkyl)Ci.3alkyl; 4-(2, 3,4,5- tetrahydrobenzo[f][ 1 ,4]oxazepine)m ethyl; Heth Het* Cj -salkyl; Het ² and Het ² Ci-3a1kyl ;

R ² is selected from the group consisting of cyano; halo; C loalky I ; Cioalkyl substituted with one or more halo substituents; Cioalkoxy substituted with one or more halo substituents; C ₃ - 7cy cloalkyl; and (Cdocycloalkyl)Ci .^alkyl;

R- ³ is selected from the group consisting of hydrogen; Ciualkyl; unsubstituted C3-7CV cloalkyl; Cs-vcydoalkyl substituted with 1 or more substituents each independently selected from the group consisting of hydroxyl, halo, Cioalkyl, tri-haloCiualkyl and Csocycloalkyl; unsubstituted phenyl; phenyl substituted with one or more substituents each independently selected from the group consisting of halo, Cnsalkyl, Ctoalkoxy, hydroxyCi. ₃ alkyl, trifluoromethyl and trifluoromethoxy; Het ³ ; un substituted pyridyl; pyridyl substituted with one or more substituents each independently selected from Cmalkyl, Cjxalkyloxy, C3- 7cycloalkyl, and halo; trihaloCioalkyl; and hydroxyCioalkyl; or

R ³ is a cyclic radical of formula (a) wherein

R ⁵ is selected from the group consisting of hydrogen; Cioalkyl; Ci-salkyloxy; and hydroxyCi 3 alkyl ; n is 1 or 2;

Z is selected from CH2 or CR ⁶ (OH) wherein R ⁶ is selected from the group consisting of hydrogen, C1.3alkyl and trifluoromethyl, or R ⁵ and R ⁶ together form a radical CH? — CH?: or

Z is a cyclic radical of formula (b) wherein rn and p are independently selected from 0, 1 and 2, provided that m+p 2^2;

R ⁴ is selected from the group consisting of hydrogen; halo; and Ci-jalkyl substituted with one or more halo substituents; and

X is selected from the group consisting of a covalent bond, Co? alkanediyl, O, NH, S, SO, SO?, C(OH)(CH ₃ ), CH?— O, O— CH ₂ , CH ₂ — NH, NH— CH?, CHF, and CF ₂ ; each Het ¹ is a saturated heterocyclic radical selected from the group consisting of pyrroiidinyl; piperidinyl; piperazinyl; and morpholinyl; each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of Cf-ealkyl, C1.3alkyl substituted with one or more halo substituents, un substituted phenyl and phenyl substituted with one or more substituents each independently selected from the group consisting of halo, trifluoromethyl, and trifluoromethoxy; each Het ² is unsubstituted pyridyl or pyrimidinyl, and each Het- ¹ is a saturated heterocyclic radical selected from the group consisting of pyrrolidinyl; piperidinyl; piperazinyh tetrahydropyranyl; and morpholinyl; each of which may be optionally substituted with one or more substituents independently selected from the group consisting of C’ _: -6alkyl, halo, hydroxyl, C malkyl substituted with one or more halo substituents, unsubstituted phenyl, and phenyl substituted with one or more substituents each independently selected from the group consisting of halo, trifluoromethyl, and trifluorom et hoxy ; or a pharmaceutically acceptable salt or a solvate thereof.

[001422] In further embodiments, the glutamate modulator is a compound selected from:

8-chloro-7-[3-fluoro-4-[(2-methyl-4-pyridinyl)oxy]phenyl] -3-(2,2,2-trifluoroethyl)- l,2,4-triazolo[4,3-a]pyridine;

3-(cyclopropylmethyl)-7-[3-fluoro-4-[(2-methyl-4-pyridiny l)oxy]phenyl]-8- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyridine;

8-chloro-7-[4-[(2,6-dimethyl-3-pyridinyl)oxy]-3-fluorophe nyl]-3-(2,2,2- trifluoroethyl)-l,2,4-triazolo[4,3-a]pyridine;

2-chloro-N-cyclopropyl-4-[3-(cyclopropylmethyl)-8-(triflu oromethyl)-l,2,4- triazolo[4,3-a]pyridin-7-yl]-benzenamine;

8-chloro-7-[4-(2-methyl-pyridin-4-yloxy)-3-fluoro-phenyl] -3-(cyclopropylmethyl)- l,2,4-triazolo[4,3-a]pyridine;

8-chloro-7-[3-chloro-4-[(2-methyl-4-pyridinyl)oxy]phenyl] -3-(ethoxymethyl)-l,2,4- triazolo[4,3-a]pyridine;

7-[4-[(2,6-dimethyl-3-pyridinyl)oxy]-3-fluorophenyl]-3-(e thoxymethyl)-8-methyl- l,2,4-triazolo[4,3-a]pyridine;

7-[3-chloro-4-[(2-cyclopropyl-4-pyridinyl)oxy]phenyl]-3-( cyclopropylmethyl)-8- (trifluoromethyl)-l,2,4-triazolo[4,3-a]pyridine;

3-(cyclopropylmethyl)-7-[4-[(3-fluoro-4-pyridinyl)oxy]phe nyl]-8-(tri fluoromethyl)- l,2,4-triazolo[4,3-a]pyridine; and 7-(3-chloro-4-piperazin-l-ylphenyl)-3-(cyclopropylmethyl)-8- (trifluoromethyl)[l,2,4]triazolo[4,3-a]pyridine; and the pharmaceutically acceptable salts thereof and the solvates thereof, or substituted variants thereof retaining glutamate modulatory activity.

Formula 372

[001423] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 372. Such compounds are described in WO 2010/130422, published November 18, 2010, corresponding to PCT/EP2010/002908, filed May 11, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 372, this reference incorporated by reference herein controls.

[001424] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein the bond drawn into the ring indicates that the bond may be attached to any carbon ring atom; R ¹ is selected from the group consisting of hydrogen; Ci-ealkyl; (Ci-3alkyloxy)-Ci-3alkyl; [(Ci- 3alkyloxy)-Ci-3alkyloxy]Ci-3alkyl; Ci-3alkyl substituted with one or more independently selected halo substituents; unsubstituted benzyl; benzyl substituted with one or more substituents each independently selected from the group consisting of halo, Ci-3alkyl, (Cn 3alkyloxy)Ci-3alkyl, Ci-3alkyloxy, hydroxyCi-3alkyl, cyano, hydroxyl, amino, (C=O)R', (C=O)OR', (C=O)NR'R", mono- or di-(Ci-3alkyl)amino, morpholinyl, (C3-7cycloalkyl)Ci- 3alkyloxy, trifluoromethyl and trifluoromethoxy, wherein R' and R" are independently selected from hydrogen and Ci-ealkyl; (benzyloxy)Ci-3alkyl; unsubstituted C3-?cycloalkyl; C3- 7cycloalkyl substituted with one or more independently selected Ci-3alkyl substituted with one or more independently selected halo substituents; (C3-7cycloalkyl)Ci-3alkyl; 4-(2,3,4,5- tetrahydro-benzo[f][l,4]oxazepine)methyl; Het ¹ ; He^Ci-salkyl; Het ² ; and Het ² Ci-3alkyl;

R ² is selected from the group consisting of cyano; halo; Ci-3alkyl substituted with one or more independently selected halo substituents; Ci-3alkyloxy substituted with one or more independently selected halo substituents; Ci-3alkyl; C3-7cycloalkyl; and (C3-7cycloalkyl)Ci- 3 alkyl; forms a radical selected from (a), (b), (c), (d) and (e):

(a) wherein the bond drawn into (a) indicates that R ⁴ may be attached to any of carbon ring atoms 2 and 3; each R ³ is independently selected from the group consisting of hydrogen; unsubstituted Ci- ealkyl; Ci-ealkyl substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, Ci-3alkoxy and trifluoromethyl; unsubstituted C3- 7cycloalkyl; C3-?cycloalkyl substituted with one or more substituents independently selected from the group consisting of halo, Ci-3alkyl, hydroxy, Ci-3alkoxy and trifluoromethyl; C3- 7cycloalkylCi-3alkyl; unsubstituted phenyl; phenyl substituted with one or more substituents independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkoxy and trifluoromethyl; Het ³ ; and Het ³ C 1-3 alkyl; or each R ³ is independently selected from a cyclic radical of formula (f) wherein R ⁸ is selected from hydrogen, Ci-3alkyl, Ci-3alkyloxy and hydroxyCi-3alkyl; q is 1 or 2; X is selected from O, CH2 and CR ⁹ (OH), wherein R ⁹ is selected from hydrogen, Ci-3alkyl and C3-?cycloalkyl; or

X is a cyclic radical of formula (g) wherein r and s are independently selected from 0, 1 and 2, provided that r+s^2; each R ⁴ , R ⁶ and R ⁷ are each independently selected from Ci-3alkyl and Ci-3alkyl substituted with one or more independently selected halo substituents; each R ⁵ is independently selected from the group consisting of hydrogen, Ci-3alkyl, and Ci- 3alkyl substituted with one or more independently selected halo substituents; n, m and p are each independently selected from 0, 1 and 2; v is 0 or 1; t and u are each independently selected from 1 and 2;

W is selected from N and C ¹⁰ ; wherein R ¹⁰ is selected from hydrogen, halo and trifluoromethyl; each Het ¹ is a saturated heterocyclic radical selected from pyrrolidinyl; piperidinyl; piperazinyl; and morpholinyl; each of which may be optionally substituted with one or more each independently selected from the group consisting of Ci-ealkyl; mono-, di- and tri-haloCi- 3alkyl; unsubstituted phenyl; and phenyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, trifluoromethyl, and trifluoromethoxy; each Het ² is pyridyl or pyrimidinyl; and each Het ³ is a heterocycle selected from the group consisting of tetrahydropyran, pyridyl; and pyrimidinyl; each of them being optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-3alkyl, Ci-3alkoxy and trifluoromethyl; and halo is selected from fluoro, chloro, bromo and iodo; or a pharmaceutically acceptable salt thereof.

Formula 373

[001425] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 373. Such compounds are described in WO 2010/060589, published June 3, 2010, corresponding to PCT/EP2009/008346, filed November 24, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 373, this reference incorporated by reference herein controls.

[001426] In an embodiment, the glutamate modulator is a compound according to: stereochemically isomeric form thereof, wherein

R ¹ is Ci-ealkyl; C3-?cycloalkyl; trifluoromethyl; Ci-3alkyl substituted with trifluoromethyl, 2,2,2-trifluoroethoxy, C3-?cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl, or trifluoromethoxy; phenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of halo, trifluoromethyl, and trifluoromethoxy; or 4-tetrahydropyranyl; R ² is cyano, halo, trifluoromethyl, Ci-3alkyl or cyclopropyl;

R ³ is hydrogen; Ci-3alkyl; Ci-3alkyl substituted with C3-7cycloalkyl, phenyl, phenyl substituted with 1 or 2 substituents selected from the group consisting of halo, cyano, Ci- 3alkyl, Ci-3alkoxy and trifluoromethyl; hydroxyC2-4alkyl; Ci-3alkyloxyC2-4alkyl; 4- tetrahydropyranyl; l-oxa-spiro[3,5]non-7-yl; 2-oxa-spiro[3,5]non-7-yl; l-oxa-spiro[4,5]dec- 8-yl; 2-oxa-spiro[4,5]dec-8-yl; 4-(hydroxy)-cyclohexanyl; 4-(hydroxy)-4-(Ci- 3alkyl)cyclohexanyl; 4-(hydroxy)-4-(C3-7cycloalkyl)-cyclohexanyl; 4-(Ci- 3alkyloxy)cyclohexanyl; phenyl; pyridinyl; pyridinylmethyl; or phenyl, pyridinyl or pyridinylmethyl substituted with one or two substituents selected from the group consisting of halo, Ci-3alkyl, Ci-3alkoxy and trifluoromethyl;

R ⁴ is hydrogen or halo; A is a radical of formula

— CH=CH— (a), or

— CH ₂ — CH ₂ — O— (b); wherein one or two hydrogen atoms may be replaced by Ci-3alkyl or polyhaloCi-salkyl; or a pharmaceutically acceptable salt thereof.

Formula 374

[001427] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 374. Such compounds are described in WO 2010/043396, published April 22, 2010, corresponding to PCT/EP2009/007404, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 374, this reference incorporated by reference herein controls.

[001428] In an embodiment, the glutamate modulator is a compound according to: wherein

R ¹ is Ci-ealkyl; or Ci-3alkyl substituted with C3-?cycloalkyl, halo, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, Ci-3alkyl or cyclopropyl;

R ³ is hydrogen, halo or trifluoromethyl; n is 1 or 2;

X is — CH ₂ CH ₂ — O— , — CH=CH— , or — CH ₂ CH ₂ — ;

Y is — O— or — CR ⁴ (OH)— ;

R ⁴ is hydrogen or C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.

Formula 375

[001429] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 375. Such compounds are described in WO 2010/025890, published March 11, 2010, corresponding to PCT/EP2009/006326, filed September 1, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 375, this reference incorporated by reference herein controls.

[001430] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is Ci-6 alkyl; or C1-3 alkyl substituted with C3-7 cycloalkyl, halo, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;

X is a covalent bond, O, NR ³ , NR ³ — CH2 or O — CH2;

R ³ is hydrogen or C 1-33 alkyl; and

Ar is unsubstituted phenyl; or phenyl substituted with n radicals R ⁴ ; wherein n is 1, 2 or 3; wherein each R ⁴ is independently selected from the group consisting of halo, C1-3 alkyl, hydroxyCnsalkyl, polyhaloCnsalkyl, cyano, hydroxyl, amino, carboxyl, C1-3 alkyloxyCn salkyl, Cnsalkyloxy, polyhaloCnsalkyloxy, Cnsalkylcarbonyl, mono- and di(Ci-3alkyl)amino, and morpholinyl; or wherein two vicinal R ⁴ radicals taken together form a bivalent radical of formula

— N=CH— NH— (a), or

— CH=CH— NH— (b), or

— O— CH ₂ — CH ₂ — NH— (c); or a pharmaceutically acceptable addition salt or a solvate thereof.

Formula 376

[001431] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 376. Such compounds are described in WO 2009/148403, published December 10, 2009, corresponding to PCT/SE2009/050682, filed June 8, 2009, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 376, this reference incorporated by reference herein controls.

[001432] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ is selected from Cnsalkyl or halogen;

R ² is selected from Cnsalkyl, Cnshaloalkyl or Cs-ecycloalkyl;

R ³ and R ⁴ at each occurrence are independently selected from hydrogen, Cnsalkyl, Ci- shydroxyalkyl, C3-6-carbocyclyl, heterocyclyl or heteroaryl, or R ³ and R ⁴ in combination with the nitrogen to which they are attached form a cyclic moiety selected from morpholino, pyrrolidinyl or piperazinyl or a pharmaceutically acceptable salt or an optical isomer thereof. [001433] In an embodiment, the glutamate modulator is 7-Chloro-2-isopropyl-5-[3- (morpholine-4-carbonyl)-isoxazol-5-yl]-2,3-dihydro-isoindol- l-one, or 5-[7-chloro-2-((S)-l- cyclopropyl-ethyl)-l-oxo-2,3-dihydro-lH-isoindol-5-yl]-isoxa zole-3-carboxylic acid dimethylamide, or 7-chloro-2-((S)-l-cyclopropyl-ethyl)-5-[3-(morpholine-4-carb onyl)- isoxazol-5-yl]-2,3-dihydro-isoindol-l-one or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate modulatory activity.

Formula 377

[001434] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 377. Such compounds are described in WO 2009/110901, published September 11, 2009, corresponding to PCT/US2008/056009, filed March 6, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 377, this reference incorporated by reference herein controls.

[001435] In an embodiment, the glutamate modulator is a compound according to: — is a single or a double bond; p is 0 or 1; n is an integer from 0 to 3;

X is oxygen, sulfur or NR21, wherein R21 is hydrogen or (Ci-C4)alkyl;

Y is oxygen or sulfur;

A is a single covalent bond or CHRi;

B is CHR2, NR2, oxygen or sulfur;

Ri and R2 are the same or different and independently of each other selected from the group consisting of hydrogen, CF3, straight or branched chain (Ci-Cio)alkyl, mono- or di-fluoro(Ci- C4)alkyl, mono- or di-fluoro(Ci-C4)alkoxy(Co-C4)alkyl, mono- or di-fluoro(Ci- C4)alkylsulfanyl(Co-C4)alkyl, mono- or difluoro(Ci-C4)alkylsulfmyl(Co-C4)alkyl, mono- or difluoro(Ci-C4)alkylsulfonyl(Co-C4)alkyl, (Ci-Cio)alkoxy(Co-C4)alkyl, (Ci- Cio)alkylsulfanyl(Co-C4)alkyl, (Ci-Cio)alkylsulfinyl(Co-C4)alkyl, (Ci-Cio)alkylsulfonyl(Co- C4)alkyl, (Ci-Cio)alkoxy mono- or di-fluoro(Ci-C4)alkyl, (Ci-Cio)alkylsulfanyl mono- or di- fluoro(Ci-C4)alkyl, (Ci-Cio)alkylsulfinyl mono- or di-fluoro(Ci-C4)alkyl, (Ci- Cio)alkyl sulfonyl mono- or di-fluoro(Ci-C4)alkyl, (Ce,Cio)aryl(Co-C4)alkyl, (Ce,Cio)aryl mono- or difluoro(Ci-C4)alkyl, (Ce,Cio)aryl mono- or difluoro(C2-C4)alkyloxy, (Ce,Cio)aryloxy(Co-C4)alkyl, (Ce,Cio)arylsulfanyl(Co-C4)alkyl, (C6,Cio)arylsulfinyl(Co- C4)alkyl, (C6,Cio)arylsulfonyl(Co-C4)alkyl, (C3-C8)cycloalkyl(Co-C4)alkyl, mono- or difluoro(C3-Cs)cycloalkyl(Co-C4)alkyl, (C3-Cs)cycloalkoxy(Co-C4)alkyl, mono- or difluoro(C3-Cs)cycloalkyloxy(Co-C4)alkyl, (C3-Cs)cycloalkyl mono- or difluoro (Ci-C4)alkyl, (C3-Cs)cycloalkyl mono- or difluoro (C2-C4)alkyloxy, (C3-Cs)cycloalkylsulfanyl(Co-C4)alkyl, (C3-Cs)cycloalkylsulfmyl(Co-C4)alkyl, (C3-Cs)cycloalkylsulfonyl(Co-C4)alkyl, hydroxy(Ci- C4)alkyl, heteroaryl(Co-C4)alkyl, heteroaryl mono- or difluoro(Ci-C4)alkyl, heteroaryloxy(Co- C4)alkyl, heteroaryloxy mono- or difluoro(C2-C4)alkyl, heteroarylsulfanyl(Co-C4)alkyl, heteroarylsulfinyl(Co-C4)alkyl, heteroarylsulfonyl(Co-C4)alkyl, saturated heterocyclic(Co- C4)alkyl, saturated heterocyclic mono- or di-fluoro(Ci-C4)alkyl, saturated heterocyclyloxy(Co-C4)alkyl, saturated heterocyclyloxy mono- or di-fluoro(C2-C4)alkyl, saturated heterocyclylsulfanyl(Co-C4)alkyl, heterocyclylsulfinyl(Co-C4)alkyl, heterocyclylsulfonyl(Co-C4)alkyl, -CO2R22 or -CONR23R24 wherein R22, R23 and R24 are the same or different and independently of each other selected from hydrogen or (Ci-C4)alkyl; and wherein Ri and R2 are optionally further substituted;

R3 and R4 are the same or different and independently of each other selected from the group consisting of hydrogen, (Ci-C4)alkyl, (C3-Cs)cycloalkyl and (Ce,Cio)aryl(Ci-C4)alkyl; or Rs and R4 taken together with the carbon atom to which they are attached form a substituted or unsubstituted C5-C7 carbocyclic ring;

Rs, Re and R7 are the same or different and independently of each other selected from the group consisting of hydrogen, (Ci-C4)alkyl and (C3-Cs)cycloalkyl;

Rs is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetralinyl, substituted or unsubstituted benzocycloheptanyl, substituted or unsubstituted hexahydrofluorenyl, substituted or unsubstituted (O-Cxjcycloalkyl, substituted or unsubstituted furanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted tetrahydroisoquinolinyl, substituted or unsubstituted tetrahydroquinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted tetrahydrodibenzofuranyl and substituted or unsubstituted hexahydrodib enzofurany 1 ; wherein said substituents are selected from the group consisting of CF3, OCF3, halogen, CN, SF5, straight or branched chain (Ci-C2o)alkyl, (Ci-C4)alkylsulfonyl, substituted or unsubstituted (C3-Cio)cycloalkyl(CR9Rio)m, substituted or unsubstituted (Ce- Ci6)spirocycloalkyl, substituted or unsubstituted (C6,Cio)aryl(CR9Rio)m, substituted or unsubstituted heteroaryl(CR9Rio)m, substituted or unsubstituted (Ce,Cio)aryl(C3- Cxjcycloalkyl, substituted or unsubstituted (Cs-Ci3)bicyclic, substituted or unsubstituted adamantyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetralinyl, substituted or unsubstituted benzocycloheptyl, straight or branched chain (Ci-C2o)alkoxy, substituted or unsubstituted (C3-Cio)cycloalkoxy, substituted or unsubstituted (Ce,Cio)aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted piperidinyl(CR9Rio)m, substituted or unsubstituted piperazinyl(CR9Rio)m, substituted or unsubstituted (C4-C7)lactam, substituted or unsubstituted tetrahydropyranyl(CR9Rio)m, substituted or unsubstituted tetrahydrofuranyl(CR9Rio)m, substituted or unsubstituted 1,3- dioxanyl, substituted or unsubstituted 1,3-dioxolanyl, (Ci-C4)alkoxy ethoxy, substituted or unsubstituted (C3-Cs)cycloalkyloxy ethoxy, substituted or unsubstituted

(Ce,Cio)aryloxy ethoxy and substituted or unsubstituted heteroaryloxy ethoxy; wherein m is an integer from 0 to 10; R9 and Rio are the same or different and independently of each other chosen from hydrogen or (Ci-C4)alkyl; or

R9 and Rio taken together with the carbon atom to which they are attached form a substituted or unsubstituted C3-C8 carbocyclic ring; and wherein said substituents are selected from the aforementioned substituents; or a salt thereof or an enantiomer, stereoisomer or a tautomer thereof or a racemic mixture thereof.

Formula 378

[001436] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 378. Such compounds are described in WO 2009/062676, published May 22, 2009, corresponding to PCT/EP2008/009534, filed November 12, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 378, this reference incorporated by reference herein controls.

[001437] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is C1-6 alkyl; C3-6 cycloalkyl; trifluoromethyl; C1-3 alkyl substituted with trifluoromethyl, C3-7 cycloalkyl, phenyl, or phenyl substituted with C1-3 alkyl, Ci-3alkyloxy, cyano, halo, trifluoromethyl; phenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of C1-3 alkyl, cyano, halo, trifluoromethyl; or 4-tetrahydropyranyl;

R ² is cyano, halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;

R ³ is a radical of formula (a) or (b) or (d)

R ⁴ is hydroxyC3-6 cycloalkyl; pyridinyl; pyridinyl substituted with one or two C1-3 alkyl groups; pyrimidinyl; pyrimidinyl substituted with one or two C1-3 alkyl groups; phenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of halo, Cn 3 alkyl, hydroxyCi-3 alkyl, mono- or polyhaloCi-3 alkyl, cyano, hydroxyl, carboxyl, Ci- 3 alkyloxyCi-3 alkyl, C1-3 alkyloxy, mono- or polyhalo-Ci-3 alkyloxy, and morpholinyl;

R ⁵ is hydrogen, fluoro, hydroxyl, hydroxyCi-3 alkyl, fluoroCi-3 alkyl, morpholinyl or cyano;

X is C or N in which case R ⁵ represent the electron pair on N; or

R ⁴ — X — R ⁵ represents a radical of formula (h) or (i) or (j) n is 0 or 1; q is 1 or 2;

R ⁶ is C1-3 alkyl; C3-ecycloalkyl; hydroxyC2-4alkyl; (C3-6cycloalkyl)Ci-3alkyl; phenyl; pyridinyl; or phenyl or pyridinyl substituted with one or two substituents selected from the group consisting of halo, Ci-3alkyl, Ci-3alkoxy, hydroxyCi-3alkyl, trifluoromethyl and (CH2) _m — CO2H, wherein m=0, 1, or 2; or R ⁶ is a cyclic radical of formula (k) wherein R ⁸ is hydrogen, Ci-3alkyl, hydroxyCi-salkyl; p is 1 or 2;

Z is O, CH2 or CR ⁹ (OH) wherein R ⁹ is hydrogen or Ci-3alkyl;

R ⁷ is hydrogen, halo or trifluoromethyl;

Y is a covalent bond, O, NH, S, C(OH)(CH ₃ ), — CH ₂ — O— , — O— CH ₂ — , CHF or CF ₂ ; or R ⁶ — Y is morpholinyl, pyrrolidinyl, or piperidinyl optionally substituted with hydroxyl or hydroxyC 1-3 alkyl; and

A is O or NH; or a pharmaceutically acceptable salt thereof.

Formula 379

[001438] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 379. Such compounds are described in WO 2009/033704, published March 19, 2009, corresponding to PCT/EP2008/007551, filed September 12, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 379, this reference incorporated by reference herein controls.

[001439] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein

R ¹ is Ci-ealkyl; or Ci-3alkyl substituted with C3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, Ci-3alkyl or cyclopropyl; R ³ is hydrogen, fluoro, hydroxyl, hydroxyCnsalkyl, hydroxyCi-salkyloxy, fluoroCi-salkyl, fluoroCi-salkyloxy or cyano; and

Ar is unsubstituted phenyl; or a pharmaceutically acceptable salt thereof.

[001440] In an embodiment, the glutamate modulator is a compound selected from 3'- chloro-l'-cyclopropylmethyl-4-phenyl-3,4,5,6-tetrahydro-2H,r H-[l,4]bipyridinyl-2'-one and r-butyl-3'-chloro-4-phenyl-3,4,5,6-tetrahydro-2H,l'H-[l,4']b ipyridinyl-2'-one, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

[001441] In an embodiment, the glutamate modulator has the structure: pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 380

[001442] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 380. Such compounds are described in WO 2009/033703, published March 19, 2009, corresponding to PCT/EP2008/007550, filed September 12, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 380, this reference incorporated by reference herein controls.

[001443] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein R ¹ is Ci-ealkyl; or C1-3 alkyl substituted with C3-?cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;

R ³ is hydrogen, halo or trifluoromethyl;

R ⁴ is hydrogen, Ci-salkyl, Ci-salkyloxy, hydroxyCi-salkyl or tetrahydropyran-2-yloxy Ci-

3 alkyl; n is 1 or 2;

X is a covalent bond, O or NR ⁵ ;

R ⁵ is hydrogen, Ci-salkyl or hydroxyC2-3alkyl;

Y is O or CR ⁶ (OH);

R ⁶ is hydrogen or Ci-salkyl; or

R ⁴ and R ⁶ form a radical — CH2 — CH2 — ;or a pharmaceutically acceptable salt thereof. Formula 381

[001444] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 381. Such compounds are described in WO 2009/033702, published March 19, 2009, corresponding to PCT/EP2008/007549, filed September 12, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 381, this reference incorporated by reference herein controls.

[001445] In an embodiment, the glutamate modulator is a compound according to: or a stereochemically isomeric form thereof, wherein R ¹ is Ci-ealkyl; or Ci-salkyl substituted with C3-?cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;

R ² is halo, trifluoromethyl, Ci-salkyl or cyclopropyl;

R ³ is hydrogen or halo;

X is O, S, SO, SO ₂ , or CF ₂ ; and Ar is unsubstituted phenyl; unsubstituted pyridinyl; or phenyl or pyridinyl substituted with one or two substituents selected from the group consisting of halo, Ci-salkyl, Ci-salkoxy, trifluoromethyl, hydroxyCi-salkyl and (CH2) _n — CO2H, wherein n=0, 1, or 2; or a pharmaceutically acceptable salt thereof, provided that when R ³ is 2'-fluoro then Ar is not 3-pyridinyl substituted with one or two C i-sal kyl substituents.

[001446] In an embodiment, the glutamate modulator is a compound selected from: l-Butyl-3-chloro-4-[4-(2-methylpyridin-4-yloxy)-phenyl]-lH-p yridin-2-one l-Butyl-3-chloro-4-[2-fluoro-4-(2-methylpyridin-4-yloxy)-phe nyl]-lH-pyridin-2-one

3-Chl oro-1 -cyclopropylmethyl-4-[4-(2,6-dimethylpyri din-3 -yloxy)-3 -fluoro-phenyl]- 1H- pyridin-2-one

4-[4-(l-Butyl-3-chloro-2-oxo-l,2-dihydro-pyridin-4-yl)-ph enoxy]-benzoic acid l-Cyclopropylmethyl-4-[4-(2,6-dimethyl-pyridin-4-yloxy)-3-fl uoro-phenyl]-3- trifluoromethyl- lH-pyridin-2-one, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 382

[001447] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 382. Such compounds are described in WO 2008/150233, published December 11, 2008, corresponding to PCT/SE2008/050666, filed June 5, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 382, this reference incorporated by reference herein controls.

[001448] In an embodiment, the glutamate modulator is a compound according to: R ² is hydrogen or Ci-3alkyl, or a pharmaceutically acceptable salt, hydrate, optical isomer, or combination thereof.

[001449] In further embodiments, the glutamate modulator is a compound selected from:

7-methyl-5-(3-piperazin-l-ylmethyl-[l,2,4]oxadiazol-5-yl) -2-(4-tri fluoromethoxy benzyl)-2,3-dihydroisoindol-l-one;

2-(4-chloro-benzyl)-5-[3-(2,5-diaza-bicyclo[2.2.1]hept-2- ylmethyl)-[l,2,4]oxadiazol-

5 -yl] -7 -methyl-2, 3 -dihy dro-i soindol- 1 -one;

2-(4-chloro-benzyl)-7-methyl-5-[3-(3-methyl-piperazin-l-y lmethyl)-[l,2,4]oxadiazol- 5-yl]-2,3-dihydro-isoindol-l-one;

2-(4-chloro-benzyl)-7-methyl-5-(3-piperazin-l-ylmethyl-[l ,2,4]oxadiazol-5-yl)-2,3- dihydro-isoindol-l-one;

2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazin-l-y lmethyl)-[l,2,4]oxadiazol- 5-yl]-2,3-dihydro-isoindol-l-one, or

2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazin-l-y lmethyl)-[l,2,4]oxadiazol-5-yl]-

2,3-dihydro-isoindol-l-one, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

[001450] In an embodiment, the glutamate modulator is a compound selected from; or a pharmaceutically acceptable salt thereof or a substituted variant retaining glutamate modulatory activity.

Formula 383

[001451] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 383. Such compounds are described in WO 2008/150232, published December 11, 2008, corresponding to PCT/SE2008/050665, filed June 5, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 383, this reference incorporated by reference herein controls. [001452] In an embodiment, the glutamate modulator is a compound according to: wherein

R ¹ is halo or Ci-shaloalkoxyl;

R ² is hydrogen or Cnsalkyl;

R ³ is Ci or CH ₃ ;

R ⁴ is hydrogen or Cnsalkyl;

Q is

R ⁵ is hydrogen or Cnsalkyl, and n is 1 or 2, wherein when n is 2 both R ⁵ moieties can be attached to the same carbon atom, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof. [001453] In an embodiment, the glutamate modulator is the compound 7-chloro-5-(5- piperazin-l-ylmethyl-[l,2,4]oxadiazol-3-yl)-2-(4-trifluorome thoxybenzyl)-2,3- dihydroisoindol-l-one, or a pharmaceutically acceptable salt, or a hydrate thereof, or substituted variant retaining glutamate modulatory activity.

Formula 384

[001454] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 384. Such compounds are described in WO 2008/145616, published December 4, 2008, corresponding to PCT/EP2008/056378, filed May 23, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 384, this reference incorporated by reference herein controls.

[001455] In an embodiment, the glutamate modulator is a compound according to: wherein

X is selected from the group consisting of O, S, S(O), S(O)2, NH, NHC(O), and NR ^X ; R ^x is Ci-Ce-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^xa , Ci-Ce-haloalkyl, Cs-Cs-cycloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, phenyl, 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members, the heteroatoms being selected from the group consisting of O, S, and N, wherein hetaryl and phenyl are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ^xb , C(=O)— R ^xl , C(=O)— OR ^x2 , C(=O)NR ^x3 R ^x4 , S(O) ₂ R ^x5 or S(O) ₂ NR ^x3 R ^X4 ; wherein

R ^xl is selected from the group consisting of hydrogen, Ci-Cs-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, and phenyl wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^xa ,

Ci-Ce-haloalkyl, Cs-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy, phenyl, and 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members, the heteroatoms being selected from the group consisting of O, S, and N, wherein phenyl and hetaryl are unsubstituted or may carry a fused benzene ring and/or 1, 2, 3, 4 or 5 identical or different radicals R ^xb ;

R ^x:i is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ^xb is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ^x2 is selected from the group consisting of Ci-Cs-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^xa , Ci-Cs-haloalkyl, and Cs-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy;

R ^x3 is selected from the group consisting of hydrogen, Ci-Cs alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^xa , Ci-Ce-haloalkyl, Ci-Csalkoxy, Ci-Cshaloalkoxy, and Cs-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy;

R ^x4 is selected from the group consisting of hydrogen and Ci-Cs-alkyl, or

R ^x3 and R ^x4 together with the nitrogen atom, to which they are bound, form a heterocyclic radical, selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, N- alkylpiperazinyl, N-phenylpiperazinyl, and morpholinyl; and

R ^x5 has one of the meanings given for R ^xl ;

Y is a chemical bond;

A is CR ^a R ^b , wherein R ^a and R ^b are, independently of each other, selected from the group consisting of hydrogen, halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and C1-C4- haloalkoxy; R ^b may also be OH, if R ^a is hydrogen, Ci-C4-alkyl, or Ci-C4-haloalkyl;

Ar is phenyl;

R ¹ is C(=O)— R ⁴ ;

R ² is selected from the group consisting of hydrogen, CN, OH, halogen, Ci-Cs-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, C3-C6- cycloalkyl, and Ci-C4-alkoxy, Cs-Ce-cycloalkyl, Ci-Cs-haloalkyl, Ci-Cs-alkoxy, and Ci-Cs-haloalkoxy;

R ³ is selected from the group consisting of hydrogen, halogen, Ci-C4-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH and C1-C4- alkoxy, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, and Cs-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy;

R ⁴ is selected from the group consisting of

Cs-Cs-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, Cs-Cs-cycloalkyl, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^4a , Ci-Cs-haloalkyl, C2-Cs-alkenyl,

C2-Cs-alkynyl, Cs-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy, phenyl, which is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^4b , and 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members, the heteroatoms being selected from the group consisting of O, S, and N, wherein hetaryl is unsubstituted or carries 1, 2, 3 or 4 identical or different radicals R ^4b , or

R ⁴ together with R ² forms a Ci-Cs-alkylene or C2-C5-alkenylene moiety, wherein one CH2- moiety may be replaced by oxygen, sulphur or a N — R ^4c -moiety and wherein Ci-Cs-alkylene and C2-C5-alkenylene may be unsubstituted or carry 1, 2, 3, or 4 radicals selected from the group consisting of halogen, CN, OH, NH2, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkylamino, di-(Ci-C4-alkyl)amino, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ^4a is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ^4b is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ^4c is selected from the group consisting of hydrogen, CN, OH,

C i-Cx-alkyl, which is unsubstituted or carries a radical selected from the group consisting of Ci-C4-alkoxy, Ci-C4-alkylthio, Ci-C4-haloalkoxy, Ci-C4-haloalkylthio, Cs-Ce-cycloalkyl, which is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals selected from the group consisting of halogen and Ci-C4-alkyl, and phenyl or benzyl, wherein the phenyl ring in the last two radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and C1-C4- haloalkoxy, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

Het is pyrazolyl, wherein Het is unsubstituted or may carry a first substituent R ¹⁰ and additionally may carry 1 or 2 further substituents selected from the group consisting of R ¹¹ , and R ¹² ;

R ¹⁰ is selected from the group consisting of halogen, cyano,

C i-Cx-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^4a , C i-Cx-alkoxy, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^4a , Ci-Cs-haloalkyl, Ci-Cs-haloalkoxy, C2-Cs-alkenyl, C2-Cs-alkynyl,

Cs-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy,

Cs-Cs-cycloalkoxy, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy, C(=O)— R ¹³ , C(=O)— OR ¹⁴ , NR ¹⁵ R ¹⁶ , C(=O)NR ¹⁵ R ¹⁶ , SO ₂ R ¹⁷ , phenyl, O-phenyl, CH2-phenyl, CH(CH3)-phenyl, CH(OH)phenyl, S-phenyl, O — CH2- phenyl, wherein the phenyl ring in the last seven mentioned radicals may be unsubstituted or may carry 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy, and 5- or 6-membered heteroaryl, having 1, 2, or 3 heteroatoms as ring members, the heteroatoms being selected from the group consisting of O, S, and N, which is unsubstituted or may carry

1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, OH, C1-C4- alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ¹¹ is selected from the group consisting of CN, OH, halogen, Ci-Cs alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH and C1-C4- alkoxy, Ci-Cs-haloalkyl, Ci-Cs-alkoxy, Ci-Cs-haloalkoxy, and phenyl, which may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, CN, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ¹² is selected from the group consisting of CN, OH, halogen, Ci-Cs-alkyl, which is unsubstituted or carries one radical selected from OH and Ci-C4-alkoxy, Ci-Cs-haloalkyl, Ci- Cs-alkoxy, and Ci-Cs-haloalkoxy, or

R ¹¹ and R ¹² together with the carbon atom, to which they are bound, form a carbonyl group;

R ¹³ is selected from the group consisting of hydrogen,

C i-Cx-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1,

2, 3, 4 or 5 identical or different radicals R ^13a , Ci-Cs-haloalkyl, Cs-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy, phenyl, and 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members, the heteroatoms being selected from the group consisting of O, S, and N, wherein phenyl and hetaryl are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ^13b ;

R ^13a is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ^13b is selected from the group consisting of halogen, CN, OH, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, and Ci-C4-haloalkoxy;

R ¹⁴ is selected from the group consisting of

Ci-Cs-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^13a , Ci-Cs-haloalkyl, and

C3-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy;

R ¹⁵ is selected from the group consisting of hydrogen,

Ci-Cs-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ^13a , and

C3-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy;

R ¹⁶ is selected from the group consisting of hydrogen and Ci-Cs-alkyl, or

R ¹⁵ and R ¹⁶ together with the nitrogen atom, to which they are bound, form a heterocyclic radical, selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, N- alkylpiperazinyl, N-phenylpiperazinyl, and morpholinyl;

R ¹⁷ is selected from the group consisting of Ci-Cs-alkyl, which is unsubstituted or carries one radical selected from the group consisting of OH, Ci-C4-alkoxy, and phenyl, wherein the phenyl ring itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R ¹⁷ , Ci-Cs-haloalkyl,

C3-Cs-cycloalkyl, which is unsubstituted or carries 1, 2, 3 or 4 radicals selected from the group consisting of halogen, Ci-C4-alkyl, and Ci-C4-alkoxy, phenyl, and 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members, the heteroatoms being selected from the group consisting of O, S, and N, wherein phenyl and hetaryl are unsubstituted or carry 1, 2, 3, 4, or 5 identical or different radicals R ^17b , wherein R ^17a is as defined for R ^13a and R ^17b is as defined for R ^13b ; or a pharmaceutically acceptable salt or tautomer thereof.

Formula 385

[001456] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 385. Such compounds are described in WO 2008/112483, published September 18, 2008, corresponding to PCT/US2008/056002, filed March 6, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 385, this reference incorporated by reference herein controls.

[001457] In an embodiment, the glutamate modulator is a compound according to: wherein: is a single or a double bond; p is 0 or 1; n is an integer from 0 to 3;

X is oxygen or sulfur;

Y is oxygen or sulfur;

Ri and R2 are the same or different and independently of each other selected from the group consisting of hydrogen, CF3, straight or branched chain (Ci-Cio)alkyl, mono- or di-fluoro(Ci- C4)alkyl, mono- or di-fluoro(Ci-C4)alkoxy(Co-C4)alkyl, mono- or di-fluoro(Ci- C4)alkylsulfanyl(Co-C4)alkyl, mono- or di-fluoro(Ci-C4)alkylsulfinyl(Co-C4)alkyl, mono- or di-fluoro(Ci-C4)alkylsulfonyl(Co-C4)alkyl, (Ci-Cio)alkoxy(Co-C4)alkyl, (Ci- Cio)alkylsulfanyl(Co-C4)alkyl, (Ci-Cio)alkylsulfinyl(Co-C4)alkyl, (Ci-Cio)alkylsulfonyl(Co- C4)alkyl, (Ci-Cio)alkoxy mono- or di-fluoro(Ci-C4)alkyl, (Ci-Cio)alkylsulfanyl mono- or di- fluoro(Ci-C4)alkyl, (Ci-Cio)alkylsulfinyl mono- or di-fluoro(Ci-C4)alkyl, (Ci-

Cio)alkyl sulfonyl mono- or di-fluoro(Ci-C4)alkyl, (C6,Cio)aryl(Co-C4)alkyl, (Ce,Cio)aryl mono- or difluoro(C2-C4)alkyloxy, (C6,Cio)aryloxy(Co-C4)alkyl, (C6,Cio)arylsulfanyl(Co- C4alkyl), (C6,Cio)arylsulfinyl(Co-C4)alkyl, (C6,Cio)arylsulfonyl(Co-C4alkyl), (C3- C8)cycloalkyl(Co-C4)alkyl, mono- or difluoro(C3-Cs)cycloalkyl(Co-C4)alkyl, C3- C8)cycloalkoxy(Co-C4)alkyl, mono- or difluoro(C3-Cs)cycloalkyloxy(Co-C4)alkyl, (C3- Cs)cycloalkyl mono- or difluoro(Ci-C4)alkyl, (C3-Cs)cycloalkyl mono- or difluoro (C2- C4)alkyloxy, (C3-Cs)cycloalkylsulfanyl(Co-C4)alkyl, (C3-Cs)cycloalkylsulfinyl(Co-C4)alkyl, (C3-Cs)cycloalkylsulfonyl(Co-C4)alkyl, hydroxy(Ci-C4)alkyl, heteroaryl(Co-C4)alkyl, heteroaryl mono- or difluoro(Ci-C4)alkyl, heteroaryloxy(Co-C4)alkyl, heteroaryloxy mono- or difluoro(C2-C4)alkyl, heteroarylsulfanyl(Co-C4)alkyl, heteroarylsulfinyl(Co-C4)alkyl, heteroarylsulfonyl(Co-C4)alkyl, saturated heterocyclic(Co-C4)alkyl, saturated heterocyclic mono- or di-fluoro(Ci-C4)alkyl, saturated heterocyclyloxy(Co-C4)alkyl, saturated heterocyclyloxy mono- or di-fluoro(C2-C4)alkyl, saturated heterocyclylsulfanyl(Co-C4)alkyl, heterocyclylsulfinyl(Co-C4)alkyl, heterocyclylsulfonyl(Co-C4)alkyl, — CO2R22 or — CONR23R24 wherein R22, R23 and R24 are the same or different and independently of each other selected from hydrogen or (Ci-C4)alkyl; and wherein Ri and R2 are optionally further substituted;

R3 and R4 are the same or different and independently of each other selected from the group consisting of hydrogen, (Ci-C4)alkyl, (C3-Cs)cycloalkyl and (Ce,Cio)aryl(Ci-C4)alkyl; or R3 and R4 taken together with the carbon atom to which they are attached form a substituted or unsubstituted C5-C7 carbocyclic ring;

Rs, Re and R7 are the same or different and independently of each other selected from the group consisting of hydrogen, (Ci-C4)alkyl and (C3-Cs)cycloalkyl;

Rs is selected from the group consisting of substituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetralinyl, substituted or unsubstituted benzocycloheptanyl, substituted or unsubstituted hexahydrofluorenyl, substituted or unsubstituted (C3-Cs)cycloalkyl, substituted or unsubstituted furanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted tetrahydroisoquinolinyl, substituted or unsubstituted tetrahydroquinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted tetrahydrodibenzofuranyl and substituted or unsubstituted hexahydrodib enzofurany 1 ; wherein substituted refers to subsrtituents are selected from the group consisting of CF3, OCF3, halogen, CN, SF5, straight or branched chain (Ci-C2o)alkyl, (Ci-C4)alkylsulfonyl, substituted or unsubstituted (C3-Cio)cycloalkyl(CR9Rio)m, substituted or unsubstituted (Ce- Ci6)spirocycloalkyl, substituted or unsubstituted (Ce ,Cio)aryl(CR9Rio)m, substituted or unsubstituted heteroaryl(CR9Rio)m, substituted or unsubstituted (Ce,Cio)aryl O-Cxcycloalkyl, substituted or unsubstituted (C8-Ci3)bicyclic, substituted or unsubstituted adamantyl, substituted or unsubstituted indanyl, substituted or unsubstituted tetralinyl, substituted or unsubstituted benzocycloheptyl, straight or branched chain (Ci-C2o)alkoxy, substituted or unsubstituted (C3-Cio)cycloalkoxy, substituted or unsubstituted (Ce,Cio)aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted piperidinyl(CR9Rio)m, substituted or unsubstituted piperazinyl(CR9Rio)m, substituted or unsubstituted (C4-C?)lactam, substituted or unsubstituted tetrahydropyranyl(CR9Rio)m, substituted or unsubstituted tetrahydrofuranyl(CR9Rio)m, substituted or unsubstituted 1,3-dioxanyl, substituted or unsubstituted 1,3-dioxolanyl, (Ci-C4)alkoxy ethoxy, substituted or unsubstituted (C3- Cs)cycloalkyloxyethoxy, substituted or unsubstituted (Ce,Cio)aryloxyethoxy and substituted or unsubstituted heteroaryloxy ethoxy; wherein m is an integer from 0 to 10;

R9 and Rio are the same or different and independently of each other chosen from hydrogen or (Ci-C4)alkyl; or

R9 and Rio taken together with the carbon atom to which they are attached form a substituted or unsubstituted C3-C8 carbocyclic ring, and wherein the substituted C3-C8 carbocyclic ring is substituted by the aforementioned substituents; or a salt thereof or an enantiomer, stereoisomer or a tautomer thereof or a racemic mixture thereof; and wherein when R ⁸ is substituted phenyl, R ² is not methyl, ethyl or propyl; and wherein R ⁸ is substituted pheny, the substitution is not 2-methyl on the phenyl ring of R ⁸ .

Formula 386

[001458] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 386. Such compounds are described in WO 2008/107481, published September 12, 2008, corresponding to PCT/EP2008/052768, filed March 7, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 386, this reference incorporated by reference herein controls.

[001459] In an embodiment, the glutamate modulator is a compound according to: including any stereochemically isomeric form thereof, wherein

Ri is C4-ealkyl, or Ci-3alkyl substituted with C3-?cycloalkyl;

R2 is hydrogen, halo or trifluoromethyl;

R3 is hydrogen or Ci-4alkyl substituted with hydroxyl;

X is O or NH; n is an integer of value 1 or 2; or a pharmaceutically acceptable salt thereof.

Formula 387

[001460] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 387. Such compounds are described in US 2008/107480, published September 12, 2008, corresponding to PCT/EP2008/052767, filed March 7, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 387, this reference incorporated by reference herein controls.

[001461] In an embodiment, the glutamate modulator is a compound according to: including any stereochemically isomeric form thereof, wherein

Ri is C4-ealkyl, or Ci-3alkyl substituted with C3-?cycloalkyl;

R2 is hydrogen or halo;

A is pyridinyl substituted with one or two substituents, each substituent independently selected from halo or Ci-4alkyl; n is an integer of value 1 or 2; or a pharmaceutically acceptable salt thereof; provided that if R2 is 2-fluoro then A is not 3-pyridinyl substituted with one or two substituents, each substituent independently selected from halo or Ci-4alkyl.

Formula 388

[001462] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 388. Such compounds are described in WO 2008/107479, published September 12, 2008, corresponding to PCT/EP2008/052766, filed March 7, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 388, this reference incorporated by reference herein controls.

[001463] In an embodiment, the glutamate modulator is a compound according to: including any stereochemically isomeric form thereof, wherein

Ri is C4-6 alkyl, or C1-3 alkyl substituted with C3-7 cycloalkyl;

R2 is hydrogen; hydroxyl; fluoro; C1-4 alkyl substituted with hydroxyl; C1-4 alkyl substituted with fluoro; or Ci-4alkyloxy substituted with fluoro;

R3 is hydrogen or halo; provided that if R3 is halo, then R2 is hydroxyl; or a pharmaceutically acceptable salt thereof or a solvate thereof.

[001464] In an embodiment, the glutamate modulator is: , or a pharmaceutically acceptable salt thereof or a solvate thereof or substituted variant retaining glutamate modulatory activity.

Formula 389

[001465] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 389. Such compounds are described in WO 2007/104783, published September 20, 2007, corresponding to PCT/EP2007/052442, filed March 15, 2007, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 389, this reference incorporated by reference herein controls.

[001466] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt thereof, or a stereochemically isomeric form thereof, wherein

V ¹ is selected from the group consisting of an unsubstituted bivalent saturated, straight or branched hydrocarbon radical having from 1 to 6 carbon atoms;

M ¹ is selected from the group consisting of hydrogen; cycloC3-?alkyl; phenyl optionally substituted with OCF3 or F; phenyloxy-; and tetrahydropyranyl;

L is selected from the group consisting of a covalent bond; — O — ; — OCH2 — ; NR ⁷ — ; wherein R ⁷ , is selected from the group consisting of hydrogen and unsubstituted Ci-3alkyl; R ² and R ³ are hydrogen;

A is piperidinyl selected from the group consisting of wherein n is an integer equal to 0, 1, or 2;

R ⁴ is, when present, at any of b, or c positions and is selected from the group consisting of Ci- 6-alkyl; Ci-6-alkyloxy; Ci-6-alkyloxycarbonyl-; polyhaloCi-3alkyl-; Het ³ ; Het ³ -Ci-6-alkyl-; Het ³ -oxy-; Het ³ -oxy-Ci-6-alkyl-; Het ³ -Ci-6-alkyloxy; — NR ^a R ^b ; Ci-6-alkyl-NR ^a R ^b ; wherein R ^a and R ^b are selected from the group consisting of hydrogen, Ci-6-alkyl, and C3-7-cycloalkyl; and

Het ³ is selected from the group consisting of pyridinyl; pyrimidinyl; pyridazinyl; pyrrolyl; indolyl; morpholinyl; oxadiazolyl; benzoxazolyl; benzofuranyl; indolinyl; 1,2,3,4-tetrahydro- isoquinolinyl; phthalazinyl; and benzo[l,3]dioxolyl wherein each radical is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halo, Ci-ealkyl, C3-7-cycloalkyl, polyhaloCi-salkyl, cyano, mono(Ci-6alkyl)amino, oxo, phenyl, morpholinyl, and Ci-salkyloxy. In another embodiment, the compound is selected from

Formula 390

[001467] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 390. Such compounds are described in WO 2009/030032, published March 23, 2006, corresponding to PCT/EP2005/054636, filed September 16, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 390, this reference incorporated by reference herein controls.

[001468] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein: R ¹ is not hydrogen and is a radical — V1-M1;

Vi is a covalent bond or a radical selected from the group consisting of — (Ci-Ce)alkyl- optionally substituted with halo(Ci-Ce)alkyl; — (C2-Ce)alkynyl-; — (C2-Ce)alkenyl-; — (Ci- C ₆ )alkyl-C(=O)— (Co-C ₆ )alkyl-; — (Ci-C ₆ )alkyl-C(=O)NR ⁷ — (Co-C ₆ )alkyl- wherein R ⁷ is hydrogen or — (Ci-Ce)alkyl; and — (Ci-Ce)alkyl-O — (Co-Ce)alkyl;

R ² is hydrogen;

R ³ is a — V2-M2 radical;

R ⁴ is hydrogen; R ⁵ is hydrogen;

V2 is a covalent bond or a radical selected from the group consisting of — O — ; — C(=O) — ; — NR ¹⁰ — ; and a radical selected from the group consisting of ethyl; n-propyl; i-propyl; n- butyl; i-butyl; s-butyl; t-butyl; n-pentyl; i-pentyl; t-pentyl; neopentyl; n-hexyl; i-hexyl; t- hexyl; — (Ci-Ce)alkyl- substituted with hydroxyl; — (C2-Ce)alkynyl-; — (Co-Ce)alkyl-O — (Ci-C ₆ )alkyl-; and — (Co-C ₆ )alkyl-NR ¹⁰ — (Ci-C ₆ )alkyl-;

Rio is hydrogen or an (Ci-Ce)alkyl radical;

(R ² and R ³ ) or (R ⁴ and R ⁵ ) taken together with the carbon atoms to which they are respectively attached may form an optionally substituted phenyl ring optionally substituted with a radical selected from the group consisting of methoxy, 4-methoxyphenyl-ethylamino, 4-hydroxyphenyl-ethylamino or 4-methoxyphenyl-ethyloxy;

Mi and M2 are each independently selected from the group consisting of hydrogen, and an optionally substituted radical selected from the group consisting of cycloalkyl, and an optionally substituted up to 10 membered ring system selected from the group consisting of aryl and heteroaryl; wherein the cycloalkyl radical is cyclopropyl, cyclopentyl or cyclohexyl; the aryl radical is phenyl and naphthyl; the heteroaryl radical is pyridyl, indolyl, pyrrolyl, pyrazolyl, furyl, thienyl, pyrimidinyl, quinolinyl, quinoxalinyl, isoxazolyl, oxadiazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, benzofuranyl, benzodioxolyl, pyrazinyl and benzothiophenyl; and wherein any of the optionally substituted aforementioned rings may carry at least one substituent selected from the group consisting of (Ci-Ce)alkyl; (Ci-Ce)alkyloxy; hydroxy(Ci- Ce)alkyloxy; (Ci-C6)alkyloxy(Ci-Ce)alkyl; (Ci-C6)alkyloxy(Ci-Ce)alkyloxy; (Ci- Ce)alkyloxycarbonyl; (Ci-C6)-alkyloxycarbonyl(Ci-Ce)alkyl; (Ci-C6)alkyloxycarbonyloxy; (Ci-C6)-alkyloxycarbonyl(Ci-Ce)alkyloxy; (Ci-Ce)alkylcarbonyl; (Ci-Ce)-alkylcarbonyl(Ci- Ce)alkyloxy; (Ci-Ce)alkylthieno; (Ci-Ce)alkylsulfonyl; morpholinyl sulfonyl; pyrrolidinylsulfonyl; (Ci-C6)alkylsulfonylamino; (C2-Ce)alkenyl; phenyl; fluoro; chloro; hydroxy; hydroxy(Ci-Ce)alkyl; cyano; cyano(Ci-Ce)alkyloxy; trifluoro(Ci-C6)alkyl; trifluoro(Ci-C6)alkyloxy; amino; amino(Ci-Ce)alkyloxy; mono- and di((Ci-C6)alkyl)amino; mono- and di((Ci-C6)alkylcarbonyl)amino; mono- and di((Ci-C6)alkyloxycarbonyl)amino; mono- and di((Ci-C6)alkylcarbonyl)amino(Ci-C6)alkyl; mono- and di((Ci-Ce)- alkylsulfonyl)amino(Ci-C6)alkyloxy; mono- and di((Ci-C6)alkyl)amino(Ci-C6)-alkyloxy; mono- and di((Ci-C6)alkylcarbonyl)amino(Ci-C6)alkyloxy; mono- and di((Ci- C6)alkyl)aminocarbonyl; mono- and di((Ci-C6)alkyl)aminocarbonyl(Ci-C6)alkyl; mono- and di((Ci-C6)alkyl)aminocarbonyl(Ci-C6)alkyloxy; mono- and di((Ci-C6)alkyl)amino(Ci- Ce)alkylamino; nitro; tri(Ci-C6)alkylsilyl; morpholinyl; heterocyclic-(Ci-Ce)alkyloxy selected from pyridinyl-(Ci-C6)alkyloxy, morpholinyl-(Ci-C6)alkyloxy, pyrrolidinyl-(Ci-Ce)alkyloxy optionally substituted with oxo, isoxazolyl-(Ci-Ce)alkyloxy, imidazolyl-(Ci-C6)alkyloxy, tetrazolyl-(Ci-Ce)alkyloxy and thiazolyl-(Ci-Ce)alkyloxy, wherein the isoxazolyl, imidazolyl, tetrazolyl or thiazolyl rings may be optionally substituted with methyl.

[001469] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein:

Mi is a phenyl group having at least one halo group; and

M2 is a phenyl group substituted with at least one substituent selected from the group consisting of (Ci-Ce)alkyloxy, pyridinyl-(Ci-C6)alkyloxy, morpholinyl-(Ci-C6)alkyloxy, pyrrolidinyl-(Ci-Ce)alkyloxy optionally substituted with oxo, isoxazolyl-(Ci-Ce)alkyloxy, imidazolyl-(Ci-C6)alkyloxy, tetrazolyl-(Ci-Ce)alkyloxy or thiazolyl-(Ci-Ce)alkyloxy, wherein the isoxazolyl, imidazolyl, tetrazolyl or thiazolyl rings may be optionally substituted with methyl.

Formula 391

[001470] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 391. Such compounds are described in WO 2006/030031, published March 23, 2006, corresponding to PCT/EP2005/054635, filed September 16, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 391, this reference incorporated by reference herein controls.

[001471] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein

Y is selected from — N — and — C(R ² ) — ;

X is selected from — S — , — S(O) — , — S(O)2 — , — O — and — N(R ³ ) — ;

R ¹ , R ² and R ³ are each independently selected from the group of hydrogen, halo, — CN, — OH, — NO2, — CF ₃ , — NH ₂ , — SH, — C(=NR ⁴ )NR ⁵ R ⁶ , — C(=O)R ⁴ , — C(=NR ⁴ )R ⁵ , — C(=O)O R ⁴ , — C(=O)NR ⁴ R ⁵ , —SR ⁴ , — S(O)R ⁴ , — S(O) ₂ R ⁴ , — NR ⁴ R ⁵ , — NR ⁴ C(=O)R ⁵ , — NR ⁴ C(=NR ⁵ ) R ⁶ , — NR ⁴ C(=NR ⁵ )NR ⁶ R ⁷ , — NR ⁴ C(=O)O R ⁵ , — NR ⁴ C(=O)NR ⁵ R ⁶ — NR ⁴ S(O) ₂ R ⁵ — S(O) ₂ NR ⁴ R ⁵ , — C(=S)NR ⁴ R ⁵ , — OC(=O)R ⁴ , — OC(=O)NR ⁴ R ⁵ , —OR ⁴ , an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)alkylhalo, — (C ₂ -Ce)alkynyl, — (C ₂ -Ce)alkenyl, — (C3-C?)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci- Ce)alkylcyano, — (Ci-Ce)alkylaryl, — (Ci-Ce)alkylheteroaryl, aryl and heteroaryl, and a radical described as — V1-T1-M1;

Zi, Z ₂ , Z ₃ and Z4 are each independently selected from a covalent bond, C, S, N and O, with the provision that a 5 or 6 membered heteroaryl or aryl ring is formed, which may optionally be substituted by 1 to 4 radicals A ⁿ ;

A ⁿ radicals are each independently selected from the group of hydrogen, halo, — CN, — OH, — NO ₂ , — CF3, — SH, — NH ₂ , an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)alkylhalo, — (C ₂ -Ce)alkynyl, — (C ₂ -Ce)alkenyl, — (C3-C?)cycloalkyl, — (Ci-Ce)alkylcyano, — O — (Ci-Ce)alkyl, — O — (Ci-Ce)alkylhalo, — O — (Ci-Ce)alkylcyano, — O— (C ₃ -C ₆ )alkynyl, — O— (C3-C ₇ )cycloalkyl, — O— (C ₂ -C ₆ )alkenyl, — O— (C ₂ -C ₆ )alkyl- OR ³ — O— (Ci-C ₆ )alkyl -heteroaryl, — O— (Co-C ₆ )alkylaryl, — (Co-C ₆ )alkyl-OR ³ , — (C ₃ - C7)cycloalkyl-(Ci-Ce)alkyl, — O — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — O-heteroaryl, heteroaryl, — (Ci-Ce)alkyl-heteroaryl, aryl, — O-aryl, — (Ci-Ce)alkylaryl, — (Ci- C ₆ )alkylhalo-OR ⁸ , — (C ₃ -C ₆ )alkynyl-OR ³ , — (C ₃ -C ₆ )alkenyl-OR ³ , — (Co-C ₆ )alkyl-SR ³ , — O— (C ₂ -C ₆ )alkyl-SR ⁸ , — (Ci-C ₆ )alkyl-S(=O)— R ⁸ , — O— (Ci-C ₆ )alkyl-S(=O)— R ³ , — (Co- C ₆ )alkyl-S(=O) ₂ — R ³ , O— (Ci-C ₆ )alkyl-S(=O) ₂ — R ³ , — (Co-C ₆ )alkyl-NR ⁸ R ⁹ , — O— (C ₂ - C ₆ )alkyl-NR ⁸ R ⁹ , — (Co-C ₆ )alkyl-S(=0) ₂ NR ⁸ R ⁹ , — (Co-C ₆ )alkyl-NR ³ — S(=O) ₂ R ⁹ , — O— (Ci- C ₆ )alkyl-S(=O) ₂ NR ⁸ R ⁹ , — O— (Ci-C ₆ )alkyl-NR ⁸ — S(=O) ₂ R ⁹ , — (Co-C ₆ )alkyl-C(=0)— NR ⁸ R ⁹ , — (C ₀ -C ₆ )alkyl-NR ⁸ C(=O)— R ⁹ , — O— (Ci-C ₆ )alkyl-C(=O)— NR ⁸ R ⁹ , — O— (Ci- C ₆ )alkyl-NR ⁸ C(=O)— R ⁹ , — (C ₀ -C ₆ )alkyl-OC(=O)— R ³⁸ , — (Co-C ₆ )alkyl-C(=0)— OR ³ , — O— (Ci-C ₆ )alkyl-OC(=O)— R ³ , — O— (Ci-C ₆ )alkyl-C(=O)— OR ³ , — (Co-C ₆ )alkyl-C(=0)— R ³ , — O— (Ci-C ₆ )alkyl-C(=O)— R ³ , — (Co-C ₆ )alkyl-NR ⁸ — C(=O)— OR ⁹ , — (Co-C ₆ )alkyl- O— C(=O)— NR ⁸ R ⁹ , — (Co-C ₆ )alkyl-NR ⁸ — C(=NR ⁹ )— NR^R ¹ \ — (Co-C ₆ )alkyl-NR ⁸ — C(=O)— NR ⁹ R ¹⁰ , — (Co-C ₆ )alkyl-NR ³ — C(=S)— NR ⁹ R ¹⁰ , and a — V ₂ -T ₂ -M ₂ radical; n is an integer ranging from 1 to 4;

Ti, Vi, T ₂ and V ₂ are each independently selected from the group of a covalent bond, — O — , — C(=O)— , — C(=O)O— , — C(=O)NR ¹² — , — S— , — S(O)— , — S(O) ₂ — , — S(O) ₂ NR ¹² , —NR ¹² , NR ¹² C(=O)— , — NR ¹² C(=O)NR ¹³ — , — NR ¹² S(O) ₂ — , — NR ¹² C(=S)NR ¹³ — , — OC(=O) — , — OC(=O)NR ¹² , — NR ^I2 C(=O)O — , and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl-, — (C ₂ -Ce)alkynyl-, — (C ₂ -Ce)alkenyl-, — (C3- C ₇ )cycloalkyl-, — (C3-C8)cycloalkenyl-, — (Ci-Ce)alkylhalo-, — (Ci-Ce)alkylcyano-, — (Co- C ₆ )alkyl-O— (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl-0— (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-0— (C ₂ - C ₆ )alkenyl-, — (Co-C ₆ )alkyl-0— (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-0— (C ₄ - Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-C(=0)— (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl-C(=0)— (C ₂ - C ₆ )alkynyl-, — (Co-C ₆ )alkyl-C(=0)— (C ₂ -C ₆ )alkenyl-, (Co-C ₆ )alkyl-C(=0)— (C ₄ - Cio)alkylcycloalkyl-, — (Co-Ce)alkyl-C(=0) — (C3-C ₇ )cycloalkyl-, — (Co-Ce)alkyl-C(=0)0 — (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl-C(=0)0— (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-C(=0)0— (C ₂ - C ₆ )alkenyl-, — (Co-C ₆ )alkyl-C(=0)0— (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-C(=0)0— (C ₄ - Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-C(=0)NR ¹² — (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl- C(=O)NR ¹² — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-C(=0)NR ¹² — (C ₂ -C ₆ )alkenyl-, — (Co- C ₆ )alkyl-C(=O)NR ¹² — (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-C(=0)NR ¹² (C ₄ - Cio)alkylcycloalkyl-, — (Co-Ce)alkyl-S — (Ci-Ce)alkyl-, — (Co-Ce)alkyl-S — (C ₂ -Ce)alkynyl-, — (Co-C ₆ )alkyl-S— (C ₂ -C ₆ )alkenyl-, — (Co-C ₆ )alkyl-S— (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl- S— (C ₄ -Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-S(0)— (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl-0— (C ₂ - C ₆ )alkynyl-, — (Co-C ₆ )alkyl-S(0)— (C ₂ -C ₆ )alkenyl-, — (Co-C ₆ )alkyl-S(0)— (C3- C ₇ )cycloalkyl-, — (Co-Ce)alkyl-S(O) — (C ₄ -Cio)alkylcycloalkyl-, — (Co-Ce)alkyl-S(0) ₂ — (Ci- C ₆ )alkyl-, — (Co-C ₆ )alkyl-S(0) ₂ — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-S(0) ₂ — (C ₂ -C ₆ )alkenyl-, — (Co-Ce)alkyl-S(0) ₂ — (C3-C ₇ )cycloalkyl-, — (Co-Ce)alkyl-S(0) ₂ — (C ₄ -Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-S(0) ₂ NR ¹² — (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl-S(0) ₂ NR ¹² — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-S(0) ₂ NR ¹² — (C ₂ -C ₆ )alkenyl-, — (Co-C ₆ )alkyl-S(0) ₂ NR ¹² — (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-S(0) ₂ NR ¹² — (C ₄ -Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² — (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl-NR ¹² — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NR ¹² — (C ₂ -C ₆ )alkenyl-, — (Co- Ce)alkyl-NR ¹² (C3-C ₇ )cycloalkyl-, — (Co-Ce)alkyl-NR ¹² — (C4-Cio)alkylcycloalkyl-, — (Co- C ₆ )alkyl-NR ¹² C(=O)— (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=0)— (C ₂ -C ₆ )alkynyl-, — (Co- C ₆ )alkyl-NR ¹² C(=O)— (C ₂ -C ₆ )alkenyl-, — (Co-C ₆ )alkyl-NR ¹² C(=0)— (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=0)— (C ₄ -Cio)alkylcycloalkyl-, — (C ₀ -C ₆ )alkyl-NR ¹² C(=O)NR ¹³ — (Ci- C ₆ )alkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=0)NR ¹³ — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl- NR ¹² C(=O)NR ¹³ — (C ₂ -C ₆ )alkenyl-, — (C ₀ -C ₆ )alkyl-NR ² C(=O)NR ¹³ — (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=0)NR ¹³ — (C ₄ -Cio)alkylcycloalkyl-, — (C ₀ -C ₆ )alkyl-NR ¹² S(O) ₂ — (Ci- C ₆ )alkyl-, — (Co-C ₆ )alkyl-NR ¹² S(0) ₂ — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NR ¹² S(0) ₂ — (C ₂ - C ₆ )alkenyl-, — (Co-C ₆ )alkyl-NR ¹² S(0) ₂ — (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² S(0) ₂ — (C ₄ -Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=S)NR ¹³ — (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl- NR ¹² C(=S)NR ¹³ — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NR ¹² C(=S)NR ¹³ — (C ₂ -C ₆ )alkenyl-, — (Co-C ₆ ) alkyl-NR ¹² C(=S)NR ¹³ — (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=S)NR ¹³ — (C ₄ - Cio)alkylcycloalkyl-, — (C ₀ -C ₆ )alkyl-OC(=O)— (Ci-C ₆ )alkyl-, — (C ₀ -C ₆ )alkyl-OC(=O)— (C ₂ -C ₆ )alkynyl-, — (C ₀ -C ₆ )alkyl-OC(=O)— (C ₂ -C ₆ )alkenyl-, — (C ₀ -C ₆ )alkyl-OC(=O)— (C ₄ - Cio)alkylcycloalkyl-, — (Co-Ce)alkyl-OC(=0) — (C3-C ₇ )cycloalkyl-, — (Co-Ce)alkyl- OC(=O)NR ¹² — (Ci-C ₆ )alkyl-, — (C ₀ -C ₆ )alkyl-OC(=O)NR ¹² — (C ₂ -C ₆ )alkynyl-, — (Co- C ₆ )alkyl-OC(=O)NR ¹² — (C ₂ -C ₆ )alkenyl-, — (C ₀ -C ₆ )alkyl-OC(=O)NR ¹² — (C ₄ - Cio)alkylcycloalkyl-, — (Co-Ce)alkyl-OC(=0)NR ¹² — (C3-C ₇ )cycloalkyl-, — (Co-Ce)alkyl- NR ¹² C(=O)O— (Ci-C ₆ )alkyl-, — (C ₀ -C ₆ )alkyl-NR ¹² C(=O)O— (C ₂ -C ₆ )alkynyl-, — (Co- C ₆ )alkyl-NR ¹² C(=O)O— (C ₂ -C ₆ )alkenyl-, — (C ₀ -C ₆ )alkyl-NR ¹² C(=O)O— (C ₃ -C ₇ )cycloalkyl- , — (C ₀ -C ₆ )alkyl-NR ¹² C(=O)O— (C ₄ -Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl- NR ¹² C(=NR ¹³ )NR ¹⁴ — (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=NR ¹³ )NR ¹⁴ — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NR ¹² C(=NR ¹³ )NR ¹⁴ — (C ₂ -C ₆ )alkenyl-, — (Co-C ₆ )alkyl- NR ¹² C(=NR ¹³ )NR ¹⁴ — (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=NR ¹³ )NR ¹⁴ — (C ₄ - Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=NR ¹³ )— (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl- NR ¹² C(=NR ¹³ )— (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-NR ¹² C(=NR ¹³ )— (C ₂ -C ₆ )alkenyl-, — (Co- C ₆ )alkyl-NR ¹² C(=NR ¹³ )— (C ₃ -C ₇ )cycloalkyl-, — (Co-C ₆ )alkyl-NR ¹² C(=NR ¹³ )— (C ₄ - Cio)alkylcycloalkyl-, — (Co-C ₆ )alkyl-C(=NR ¹² )NR ¹³ — (Ci-C ₆ )alkyl-, — (Co-C ₆ )alkyl- C(=NR ¹² )NR ³ — (C ₂ -C ₆ )alkynyl-, — (Co-C ₆ )alkyl-C(=NR ¹² )NR ¹³ — (C ₂ -C ₆ )alkenyl-, — (Co- C ₆ )alkyl-C(=NR ¹² )NR ¹³ — (C ₃ -C ₇ )cycloalkyl- and — (Co-C ₆ )alkyl-C(=NR ¹² )NR ¹³ — (C ₄ - Cio)alkylcycloalkyl-; Mi and M2 are each independently selected from the group of hydrogen, — CN, — OH, — NO ₂ , — CF ₃ , — NH ₂ , — SH, — C(=O)R ¹⁵ , — C(=NR ¹⁵ )R ¹⁶ , — C(=O)OR ¹ — C(=O)NR ¹⁵ R ¹⁶ — SR ¹⁵ , — S(O)R ¹⁵ , — S(O) ₂ R ¹⁵ , — NR ¹⁵ R ¹⁶ , — NR ¹⁵ C(=O)R ¹⁶ , — NR ¹⁵ C(=NR ¹⁶ )R ¹⁷ , NR ¹⁵ C(=NR ¹⁶ )NR ¹⁷ R ¹⁸ , — NR ¹⁵ C(=O)OR ¹⁶ , — NR ¹⁵ C(=O)NR ¹⁶ R ¹⁷ , — NR ¹⁵ S(O) ₂ R ¹⁶ , — C(=S)NR ¹⁵ R ¹⁶ — OC(=O)R ¹⁵ — OC(=O)NR ¹⁵ R ¹⁶ , —OR ¹⁵ , — S(O) ₂ NR ¹⁵ R ¹⁶ , an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (C2-Ce)alkynyl, — (C2- Ce)alkenyl, — (C3-C?)cycloalkyl and — (C3-C8)cycloalkenyl, and an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl rings;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)alkylhalo, — (Ci-Ce)alkyl, — (Ci-Ce)alkylcyano, — (C2-Ce)alkynyl, — (C2-Ce)alkenyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylcycloalkyl, heteroaryl, — (Ci-Ce)alkylheteroaryl, aryl, — (Ci- Ce)alkylaryl, — (C2-C6)alkynyl-(C3-C7)cycloalkyl, — (C2-Ce)alkynyl-heteroaryl, — (C2- Ce)alkynyl-aryl, — (C2-C6)alkenyl-(C3-C?)cycloalkyl, — (C2-C6)alkenyl-heteroaryl and — (C2- Ce)alkenyl-aryl;

R ⁴ , R ⁵ , R ⁶ and R ⁷ may be taken together to form an optionally substituted 3 to 10 membered non-aromatic heterocyclic ring or an optionally substituted 5 to 10 membered aromatic heterocyclic ring;

R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ may be taken together to form an optionally substituted 3 to 10 membered non-aromatic heterocyclic ring or an optionally substituted 5 to 10 membered aromatic heterocyclic ring;

R ¹² , R ¹³ and R ¹⁴ may be taken together to form an optionally substituted 3 to 10 membered non-aromatic heterocyclic ring or an optionally substituted 5 to 10 membered aromatic heterocyclic ring; and

R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ may be taken together to form an optionally substituted 3 to 10 membered non-aromatic heterocyclic ring or an optionally substituted 5 to 10 membered aromatic heterocyclic ring.

Formula 392

[001472] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 392. Such compounds are described in WO 2004/092135, published October 28, 2004, corresponding to PCT/US2004/011544, filed April 15, 2004, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 392, this reference incorporated by reference herein controls.

[001473] In an embodiment, the glutamate modulator is a compound according to: wherein

R is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkylamino, optionally substituted cycloalkylamino, optionally substituted arylamino, optionally substituted aminoaryl, optionally substituted heteroarylamino, optionally substituted aminoheteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, heteroaryl substituted with an optionally substituted heteroaryl group, or

R ¹ and R ² are each, independently, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkylamino, or a divalent Ci-8 group, or R ¹ , R ² , and the N to which they are attached, in combination, form a heterocycle which is optionally substituted with one or more substituents;

W is C=O, CH2, C=NR ⁷ , C=S, or optionally substituted alkyl;

Y is CH ₂ , NR ⁸ , O, S, SO, or SO ₂ ; or

W and Y together are — CH=CH — ;

V is C or S; m is 0 or 1;

Z is, at each position, independently, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted alkylamino; n is 0, 1, 2,3, or 4; and

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁵ are each, independently, H or optionally substituted alkyl.

Formula 393

[001474] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 393. Such compounds are described in WO 2020/021064, published January 30, 2020, corresponding to PCT/EP2019/070178, filed July 26, 2019 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 393, this reference incorporated by reference herein controls.

[001475] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ is either selected from any one of the following groups:

wherein each one of the above-depicted groups is optionally substituted with one or more groups R ¹¹ ; or R ¹ is a group which is optionally substituted with one or more groups R ^11A ; each R ¹¹ is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — (Co-

3 alkylene)-OH, — (C0-3 alkylene)-O(Ci-5 alkyl), — (C0-3 alkylene)-SH, — (C0-3 alkyl ene)-S(Ci-

5 alkyl), — (C0-3 alkylene)-NH2, — (C0-3 alkylene)-NH(Ci-5 alkyl), — (C0-3 alkylene)-N(Ci-

5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-halogen, — (C0-3 alkylene)-(Ci-5 haloalkyl), — (Co-

3 alkylene)-0 — (C1-5 haloalkyl), — (C0-3 alkylene)-CN, — (C0-3 alkylene)-CHO, — (Co-

3 alkylene)-CO— (Ci-5 alkyl), — (C0-3 alkylene)-COOH, — (C0-3 alkylene)-CO— O— (Ci-

₅ alkyl), —(C0-3 alkylene)-O— CO— (C1.5 alkyl), — (C0-3 alkylene)-CO— NH ₂ , — (Co-

3 alkylene)-CO— NH(CI-5 alkyl), — (C0-3 alkylene)-CO— N(CI- ₅ alkyl)(Ci- ₅ alkyl), — (Co-

3 alkylene)-NH— CO— (Ci-5 alkyl), — (C0-3 alkylene)-N(Ci- ₅ alkyl)-CO— (C1.5 alkyl), — (Co-

3 alkylene)-SO2 — NH2, — (C0-3 alkylene)-SO2 — NH(CI-5 alkyl), — (C0-3 alkylene)-SO2 — N(Ci- 5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-NH — SO2 — (C1-5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)- SO2 — (C1-5 alkyl), — (C0-3 alkylene)-aryl, — (C0-3 alkyl ene)-heteroaryl, — (C0-3 alkylene)- cycloalkyl, and — (C0-3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said — (Co-

3 alkylene)-aryl, the heteroaryl moiety in said — (C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said — (C0-3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said — (Co-

3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups R ¹² ; each R ^11A is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — (Co-

3 alkylene)-OH, — (C0-3 alkylene)-O(Ci-5 alkyl), — (C0-3 alkylene)-SH, — (C0-3 alkyl ene)-S(Ci- 5 alkyl), — (C0-3 alkylene)-NH2, — (C0-3 alkylene)-NH(Ci-5 alkyl), — (C0-3 alkylene)-N(Ci-

5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-halogen, — (C0-3 alkylene)-(Ci-5 haloalkyl), — (Co-

3 alkylene)-0 — (C1-5 haloalkyl), — (C0-3 alkylene)-CN, — (C0-3 alkylene)-CHO, — (Co-

3 alkylene)-CO— (Ci-5 alkyl), — (C0-3 alkylene)-COOH, — (C0-3 alkylene)-CO— O— (Ci-

₅ alkyl), —(C0-3 alkylene)-O— CO— (C1.5 alkyl), — (C0-3 alkylene)-CO— NH ₂ , — (Co-

3 alkylene)-CO— NH(CI-5 alkyl), — (C0-3 alkylene)-CO— N(CI- ₅ alkyl)(Ci- ₅ alkyl), — (Co-

3 alkylene)-NH— CO— (Ci-5 alkyl), — (C0-3 alkylene)-N(Ci- ₅ alkyl)-CO— (C1.5 alkyl), — (Co-

3 alkylene)-SO2 — NH2, — (C0-3 alkylene)-SO2 — NH(CI-5 alkyl), — (C0-3 alkylene)-SO2 — N(Ci- 5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-NH — SO2 — (C1-5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)- SO2 — (C1-5 alkyl), — (C0-3 alkylene)-heteroaryl, — (C0-3 alkylene)-cycloalkyl, and — (Co-

3 alkylene)-heterocycloalkyl, wherein the heteroaryl moiety in said — (C0-3 alkylene)- heteroaryl, the cycloalkyl moiety in said — (C0-3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said — (C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups R ¹² ; each R ¹² is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — OH, — O(Ci- 5 alkyl), — SH, — S(Ci-5 alkyl), — NH2, — NH(Ci-s alkyl), — N(CI-5 alkyl)(Ci-5 alkyl), halogen, Ci-5 haloalkyl, — O— (C1.5 haloalkyl), — CN, — CHO, — CO— (C1.5 alkyl), — COOH, — CO— O— (Ci-5 alkyl), — O— CO— (C1.5 alkyl), — CO— NH ₂ , — CO— NH(CI- ₅ alkyl), — CO— N(CI-5 alkyl)(Ci-5 alkyl), — NH— CO— (C1.5 alkyl), — N(CI- ₅ alkyl)-CO— (C1.5 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(CI- ₅ alkyl), — SO ₂ — N(CI- ₅ alkyl)(Ci- ₅ alkyl), — NH— SO ₂ — (Cn 5 alkyl), — N(CI-5 alkyl)-SO2 — (C1-5 alkyl), cycloalkyl, and heterocycloalkyl;

Xi is C(R ^X1 ) or N;

X ₂ is C(-L-R ^X2 ) or N;

X ₃ is C(R ^X3 ) or N;

X ₄ is C(R ^X4 ) or N; wherein at least one of the ring atoms X2, X3 and X ₄ is not N;

R ^X1 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — (C0-3 alkylene)-OH, — (Co-3 alkylene)-O(Ci-5 alkyl), — (C0-3 alkylene)-SH, — (C0-3 alkylene)-S(Ci-5 alkyl), — (Co- 3 alkylene)-NH2, — (C0-3 alkylene)-NH(Ci-5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-halogen, — (C0-3 alkylene)-(Ci-5 haloalkyl), — (C0-3 alkylene)-0 — (Ci- 5 haloalkyl), — (C0-3 alkylene)-CN, — (C0-3 alkylene)-CHO, — (C0-3 alkylene)-CO — (Ci- 5 alkyl), — (C0-3 alkylene)-COOH, — (C0-3 alkylene)-CO — O — (C1-5 alkyl), — (C0-3 alkylene)- O— CO— (Ci-5 alkyl), — (C0-3 alkylene)-CO— NH ₂ , — (C0-3 alkylene)-CO— NH(CI- ₅ alkyl), — (C0-3 alkylene)-CO— N(CI-5 alkyl)(Ci- ₅ alkyl), — (C0-3 alkylene)-NH— CO— (C1.5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)-CO— (C1.5 alkyl), — (C0-3 alkylene)-SO ₂ — NH ₂ , — (Co-

3 alkylene)-SO ₂ — NH(CI-5 alkyl), — (C0-3 alkylene)-SO ₂ — N(CI- ₅ alkyl)(Ci- ₅ alkyl), — (Co- 3 alkylene)-NH— SO ₂ — (Ci-5 alkyl), — (C0-3 alkylene)-N(Ci- ₅ alkyl)-SO ₂ — (C1.5 alkyl), — (Co- 3 alkylene)-aryl, — (C0-3 alkylene)-heteroaryl, — (C0-3 alkylene)-cycloalkyl, and — (Co-

3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said — (C0-3 alkylene)-aryl, the heteroaryl moiety in said — (C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said — (Co- 3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said — (C0-3 alkylene)- heterocycloalkyl are each optionally substituted with one or more groups R ^X11 ; each R ^X11 is independently selected from C1-5 alkyl, C ₂ -5 alkenyl, C ₂ -5 alkynyl, — OH, — O(Ci- 5 alkyl), — SH, — S(Ci-5 alkyl), — NH ₂ , — NH(Ci-s alkyl), — N(CI-5 alkyl)(Ci-5 alkyl), halogen, Ci-5 haloalkyl, — O— (C1.5 haloalkyl), — CN, — CHO, — CO— (C1.5 alkyl), — COOH, — CO— O— (Ci-5 alkyl), — O— CO— (C1.5 alkyl), — CO— NH ₂ , — CO— NH(CI- ₅ alkyl), — CO— N(CI-5 alkyl)(Ci-5 alkyl), — NH— CO— (C1.5 alkyl), — N(CI- ₅ alkyl)-CO— (C1.5 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(CI- ₅ alkyl), — SO ₂ — N(CI- ₅ alkyl)(Ci- ₅ alkyl), — NH— SO ₂ — (Cn 5 alkyl), — N(CI-5 alkyl)-SO ₂ — (C1-5 alkyl), cycloalkyl, and heterocycloalkyl;

L is selected from a covalent bond, Cnio alkylene, C2-10 alkenylene, and C2-10 alkynylene, wherein one or more — CH ₂ — units comprised in said Cnio alkylene, said C2-10 alkenylene, or said C2-10 alkynylene are each optionally replaced by a group independently selected from — O— , —CO—, — C(=O)O— , — O— C(=O)— , — NH— , — N(CI-5 alkyl)-, — NH— CO— , — N(CI- ₅ alkyl)-CO— , — CO— NH— , — CO— N(CI- ₅ alkyl)-, — S— , —SO—, — SO ₂ — , — SO ₂ — NH — , — SO ₂ — N(CI-5 alkyl)-, — NH — SO ₂ — , — N(CI-5 alkyl)-SO ₂ — , carbocyclylene, and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each optionally substituted with one or more groups independently selected from C1-4 alkyl, — OH, — O(Ci- ₄ alkyl), — SH, — S(Ci- ₅ alkyl), — NH ₂ , — NH(CI- ₄ alkyl), — N(CI- ₄ alkyl)(Ci- ₄ alkyl), halogen, C1-5 haloalkyl, — O — (C1-5 haloalkyl), and — CN, and further wherein said Ci- 10 alkylene, said C2-10 alkenylene, and said C2-10 alkynylene are each optionally substituted with one or more groups independently selected from halogen, C1-5 haloalkyl, — O — (Cn ₅ haloalkyl), — CN, —OH, — O(Ci- ₅ alkyl), — SH, — S(Ci- ₅ alkyl), — NH ₂ , — NH(CI- ₅ alkyl), and — N(CI-5 alkyl)(Ci-5 alkyl); _RX 2 is selected from C2-10 alkyl, carbocyclyl, heterocyclyl, and -L ^I -R ^X21 , wherein said C2- 10 alkyl, said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R ^X22 ;

L ¹ is selected from a covalent bond, CMO alkylene, C2-10 alkenylene, and C2-10 alkynylene, wherein one or more — CH2 — units comprised in said C O alkylene, said C2-10 alkenylene, or said C2-10 alkynylene are each optionally replaced by a group independently selected from — O— , —CO—, — C(=O)O— , — O— C(=O)— , — NH— , — N(CI-5 alkyl)-, — NH— CO— , — N(CI-5 alkyl)-CO— , — CO— NH— , — CO— N(CI- ₅ alkyl)-, — S— , —SO—, — SO ₂ — , — SO2 — NH — , — SO2 — N(CI-5 alkyl)-, — NH — SO2 — , and — N(CI-5 alkyl)-SO2 — , and further wherein said CMO alkylene, said C2-10 alkenylene, and said C2-10 alkynylene are each optionally substituted with one or more groups independently selected from halogen, Ci- ₅ haloalkyl, — O— (C1-5 haloalkyl), — CN, —OH, — O(Ci- ₅ alkyl), — SH, — S(Ci- ₅ alkyl), — NH2, — NH(CI-5 alkyl), and — N(CI-5 alkyl)(Ci-5 alkyl);

R ^X21 is selected from C2-5 alkyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R ^X22 ; each R ^X22 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — (Co-

3 alkylene)-OH, — (C0-3 alkylene)-O(Ci-5 alkyl), — (C0-3 alkylene)-SH, — (C0-3 alkyl ene)-S(Ci- 5 alkyl), — (C0-3 alkylene)-NH2, — (C0-3 alkylene)-NH(Ci-5 alkyl), — (C0-3 alkylene)-N(Ci-

5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-halogen, — (C0-3 alkylene)-(Ci-5 haloalkyl), — (Co- 3 alkylene)-0 — (C1-5 haloalkyl), — (C0-3 alkylene)-CN, — (C0-3 alkylene)-CHO, — (Co-

3 alkylene)-CO— (Ci-5 alkyl), — (C0-3 alkylene)-COOH, — (C0-3 alkylene)-CO— O— (Ci-

₅ alkyl), —(C0-3 alkylene)-O— CO— (C1.5 alkyl), — (C0-3 alkylene)-CO— NH ₂ , — (Co-

3 alkylene)-CO— NH(CI-5 alkyl), — (C0-3 alkylene)-CO— N(CI- ₅ alkyl)(Ci- ₅ alkyl), — (Co- 3 alkylene)-NH— CO— (Ci-5 alkyl), — (C0-3 alkylene)-N(Ci- ₅ alkyl)-CO— (C1.5 alkyl), — (Co- 3 alkylene)-SO2 — NH2, — (C0-3 alkylene)-SO2 — NH(CI-5 alkyl), — (C0-3 alkylene)-SO2 — N(Ci- 5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-NH — SO2 — (C1-5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)- SO2 — (C1-5 alkyl), — (C0-3 alkylene)-SO — (C1-5 alkyl), — (C0-3 alkylene)-SO2 — (C1-5 alkyl), — (C0-3 alkylene)-aryl, — (C0-3 alkyl ene)-heteroaryl, — (C0-3 alkylene)-cycloalkyl, and — (Co- 3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said — (C0-3 alkylene)-aryl, the heteroaryl moiety in said — (C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said — (Co- 3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said — (C0-3 alkylene)- heterocycloalkyl are each optionally substituted with one or more groups R ^X23 ; each R ^X23 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — OH, — O(Ci- 5 alkyl), — SH, — S(Ci-5 alkyl), — NH2, — NH(CI-5 alkyl), — N(CI-5 alkyl)(Ci-5 alkyl), halogen, Ci-5 haloalkyl, — O— (C1-5 haloalkyl), — CN, —CHO, — CO— (C1-5 alkyl), — COOH, — CO— O— (Ci-5 alkyl), — O— CO— (C1-5 alkyl), — CO— NH ₂ , — CO— NH(CI- ₅ alkyl), — CO— N(CI- ₅ alkyl)(Ci- ₅ alkyl), — NH— CO— (C1-5 alkyl), — N(CI- ₅ alkyl)-CO— (C1-5 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(CI- ₅ alkyl), — SO ₂ — N(CI- ₅ alkyl)(Ci- ₅ alkyl), — NH— SO ₂ — (Ci- ₅ alkyl), — N(CI- ₅ alkyl)-SO ₂ — (CI-5 alkyl), — SO— (C1-5 alkyl), — SO ₂ — (C1-5 alkyl), cycloalkyl, and heterocycloalkyl;

R ^X3 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — (C0-3 alkylene)-OH, — (C0-3 alkylene)-O(Ci-5 alkyl), — (C0-3 alkylene)-SH, — (C0-3 alkylene)-S(Ci-5 alkyl), — (Co- 3 alkylene)-NH2, — (C0-3 alkylene)-NH(Ci-5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-halogen, — (C0-3 alkylene)-(Ci-5 haloalkyl), — (C0-3 alkylene)-0 — (Ci- 5 haloalkyl), — (C0-3 alkylene)-CN, — (C0-3 alkylene)-CHO, — (C0-3 alkylene)-CO — (Ci- 5 alkyl), — (C0-3 alkylene)-COOH, — (C0-3 alkylene)-CO — O — (C1-5 alkyl), — (C0-3 alkylene)- O— CO— (Ci-5 alkyl), — (C0-3 alkylene)-CO— NH ₂ , — (C0-3 alkylene)-CO— NH(CI- ₅ alkyl), — (C0-3 alkylene)-CO— N(CI-5 alkyl)(Ci- ₅ alkyl), — (C0-3 alkylene)-NH— CO— (C1.5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)-CO— (C1.5 alkyl), — (C0-3 alkylene)-SO ₂ — NH ₂ , — (Co- 3 alkylene)-SO ₂ — NH(CI-5 alkyl), — (C0-3 alkylene)-SO ₂ — N(CI- ₅ alkyl)(Ci- ₅ alkyl), — (Co- 3 alkylene)-NH— SO ₂ — (Ci-5 alkyl), — (C0-3 alkylene)-N(Ci- ₅ alkyl)-SO ₂ — (C1.5 alkyl), — (Co- 3 alkylene)-aryl, — (C0-3 alkylene)-heteroaryl, — (C0-3 alkylene)-cycloalkyl, and — (Co- 3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said — (C0-3 alkylene)-aryl, the heteroaryl moiety in said — (C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said — (Co- 3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said — (C0-3 alkylene)- heterocycloalkyl are each optionally substituted with one or more groups R ^X31 ; each R ^X31 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — OH, — O(Ci- 5 alkyl), — SH, — S(Ci-5 alkyl), — NH2, — NH(CI-5 alkyl), — N(CI-5 alkyl)(Ci-5 alkyl), halogen, Ci-5 haloalkyl, — O— (C1.5 haloalkyl), — CN, —CHO, — CO— (C1.5 alkyl), —COOH, — CO— O— (Ci-5 alkyl), — O— CO— (C1.5 alkyl), — CO— NH ₂ , — CO— NH(C 1.5 alkyl), — CO— N(CI-5 alkyl)(Ci-5 alkyl), — NH— CO— (C1.5 alkyl), — N(CI- ₅ alkyl)-CO— (C1.5 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(CI- ₅ alkyl), — SO ₂ — N(CI- ₅ alkyl)(Ci- ₅ alkyl), — NH— SO ₂ — (Cn 5 alkyl), — N(CI-5 alkyl)-SO2 — (C1-5 alkyl), cycloalkyl, and heterocycloalkyl;

R ^X4 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, — (C0-3 alkylene)-OH, — (C0-3 alkylene)-O(Ci-5 alkyl), — (C0-3 alkylene)-SH, — (C0-3 alkylene)-S(Ci-5 alkyl), — (Co- 3 alkylene)-NH2, — (C0-3 alkylene)-NH(Ci-5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)(Ci-5 alkyl), — (C0-3 alkylene)-halogen, — (C0-3 alkylene)-(Ci-5 haloalkyl), — (C0-3 alkylene)-0 — (Ci- 5 haloalkyl), — (C0-3 alkylene)-CN, — (C0-3 alkylene)-CHO, — (C0-3 alkylene)-CO — (Cn 5 alkyl), — (Co-3 alkylene)-COOH, — (C0-3 alkylene)-CO — O — (C1-5 alkyl), — (C0-3 alkylene)- O— CO— (Ci-5 alkyl), — (C0-3 alkylene)-CO— NH ₂ , — (C0-3 alkylene)-CO— NH(CI- ₅ alkyl), — (C0-3 alkylene)-CO— N(CI-5 alkyl)(Ci- ₅ alkyl), — (C0-3 alkylene)-NH— CO— (C1.5 alkyl), — (C0-3 alkylene)-N(Ci-5 alkyl)-CO— (C1.5 alkyl), — (C0-3 alkylene)-SO ₂ — NH ₂ , — (Co-

3 alkylene)-SO ₂ — NH(CI-5 alkyl), — (C0-3 alkylene)-SO ₂ — N(CI- ₅ alkyl)(Ci- ₅ alkyl), — (Co-

3 alkylene)-NH— SO ₂ — (Ci-5 alkyl), — (C0-3 alkylene)-N(Ci- ₅ alkyl)-SO ₂ — (C1.5 alkyl), — (Co-

3 alkylene)-aryl, — (C0-3 alkylene)-heteroaryl, — (C0-3 alkylene)-cycloalkyl, and — (Co-

3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said — (C0-3 alkylene)-aryl, the heteroaryl moiety in said — (C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said — (Co-

3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said — (C0-3 alkylene)- heterocycloalkyl are each optionally substituted with one or more groups R ^X41 ; each R ^X41 is independently selected from C1-5 alkyl, C ₂ -5 alkenyl, C ₂ -5 alkynyl, — OH, — O(Ci- 5 alkyl), — SH, — S(Ci-5 alkyl), — NH ₂ , — NH(Ci-s alkyl), — N(CI-5 alkyl)(Ci-5 alkyl), halogen, Ci-5 haloalkyl, — O— (C1.5 haloalkyl), — CN, — CHO, — CO— (C1.5 alkyl), — COOH, — CO— O— (Ci-5 alkyl), — O— CO— (C1.5 alkyl), — CO— NH ₂ , — CO— NH(CI- ₅ alkyl), — CO— N(CI-5 alkyl)(Ci-5 alkyl), — NH— CO— (C1.5 alkyl), — N(CI- ₅ alkyl)-CO— (C1.5 alkyl), — SO ₂ — NH ₂ , — SO ₂ — NH(CI- ₅ alkyl), — SO ₂ — N(CI- ₅ alkyl)(Ci- ₅ alkyl), — NH— SO ₂ — (Cn 5 alkyl), — N(CI-5 alkyl)-SO ₂ — (C1-5 alkyl), cycloalkyl, and heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

Formula 394

[001476] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 394. Such compounds are described in WO 2019/063596, published April 4, 2019, corresponding to PCT/EP2018/076080, filed September 26, 2018, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 394, this reference incorporated by reference herein controls.

[001477] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ , identical or different, are each independently selected from hydrogen, halogen, — CN, — CF ₃ — C(=O)R ¹⁰ , — C(=O)OR ¹⁰ , — C(=O)NR ¹⁰ R ⁿ , —OR ¹⁰ , — OC(=O)R ¹⁰ , — OC(=O)NR ¹⁰ R ¹¹ , —SR ¹⁰ , — S(O)R ¹⁰ , — S(O) ₂ R ¹⁰ , — S(O)2NR ¹⁰ R ⁿ , — NR ¹⁰ R ⁿ , — NR ¹⁰ C(=O)R ¹¹ , — NR ¹⁰ C(=O)OR ⁿ , — NR ¹⁰ S(O)2R ⁿ , or an optionally substituted radical chosen among: — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C3-C?)cycloalkyl, — (Ci-C6)alkylene-(C3-C7)cycloalkyl, or — (Ci-Ce)cyanoalkyl, wherein any two radicals R ¹ and R ² , R ³ and R ⁴ , and R ⁵ and R ⁶ may be taken together to form an oxo (=0), wherein R ¹⁰ and R ¹¹ , identical or different, are each independently selected from hydrogen, an optionally substituted radical chosen among: — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (Ci- Ce)cyanoalkyl, — (C3-C?)cycloalkyl or — (Ci-C6)alkylene-(C3-C7)cycloalkyl;

Ar ¹ is an aryl or heteroaryl chosen among: wherein m is the number of substituents A and is an integer equal to 0, 1, 2, 3, 4 or 5;

Ar ² is an aryl or heteroaryl chosen among: wherein p is the number of substituents B and is an integer equal to 0, 1, 2, 3, 4 or 5;

A and B, identical or different, are each independently selected from the group consisting of hydrogen, halogen, — CN, — NO2, — OH, — NH2, — CF3, an optionally substituted radical selected from the group consisting of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C3- C?)cycloalkyl, — (Ci-C6)alkylene-(C3-C7)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci- Ce)cyanoalkyl, — (Ci-C6)alkylene-heteroaryl, — (Ci-Ce)alkylene-aryl, — (Ci-Ce)alkylene- heterocycle, aryl, heteroaryl, heterocycle, — OR ¹³ , — (Ci-Ce)alkylene-OR ¹³ , — O — (C2- C ₆ )alkylene-OR ¹³ , — NR ¹³ (C ₂ -C ₆ )alkylene-OR ¹⁴ , — (C ₂ -C ₆ )alkenylene-OR ¹³ , — (C ₂ - C ₆ )alkynylene-OR ¹³ , — NR ¹³ R ¹⁴ , — (Ci-C ₆ )alkylene-NR ¹³ R ¹⁴ , — O— (C ₂ -C ₆ )alkylene- NR ¹³ R ¹⁴ , — NR ¹³ — (C ₂ -C ₆ )alkylene-NR ¹⁴ R ¹⁵ , — (C ₂ -C ₆ )alkenylene-NR ¹³ R ¹⁴ , — (C ₂ - C ₆ )alkynylene-NR ¹³ R ¹⁴ , —SR ¹³ , — (Ci-C ₆ )alkylene-SR ¹³ , — O— (C ₂ -C ₆ )alkylene-SR ¹³ , — NR ¹³ — (C ₂ -C ₆ )alkylene-SR ¹⁴ , — S(=O)— R ¹³ , — (Ci-C ₆ )alkylene-S(=O)— R ¹³ , — O— (Ci- C ₆ )alkylene-S(=O)— R ¹³ , — NR ¹³ — (Ci-C ₆ )alkylene-S(=O)— R ¹⁴ , — S(=O) ₂ — R ¹³ , — (Ci- C ₆ )alkylene-S(=O)2— R ¹³ , — O— (Ci-C ₆ )alkylene-S(=O) ₂ — R ¹³ , — NR ¹³ — (Ci-C ₆ )alkylene- S(=O) ₂ — R ¹⁴ , — S(=O) ₂ NR ¹³ R ¹⁴ , — (Ci-C ₆ )alkylene-S(=O) ₂ NR ¹³ R ¹⁴ , -O—(Ci- C ₆ )alkylene-S(=O) ₂ NR ¹³ R ¹⁴ , — NR ¹³ — (Ci-C ₆ )alkylene-S(=O) ₂ NR ¹⁴ R ¹⁵ , — NR ¹³ — S(=O) ₂ R ¹⁴ , — (Ci-C ₆ )alkylene-NR ¹³ — S(=O) ₂ R ¹⁴ , — O— (C ₂ -C ₆ )alkylene-NR ¹³ — S(=O) ₂ R ¹⁴ , —NR ¹³ —(C2-C6)alkylene-NR ¹⁴ —S(=O) ₂ R ¹⁵ , —C(=O)—NR ¹³ R ¹⁴ , —(Ci-C6)alkylene- C(=O)— NR ¹³ R ¹⁴ , — O— (Ci-C ₆ )alkylene-C(=O)— NR ¹³ R ¹⁴ , — NR ¹³ — (Ci-C ₆ )alkylene- C(=O)— NR ¹⁴ R ¹⁵ , — NR ¹³ C(=O)— R ¹⁴ , — (Ci-C ₆ )alkylene-NR ¹³ C(=O)— R ¹⁴ , — O— (C ₂ - C ₆ )alkylene-NR ¹³ C(=O)— R ¹⁴ , — NR ¹³ — (C ₂ -C ₆ )alkylene-NR ¹⁴ C(=O)— R ¹⁵ , — C(=O)— R ¹³ , — (Ci-C ₆ )alkylene-C(=O)— R ¹³ , — O— (Ci-C ₆ )alkylene-C(=O)— R ¹³ , — NR ¹³ — (Ci- C ₆ )alkylene-C(=O)— R ¹⁴ , — C(=O)— OR ¹³ , — (Ci-C ₆ )alkylene-C(=O)— OR ¹³ , — O— (Ci- C ₆ )alkylene-C(=O)— OR ¹³ , — NR ¹³ — (Ci-C ₆ )alkylene-C(=O)— OR ¹⁴ , — OC(=O)— R ¹³ , — (Ci-C ₆ )alkylene-OC(=O)— R ¹³ , — O— (C ₂ -C ₆ )alkylene-OC(=O)— R ¹³ , — NR ¹³ — (C ₂ - C ₆ )alkylene-OC(=O)— R ¹⁴ , — NR ¹³ — C(=O)— NR ¹⁴ R ¹⁵ , — (Ci-C ₆ )alkylene-NR ¹³ — C(=O)— NR ¹⁴ R ¹⁵ , — O— (C ₂ -C ₆ )alkylene-NR ¹³ — C(=O)— NR ¹⁴ R ¹⁵ , — NR ¹³ — (C ₂ - C ₆ )alkylene-NR ¹⁴ — C(=O)— NR ¹⁵ R ¹⁶ , — NR ¹³ — C(=O)— OR ¹⁴ , — (Ci-C ₆ )alkylene-NR ¹³ — C(=O)— OR ¹⁴ , — O— (C ₂ -C ₆ )alkylene- NR ¹³ — C(=O)— OR ¹⁴ , — NR ¹³ — (C ₂ -C ₆ )alkylene- NR ¹⁴ — C(=O)— OR ¹⁵ , — O— C(=O)— NR ¹³ R ¹⁴ , — (Ci-C ₆ )alkylene-O— C(=O)— NR ¹³ R ¹⁴ , —O—(C2-C6)alkylene-O—C(=O)—NR ¹³ R ¹⁴ , —NR ¹³ —(C2-C ₆ )alkylene-O—C(=O)— NR ¹⁴ R ¹⁵ , —C(=O)—(Ci-C6)alkylene-NR ¹³ R ¹⁴ , —(Ci-C6)alkylene-C(=O)—(Ci-C ₆ )alkylene- NR ¹³ R ¹⁴ , — C(=O)— (Ci-C ₆ )alkylene-OR ¹³ , — (Ci-C ₆ )alkylene-C(=O)— (Ci-C ₆ )alkylene- OR ¹³ , — NR ¹³ — C(=S)— NR ¹⁴ R ¹⁵ , — (Ci-Ce)alkylene-NR ¹³ — C(=S)— NR ¹⁴ R ¹⁵ , — NR ¹³ — C(=NR ¹⁴ )— NR ¹⁵ R ¹⁶ and — (Ci-C ₆ )alkylene-NR ¹³ — C(=NR ¹⁴ )— NR ¹⁵ R ¹⁶ ; wherein R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently selected from hydrogen, an optionally substituted — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3-C?)cycloalkyl, — (Ci-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, aryl, heterocycle, — (Ci-Ce)alkylene- heteroaryl, — (Ci-C6)alkylene-heterocycle and — (Ci-Ce)alkylene-aryl; wherein optionally any two radicals selected from R ¹³ , R ¹⁴ , R ¹⁵ or R ¹⁶ may be taken together to form a 3 to 10-membered carbocycle, heterocycle, aryl or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 radicals independently selected from halogen, cyano, nitro, hydroxyl, amino, — (Ci-Ce)alkyl, — O — (Ci-Ce)alkyl and — N — ((Ci-Ce)alkyl)2; the term “optionally substituted”, unless otherwise defined, refers to an optional substitution with one or more substituents selected from the group consisting of (Ci-Ce)alkyl, hydroxy, (Ci-Ce)alkylene-OH, (Ci-Ce)alkylene-O — (Ci-Ce)alkyl, mercapto, aryl, heteroaryl, heterocycle, (Ci-Ce)alkylene-aryl, (Ci-C6)alkylene-heterocycle, (Ci-Ce)alkylene-(C3- C?)cycloalkyl, (Ci-C6)alkylene-heteroaryl, halogen, trifluoroalkyl, trifluoroalkoxy, cyano, cyanoakyl, nitro, amino, carboxyl, carboxamide, NH — C(=O)O — (Ci-Ce)alkyl, S(=O)2 — NH ₂ , C(O)O— (Ci-C ₆ )alkyl, and S(=O)— (Ci-C ₆ )alkyl; or an N-oxide form thereof, a pharmaceutically acceptable salt or solvate thereof, or an optical isomer, racemate, diastereoisomer, enantiomer or tautomer thereof.

[001478] In another embodiment, the glutamate modulator is a compound according to: wherein:

G is chosen among N or CR ⁷ ,

E is chosen among N or CR ⁸ , provided that at least one of G or E is N

Y is CR ⁹ ,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ , identical or different, are each independently selected in the groups consisted of hydrogen, halogen, — CN, — CF3 — C(=O)R ¹⁰ , — C(=O)OR ¹⁹ , — C(=O)NR ¹⁰ R ⁿ , —OR ¹⁰ , — OC(=O)R ¹⁰ , — OC(=O)NR ¹⁰ R ⁿ , —SR ¹⁰ , — S(O)R ¹⁰ , — S(O) ₂ R ¹⁰ , — S(O)2NR ¹⁰ R ^U , — NR ¹⁰ R ⁿ , — NR ¹⁰ C(=O)R ⁿ , — NR ¹⁰ C(=O)OR ⁿ , — NR ¹⁰ S(O)2R ⁿ , an optionally substituted radical chosen among: — (Ci-Ce)alkyl, — (Ci- Ce)haloalkyl, — (C3-C?)cycloalkyl, — (Ci-C6)alkylene-(C3-C7)cycloalkyl, or — (Ci- Ce)cy anoalkyl, wherein any two radicals R ¹ and R ² , R ³ and R ⁴ , and R ⁵ and R ⁶ may be taken together to form an oxo (=0), wherein R ¹⁹ and R ¹¹ , identical or different, are each independently selected from hydrogen, an optionally substituted radical chosen among: — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (Ci- Ce)cyanoalkyl, — (C3-C?)cycloalkyl or — (Ci-C6)alkylene-(C3-C7)cycloalkyl, wherein optionally any two radicals selected from R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R ¹⁰ and R ¹¹ may be taken together to form an optionally substituted 3 to 10-membered non-aromatic carbocyclic or heterocyclic ring or a 5 to 10-membered aromatic heterocyclic ring, n is an integer selected from 0 or 1,

Ar ¹ is an optionally substituted aryl or heteroaryl,

Ar ² is an optionally substituted aryl or heteroaryl, and the N-oxide forms thereof, the pharmaceutically acceptable salts and solvates thereof, or their optical isomers, racemates, diastereoisomers, enantiomers or tautomers thereof.

Formula 395

[001479] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 395. Such compounds are described in, WO 2019/036534, published February 21, 2019, corresponding to PCT/US2018/046801, filed August 16, 2018 , which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 395, this reference incorporated by reference herein controls.

[001480] In an embodiment, the glutamate modulator is a compound according to: wherein:

A is

XIA: CH, CRi, or N;

XIB: CH, CRI, or N;

Xie: CH, CRi, or N;

X ₂ : CH, CRi, or N;

X ₃ : CH, CRi, or N;

X ₄ : CH, CRi, or N; each Ri is independent and chosen from H, D, OH, NH ₂ , NR3R4, OR5, F, CHF ₂ , CF3, halogen, F, alkyl, Me, CD3, cycloalkyl, CN, methoxy, alkoxy, alkyl-methoxy, or alkylalkoxy; each R ₂ is optionally present, independent and chosen from H, D, OH, CONH ₂ , NH ₂ , NR3R4, OR5, F, CHF ₂ , CF3, halogen, F, alkyl, Me, O-Me, alkyl-O-Me, CD3, cycloalkyl, CN, methoxy, alkoxy, alkyl-methoxy, or alkyl-alkoxy;

R3 is chosen from H, alkyl, alkoxy, or OH;

R ₄ is chosen from H, alkyl, alkoxy, or OH;

Rs is chosen from H, or alkyl;

R ₆ is H, CH ₃ or CD ₃ ;

R? is O or — CO — ;

Rs is a bond, alkyl, — NH — , — O — , alkyl-O-;

R ₉ is substituted or unsubstituted and chosen from H, heteroaryl, aryl, heterocycloalkyl, oxygen-containing heterocycle, cycloalkyl, CD3, CF ₂ , CD ₂ -CH ₃ , alkyl, CH3, n is 0-6; wherein each heteroaryl, aryl, heterocycloalkyl, cycloalkyl, when chosen, can be optionally substituted with one or more of the following: H, D, OH, CONH ₂ , NH ₂ , NR3R4, OR5, F, CHF ₂ , CF3, halogen, F, alkyl, Me, O-Me, alkyl-O-Me, CD3, CN, methoxy, alkoxy, alkyl- methoxy, or alkyl-alkoxy; or a pharmaceutically acceptable salt thereof.

[001481] In further embodiments, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate-modulatory activity.

[001482] In further embodiments, the glutamate modulator is a compound according to: wherein:

XIA: CH, CRi, or N; each R2 is optionally present, independent and chosen from H, D, NH2, CF3, halogen, F, alkyl, Me, or CD3;

R ₆ is H, CH ₃ or CD ₃ ;

R? is O or — CO — ;

Rs is a bond, alkyl, — NH — , — O — , alkyl-0 — ;

R ₉ is substituted or unsubstituted and chosen from cycloalkyl, tetrahydrofuran, 1,4 dioxane, cyclobutyl, tetrahydropyran; and n is 0-6; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

[001483] In another embodiment, the glutamate modulator is a compound according to: , wherein X4 is CH or C-NH2.

Formula 396

[001484] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 396. Such compounds are described in WO 2019/006157, published January 3, 2019, corresponding to PCT/US2018/040076, filed June 28, 2018, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 396, this reference incorporated by reference herein controls.

[001485] In an embodiment, the glutamate modulator is a compound according to:

Xiis CH, CRi, orN;

X ₂ is CH, CRi, orN;

X ₃ is CH, CRi, orN; each X4 is independent and is CH, CRi, or N;

X ₅ is CH, CRi, orN;

X ₆ is CH, CRi, S, NH, NCH ₃ , or N;

X ₇ is CH, CRi, S, NH, orN;

X ₈ is CH, CRi, orNH, N;

X ₉ is CH, CRi, orNH, N;

XnisO, NH

X13 is O, S, SO2, N, alkyl-0 — , or — O-alkyl; Xu is CH or CRi; the R groups joining with each other to form a 4, 5, 6, or 7-membered ring, optionally substituted with one or more substituent independently selected from H, CD3, Me, halogen, F, alkyl, alkoxy, OMe, alkyl-OMe, CONH2, CN, O; each Ri is independent and chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen,

F, alkyl, Me, CD3, cycloalkyl, CN, methoxy, alkoxy, alkyl-methoxy, or alkyl-alkoxy; each R2 is independent and is chosen from H, D, OH, NH2, NR3R4, OR5, CHF2, CF3, halogen, F, alkyl, Me, CD3, cycloalkyl, CN, methoxy, alkoxy, alkyl-methoxy, or alkyl-alkoxy;

R3 is chosen from H, alkyl, alkoxy, or OH;

R4 is chosen from H, alkyl, alkoxy, or OH;

Rs is chosen from H, or alkyl; n is 0-6; and is an attachment point; or a pharmaceutically acceptable salt thereof.

[001486] In further embodiments, the glutamate modulator is a compound according to:

9011 , or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate modulatory activity.

Formula 397

[001487] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 397. Such compounds are described in WO 2018/092921, published May 24, 2018, corresponding to PCT/JP2017/042308, filed November 17, 2017 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 397, this reference incorporated by reference herein controls.

[001488] In an embodiment, the glutamate modulator is a compound according to: wherein

R ¹ represents hydrogen or halogen;

R ² represents hydrogen, hydroxyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-

Ce haloalkoxy, — N(R ⁷ )2 or — SO2R ⁸ ;

R ³ represents hydrogen or C1-C3 alkyl; or R ² and R ³ together form =0;

R ⁴ represents cyano, hydroxyl, — N(R ⁹ )2, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce alkoxy, C3- Ce cycloalkoxy, Ci-Ce alkylcarbonyl, C3-C6 cycloalkylcarbonyl, Ci-Ce alkoxycarbonyl, C3- Ce cycloalkoxycarbonyl, — (CH2) _m R ¹⁰ , — O(CH2) _m R ¹⁰ or — NH(CH2) _m R ¹⁰ , wherein each of the alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl and cycloalkoxycarbonyl moieties is independently unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy;

R ⁵ represents hydrogen or halogen; or R ⁴ and R ⁵ together with the benzyl group to which they are attached form a 5- to 7- membered carbocyclic or heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, — (CH^nR ¹¹ and — 0(CH2) _n R ^u ; provided that either:

(i) the heterocyclic ring comprises at least one ring nitrogen atom and the heterocyclic or carbocyclic ring is substituted with two, three, four, five, six or seven substituents independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, — (CH ₂ )nRn and — O(CH ₂ )nRn; or

(ii) the carbocyclic or heterocyclic ring is substituted with oxo and with at least one further substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, — (CH ₂ ) _n R ⁿ and — O(CH ₂ ) _n Rn; or

(iii) the carbocyclic or heterocyclic ring comprises one double bond and is substituted with oxo and optionally with at least one further substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci- Ce alkoxy, Ci-Ce haloalkoxy, — (CH ₂ ) _n R ^u and — 0(CH ₂ ) _n R ^u ;

R ⁶ represents hydrogen, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl;

R ⁷ independently represents hydrogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C4-C6 cycloalkyl, (C3- Ce cycloalkyl)methyl, 4- to 6-membered heterocycloalkyl, (3- to 6-membered heterocycloalkyl)methyl or — COR ¹² , or two R ⁷ together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7-membered heterocyclic ring optionally comprising one or more further ring heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, the heterocyclic ring being unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and Ci- C3 haloalkoxy;

R ⁸ represents C1-C3 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl)methyl;

R ⁹ independently represents methyl, C3-C6 alkyl or Ci-Ce haloalkyl, or two R ⁹ together with the nitrogen atom to which they are attached form a saturated or unsaturated 4- to 7- membered heterocyclic ring optionally comprising one or more further ring heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, the heterocyclic ring being unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, Ci- C3 alkoxy and C1-C3 haloalkoxy;

R ¹⁰ represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; R ¹¹ represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy;

R ¹² represents a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and — CON(R ¹³ ) ₂ ;

R ¹³ independently represents hydrogen or C1-C3 alkyl;

Z represents — CH ₂ — or — O — ; m is 0, 1, 2 or 3; and n is 0, 1, 2 or 3.

Formula 398

[001489] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 398. Such compounds are described in WO 2018/089546, published May 17, 2018, corresponding to PCT/US2017/060713, filed November 8, 2017, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 398, this reference incorporated by reference herein controls.

[001490] In an embodiment, the glutamate modulator is a compound according to: wherein:

X is CH, or N; X1 is CH, or N;

X ₂ is CH, or N;

Y is CH, or N;

Ri is tetrahydrofuran optionally substituted by at least one R ₂ , morpholine optionally substituted by one or more R ₂ , dioxane, or alkoxy;

R ₂ is H, CD3, halogen, alkyl, alkoxy, CONH ₂ , CN, or =0;

R3 is independently H, halogen, alkyl, CD3, cycloalkyl, CF3, CN, or alkoxy;

RHs H, halogen, alkyl, CD3, cycloalkyl, CF3, or CN; n is 0-6; provided that at least one of Y and X is N; and provided that one of Xi and X ₂ is N; or a pharmaceutically acceptable salt thereof.

[001491] In an embodiment, the glutamate modulator is a compound selected from: , including pharmaceutically acceptable salts and substituted variants retaining glutamate modulatory activity.

Formula 399 till [001492] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 399. Such compounds are described in WO 2018/089544, published May 17, 2018, corresponding to PCT/US2017/060711, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 399, this reference incorporated by reference herein controls.

[001493] In an embodiment, the glutamate modulator is a compound according to: wherein the variables are substituted or unsubstituted and:

X is N, CH;

Xi is CH, or N;

X ₂ is CH, or N;

Y is N, or CH;

Ri is chosen from tetrahydropyran, tetrahydrofuran, fluoropyridine, fluoropyrrolidine, difluoropyrrolidine, or optionally forms a ring with R ₂ , which is optionally substituted with one or more Rs;

R ₂ is H, Me, CD ₃ ; CF ₃ , alkyl;

R ₃ is independently H, halogen, F, alkyl, Me, cycloalkyl, CF ₃ , CN, methoxy, alkoxy, alkylmethoxy, alkyl-alkoxy;

RHs H, halogen, F, alkyl, Me, cycloalkyl, CF ₃ , or CN;

Rs is selected from H, D, halo, alkyl, alkyl-methoxy, alkyl-alkoxy, — OH, — CN, — NH ₂ , — CF ₃ , — Cyi, — ORe, or — NReR?

Re is H, halogen, F, alkyl, Me, cycloalkyl, CF ₃ , or CN;

R? is H, halogen, F, alkyl, Me, cycloalkyl, CF ₃ , or CN;

Cyi is selected from C ₃ -Cs aryl, C ₃ -Cs heteroaryl, C ₃ -Cs cycloalkyl and C ₃ -

Cs heterocycloalkyl; and Cyl is substituted with 0, 1, 2, or 3 groups independently selected from halo, — OH, — CN, — NH2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, or Ci- Ce polyhaloalkyl, Ci-Ce alkylamino, Ci-Ce dialkylamino, aryl, and heteroaryl; n is an integer from 0-6; provided that at least one of X or Y is N; and provided that one of Xi and X2 is N; wherein when optionally forming a ring, Ri and R2 together form:

(i) fluoropiperidine, difluoropiperidine, or fluoropyrrolidine;

(ii) a 7-12 membered spiro or bridged, ring system with at least one hetero atom;

(iii) an oxa-aza-bicyclooctane ring, an aza-bicyclononane ring, an oxa-aza-spirodecane ring, or an oxa-aza-bicycloheptane ring; or a pharmaceutically acceptable salt thereof.

Formula 400

[001494] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 400. Such compounds are described in WO 2018/047983, published March 15, 2018, corresponding to PCT/JP2017/033368, filed September 7, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 400, this reference incorporated by reference herein controls.

[001495] In an embodiment, the glutamate modulator is a compound according to:

X, Y and Z have the following meanings:

(i) Z is >CH2, >CHCH3 or >0, Y is >CH2 or >C=O and X is >NR5 where R5 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylmethyl or, alternatively, R and R may together form a C2-C3 alkylene chain, or

(ii) Z is >CHR6a, X is >C=O and Y is >NR6b where R6a represents hydrogen, (halo)Cl-C6 alkyl, (halo)C3~C6 cycloalkyl or (halo)phenyl and

R ^A represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylmethyl, or

(iii) Z is >CH2, X is >CH2 and Y is >NR7, >NC(0)R7 or >NS02R7 where

R represents either a C3-C6 cycloalkyl group, or, a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from C1-C6 alkoxy and C3-C6 cycloalkyl, or

(iv) Z is >C=O, X is >CH2 and Y is >NR7 , or

(v) X is >CH2, Y is >CH2 and Z is >NR8, >NC(0)R9, >NC(0)NHR9 or >NS02R9 where R8 represents hydrogen or a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from halogen, C3-C6 cycloalkyl and a S- to 6-membered saturated or unsaturated heterocycle, wherein the heterocycle is optionally substituted by at least one C1-C3 alkyl substituent, and R9 represents a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, or a C1-C6 alkyl group optionally substituted by at least one substituent independently selected from halogen, cyano, C1-C6 alkoxy and C3-C6 cycloalkyl, or

(vi) X is >CH2, Y is >C=O and Z is >NR10 where RIO represents a C1-C6 alkyl group optionally substituted by. at least one- substituent -independently - selected from halogen, C1-C6 alkoxy, C3-C6 cycloalkyl, phenyl or a S- to

6-membered saturated or unsaturated heterocycle;

R1 , R2 and R3 each independently represent hydrogen or halogen;

R4 represents hydrogen, halogen or is joined to R as defined above;

D represents >C(R11)- or, when Z is >CH2, D may additionally represent a nitrogen atom;

R11 represents hydrogen, halogen or C1-C6 alkyl;

R12 represents hydrogen, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl sulphonyl or NR13R14 ;

R12 and R14 each independently represent hydrogen, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, C1-C6 alkoxy carbonyl, or C1-C6 alkyl optionally substituted by at least one substituent independently selected from halogen, C3-C6 cycloalkyl or a 5- to 6- membered saturated or unsaturated heterocycle, or R and R together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally containing a further ring heteroatom selected from nitrogen and oxygen, wherein the heterocyclic ring is optionally substituted by at least one substituent independently selected from halogen, cyano, C1-C5 alkyl and C1-C6 alkoxy;

R15 represents hydrogen or halogen; and

R16 represents hydrogen or halogen.

Formula 401

[001496] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 401. Such compounds are described in US 2018/0057490, published March 1, 2018, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 401, this reference incorporated by reference herein controls.

[001497] In an embodiment, the glutamate modulator is a compound according to: or unsubstituted and:

X is N, CH, CD, C-alkyl;

Y is N, CH, CD, C-alkyl;

R1 is H, alkyl, cycloalkyl (optionally substituted with one or more R), cycloheteroaryl (optionally substituted with one or more R), aryl (optionally substituted with one or more R), heteroaryl (optionally substituted with one or more R), CF3, alkoxy, CO, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl-heteroaryl (optionally substituted with one or more R); alkyl-cycloheteroaryl (optionally substituted with one or more R), CO-amino-cycloalkyl (optionally substituted with one or more R); or together with R2 forms a 4-7 membered ring optionally substituted with one or more R;

R3 is H, alkyl, cycloalkyl, CF3, CH2F, CHF2, alkyl-aryl (optionally substituted with one or more R), alkyl-cycloalkyl (optionally substituted with one or more R), alkyl- heteroaryl (optionally substituted with one or more R); alkyl-cycloheteroaryl (optionally substituted with one or more R); or together with R1 forms a 4-7 membered ring optionally substituted with one or more R;

R is independently H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O- cycloalkyl, CO — RA, SO2RA, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2- alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;

RA is H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, hydroxyl, amino, aminoalkoxy, halogen, SO2, SO2-alkyl, SO2-Me, CONH2, CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl; provided that at least one of XI or X2 is N; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

[001498] In an embodiment, the glutamate modulator is a compound selected from: pharmaceutically acceptable salt or substituted variant retaining glutamate modulatory activity.

Formula 402

[001499] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 402. Such compounds are described in US 20180057491, published March 1, 2018, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 402, this reference incorporated by reference herein controls.

[001500] In an embodiment, the glutamate modulator is a compound according to: wherein the variables are substituted or unsubstituted and:

X is N, CH, CD, C-alkyl;

Xi is CH, or N;

X ₂ is CH, or N;

Y is N, CH, CD, C-alkyl;

Ri is H, alkyl, aklene, cycloalkyl, halogen, CF3, alkoxy, OH, CN, Oalkyl, CH ₂ F, CHF ₂ , or together with R ₂ forms a 4-7 membered ring optionally substituted with one or more R;

R ₂ is optionally substituted with one or more R, and is chosen from cycloaklyl, cycloheteroaryl, aryl, heteroaryl, or together with Ri forms a 4-7 membered ring optionally substituted with one or more R;

R is independently H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, CO — RA, SO ₂ RA, hydroxyl, amino, aminoalkoxy, halogen, SO ₂ , SO ₂ -alkyl, SO ₂ -Me, CONH ₂ , CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;

RA IS H, alkyl, alkene, hydroxyl, alkoxy, CF3, O, O-Me, O-alkyl, O-cycloalkyl, hydroxyl, amino, aminoalkoxy, halogen, SO ₂ , SO ₂ -alkyl, SO ₂ -Me, CONH ₂ , CN, O, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl;

R3 is H, alkyl, alkene, cycloalkyl, aryl, heteroaryl, alkoxy, hydroxyl, amino, aminoalkoxy, or halogen; provided that at least one of Xi or X ₂ is N; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

Formula 403 [001501] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 403. Such compounds are described in WO 2018/015235, published January 25, 2018, corresponding to PCT/EP2017/067495, filed July 12, 2017, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 403, this reference incorporated by reference herein controls.

[001502] In an embodiment, the glutamate modulator is a compound selected from: modulatory activity.

Formula 404

[001503] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 404. Such compounds are described in WO 2017/021384, published February 9, 2017, corresponding to PCT/EP2016/068359, filed August 2, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 404, this reference incorporated by reference herein controls.

[001504] In an embodiment, the glutamate modulator is a compound according to: wherein

R ¹ is hydrogen, F or Cl;

L is a bond or lower alkylene;

R ² is — (CH2)nO-lower alkyl, lower alkyl substituted by halogen, — (CH2) _n C(O)O-lower alkyl, phenyl substituted by lower alkyl or halogen, or is a 5 or 6-membered heteroaryl group, selected from pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, imidazolyl, pyrazolyl or triazolyl, which are optionally substituted by lower alkyl, halogen, lower alkoxy, =0, benzyloxy, cycloalkyloxy, hydroxy, cyano, lower alkyl substituted by halogen, or by — (CH2) _n O-lower alkyl; n is 1, 2 or 3;

R ³ is hydrogen, lower alkyl or — (CH2) _n O-lower alkyl;

R ⁴ is phenyl, pyridinyl or pyrimidinyl, each optionally substituted by F;

Y is CF or CC1; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomers thereof.

[001505] In an embodiment, the glutamate modulator is a compound selected from: (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(2-methox yethyl)-9a-methyl-4,9- dihydro-3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-(3-met hoxypropyl)-9a-methyl-4,9- dihydro-3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methy l-2-(2,2,2-trifluoroethyl)-4,9- dihydro-3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6,8-trione;

Ethyl 4-[(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-methy l-l,6,8-trioxo-4,9- dihydro-3H-pyrazino[ 1 ,2-c]pyrimidin-2-yl]butanoate;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-meth yl-2-(m-tolylmethyl)-4,9- dihydro-3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6,8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-meth yl-2-(p-tolylmethyl)-4,9-dihydro- 3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6, 8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-9a-meth yl-2-(o-tolylmethyl)-4,9-dihydro- 3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6, 8-trione;

(9aRS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(2,6 -dimethylphenyl)methyl]-9a- methyl-4,9-dihydro-3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6, 8-trione;

(9aRS)-2-[(2-chlorophenyl)methyl]-7-[2,6-difluoro-4-(2-ph enylethynyl)phenyl]-9a-methyl- 4, 9-dihydro-3H-pyrazino[l,2-c]pyrimidine-l, 6, 8-trione;

(9aRS)-2-[(3-chlorophenyl)methyl]-7-[2,6-difluoro-4-(2-ph enylethynyl)phenyl]-9a-methyl-

4, 9-dihydro-3H-pyrazino[l,2-c]pyrimidine-l, 6, 8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(2-fl uorophenyl)methyl]-9a-methyl-4,9- dihydro-3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6,8-trione;

(9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(3-fl uorophenyl)methyl]-9a-methyl-4,9- dihydro-3H-pyrazino[ 1 ,2-c]pyrimidine- 1 ,6,8-trione; or, (9aS)-7-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-[(4-fluor ophenyl)methyl]-9a-methyl-4,9- dihydro-3H-pyrazino[l,2-c]pyrimi dine- 1,6, 8-trione, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 405

[001506] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 405. Such compounds are described in WO 2017/009275, published January 19, 2017, corresponding to PCT/EP2016/066393, filed July 11, 2016 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 405, this reference incorporated by reference herein controls.

[001507] In an embodiment, the glutamate modulator is a compound according to: wherein

R ¹ is lower alkyl;

R ² is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions; n is 0, 1 or 2;

V7U are independently from each other O or CH2, wherein V and U cannot be simultaneously O;

L is a five or six membered heteroaryl group, selected from

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

[001508] In an embodiment, the glutamate modulator is a compound according to: (6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-l-methy l-spiro[hexahydropyrimidine- 6, 4'-isochromane]-2, 4-dione,

(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-l-me thyl-spiro[hexahydropyrimidine- 6, 1 '-tetralin] -2, 4-dione,

(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-l-me thyl-spiro[hexahydropyrimidine- 6, 1 '-indane]-2, 4-dione,

((5S)-3'-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-r-methy l-spiro[7,8-dihydro-6H- quinoline-5,6'-hexahydropyrimidine]-2',4'-dione,

(5S)-3 [2,6-Difluoro-4-(2-phenylethynyl)phenyl]-l'-methyl-spiro[7,8 -dihydro-6H- quinazoline-5 , 6 '-hexahydropyrimidine] -2 ',4 '-di one, or

(4S)-3'-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-l'-methy l-spiro[2,3-dihydropyrano[2,3- b]pyridine-4,6'-hexahydropyrimidine]-2',4'-dione, including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

Formula 406

[001509] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 406. Such compounds are described in WO 2016/146600, published September 22, 2016, corresponding to PCT/EP/2016/055487, filed March 15, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 406, this reference incorporated by reference herein controls.

[001510] In an embodiment, the glutamate modulator is a compound according to: wherein

Y is C— R ¹ ';

R ¹ ' is hydrogen, F or Cl;

R ¹ is F or Cl;

R ² is hydrogen or lower alkyl;

R ³ is phenyl, pyridinyl or isothiazolyl, wherein the N atom in the pyridinyl group may be in different positions, optionally substituted by one or two halogen atoms;

R ⁴ is hydrogen or lower alkyl;

Het is a 5-membered heteroaryl group, containing two or three heteroatoms, selected from N,0 or S, optionally substituted by lower alkyl, cycloalkyl, lower alkoxyalkyl, heterocycloalkyl, wherein the hetero-atom is O, or lower alkyl substituted by hydroxy, or is a bicyclic heteroaromatic ring, containing two or three N-heteroatoms selected from the groups

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

[001511] In further embodiments, the glutamate modulator is a compound selected from:

(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-l,6-dimet hyl-6-(l-methylindazol-3- yl)hexahydropyrimidine-2, 4-dione

(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-l,6-dimet hyl-6-(l-methylpyrrolo[2,3- b]pyridin-3-yl)hexahydropyrimidine-2, 4-dione

(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-l,6-dimet hyl-6-pyrazolo[l,5-a]pyri din-3- yl-hexahydropyrimidine-2, 4-dione

(6S)-3-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-l,6-dimet hyl-6-(l-methylpyrazolo[3,4- b]pyridin-3-yl)hexahydropyrimidine-2, 4-dione

(6S)-3-[2-Chloro-4-(2-phenylethynyl)phenyl]-l,6-dimethyl- 6-(l-methylpyrazol-4- yl)hexahydropyrimidine-2, 4-dione, or

(6S)-3-[2-Chloro-6-fluoro-4-(2-phenylethynyl)phenyl]-l,6- dimethyl-6-(l -methyl pyrazol-4- yl)hexahydropyrimidine-2, 4-dione, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 407

[001512] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 407. Such compounds are described in WO 2016/123627, published August 4, 2016, corresponding to PCT/US2016/016012, filed February 1, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 407, this reference incorporated by reference herein controls. [001513] In an embodiment, the glutamate modulator is a compound according to: wherein the variables are substituted or unsubstituted and:

W is CH, CD, N, C-alkyl, C-halogen;

X is N, CH, CD, C-alkyl, or may form a 6-membered ring with Y optionally substituted with at least one R;

Xi is CH, CD, C — R2, N, or is N and together with Ri forms a 5 or 6 membered ring;

X2 is CH, CD, C — R2, or N, or together with R3 forms a 5 or 6 membered ring;

Y is N, CH, CD, C-alkyl, or may form a 6-membered ring with X optionally substituted with at least one R;

Zi is CH, CD, C-alkyl, N, C-halogen, C-alkoxy;

Z2 is CH, CD, C-alkyl, N, C-halogen, C-alkoxy;

R is halogen, CN, Me, alkyl, OMe, alkoxy;

Ri H, alkyl, aklene, cycloalkyl, NR4R5, aryl, halogen, CF3, cycloheteroalkyl, alkoxy, OH, CN, Oalkyl, Oaryl, Oheteroaryl, NHalkyl, NHaryl, NHheteroaryl, heteroaryl, CH2F, CHF2, NR4R5, CO-heteroaryl, CO — NH-alkyl, CO — NH-methoxyalkyl, CO-amino, CO-aryl, CO- heteroaryl, CO-aminocycloalkyl, CO-amino-alkoxy, CO-alkyl, Nalkylalkyl, NH-alkoxy, or together with Xi forms a 5 or 6 membered ring;

R2 is H, halogen, alkyl, alkoxy, OMe, CONH2, CN, O;

R3 is H, alkyl, alkene, cycloalkyl, aryl, heteroaryl, alkoxy, hydroxyl, amino, aminoalkoxy, halogen, or together with X2 forms a 5 or 6 membered ring;

R4 is H, alkyl, cycloalkyl, aryl, heteroaryl, alkyl-aryl, methoxyalkyl;

Rs is H, alkyl, cycloalkyl, aryl, heteroaryl; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof. [001514] In further embodiments, the glutamate modulator is a compound selected pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 408

[001515] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 408. Such compounds are described in WO 2016/123629, published August 4, 2016, corresponding to PCT/US2016/016018, filed February 1, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 408, this reference incorporated by reference herein controls.

[001516] In an embodiment, the glutamate modulator is a compound according to: wherein the variables are substituted when permissible or unsubstituted and: X and Y together form:

Z is N, CH, CD, or C-halogen, C-Me, C— O-Me, C— CN;

R is independently chosen from H, Cl, F, CN, alkyl, cycloalkyl, Me, OMe, alkoxy;

Xi is N, C, CH, CD, CRi;

X2 is N, NRi, or NR2;

X ₃ is N, C, CH, CD, CRi; provided that one of Xi or X3 is C or CRi;

Ri is independently H, alkyl, cycloalkyl, phenyl, halogen, CF3, Cl, CD3, CD2R, CDRR2, aryl, heteroaryl, SO2R3, O — R, O-aryl, O-heteroaryl, NHR, NR2R2, perfluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), alkenyl, alkyl-cycloalkyl, O-alkyl- cycloalkyl, CH2-cycloalkyl, CH2 — CF3, hydroxyalkyl, alkyl-alkoxy, alkyl-heterocycloalkyl, alkyl-heteroaryl, alkyl-carboxylic acid, CO — CF3, alkyl-CO — O-alkyl, CO-alkyl-sulfonyl- alkyl, CO-heterocycloalkyl, CO — NH-cycloalkyl, CN, alkoxy-cycloalkyl, alkoxyheterocycloalkyl, O-alkoxy, O-phenyl, O-alkoxyphenyl, O-dioxothianyl, hydroxyl, alkoxy, O-alkyl-heteroaryl, O-alkyl-heterocycloalkyl, alkoxy-heteroalkyl, methyl sulfonyl, O- heterocycloalkyl, O-alkoxy-heterocycloalkyl, O-alkoxyaryl, alkoxy-heteroaryl, alkyl-phenyl, heterocycloalkyl, O — CD3, O — CD2R, hydroxyl, amino, CO-alkyl, CO-cycloalkyl, CO-alkyl- cycloalkyl, CO-amino-alkyl-sulfonylmethyl, CO-amino-cycloalkyl;

R2 is independently H, heteroaryl, alkyl, phenyl, aryl, O-heterocycloalkyl, alkoxyheterocycloalkyl, O-alkoxy-heterocycloalkyl, O-alkoxyaryl, O-heteroaryl, alkoxy-heteroaryl, alkoxy, alkoxy-heterocycloalkyl, alkyl-phenyl, heterocycloalkyl, O — CD3, O — CD2R, hydroxyl, amino, cycloalkyl, CH2-cycloalkyl, CO-alkyl; heterocycloalkyl, H, CF3, halogen, CD3, CD2R, CDRR2, SO2R3, OR, O-aryl, NHR, NR1R1, perfluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), alkenyl, alkyl-cycloalkyl, CH2-cycloalkyl, CH2 — CF3, hydroxyalkyl, alkyl-alkoxy, alkyl-heterocycloalkyl, alkyl-heteroaryl, O-alkyl-heteroaryl, alkyl-carboxylic acid, CO — CF3, alkyl-CO — O-alkyl, CO-alkyl-sulfonyl-alkyl, CO- heterocycloalkyl, CO — NH-cycloalkyl, CN, alkoxy-cycloalkyl, O-dioxothianyl, methyl sulfonyl;

R3 is H, alkyl, alkoxyphenyl, pyridinyl, nitrilepyridinyl, chloropyridinyl; or a pharmaceutically acceptable salt thereof.

[001517] In an embodiment, the glutamate modulator is a compound selected from: including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

Formula 409

[001518] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 409. Such compounds are described in WO 2016/115282, published July 21, 2016, corresponding to PCT/US2016/013300, filed January 13, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 409, this reference incorporated by reference herein controls.

[001519] In an embodiment, the glutamate modulator is a compound according to: , wherein X is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R;

Y is CH, C-alkyl, N, or may form a 6-membered ring with X optionally substituted with at least one R;

Z is independently, CH, C-alkyl, C-halogen, C-Me, C — Oalkyl C — OMe;

Xi is O or C — Ri;

X2 is O or C — R2;

R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, cycloalkyl, alkyl-cycloalkyl; Ri is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD2R, CDRR2, CONR3R4, aryl , heteroaryl, alkyl-aryl, alkyl-heteroaryl, SO2R2, OR, OR2, Oaryl, Oheteroaryl, NHR, NR3R4, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (ClHhheteroaryl), propanamide, diethylpropanamide, CH2CONR3R4; CH2NHR; CH2NHR3R4;

R2 is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD2R, CDRRi, CONR3R4, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, SO2R1, OR, ORi, Oaryl, Oheteroaryl, NHR, NR3R4, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), propanamide, diethylpropanamide, CH2CONR3R4; CH2NHR; CH2NHR3R4;

R3 is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD2R, CDRR2, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, SO2R2, OR, OR2, Oaryl, Oheteroaryl, NHR, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), propanamide, diethylpropanamide, CH2NHR;

R4 is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD2R, CDRR2, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, SO2R2, OR, OR2, Oaryl, Oheteroaryl, NHR, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), propanamide, diethylpropanamide, CH2NHR; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable derivative thereof.

Formula 410

[001520] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 410. Such compounds are described in WO 2016/115272, published July 21, 2016, corresponding to PCT/US2016/013289, filed January 13, 2016, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 410, this reference incorporated by reference herein controls.

[001521] In an embodiment, the glutamate modulator is a compound according to: , wherein X is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R;

Y is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with X optionally substituted with at least one R;

Z is independently N, CH, C-alkyl, C-halogen, C-Me, C-Oalkyl, C — OMe

Xi is S, SO ₂ , C— Ri; C— CO— Ri;

X ₂ is S, SO ₂ , C— R ₂ , C— CO— R ₂ ;

R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, cycloalkyl, alkyl-cycloalkyl;

Ri is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD ₂ R, CDRR2, CONR2R2, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl, SO2R2, OR, OR2, Oaryl, Oheteroaryl, NHR, NR2R2, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (OHhheteroaryl), propanamide, diethylpropanamide, CH2CONR2R2;

R2 is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF3, halogen, CD3, CD ₂ R aryl, heteroaryl, alkyl- aryl, alkyl-heteroaryl, OR, Oaryl, Oheteroaryl, NHR, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH2heteroaryl), propanamide, diethylpropanamide; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable derivative thereof.

[001522] In further embodiments, the glutamate modulator is a compound according to: , including pharmaceutically acceptable salts and substituted variants retaining glutamate modulatory activity.

Formula 411

[001523] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 411. Such compounds are described in WO 2016/030444, published March 3, 2016, corresponding to PCT/EP2015/069601, filed August 27, 2015 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 411, this reference incorporated by reference herein controls.

[001524] In an embodiment, the glutamate modulator is a compound selected from , including pharmaceutically acceptable salts, solvates, and stereoisomers thereof, and substituted variants retaining glutamate modulatory activity.

Formula 412

[001525] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 412. Such compounds are described in WO 2011/050316, published April 28, 2011, corresponding to PCT/US2010/053837, filed October 22, 2010 and WO 2011/050305, published April 28, 2011, corresponding to PCT/US2010/053825, filed October 22, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 412, this reference incorporated by reference herein controls.

[001526] In an embodiment, the glutamate modulator is a compound according to: wherein:

XUs selected from: CH2, CR2R3, or CR4R4;

R is heteroaryl optionally substituted with one or more R4, and chosen from furan, pyridine, thiazole, or pyrimidine;

Ri is selected from: heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;

R2 is selected from: H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more Rs; R3 is selected from: H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more Rs; RHs selected from: H, OH, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, OC1-6 alkyl, CF3, OCF3, OCOCH3, CO, —COO—, and COOH; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

[001527] In an embodiment, the glutamate modulator is a compound according to: , including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity.

Formula 413

[001528] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 413. Such compounds are described in WO 2015/128307, published September 3, 2015, corresponding to PCT/EP2015/053785, filed February 24, 2015, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 413, this reference incorporated by reference herein controls.

[001529] In an embodiment, the glutamate modulator is a compound according to: wherein

Y is N or C— R ¹ ;

R ¹ is hydrogen or F;

R ¹ is hydrogen, halogen or lower alkyl substituted by halogen;

R ² is hydrogen or lower alkyl; or R ² forms together with R ⁴ a 6 membered heterocyclic ring containing — CH2 — CH2 — O — CH ₂ — or — CH ₂ — CH ₂ — NR— C(O)— ;

R is hydrogen, lower alkyl, phenyl or benzyl;

R ³ is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;

R ⁴ is hydrogen, lower alkyl or lower alkoxyalkyl;

R ⁴ is hydrogen, lower alkyl, phenyl optionally substituted by halogen or lower alkoxy, or is cycloalkyl, or is pyridinyl optionally substituted by halogen, lower alkyl, lower alkoxy or =0, or is pyrimidinyl optionally substituted by lower alkyl, lower alkoxy or =0, or is 1- lower alkyl-pyridinyl, or is pyrazinyl, or is pyridazinyl optionally substituted by lower alkyl, lower alkoxy or =0, or is l-methylpyrrolo[2,3-b]pyridine-5-yl, or is 6-imidazo[l,2- b]pyridazin-6-yl; or R ⁴ forms together with R ⁴ a 4, 5 or 6 membered heterocyclic ring containing — (CkF)? — , — CH ₂ — CH ₂ — O— CH ₂ — CH ₂ — , — CH ₂ — CH ₂ — CH ₂ — , — CH ₂ — CH ₂ — CH ₂ — CH ₂ — , — CH ₂ — O— CH ₂ — CH ₂ — or CH ₂ — CH ₂ — CH ₂ — O— CH ₂ ; and

R ⁵ and R ⁵ 'are hydrogen or lower alkyl; or R ⁴ forms together with R ⁵ a saturated 5-membered ring containing — CH2 — CH2 — CH2 — ; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

Formula 414

[001530] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 414. Such compounds are described in WO 2015/104271, published July 16, 2015, corresponding to PCT/EP2015/050127, filed January 7, 2015, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 414, this reference incorporated by reference herein controls.

[001531] In an embodiment, the glutamate modulator is a compound according to:

Y is C— R ¹ ;

R ¹ ' is hydrogen or halogen;

R ¹ is hydrogen or halogen;

R ² is hydrogen, lower alkyl or phenyl;

R ⁴ is hydrogen or lower alkyl; or R ² and R ⁴ may form together with the corresponding atoms, to which they are attached the following rings

R ⁵ is hydrogen or lower alkyl; and if R ² and R ⁴ form a ring as described above, than R ⁵ is hydrogen; or

R ⁴ and R ⁵ may form together with the C-atom to which they are attached a heterocycloalkyl ring;

R ³ is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.

[001532] In an embodiment, the glutamate modulator is a compound selected from: (5RS,8aRS)-2-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-5-meth yl-5,6,8,8a- tetrahydroimidazo[5, 1 -c] [ 1 ,4]oxazine- 1 ,3 -di one (3aRS)-2-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-3a,4-dihyd roimidazo[l,5- a]indole-l,3-dione (3aRS)-2-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-4,5-dihydr o-3aH-imidazo[l,5- a]quinoline- 1 ,3 -di one

( 10aRS)-2-[2,6-difluoro-4-(2-phenylethynyl)phenyl]- 10,10a-dihydro-5H-imidazo[ 1,5- b]isoquinoline- 1 ,3 -di one (5RS,8aRS)-2-[2-chloro-4-(2-phenylethynyl)phenyl]-5-methyl-6 ,7,8,8a-tetrahydro- 5H-imidazo[l,5-a]pyridine-l, 3-dione or

(5RS,8aRS)-2-[2-chloro-6-fluoro-4-[2-(3-pyridyl)ethynyl]p henyl]-5-methyl-6,7,8,8a- tetrahydro-5H-imidazo[l,5-a]pyridine-l, 3-dione, including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 415

[001533] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 415. Such compounds are described in WO 2015/044075, published April 2, 2015, corresponding to PCT/EP2014/070100, filed September 22, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 415, this reference incorporated by reference herein controls.

[001534] In an embodiment, the glutamate modulator is a compound according to:

, wherein

Y is N or C— R ¹ ; G is a 5 or 6-membered aromatic or heteroaromatic ring containing 0, 1, 2 or 3 heteroatoms, selected from the group consisting of phenyl, pyridinyl with different N-positions, imidazolyl, pyrazinyl, pyrimidinyl, thiophenyl, thiazolyl, pyrazolyl or thiadiazolyl, which are optionally substituted by 1, 2 or 3 substituents, selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkoxy substituted by halogen or NRR';

R and R' are independently from each other hydrogen or lower alkyl, or may form together with the N atom to which they are attached a five or six membered saturated heterocyclic group which may contain an additional oxygen, NH, or N-lower alkyl group;

R ¹ is hydrogen, halogen or lower alkyl substituted by halogen;

R ¹ ' is hydrogen, halogen or lower alkyl substituted by halogen;

R ² is hydrogen, lower alkyl, lower alkoxyalkyl, cycloalkyl or heterocycloalkyl; or R ² may form together with the closest carbon atom in group G a group for A being — CH ₂ — , — CH ₂ CH ₂ , or — C(CH ₃ ) ₂ — ,

R ³ is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer, optical isomer, or stereoisomer thereof.

Formula 416

[001535] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 416. Such compounds are described in WO 2011/100614, published August 18, 2011, corresponding to PCT/US2011/024627, filed February 11, 2011 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 416, this reference incorporated by reference herein controls.

[001536] In an embodiment, the glutamate modulator is a compound according to: wherein: A is aryl or heteroaryl or a 3-8 membered ring comprising C, O, S, and/or N;

R is selected from hydrogen, halogen, Ci-io alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ⁴ ), NR ³ R ⁴ , CONR ³ R ⁴ , S(0)o- ₂ NR ³ R ⁴ , CN or CF ₃ ;

R ¹ is independently selected from hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, OCn 10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ⁴ ), NR ³ R ⁴ , CR ³ R ⁴ , CONR ³ R ⁴ , S(0)o- ₂ NR ³ R ⁴ , CN; CF ₃ , or S(0)o- ₂ Cnio alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ⁴ , COC1-10 alkyl;

R ² is independently selected from hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, OCn 10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), NR3R4, CR ³ R ⁴ , CONR ³ R ⁴ , S(0)o- ₂ NR ³ R ⁴ , CN or CF3, or S(0)o- ₂ Cnio alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ⁴ , COC1-10 alkyl;

R ¹ and R ² can optionally cyclize to form a ring comprising Cs-Ci ₂ cycloalkyl or C3-

Ci ₂ cycloalkenyl or aryl or heteroaryl or Cs-Ci ₂ heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R4;

R ³ is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF ₃ ;

R ⁴ is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF ₃ ;

R ³ and R ⁴ can optionally cyclize to form a ring comprising Cs-Ci ₂ cycloalkyl or C3-

Ci ₂ cycloalkenyl or aryl or heteroaryl or Cs-Ci ₂ heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R ⁵ ;

R ⁵ is selected from hydrogen, halogen, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ⁴ ), CN, CF3; provided that R ¹ cannot be CF3 when R ₂ is H and R ² cannot be CF3 when R ¹ is H; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

Formula 417

[001537] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 417. Such compounds are described in WO 2014/121883, published August 14, 2014, corresponding to PCT/EP2014/000087, filed January 15, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 417, this reference incorporated by reference herein controls.

[001538] In an embodiment, the glutamate modulator is a compound according to:

Xi, X2, X3 independently from each other denote N or CT, wherein one of Xi, X2, and X3 is N and the other two are CT;

V phenyl which is optionally substituted by one or more identical or different substituents T; W denotes

R _a , Rb, Rc, Rd together with the carbon atoms to which they are attached to and the C — C- bond between these carbon atoms form ethynyl ( — C=C — );

Rl, R2 together with the atoms to which they are attached to form a 5-6 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring;

T denotes independently from each other H, alkyl, F, Cl, Br, I, OH, CN, NO2, CF3, or OCF3;

Y denotes independently from each other H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

Formula 418

[001539] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 418. Such compounds are described in WO 2014/121885, published August 14, 2014, corresponding to PCT/EP2014/000101, filed January 16, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 418, this reference incorporated by reference herein controls.

[001540] In an embodiment, the glutamate modulator is a compound according to: wherein:

X independently from each other denotes N or C, with the proviso that only one X is N or no X is N;

Ri, R2 independently from each other denote aryl, heteroaryl or heterocyclyl, which can optionally be substituted by one or more identical or different substituents T;

Rsa, Rsb, R4a, independently from each other denotes substituent T, R4b, Rsa, Rsb, if the individual X is C; if the individual X is N, then one Rea, Reb of the R3/4/5/6a/b substituents is absent and the other one of the R3/4/5/6a/b substituents denotes substituent T or forms a double bond with one of the R3/4/5/6a/b substituents of an adjacent X;

T denotes independently from each other H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, F, Cl, Br, I, OH, CN, NO2, NYY, CF3, OCF3, alkyl-OH, alkyl-NYY, alkyl-CN, O-alkyl, O-cycloalkyl, O-alkyl- cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl- heterocyclyl, C(O)-alkyl, C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl- aryl, C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl, C(O)-alkyl-heterocyclyl, C(O)O-alkyl, C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl, C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl, C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH- alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH-heterocyclyl, C(O)NH- alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-alkyl-cycloalkyl, NHC(O)- aryl, NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl, NHC(O)- heterocyclyl, NHC(O)-alkyl-heterocyclyl, O-alkyl-NYY, C(O)H, C(O)OY, C(O)NY-alkyl- NYY, C(O)NYY, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl moieties can optionally be substituted by one or more identical or different substituents Z;

Y denotes independently from each other H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl can optionally be substituted by one or more identical or different substituents Z;

Z denotes independently from each other alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, F, Cl, Br, I, OH, CN, NO ₂ , NH ₂ , NH-alkyl, N(alkyl) ₂ , NH-alkyl-OH, NH-alkyl-O-alkyl, NH-alkyl-aryl, CF ₃ , OCF3, alkyl-OH, alkyl-NH ₂ , alkyl-NH-alkyl, alkyl-N(alkyl) ₂ , alkyl-CN, alkyl-C(O)-heterocyclyl, O- alkyl, O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl, O-alkyl- heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, O-alkyl-NH ₂ , C(O)H, C(O)OH, C(O)NH- alkyl-NH ₂ , C(O)NH ₂ , C(O)— C(O)— NH ₂ , C(O)-alkyl-NH-alkyl, C(O)-alkyl-NH-alkyl-O- alkyl, C(O)-alkyl, C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl, C(O)- heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl, C(O)-alkyl-heterocyclyl, C(O)- heterocyclyl-alkyl, C(O)O-alkyl, C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl, C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl, C(O)O- alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH- aryl, C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH- heterocyclyl, C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)- alkyl-cycloalkyl, NHC(O)-aryl, NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl- heteroaryl, NHC(O)-heterocyclyl, NHC(O)-alkyl-heterocyclyl, C(O)NH-aryl-halogen, C(O)NH-aryl-O-alkyl, C(O)N(alkyl)-aryl, C(O)N(aryl) ₂ , S-alkyl, S-cycloalkyl, S-alkyl- cycloalkyl, S-aryl, S-alkyl-aryl, S-heteroaryl, S-alkyl -heteroaryl, S-heterocyclyl, S-alkyl- heterocyclyl; and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

Formula 419

[001541] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 419. Such compounds are described in WO 2014/117920, published August 7, 2014, corresponding to PCT/EP2014/000169, filed January 23, 2014, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 419, this reference incorporated by reference herein controls.

[001542] In an embodiment, the glutamate modulator is a compound according to: wherein:

W denotes N, 0 or CH, X denotes N or CH;

R1 denotes cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, which can optionally be substituted by one or more identical or different substituents T;

R2 denotes, (NY)p-cycloalkyl, (NY)p-cycloalkylalkyl, (NY)p-heterocyclyl, (NY) _P - heterocyclylalkyl, (NY) _p -aryl, (NY)p-arylalkyl, (NY)p-heteroaryl, (NY)p-heteroarylalkyl, (NY)p— C(O)-alkyl, (NY) _P — C(O)-cycloalkyl, (NY) _P — C(O)-alkyl-cycloalkyl, (NY) _P — C(O)- heterocyclyl, (NY)p — C(O)-alkyl-heterocyclyl, (NY) _P — C(O)-aryl, (NY)p — C(O)-alkyl-aryl, (NY) _P — C(O)-heteroaryl, (NY)p — C(O)-alkyl-heteroaryl, (NY)P — C(O)O-cycloalkyl, (NY) _P — C(O)O-alkyl-cycloalkyl, (NY)p — C(O)O-heterocyclyl, (NY)p — C(O)O-alkyl- heterocyclyl, (NY)p — C(O)O-aryl, (NY) _P — C(O)O-alkyl-aryl, (NY)p — C(O)O-heteroaryl, (NY) _P — C(O)O-alkyl-heteroaryl, (NY)p — C(O)NH-alkyl, (NY)p — C(O)NH-cycloalkyl, (NY) _P — C(O)NH-alkyl-cycloalkyl, (NY)p — C(O)NH-heterocyclyl, (NY)p — C(O)NH-alkyl- heterocyclyl, (NY) _P — C(O)NH-aryl, (NY) _P — C(O)NH-alkyl-aryl, (NY) _P — C(O)NH- heteroaryl, (NY)p — C(O)NH-alkyl-heteroaryl, (NY)p — S(O)2-alkyl, (NY) _P — S(O)2- cycloalkyl, (NY)p — S(O)2-alkyl-cycloalkyl, (NY)p — S(O)2-heterocyclyl, (NY)p — S(O)2-alkyl- heterocyclyl, (NY)p — S(O)2-aryl, (NY) _P — S(O)2-alkyl-aryl, (NY)p — S(O)2-heteroaryl, (NY) _P — S(O)2-alkyl-heteroaryl, which can optionally be substituted by one or more identical or different substituents T;

R3 if W is N or CH, R3 denotes H or alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl; which can optionally be substituted by one or more identical or different substituents T; if W is O, R3 is absent;

R4, R5, R6, R7 independently from each other denote H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, halogen, F, Cl, Br, I, OH, CN, NO2, NYY, CF3, OCF3, O-alkyl-heterocyclyl, O- alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-NYY, O-alkyl-O-alkyl, C(O)OY, C(O)NY-alkyl- NYY, C(O)NYY, C(O)-alkyl, C(O)-heterocyclyl, S(O) ₂ — Y; whereby alkyl, heterocyclyl, aryl, heteroaryl can optionally be substituted by one or more identical or different substituents T;

T denotes independently from each other H, alkyl, halogen, F, Cl, Br, I, OH, CN, NO ₂ , NYY, CF3, OCF3, O-alkyl, O-alkyl-heterocyclyl, alkyl-NYY, O-alkyl-aryl, O-alkyl-heteroaryl, O- alkyl-NYY, O-alkyl-O-alkyl, C(O)OY, C(O)NY-alkyl-NYY, C(O)NYY, S(O) ₂ — Y, S-alkyl; or two adjacent substituents T can also form together with the atoms to which they are attached to cycloalkyl or heterocyclyl;

Y denotes independently from each other H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl-O-alkyl; n, m independently from each other denote 1 or 2; p denotes independently from each other 0 if X is N or denotes independently from each other 1 if X is CH; and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

Formula 420

[001543] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 420. Such compounds are described in WO 2010/079238, published July 15, 2010, corresponding to PCT/EP2010/050304, filed January 12, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 420, this reference incorporated by reference herein controls.

[001544] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable acid or base addition salt thereof, a sterochemically isomeric form thereof or an N-oxide form thereof, wherein: M is selected from a 3 to 10 membered ring selected from the group consisting of aryl, heteroaryl, heterocyclyl and cycloalkyl which can be substituted by a substituent selected from the group consisting of — (Ci-Ce)alkyl, halogen and — (Ci-Ce)alkyl-O — (Ci-Ce)alkyl; X ¹ is N;

X ² is S;

Y is — CR ⁴ R ⁵ — CR ⁶ R ⁷ ;

Z ¹ is N; Z ² is N; and Z ³ is C; representing a 5 membered heteroaryl ring which may further be substituted by 1 to 2 radicals (A) _m ; m is 1 or 2;

(A)m radicals are each independently selected from the group consisting of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH2 and a radical selected from the group consisting of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C2-Ce)alkynyl, — (C2-Ce)alkenyl, — (C3- C?)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci-Ce)cyanoalkyl, — (Ci -C 6)alkylene-heteroaryl, — (Ci -Ce)alkylene-aryl, aryl, heteroaryl, heterocyclyl, — (Co-C6)alkyl-OR ¹⁰ , — O — (C2- C ₆ )alkylene-OR ¹⁰ , — NR ¹⁰ (C2-C ₆ )alkylene-OR ¹¹ , — (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C3-C ₇ )cycloalkyl-(Ci -C ₆ )alkyl, — NR ¹⁰ — (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — (Ci- C ₆ )haloalkyl-OR ¹⁰ , — (Ci-C ₆ )haloalkyl-NR ¹⁰ R ¹¹ , — (C3-C ₆ )alkynyl-OR ¹⁰ , — (C ₃ -C ₆ )alkynyl- NR ¹⁰ R ⁿ , — (C ₃ -C ₆ )alkenyl-OR ¹⁰ , — (C ₃ -C ₆ )alkenyl -NR ¹⁰ R ⁿ , — (Co-C ₆ )alkyl-S— R ¹⁰ ,— O— (C ₂ -C ₆ )alkylene-S— R ¹⁰ , — NR ¹⁰ — (C2-C ₆ )alkylene-S— R ¹¹ , — (Co-C ₆ )alkyl-S(=0)— R ¹⁰ , — O— (Ci-C ₆ )alkylene-S(=O)— R ¹⁰ , — NR ¹⁰ — (Ci-C ₆ )alkylene-S(=O)— R ¹¹ , — (Co-C ₆ )alkyl- S(=O) ₂ -R ¹⁰ , — O— (Ci-C ₆ )alkylene-S(=O)2— R ¹⁰ , — NR ¹⁰ — (Ci-C ₆ )alkylene-S(=O)2— R ¹¹ , — (Co-C ₆ )alkyl-NR ^1O R ¹¹ , — O— (C2-C ₆ )alkylene-NR ¹⁰ R ¹¹ , — NR ¹⁰ — (C ₂ -C ₆ )alkylene- NR ⁿ R ¹² , — (Co-C ₆ )alkyl-S(=0)2NR ¹ °R ¹¹ , — O— (Ci-C ₆ )alkylene-S(=O)2NR ¹⁰ R ¹¹ , — NR ¹⁰ — (Ci-C ₆ )alkylene -S(=O) ₂ NR ⁿ R ¹² , — (Co-C ₆ )alkyl-NR ¹⁰ — S(=O) ₂ R ⁿ , — O— (C ₂ -C ₆ )alkylene- NR ¹⁰ — S(=O) ₂ R ¹ \ — NR ¹⁰ — (C ₂ -C ₆ )alkylene-NR ¹ S(=O) ₂ R ¹² , — (Co-C ₆ )alkyl-C(=0)—

NR ¹⁰ R ⁿ ,— O— (Ci-C ₆ )alkylene -C(=O)— NR ¹⁰ R ⁿ , — NR ¹⁰ — (Ci-C ₆ )alkylene-C(=O)— NR ⁿ R ¹² , — (Co-C ₆ )alkyl-NR ¹⁰ C(=0)— R ¹¹ , — O— (C2-C ₆ )alkylene-NR ¹⁰ C(=O)— R ¹¹ , — NR ¹⁰ — (C2-C6)alkylene-NR ⁿ C(=O)— R ¹² , — (Co-C ₆ )alkyl -OC(=O)— R ¹⁰ , -O—(C ₂ - C6)alkylene-OC(=0)—R ¹⁰ , —NR ¹ °—(C2-C6)alkylene-OC(=0)—R ¹¹ , —(Co-C6)alkyl- C(=O)— OR ¹⁰ , — O— (Ci-C ₆ )alkylene-C(=O)— OR ¹⁰ , — NR ¹⁰ — (Ci-C ₆ )alkylene-C(=O)— OR ¹¹ , — (Co-C ₆ )alkyl-C(=0)— R ¹⁰ , — O— (Ci -C ₆ )alkylene-C(=O)— R ¹⁰ , — NR ¹⁰ — (Ci - C ₆ )alkylene -C(=O)— R ¹¹ , — (Co-C ₆ )alkyl-NR ¹⁰ — C(=O)— OR ¹¹ , —(Co-C ₆ )alkyl-0— C(=O)— NR ¹⁰ R ⁿ , — (Co-C ₆ )alkyl-NR ¹⁰ — C(=NR ⁿ )— NR ¹² R ¹³ , — (Co-C ₆ )alkyl-NR ¹⁰ - C(=O)— NR ¹¹ R ¹² ,— O— (C ₂ -C ₆ )alkylene-NR ¹⁰ — C(=O)— NR ¹³ R ¹² , — NR ¹⁰ — (C ₂ - C6)alkylene-NR ⁿ — C(=O)— NR ¹² R ¹³ and — (Co-Ce)alkyl-NR ¹⁰ — C(=S)— NR ⁿ R ¹² ;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and a radical selected from the group consisting of — (Ci- Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cy anoalkyl, — (C3-C?)cycloalkyl, — (C4- Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocyclyl and — (C 1 -Ce)alkylene-aryl .

Formula 421

[001545] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 421. Such compounds are described in WO 2010/088406, published August 5, 2010, corresponding to PCT/US2010/022430, filed January 28, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 421, this reference incorporated by reference herein controls.

[001546] In an embodiment, the glutamate modulator is a compound according to: wherein R is four substituents independently selected from hydrogen, halogen, hydroxyl, methoxy, nitrile, nitro, thiol, optionally substituted amino, alkyl, Ci-6 alkyl, cycloalkyl, C3-10 cycloalkyl, alkoxy, aryl, heteroaryl, and CONR ⁷ R ⁸ , CF ₃ ; wherein each R ¹ is one or more substituents independently selected from hydrogen, halogen, hydroxyl, methoxy, alkoxy, nitrile, nitro, thiol, optionally substituted amino, aryl, heteroaryl, CF3, alkyl, C1-6 alkyl, cycloalkyl, C3-10 cycloalkyl, and CONR ⁷ R ⁸ ; wherein each R ² is one or more substituents independently selected from hydrogen, halogen, hydroxyl, methoxy, alkoxy, nitrile, nitro, thiol, optionally substituted amino, aryl, heteroaryl, CF3, NR ⁷ R ⁸ , alkyl, C1-6 alkyl, cycloalkyl, C3-10 cycloalkyl, and CONR ⁷ R ⁸ , SO ₂ NR ⁷ R ⁸ ; wherein R ³ is hydrogen, NH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, mono or disubstituted amino, and amide; wherein R ⁵ and R ⁶ are independently hydrogen, halogen, carbonyl, thiocarbonyl, CF3, nitrile, alkyl, C1-6 alkyl, cycloalkyl, C3-10 cycloalkyl, or 3-8 membered ring comprising C, O, S, and/or N; wherein R ⁷ and R ⁸ are independently hydrogen, halogen, alkyl, Ci-6 alkyl, cycloalkyl, C3-

10 cycloalkyl, alkoxy, aryl, heteroaryl, nitrile, CF3; wherein M is NR ³ , CR ⁵ R ⁶ ; wherein K is NR ³ , CR ⁵ R ⁶ ; wherein Y is C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3-

C 12 heterocycloalkyl or C3-C12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N; wherein Z is C3-C12 cycloalkylene or C3-C12 cycloalkenylene or arylene or heteroarylene or

C3-C12 heterocycloalkylene or C3-C12 heterocycloalkenylene; wherein k is an integer from 0 to 25; wherein m is an integer from 0 to 24; and wherein each n is independently an integer from 0 to 1; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

[001547] In an embodiment, the glutamate modulator is a compound selected from: including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 422

[001548] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 422. Such compounds are described in WO 2011/086163, published July 21, 2011, corresponding to PCT/EP2011/050476, filed January 14, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 422, this reference incorporated by reference herein controls.

[001549] In an embodiment, the glutamate modulator is a compound according to: pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein:

X is selected from N or from C which may further be substituted by A;

A radical is selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH2 and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci- Ce)haloalkyl, — (C2-Ce)alkynyl, — (C2-Ce)alkenyl, — (C3-C?)cyclo alkyl, — (C3- Cs ycloalkenyl, — (Ci-Ce)cyano alkyl, — (Ci-C6)alkylene-hetero aryl, — (Ci-Ce)alkylene- aryl, — (Ci-C6)alkylene-heterocycle, — (Ci-C6)alkylene-cycloalkyl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ¹ , — O — (C2-Ce)alkylene-OR ¹ , — NR ¹ (C2-Ce)alkylene-OR ² , — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — NR ¹ — (C ₃ - C7)cycloalkyl-(Ci-Ce)alkyl, — (Ci-Ce)haloalkylene-OR ¹ , — (Ci-Ce)haloalkylene-NR ¹ R ² , — (C ₃ -C ₆ )alkynyl-OR ¹ , — (C ₃ -C ₆ )alkynyl-NR ¹ R ² , — (C ₃ -C ₆ )alkenyl-OR ¹ , — (C ₃ -C ₆ )alkenyl- NR’R ² , — (Co-C ₆ )alkyl-S— R ¹ , — O— (C2-C ₆ )alkylene-S— R ¹ , — NR ¹ — (C ₂ -C ₆ )alkylene-S— R ² , — (Co-C ₆ )alkyl-S(=0)— R', — O— (Ci-C ₆ )alkylene-S(=O)— R ¹ , — NR ¹ — (Ci- C ₆ )alkylene-S(=O)— R ² , — (Co-C ₆ )alkyl-S(=0)2— R', — O— (Ci-C ₆ )alkylene-S(=O)2— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-S(=O)2— R ² , — (Co-C ₆ )alkyl-NR ¹ R ² , — O— (C ₂ -C ₆ )alkylene- NR’R ² , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² R ³ , — (Co-C ₆ )alkyl-S(=0) ₂ NR ¹ R ² , -O—(Ci- C6)alkylene-S(=0)2NR ¹ R ² , —NR ¹ —(Ci-C6)alkylene-S(=0)2NR ² R ³ , —(Co-C ₆ )alkyl-NR ¹ — S(=O) ₂ R ² , — O— (C ₂ -C ₆ )alkylene-NR ¹ — S(=O) ₂ R ² , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² — S(=O) ₂ R ³ , — (Co-C ₆ )alkyl-C(=0)— NR'R ² , — O— (Ci-C ₆ )alkylene-C(=O)— NR’R ² , — NR ¹ —(Ci-C6)alkylene-C(=0)—NR ² R ³ , —(Co-C ₆ )alkyl-NR ¹ C(=0)—R ² , —0—(C2- C ₆ )alkylene-NR ¹ C(=O)— R ² , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² C(=O)— R ³ , — (Co-C ₆ )alkyl- C(=O)— R', — O— (Ci-C ₆ )alkylene-C(=O)— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-C(=O)— R ² , — (Co-Ce)alkyl-NR ¹ — C(=0)— NR ² R ³ , — O— (C ₂ -C ₆ )alkylene-NR ¹ — C(=0)— NR ² R ³ , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² — C(=O)— NR ³ R ⁴ and — (Co-Ce)alkyl-NR ¹ — C(=S)— NR ² R ³ ; R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)alkylene-heterocycle, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

Any two radicals of R(R R ² , R ³ or R ⁴ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; n is an integer ranging from 1 to 2;

B radicals are each independently selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C ₂ -Ce)alkynyl, — (C ₂ -Ce)alkenyl, — (C3-C?)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci-Ce)cyanoalkyl, — (Ci-C6)alkylene-heteroaryl, — (Ci- Ce)alkylene-aryl, — (Ci-C6)alkylene-heterocycle, — (Ci-C6)alkylene-cycloalkyl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ⁵ , — O — (C ₂ -Ce)alkylene-OR ⁵ , — NR ⁵ (C ₂ - Ce)alkylene-OR ⁶ , — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — O — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — NR ⁵ — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — (Ci-C ₆ )haloalkyl-OR ⁵ , — (Ci-C ₆ )haloalkyl- NR ⁵ R ⁶ , — (C ₃ -C ₆ )alkynyl-OR ⁵ , — (C ₃ -C ₆ )alkynyl-NR ⁵ R ⁶ , — (C ₃ -C ₆ )alkenyl-OR ⁵ , — (C3- C ₆ )alkenyl-NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-S— R ⁵ , — O— (C ₂ -C ₆ )alkylene-S— R ⁵ , — NR ⁵ — (C ₂ - C ₆ )alkylene-S— R ⁶ , — (Co-C ₆ )alkyl-S(=0)— R ⁵ , — O— (Ci-C ₆ )alkylene-S(=O)— R ⁵ , — NR ⁵ — (Ci-C ₆ )alkylene-S(=O)— R ⁶ , — (Co-C ₆ )alkyl-S(=0) ₂ — R ⁵ , — O— (Ci-C ₆ )alkylene- S(=O) ₂ — R ⁵ , — NR ⁵ — (Ci-C ₆ )alkylene-S(=O) ₂ — R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ R ⁶ , — O— (C ₂ - C ₆ )alkylene-NR ⁵ R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkylene-NR ⁶ R ⁷ , — (Ci-C ₆ )alkyl-S(=O) ₂ NR ⁵ R ⁶ , —O— (Ci-C ₆ )alkylene-S(=O) ₂ NR ⁵ R ⁶ , — NR ⁵ — (Ci-C ₆ )alkylene-S(=O) ₂ NR ⁶ R ⁷ , — (Co-C ₆ )alkyl- NR ⁵ — S(=O) ₂ R ⁶ , — O— (C ₂ -C ₆ )alkylene-NR ⁵ — S(=O) ₂ R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkylene-NR ⁶ — S(=O) ₂ R ⁷ , — (Co-C ₆ )alkyl-C(=0)— NR ⁵ R ⁶ , — O— (Ci-C ₆ )alkylene-C(=O)— NR ⁵ R ⁶ , — NR ⁵ —(Ci-C6)alkylene-C(=0)—NR ⁶ R ⁷ , —(Co-C ₆ )alkyl-NR ⁵ C(=0)—R ⁶ , —0—(C ₂ - C ₆ )alkylene-NR ⁵ C(=O)— R ⁶ , — NRS— (C ₂ -C ₆ )alkylene-NR ⁶ C(=O)— R ⁷ , — (Co-C ₆ )alkyl- C(=O)— R ⁵ , — O— (Ci-C ₆ )alkylene-C(=O)— R ⁵ , — NR ⁵ — (Ci-C ₆ )alkylene-C(=O)— R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ — C(=O)— NR ⁶ R ⁷ , — O— (C ₂ -C ₆ )alkylene-NR ⁵ — C(=O)— NR ⁶ R ⁷ , — NR ⁵ — (C ₂ -C ₆ )alkylene-NR ⁶ — C(=O)— NR ⁷ R ⁸ and — (Co-Ce)alkyl-NR ⁵ — C(=S)— NR ⁶ R ⁷ ; R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C7)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)alkylene-heterocycle, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

M is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;

P is selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Co-C ₆ )alkyl-C(=0)— R ⁹ , — (Ci-C ₆ )alkyl-CN, — (C ₂ -C ₆ )alkyl-S(O)— R ⁹ , — (Co-C ₆ )alkyl-C(=0)NR ⁹ R ¹⁰ , — (C ₂ -C ₆ )alkyl-NR ⁹ C(=O)R ¹⁰ , — (Co-C ₆ )alkyl-S(0) ₂ — R ⁹ , — (Co-C ₆ )alkyl-R ⁹ , — (C ₂ -C ₆ )alkyl-NR ⁹ R ¹⁰ , — (C ₂ -C ₆ )alkyl-OR ⁹ and — (C ₂ -C ₆ )alkyl-SR ⁹ ;

R ⁹ and R ¹⁰ are selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)alkylene-heterocycle, aryl, heterocycle and — (Ci-Ce)alkylene-aryl.

Formula 423

[001550] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 423. Such compounds are described in WO 2011/010222, published January 27, 2011, corresponding to PCT/IB2010/002092, filed July 14, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 423, this reference incorporated by reference herein controls.

[001551] In an embodiment, the glutamate modulator is a compound according to:

(A) _m pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein: X ² is selected from the group of C and N representing a 5 membered heteroaryl ring which may further be substituted by radical (A) _m where: m is an integer ranging from 0 to 1;

(A)m radical is selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci- Ce)haloalkyl, — (C ₂ -Ce)alkynyl, — (C ₂ -Ce)alkenyl, — (C3-C?)cycloalkyl, — (C3- CsXycloalkenyl, — (Ci-Ce)cyanoalkyl, aryl, — (Ci-C6)alkylene-aryl, heteroaryl, — (Ci- Ce)alkylene-heteroaryl, heterocycle, — (Co-Ce)alkylene-OR ¹ , — O — (C2-Ce)alkylene-OR ¹ , — NR ¹ (C ₂ -C ₆ )alkylene-OR ² , — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C3-C ₇ )cycloalkyl-(Ci- Ce)alkyl, — NR ¹ — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — O — (Ci-C6)alkylene-(C3-C7)cycloalkyl, — NR ¹ — (Ci-C6)alkylene-(C3-C7)cycloalkyl, — (Ci-Ce^aloalkylene-OR ¹ , — (Ci- C6)haloalkylene-NR ¹ R ² , — (Co-C6)alkylene-S — R ¹ , — O — (C2-C6)alkylene-S — R ¹ , — NR ¹ - (C2-C ₆ )alkylene-S— R ² , — (Co-C ₆ )alkylene-S(=0)— R ¹ , — O— (Ci-C ₆ )alkylene-S(=O)— R ¹ , —NR ¹ —(Ci-C6)alkylene-S(=0)—R ² , —(Co-C ₆ )alkylene-S(=0)2—R ¹ , —0—(Ci- C ₆ )alkylene-S(=O)2— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-S(=O)2— R ² , — (Co-C ₆ )alkylene-NR ¹ R ² , — O — (C2-C6)alkylene-NR ¹ R ² , — NR ¹ — (C2-C6)alkylene-NR ² R ³ , — (Co-Ce)alkylene- S(=O)2NR ¹ R ² , —O—(Ci-C6)alkylene-S(=O)2NR ¹ R ² , —NR ¹ —(Ci-C ₆ )alkylene- S(=O) ₂ NR ² R ³ , — (Co-C ₆ )alkylene-NR ¹ — S(=O) ₂ R ² , — O— (C2-C ₆ )alkylene-NR ¹ — S(=O) ₂ R ² , — NR ¹ — (C2-C ₆ )alkylene-NR ² — S(=O) ₂ R ³ , — (Co-C ₆ )alkylene-C(=0)— NR ³ R ² , — O— (Ci- C ₆ )alkylene- C(=0)-NR ¹ R ² , —NR ¹ —(Ci-C6)alkylene-C(=0)-NR ² R ³ ,—(Co-C ₆ )alkylene- NR'C(=O)-R ² , — O— (C2-C ₆ )alkylene-NR ^I C(=O))— R ² , — NR ¹ — (C ₂ -C ₆ )alkylene- NR ² C(=O)— R ³ , — (Co-C ₆ )alkylene-C(=0)— R ¹ , — O— (Ci-C ₆ )alkylene-C(=O)— R ¹ and — NR ¹ — (Ci-C ₆ )alkylene-C(=O)— R ² ;

R ¹ , R ² and R ³ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

Any two radicals of R(R\ R ² or R ³ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;

M is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;

B radical is selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci- Ce)haloalkyl, — (C2-Ce)alkynyl, — (C2-Ce)alkenyl, — (C3-C?)cycloalkyl, — (C3- Cs)cycloalkenyl, — (Ci-Ce)cyanoalkyl, — (Ci-C6)alkylene-heteroaryl, — (Ci-Ce)alkylene- aryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkylene-OR ⁴ , — O — (C2-Ce)alkylene-OR ⁴ , — NR ⁴ (C ₂ -C ₆ )alkylene-OR ⁵ , — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — O-(C3-C ₇ )cycloalkyl-(Ci- Ce)alkyl, — NR ⁴ — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — O — (Ci-C6)alkylene-(C3-C7)cycloalkyl, — NR ⁴ — (Ci-C ₆ )alkylene-(C3-C7)cycloalkyl, — (Ci-C ₆ )haloalkylene-OR ⁴ , — (Ci- C ₆ )haloalkylene-NR ⁴ R ⁵ , — (Co-C ₆ )alkylene-S— R ⁴ , — O— (C ₂ -C ₆ )alkylene-S— R ⁴ , —NR ⁴ — (C ₂ -C ₆ )alkylene-S— R ⁵ , — (Co-C ₆ )alkylene-S(=0)— R ⁴ , — O— (Ci-C ₆ )alkylene-S(=O)— R ⁴ , — NR ⁴ -(Ci-C ₆ )alkylene-S(=O)— R ⁵ , — (Co-C ₆ )alkylene-S(=0) ₂ — R ⁴ , — O— (Ci-C ₆ )alkylene- S(=O) ₂ — R ⁴ , — NR ⁴ — (Ci-C ₆ )alkylene-S(=O) ₂ — R ⁵ , — (Co-C ₆ )alkylene-NR ⁴ R ⁵ , — O— (C ₂ - C ₆ )alkylene-NR ⁴ R ⁵ , — NR ⁴ — (C ₂ -C ₆ )alkylene-NR ⁵ R ⁶ , — (C ₀ -C ₆ )alkylene-S(=O) ₂ NR ⁴ R ⁵ , — 0—(Ci-C6)alkylene-S(=0) ₂ NR ⁴ R ⁵ , —NR ⁴ —(Ci-C ₆ )alkylene-S(=0) ₂ NR ⁵ R ⁶ , —(Co- C6)alkylene-NR ⁴ —S(=O) ₂ R ⁵ , —O—(C ₂ -C6)alkylene-NR ⁴ —S(=O) ₂ R ⁵ , —NR ⁴ —(C ₂ - C ₆ )alkylene-NR ⁵ — S(=O) ₂ R ⁶ , — (Co-C ₆ )alkylene-C(=0)— NR ⁴ R ⁵ , — O— (Ci-C ₆ )alkylene- C(=O)— NR ⁴ R ⁵ , — NR ⁴ — (Ci-C ₆ )alkylene-C(=O)— NR ⁵ R ⁶ , — (Co-C ₆ )alkylene- NR ⁴ C(=O)— R ⁵ , — O— (C ₂ -C ₆ )alkylene-NR ⁴ C(=O)— R ⁵ , — NR ⁴ — (C ₂ -C ₆ )alkylene- NR ⁵ C(=O)— R ⁶ , — (Co-C ₆ )alkylene-C(=0)— R ⁴ , — O— (Ci-C ₆ )alkylene-C(=O)— R ⁴ and — NR ⁴ — (Ci-C ₆ )alkylene-C(=O)— R ⁵ ;

R ⁴ , R ⁵ and R ⁶ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

Any two radicals of R(R ⁴ , R ⁵ or R ⁶ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;

Formula 424

[001552] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 424. Such compounds are described in WO 2013/107862, published July 25, 2013, corresponding to PCTZEP2013/050945, filed January 18, 2013 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 424, this reference incorporated by reference herein controls.

[001553] In an embodiment, the glutamate modulator is a compound according to : a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein:

M is an optionally substituted heteroaryl; R ¹ is hydrogen or an optionally substituted radical selected from the group of — (C3- C?)cycloalkyl, — (Ci-C6)alkylene-(C3-C7)cycloalkyl, — (C3-C7)cycloalkylene-(Ci-Ce)alkyl, — (Co-C6)alkylene-(C3-C7)spiroalkylene-(Co-Ce)alkyl, — (Ci-Ce)alkylene-aryl, aryl, — (Ci- Ce)alkylene-hetero aryl, heteroaryl, — (Ci-C6)alkylene-hetero cycle, heterocycle, — (C2- C ₆ )alkylene-OR ² , — (C ₂ -C ₆ )alkylene-NR ² R ³ , — (Co-C ₆ )alkylene-C(=0)— NR ² R ³ , — (Co- C ₆ )alkylene-C(=O)— R ² ;

R ² and R ³ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3-C7)cycloalkyl, — (Ci-C6)alkylene-(C3-C7)cycloalkyl, — (C3-C7)cycloalkylene-(Ci-Ce)alkyl, — (Co- C6)alkylene-(C3-C7)spiroalkylene-(Co-Ce)alkyl, heteroaryl, — (Ci-C6)alkylene-hetero aryl, aryl, — (Ci-Ce)alkylene-aryl, — (Ci-C6)alkylene-heterocycle, heterocycle, — (C2-Ce)alkylene- O— (Co-C ₆ )alkyl and — (C2-C6)alkylene-N-((Co-C ₆ )alkyl)2;

R ² and R ³ may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring.

Formula 425

[001554] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 425. Such compounds are described in WO 2011/100607, published August 18, 2011, corresponding to PCT/US2011/024618, filed February 11, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 425, this reference incorporated by reference herein controls.

[001555] In an embodiment, the glutamate modulator is a compound according to: wherein:

X is selected from CH, N or NH;

X ^I is selected from N or NH;

X ² is independently selected from CH, N or NH; m is 0, 1 or 2; n is 1 or 2;

D, when present, is CH2, CR ³ R ⁴ , CONH, or CONR ³ ; Y is selected from N, or NH;

W is NH;

A is selected from substituted or unsubstituted C3-C12 cycloalkyl, C3-C12 cycloalkenyl, pyridinyl, or phenyl;

R ¹ is independently selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may optionally contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R ⁴ ), OAryl (optionally substituted with one or more R ² ), OHeteroaryl (optionally substituted with one or more R ² ), NR ³ R ⁴ , CHR ³ R ⁴ , CONR ³ R ⁴ , COCR ³ R ⁴ , COAryl (optionally substituted with one or more R ² ), COHeteroaryl (optionally substituted with one or more R ² ), CN or CF3;

R ² is independently selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may optionally contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with one or more R ² ), OHeteroaryl (optionally substituted with one or more R ² ), NR3R4, CHR ³ R ⁴ , CONR ³ R ⁴ , COCR ³ R ⁴ , COAryl (optionally substituted with R ¹ and/or R ² ), COHeteroaryl (optionally substituted with one or more R ² ), CN or CF3;

R ³ is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF ₃ ;

R ⁴ is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF ₃ ; provided that when X ¹ ' ⁴ , Y, and Z are part of pyrazolopyridine, W is NH, m is 0, and A is phenyl, then R ¹ is not Cl when R ² is H and R2 is not Cl when Ri is H; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

[001556] In an embodiment, the glutamate modulator is a compound selected from:

, including pharmaceutically acceptable salts thereof and substituted variants having glutamate modulatory activity. Formula 426

[001557] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 425. Such compounds are described in WO 2010/009001, published January 19, 2012, corresponding to PCT/US2011/001207, filed July 11, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 425, this reference incorporated by reference herein controls.

[001558] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt, a stereochemically isomeric form or an N-oxide form thereof, wherein M is a an optionally substituted heteroaryl;

A is NH or O;

Y is — CR ³ R ⁴ — NR ⁵ — ;

R ¹ , R ² , R ³ or R ⁴ are each independently selected from the group of hydrogen, halogen, — CN, — CF3 or an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci- Ce)haloalkyl, — (C3-C?)cycloalkyl, aryl, heteroaryl, heterocycle, — (Ci-Ce)alkylene-aryl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)alkylene-heterocycle, — O — (Co-Ce)alkyl, — N — ((Co- C ₆ )alkyl) ₂ , — (Ci-C ₆ )alkyl-O— (Co-C ₆ )alkyl, or — (Ci-C ₆ )alkyl-N— ((Co-C ₆ )alkyl) ₂ ; or optionally, any two radicals of R (R ¹ , R ² , R ³ or R ⁴ ) are taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; and

R ⁵ is selected from the group of hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C3-C?)cycloalkyl, — (Ci-Ce)alkylene- (Ci-Ce)haloalkyl, — (Ci-C6)alkylene-(C3-C7)halocycloalkyl, aryl, heteroaryl, heterocycle, — (Ci-Ce)alkylene-aryl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)alkylene-heterocycle, — (C ₂ - C ₆ )alkyl-O— (Co-C ₆ )alkyl, or — (C ₂ -C ₆ )alkyl-N— ((Co-C ₆ )alkyl) ₂ .

Formula 427 [001559] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 427. Such compounds are described in WO 2012/009009, published January 19, 2012, corresponding to PCT/US2011/001222, filed July 12, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 427, this reference incorporated by reference herein controls.

[001560] In an embodiment, the glutamate modulator is a compound according to:

, wherein A radical is selected from the group of hydrogen, halogen, — CN, — CF3 and an optionally substituted radical selected from the group of — (Ci- Ce)alkyl, — (Ci-Ce)haloalkyl, — (C3-C?)cycloalkyl, — (Ci-Ce)cyanoalkyl, — (Ci-Ce)alkylene- heteroaryl, — (Ci-C6)alkylene-heterocycle, — (Ci-Ce)alkylene-aryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ¹ , — O — (C2-Ce)alkylene-OR ¹ , — NR ¹ (C2-Ce)allylene-OR ² , — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — NR ¹ — (C ₃ - C7)cycloalkyl-(Ci-Ce)alkyl, — (Ci-Ce)haloalkylene-OR ¹ , — (Ci-Ce)haloalkylene-NR ¹ R ² , — (Co-C ₆ )alkyl-S— R ¹ , — O— (C2-C ₆ )alkylene-S— R ¹ , — NR ¹ — (C2-C ₆ )alkylene-S— R ² , — (Co- C ₆ )alkyl-S(=O)— R ¹ , — O— (Ci-C ₆ )alkylene-S(=O)— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-S(=O)— R ² , — (Co-C ₆ )alkyl-S(=0)2— R ¹ , — O— (Ci-C ₆ )alkylene-S(=O)2— R ¹ , — NR ¹ — (Ci- C ₆ )alkylene-S(=O) ₂ — R ² , — (Co-C ₆ )alkyl-NR ¹ R ² , — O— (C ₂ -C ₆ )alkylene-NR ¹ R ² , —NR. ¹ — (C ₂ -C ₆ )alkylene-NR ² R ³ , — (Co-C ₆ )alkyl-S(=0) ₂ NR ¹ R ² , — O— (Ci-C ₆ )alkylene- S(=O) ₂ NR ¹ R ² , — NR ¹ — (Ci-C ₆ )alkylene-S(=O) ₂ NR ² R ³ , — (Co-C ₆ )alkyl-NR ¹ — S(=O) ₂ R ² , — 0—(C2-C6)allylene-NR ¹ —S(=0)2R ² , —NR ¹ —(C2-C6)alkylene-NR ² —S(=0) ₂ R ³ , —(Co- C6)alkyl-C(=O)—NR ¹ R ² , —O—(Ci-C6)alkylene-C(=O)—NR ¹ R ² , —NR ¹ —(Ci-C ₆ )alkylene- C(=O)— NR ² R ³ , — (Co-C ₆ )alkyl-NR ¹ C(=0)— R ² , — O— (C ₂ -C ₆ )alkylene-NR ¹ C(=O)— R ² , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² C(=O)— R ³ , — (Co-C ₆ )alkyl-C(=0)— R ¹ , — O— (Ci- C ₆ )alkylene-C(=O)— R ¹ and — NR ¹ — (Ci-C ₆ )alkylene-C(=O)— R ² ;

R ¹ , R ² and R ³ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C7)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle, — (Ci-C6)alkylene-heterocycle and — (Ci-Ce)alkylene-aryl; Any two radicals of R(R R ² or R ³ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;

B radical is selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH2 and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci- Ce)haloalkyl, — (C3-C?)cycloalkyl, — (Ci-Ce)cyanoalkyl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)allylene-heterocycle, — (Ci-Ce)alkylene-aryl, aryl, heteroaryl, heterocycle, — (Co- C ₆ )alkyl-OR ⁴ , — O— (C ₂ -C ₆ )alkylene-OR ⁴ , — NR ⁴ (C ₂ -C ₆ )alkylene-OR ⁵ , — (C3- C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — NR ⁴ — (C ₃ - C7)cycloalkyl-(Ci-C6)allyl, — (Ci-Ce)haloalkylene-OR ⁴ , — (Ci-C6)haloalkylene-NR ⁴ R ⁵ , — (Co-C ₆ )alkyl-S— R ⁴ , — O— (C ₂ -C ₆ )alkylene-S— R ⁴ , — NR ⁴ — (C ₂ -C ₆ )alkylene-S— R ⁵ , — (Co- C ₆ )alkyl-S(=O)— R ⁴ , — O— (Ci-C ₆ )alkylene-S(=O)— R ⁴ , — NR ⁴ — (Ci-C ₆ )alkylene-S(=O)— R ⁵ , — (Co-C ₆ )alkyl-S(=0) ₂ — R ⁴ , — O— (Ci-C ₆ )alkylene-S(=O) ₂ — R ⁴ , — NR ⁴ — (Ci- C ₆ )alkylene-S(=O) ₂ — R ⁵ , — (Co-C ₆ )alkyl-NR ⁴ R ⁵ , — O— (C ₂ -C ₆ )alkylene-NR ⁴ R ⁵ , — NR ⁴ — (C ₂ -C ₆ )alkylene-NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-S(=0) ₂ NR ⁴ R ⁵ , — O— (Ci-C ₆ )alkylene- S(=O) ₂ NR ⁴ R ⁵ , — NR ⁴ — (Ci-C ₆ )alkylene-S(=O) ₂ NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-NR ⁴ — S(=O) ₂ R ⁵ , — O—(C ₂ -C6)alkylene-NR ⁴ —S(=O) ₂ R ⁵ , —NR ⁴ —(C ₂ -C6)alkylene-NR ⁵ —S(=O) ₂ R ⁶ , —(C ₀ - C ₆ )alkyl-C(=O)— NR ⁴ R ⁵ , — O— (Ci-C ₆ )alkylene-C(=O)— NR ⁴ R ⁵ , — NR ⁴ — (Ci-C ₆ )alkylene- C(=O)— NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-NR ⁴ C(0)R ⁵ , — O— (C ₂ -C ₆ )alkylene-NR ⁴ C(=O)— R ⁵ , — NR ⁴ — (C ₂ -C ₆ )alkylene-NR ⁵ C(=O)— R ⁶ , — (Co-C ₆ )alkyl-C(=0)— R ⁴ , — O— (Ci-C ₆ )alkylene- C(=O)— R ⁴ and — NR ⁴ — (Ci-C ₆ )alkylene-C(=O)— R ⁵ ;

R ⁴ , R ⁵ and R ⁶ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-C6)cyanoallyl, — (C3- C7)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)alkylene-heterocycle, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

Any two radicals of R (R ⁴ , R ⁵ or R ⁶ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;

M is an optionally substituted heteroaryl;

Formula 428

[001561] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 428. Such compounds are described in WO 2012/009888, published January 19, 2012, corresponding to PCT/US2011/001201, filed July 9, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 428, this reference incorporated by reference herein controls. [001562] In an embodiment, the glutamate modulator is a compound selected from:

, or a pharmaceutically acceptable salt thereof or substituted variant retaining glutamate modulatory activity.

Formula 429 [001563] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 429. Such compounds are described in WO 2011/143466, published November 17, 2011, corresponding to PCT/US2011/036308, filed May 12, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 429, this reference incorporated by reference herein controls.

[001564] In an embodiment, the glutamate modulator is a compound according to: wherein:

W is selected from O, S, CR4, N or NR.4;

Y is selective from O, S, C, CR4, N or NR4;

Z is selective from O, S, N, NR4 or CR4;

X4 is selected from CH2, CR2R3, aryl optionally substituted with R4, heteroaryl optionally substituted with R4;

R is pyridine optionally substituted with one or more R4;

Ri is selected from heteroaryl optionally substituted with one or more R4, aryl optionally substituted with one or more R4, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4;

R2 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more Rs; R3 is selected from H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, R2 and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more Rs; and

R4 is selected from H, OH, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, alkoxy, CF3;

Rs is selected from H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CH2F, CHF2, CF3, C1-6 alkyl-hydroxyl; and n is 0-6; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof. [001565] In an embodiment, the glutamate modulator is a compound selected from: or a pharmaceutically acceptable salt thereof, or substituted variant having glutamate modulatory activity.

Formula 430

[001566] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 430. Such compounds are described in WO 2011/100614, published August 18, 2011, corresponding to PCT/US2011/024627, filed February 11, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 430, this reference incorporated by reference herein controls.

[001567] In an embodiment, the glutamate modulator is a compound according to: wherein:

A is aryl or heteroaryl or a 3-8 membered ring comprising C, O, S, and/or N;

R is selected from hydrogen, halogen, Cl-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), NR3R4, CONR3R4, S(O)0-2NR3R4, CN or CF3; R1 is independently selected from hydrogen, halogen, Cl-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), NR3R4, CR3R4, CONR3R4, S(O)0- 2NR3R4, CN; CF3, or S(0)0-2C1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, COCl-lO alkyl;

R2 is independently selected from hydrogen, halogen, Cl-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), NR3R4, CR3R4, CONR3R4, S(O)0- 2NR3R4, CN or CF3, or S(0)0-2C1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4, COCl-lO alkyl;

R1 and R2 can optionally cyclize to form a ring comprising C3-C12 cycloalkyl or C3- C12 cycloalkenyl or aryl or heteroaryl or C3-C12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R4;

R3 is selected from hydrogen, Cl-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF3;

R4 is selected from hydrogen, Cl-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF3;

R3 and R4 can optionally cyclize to form a ring comprising C3-C12 cycloalkyl or C3- C12 cycloalkenyl or aryl or heteroaryl or C3-C12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R5;

R5 is selected from hydrogen, halogen, OC1-10 alkyl (which may contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R4), CN, CF3;

[001568] In an embodiment, the glutamate modulator is a compound selected from:

pharmaceutically acceptable salt thereof having glutamate modulatory activity.

Formula 431

[001569] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 431. Such compounds are described in WO 2011/100607, published August 18, 2011, corresponding to PCT/US2011/024618, filed February 11, 2011, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 431, this reference incorporated by reference herein controls.

[001570] In an embodiment, the glutamate modulator is a compound according to: wherein:

X is selected from CH, N or NH;

X ^I is selected from N or NH; X ² is independently selected from CH, N or NH; m is 0, 1 or 2; n is 1 or 2;

D, when present, is CH2, CR ³ R ⁴ , CONH, or CONR ³ ;

Y is selected from N, or NH;

W is NH;

A is selected from substituted or unsubstituted C3-C12 cycloalkyl, C3-C12 cycloalkenyl, pyridinyl, or phenyl;

R ¹ is independently selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may optionally contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R ⁴ ), OAryl (optionally substituted with one or more R ² ), OHeteroaryl (optionally substituted with one or more R ² ), NR ³ R ⁴ , CHR ³ R ⁴ , CONR ³ R ⁴ , COCR ³ R ⁴ , COAryl (optionally substituted with one or more R ² ), COHeteroaryl (optionally substituted with one or more R ² ), CN or CF3;

R ² is independently selected from hydrogen, halogen, hydroxyl, aryl, heteroaryl, C1-10 alkyl, C3-10 cycloalkyl, OC1-10 alkyl (which may optionally contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with one or more R ² ), OHeteroaryl (optionally substituted with one or more R ² ), NR3R4, CHR ³ R ⁴ , CONR ³ R ⁴ , COCR ³ R ⁴ , COAryl (optionally substituted with R ¹ and/or R ² ), COHeteroaryl (optionally substituted with one or more R ² ), CN or CF3;

R ³ is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF ₃ ;

R ⁴ is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF ₃ ; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

[001571] In further embodiments, the glutamate modulator is a compound according to: wherein: A is selected from C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3-

C 12 heterocycloalkyl or C3-C12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N;

D, when present, is CH2, CR ³ R ⁴ , CONH, or CONR ³ ; m is 0, 1 or 2;

R ¹ is independently halogen;

R ² is OCi-10 alkyl (which may contain a C3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R4), OAryl (optionally substituted with at least one R ¹ , R ² and/or R ⁴ ), OHeteroaryl (optionally substituted with at least one R ¹ , R ² and/or R ⁴ ), OCi-10 alkylaryl (optionally substituted with at least one R ¹ , R ² and/or R ⁴ ), OCn

10 alkylheteroaryl (optionally substituted with at least one R ¹ , R ² and/or R ⁴ ), or NR3R4;

R ³ is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF ₃ , CONR ³ R ⁴ , S(0)O- ₂ NR ³ R ⁴ ;

R ⁴ is selected from hydrogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF3, CONR ³ R ⁴ , CO, S(0)O-2NR ³ R ⁴ ; R ³ and R ⁴ can optionally cyclize to form a ring comprising C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3- C 12 heterocycloalkyl or 3-8 membered ring comprising C, O, S, and/or N, optionally substituted with one or more R ⁵ ;

R ⁵ is selected from hydrogen, halogen, C1-6 alkyl, C3-10 cycloalkyl, aryl, heteroaryl, benzyl, OCi-10 alkyl (which may optionally contain a C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ⁴ ), CN, CF3; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

Formula 432

[001572] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 432. Such compounds are described in WO 2011/086163, published July 21, 2011, corresponding to PCT/EP2011/050476, filed January 14, 2011 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 432, this reference incorporated by reference herein controls.

[001573] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein: X is selected from N or from C which may further be substituted by A;

A radical is selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH2 and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci- Ce)haloalkyl, — (C2-Ce)alkynyl, — (C2-Ce)alkenyl, — (C3-C?)cyclo alkyl, — (C3- C8)cycloalkenyl, — (Ci-Ce)cyano alkyl, — (Ci-C6)alkylene-hetero aryl, — (Ci-Ce)alkylene- aryl, — (Ci-C6)alkylene-heterocycle, — (Ci-C6)alkylene-cycloalkyl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ¹ , — O — (C2-Ce)alkylene-OR ¹ , — NR ¹ (C2-Ce)alkylene-OR ² , — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — NR ¹ — (C ₃ - C7)cycloalkyl-(Ci-Ce)alkyl, — (Ci-Ce)haloalkylene-OR ¹ , — (Ci-Ce)haloalkylene-NR ¹ R ² , — (C ₃ -C ₆ )alkynyl-OR ¹ , — (C ₃ -C ₆ )alkynyl-NR ¹ R ² , — (C ₃ -C ₆ )alkenyl-OR ¹ , — (C ₃ -C ₆ )alkenyl- NRjR ² , — (Co-C ₆ )alkyl-S— R ¹ , — O— (C2-C ₆ )alkylene-S— R ¹ , — NR ¹ — (C ₂ -C ₆ )alkylene-S— R ² , — (Co-C ₆ )alkyl-S(=0)— R', — O— (Ci-C ₆ )alkylene-S(=O)— R ¹ , — NR ¹ — (Ci- C ₆ )alkylene-S(=O)— R ² , — (Co-C ₆ )alkyl-S(=0)2— R', — O— (Ci-C ₆ )alkylene-S(=O)2— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-S(=O)2— R ² , — (Co-C ₆ )alkyl-NR ¹ R ² , — O— (C ₂ -C ₆ )alkylene- NR’R ² , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² R ³ , — (Co-C ₆ )alkyl-S(=0) ₂ NR ¹ R ² , -O—(Ci- C6)alkylene-S(=0)2NR ¹ R ² , —NR ¹ —(Ci-C6)alkylene-S(=0)2NR ² R ³ , —(Co-C ₆ )alkyl-NR ¹ — S(=O) ₂ R ² , — O— (C ₂ -C ₆ )alkylene-NR ¹ — S(=O) ₂ R ² , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² — S(=O) ₂ R ³ , — (Co-C ₆ )alkyl-C(=0)— NR'R ² , — O— (Ci-C ₆ )alkylene-C(=O)— NR’R ² , — NR ¹ —(Ci-C6)alkylene-C(=0)—NR ² R ³ , —(Co-C ₆ )alkyl-NR ¹ C(=0)—R ² , —0—(C2- C ₆ )alkylene-NR ¹ C(=O)— R ² , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² C(=O)— R ³ , — (Co-C ₆ )alkyl- C(=O)— R', — O— (Ci-C ₆ )alkylene-C(=O)— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-C(=O)— R ² , — (Co-C ₆ )alkyl-NR ¹ — C(=O)— NR ² R ³ , — O— (C ₂ -C ₆ )alkylene-NR ¹ — C(=O)— NR ² R ³ , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² — C(=O)— NR ³ R ⁴ and — (Co-Ce)alkyl-NR ¹ — C(=S)— NR ² R ³ ; R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C7)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)alkylene-heterocycle, aryl, heterocycle and — (Ci-Ce)alkylene-aryl; Any two radicals of R(R R ² , R ³ or R ⁴ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; n is an integer ranging from 1 to 2;

B radicals are each independently selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C2-Ce)alkynyl, — (C2-Ce)alkenyl, — (C3-C?)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci-Ce)cyanoalkyl, — (Ci-C6)alkylene-heteroaryl, — (Ci- Ce)alkylene-aryl, — (Ci-C6)alkylene-heterocycle, — (Ci-C6)alkylene-cycloalkyl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ⁵ , — O — (C2-Ce)alkylene-OR ⁵ , — NR ⁵ (C2- Ce)alkylene-OR ⁶ , — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — O — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — NR ⁵ — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — (Ci-C ₆ )haloalkyl-OR ⁵ , — (Ci-C ₆ )haloalkyl- NR ⁵ R ⁶ , — (C ₃ -C ₆ )alkynyl-OR ⁵ , — (C ₃ -C ₆ )alkynyl-NR ⁵ R ⁶ , — (C ₃ -C ₆ )alkenyl-OR ⁵ , — (C3- C ₆ )alkenyl-NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-S— R ⁵ , — O— (C2-C ₆ )alkylene-S— R ⁵ , — NR ⁵ — (C2- C ₆ )alkylene-S— R ⁶ , — (Co-C ₆ )alkyl-S(=0)— R ⁵ , — O— (Ci-C ₆ )alkylene-S(=O)— R ⁵ , — NR ⁵ — (Ci-C ₆ )alkylene-S(=O)— R ⁶ , — (Co-C ₆ )alkyl-S(=0)2— R ⁵ , — O— (Ci-C ₆ )alkylene- S(=O) ₂ — R ⁵ , — NR ⁵ — (Ci-C ₆ )alkylene-S(=O)2— R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ R ⁶ , — O— (C ₂ - C ₆ )alkylene-NR ⁵ R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkylene-NR ⁶ R ⁷ , — (Ci-C ₆ )alkyl-S(=O) ₂ NR ⁵ R ⁶ , —O— (Ci-C6)alkylene-S(=0)2NR ⁵ R ⁶ , —NR ⁵ —(Ci-C6)alkylene-S(=0)2NR ⁶ R ⁷ , —(Co-C ₆ )alkyl- NR ⁵ — S(=O) ₂ R ⁶ , — O— (C ₂ -C ₆ )alkylene-NR ⁵ — S(=O) ₂ R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkylene-NR ⁶ — S(=O) ₂ R ⁷ , — (Co-C ₆ )alkyl-C(=0)— NR ⁵ R ⁶ , — O— (Ci-C ₆ )alkylene-C(=O)— NR ⁵ R ⁶ , — NR ⁵ —(Ci-C6)alkylene-C(=0)—NR ⁶ R ⁷ , —(Co-C ₆ )alkyl-NR ⁵ C(=0)—R ⁶ , —0—(C2- C ₆ )alkylene-NR ⁵ C(=O)— R ⁶ , — NRS— (C ₂ -C ₆ )alkylene-NR ⁶ C(=O)— R ⁷ , — (Co-C ₆ )alkyl- C(=O)— R ⁵ , — O— (Ci-C ₆ )alkylene-C(=O)— R ⁵ , — NR ⁵ — (Ci-C ₆ )alkylene-C(=O)— R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ — C(=O)— NR ⁶ R ⁷ , — O— (C ₂ -C ₆ )alkylene-NR ⁵ — C(=O)— NR ⁶ R ⁷ , — NR ⁵ — (C ₂ -C ₆ )alkylene-NR ⁶ — C(=O)— NR ⁷ R ⁸ and — (Co-Ce)alkyl-NR ⁵ — C(=S)— NR ⁶ R ⁷ ; R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C7)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, — (Ci-C6)alkylene-heterocycle, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

M is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;

P is selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Co-C ₆ )alkyl-C(=0)— R ⁹ , — (Ci-C ₆ )alkyl-CN, — (C ₂ -C ₆ )alkyl-S(O)— R ⁹ , — (Co-C ₆ )alkyl-C(=0)NR ⁹ R ¹⁰ , — (C2-C ₆ )alkyl-NR ⁹ C(=O)R ¹⁰ , — (Co-C ₆ )alkyl-S(0)2— R ⁹ , — (Co-C ₆ )alkyl-R ⁹ , — (C2-C ₆ )alkyl-NR ⁹ R ¹⁰ , — (C ₂ -C ₆ )alkyl-OR ⁹ and — (C ₂ -C ₆ )alkyl-SR ⁹ ;

R ⁹ and R ¹⁰ are selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-Cejalkylene-heteroaryl, — (Ci-Cejalkylene-heterocycle, aryl, heterocycle and — (Ci-Ce)alkylene-aryl.

Formula 433

[001574] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 433. Such compounds are described in, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 433, this reference incorporated by reference herein controls.

[001575] In an embodiment, the glutamate modulator is a compound according to: wherein:

X, Y and Z are independently CH, N or CR4;

Ri is selected from: heteroaryl optionally substituted with one or more R9, aryl optionally substituted with one or more R9, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R9;

R2 is selected from: H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl;

R3 is selected from: H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl;

R2, and R3 may join together to form carbonyl, thiocarbonyl, or may cyclize to form a C3-

8 membered ring containing C, O, S or N, optionally substituted with one or more R9;

RHs selected from: halogen, C1-6 alkyl, C3-10 cycloalkyl, OC1-6 alkyl, aryl optionally substituted with one or more R9, heteroaryl, CONR1R2, CN or CF3;

Rs is selected from: H, C1-6 alkyl, C3-10 cycloalkyl, aryl optionally substituted with one or more R9, heteroaryl optionally substituted with one or more R9, may cyclize with Rs to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9, may cyclize with R?to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9, or may cyclize with Rio to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9;

Re is selected from: H, C1-6 alkyl, C3-10 cycloalkyl, aryl optionally substituted with one or more R9, heteroaryl optionally substituted with one or more R9, or may cyclize with R5 to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9; R? is selected from: H, C1-6 alkyl, C3-10 cycloalkyl, aryl optionally substituted with one or more R9, heteroaryl optionally substituted with one or more R9, may cyclize with R5 to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9, may cyclize with Rs to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R7, or may cyclize with Rio to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9;

Rs is selected from: H, C1-6 alkyl, C3-10 cycloalkyl, aryl optionally substituted with one or more R9, heteroaryl optionally substituted with one or more R9, or may cyclize with R?to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9; R ₉ is selected from: H, OH, NR1R2, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, CONR1R2, SO2NR1R2, OC1-6 alkyl, CF ₃ ;

Rio is selected from: H, C1-6 alkyl, C3-10 cycloalkyl, aryl optionally substituted with one or more R9, heteroaryl optionally substituted with one or more R9, may cyclize with R5 to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9, may cyclize with R?to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9, or may cyclize with Rn to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9;

Rn is selected from: H, C1-6 alkyl, C3-10 cycloalkyl, aryl optionally substituted with one or more R9, heteroaryl optionally substituted with one or more R9, or may cyclize with Rio to form a C3-10 member ring containing C, O, S or N, optionally substituted with one or more R9; n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof;

Formulal 434

[001576] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 434. Such compounds are described in WO 2011/051478, published May 5, 2011, corresponding to PCT/EP2010/066537, filed October 29, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 434, this reference incorporated by reference herein controls. [001577] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ , R ² , R ³ , and R ⁴ each independently represent a -L-R group, wherein:

L is selected from a bond, C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from halogen, — CF3, — CN, — OH, or — NH2, and further wherein one or more — CH2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from: — O — , — NR ¹¹ —, —CO—, — S— , —SO—, or — SO ₂ — ;

R is selected from hydrogen, C1-C10 alkyl, halogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, — NR ⁿ R ¹² , —OR ¹¹ , —SR ¹¹ , — SOR ¹¹ , — SO2R ¹¹ , — CF ₃ , or — CN, wherein said optionally substituted aryl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from C1-C4 alkyl, halogen, — CF3, — CN, — OH, — O(Ci-C4 alkyl), — NH2, — NH(CI-C4 alkyl), — N(CI-C4 alkyl)(Ci-C4 alkyl) wherein the two C1-C4 alkyl moieties of said — N(CI-C4 alkyl)(Ci-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, or -IJ-R ¹³ ;

R ¹¹ and R ¹² are each independently selected from hydrogen, optionally substituted Ci-

C10 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or — CF3, wherein said optionally substituted alkyl, said optionally substituted aryl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from C1-C4 alkyl, halogen, — CF ₃ , — CN, —OH, — O(Ci-C ₄ alkyl), — NH ₂ , — NH(CI-C ₄ alkyl), or — N(CI-C ₄ alkyl)(Ci- C4 alkyl) wherein the two C1-C4 alkyl moieties of said — N(CI-C4 alkyl)(Ci-C4 alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to; L ¹ is selected from a bond, C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene, wherein one or two — CH2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from — O — , — NH — , — N(Ci- C ₄ alkyl)-, —CO—, — S— , —SO—, or — SO ₂ — ;

R ¹³ is selected from hydrogen, C1-C4 alkyl, halogen, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, — NH2, — NH(CI-C ₄ alkyl), — N(CI-C ₄ alkyl)(Ci-C ₄ alkyl), — OH, — O(Ci- C ₄ alkyl), — SH, — S(Ci-C ₄ alkyl), — CF3, or — CN, wherein said optionally substituted phenyl, said optionally substituted heteroaryl, said optionally substituted cycloalkyl, or said optionally substituted heterocycloalkyl may be substituted with one or more groups independently selected from Ci-C ₄ alkyl, halogen, — CF3, — CN, — OH, — O(Ci-C ₄ alkyl), — NH2, — NH(CI-C ₄ alkyl), or — N(CI-C ₄ alkyl)(Ci-C ₄ alkyl) wherein the two Ci-C ₄ alkyl moieties of said — N(CI-C ₄ alkyl)(Ci-C ₄ alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to;

R ⁵ is selected from hydrogen, Ci-C ₄ alkyl, halogen, — CF3, — CN, — OH, — O(Ci-C ₄ alkyl), — COOH, — COO(Ci-C ₄ alkyl), — CONH ₂ , — CONH(CI-C ₄ alkyl), — CON(CI-C ₄ alkyl)(Ci- C ₄ alkyl), wherein the two Ci-C ₄ alkyl moieties of said — CON(CI-C ₄ alkyl)(Ci-C ₄ alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to, — NH2, — NH(CI-C ₄ alkyl), or — N(CI-C ₄ alkyl)(Ci-C ₄ alkyl), wherein the two Ci-C ₄ alkyl moieties of said — N(CI-C ₄ alkyl)(Ci-C ₄ alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to;

A is a bicyclic moiety corresponding to formula (II): which may be saturated or unsaturated, and wherein: n is 0 or 1;

X ¹ to X ⁶ are each independently selected from N, N(R ^xl ), C(R ^x2 ), C(R ^x2 )(R ^x3 ), O, S, S(O), S(O) ₂ , or C(O);

X ⁷ is N or N(R ^xl ); any of groups X ¹ to X ⁷ containing a nitrogen atom may form an N-oxide group;

X ⁸ and X ⁹ are each independently selected from N, C, or C(R ^x2 ); each R ^xl is independently selected from hydrogen, Ci-C ₄ alkyl, — OH, — O(Ci-C ₄ alkyl), or — (Ci-C ₄ alkylene)-phenyl; and each R ^x2 and each R ^x3 is independently selected from hydrogen, C1-C4 alkyl, halogen, — CF3, — CN, —OH, — O(Ci-C ₄ alkyl), — COOH, — COO(Ci-C ₄ alkyl), — CONH ₂ , — CONH(Ci- C ₄ alkyl), — CON(CI-C ₄ alkyl)(Ci-C ₄ alkyl), — NH ₂ , — NH(CI-C ₄ alkyl), or — N(Ci- C ₄ alkyl)(Ci-C ₄ alkyl), wherein the two Ci-C ₄ alkyl moieties of said — N(CI-C ₄ alkyl)(Ci- C ₄ alkyl) or of said — CON(CI-C ₄ alkyl)(Ci-C ₄ alkyl) are optionally mutually linked to form a ring together with the nitrogen atom which they are attached to; or a pharmaceutically acceptable salt or solvate thereof.

Formula 435

[001578] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 435. Such compounds are described in WO 2011/050316, published April 28, 2011, corresponding to PCT/US2010/053837, filed October 22, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 435, this reference incorporated by reference herein controls.

[001579] In an embodiment, the glutamate modulator is a compound according to: wherein:

X ₄ is selected from: CH ₂ , CR ₂ R ₂ , or CR ₄ R ₄ ;

R is heteroaryl optionally substituted with one or more R ₄ , and chosen from furan, pyridine, thiazole, or pyrimidine;

Ri is selected from: heteroaryl optionally substituted with one or more R ₄ , aryl optionally substituted with one or more R ₄ , C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ₄ ;

R ₂ is selected from: H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ₄ , R ₂ and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more Rs; R3 is selected from: H, halogen, CF3, C1-6 alkyl, C3-10 cycloalkyl, C3-8 membered ring containing C, O, S or N, optionally substituted with one or more R ₄ , R ₂ and R3 may cyclize to form C3-8 membered ring containing C, O, S or N, optionally substituted with one or more Rs; R ₄ is selected from: H, OH, halogen, C1-6 alkyl, C3-10 cycloalkyl, CN, OC1-6 alkyl, CF3, OCF3, OCOCH3, CO, —COO—, and COOH; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, optionally wherein the compound is selected from:

Formula 437

[001580] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 437. Such compounds are described in WO 2011/009947, published January 27, 2011, corresponding to PCT/EP2010/060726, filed July 23, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 437, this reference incorporated by reference herein controls.

[001581] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable salt, a stereoisomer or a mixture in all proportions of stereoisomers thereof, wherein R represents a (Cl-C6)alkyl or (Cl-C6)alkenyl group, optionally substituted by one or more groups chosen among an halogen atom, ORa, SRb, NRcRd, PO(ORe)(ORf), CO2Rg, SO2Rh SO3Ri, PO(OH)(CH(OH)Rk), CN, N3 and NH— C(=NH)NH2, with Ra, Rb, Rc and Rd, representing, independently of each other, an hydrogen atom, a (Cl-C6)alkyl group or a — CO — (Cl-C6)alkyl group, Re, Rf, Rg, Rh and Ri representing, independently of each other, an hydrogen atom or a (Cl-C6)alkyl group, and

Rk representing an aryl or heteroaryl group, said group being optionally substituted by one or more groups selected from an halogen atom and NO2.

Formula 438

[001582] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 438. Such compounds are described in WO 2011/010222, published January 27, 2011, corresponding to PCT/IB2010/002092, filed July 14, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 438, this reference incorporated by reference herein controls.

[001583] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein:

X ¹ and X ² are each independently selected from the group of C, N, S and C=C representing a 5 or 6 membered heteroaryl ring which may further be substituted by radicals (A) _m , and when X ¹ is N, X ² can not be C=C and when X ² is N, X ¹ can not be C=C; m is an integer ranging from 0 to 2;

(A)m radicals are each independently selected from the group of hydrogen, halogen, — CN, — OH, — NO2, — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C ₂ -Ce)alkynyl, — (C2-Ce)alkenyl, — (C3- C?)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci-Ce)cyanoalkyl, aryl, — (Ci-Ce)alkylene-aryl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, heterocycle, — (Co-Ce)alkylene-OR ¹ , — O — (C2- C ₆ )alkylene-OR ¹ , — NR ¹ (C ₂ -C ₆ )alkylene-OR ² , — (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C ₃ - C7)cycloalkyl-(Ci-Ce)alkyl, — NR ¹ — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — O — (Ci-Ce)alkylene- (C3-C7)cycloalkyl, — NR ¹ — (Ci-C6)alkylene-(C3-C7)cycloalkyl, — (Ci-Ce)haloalkylene-OR ¹ , — (Ci-Ce^aloalkylene-NR^ ² , — (C3-Ce)alkynylene-OR ¹ , — (C3-Ce)alkynylene-NR ¹ R ² , — (C3-Ce)alkenylene-OR ¹ , — (C3-Ce)alkenyl ene-NRjR ² , — (Co-Ce)alkylene-S — R ¹ , — O — (C ₂ - C ₆ )alkylene-S— R ¹ , — NR ¹ — (C ₂ -C ₆ )alkylene-S— R ² , — (Co-C ₆ )alkylene-S(=0)— R ¹ , — O— (Ci-C ₆ )alkylene-S(=O)— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-S(=O)— R ² , — (Co-C ₆ )alkylene- S(=O) ₂ — R ¹ , — O— (Ci-C ₆ )alkylene-S(=O) ₂ — R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-S(=O) ₂ — R ² , — (Co-C ₆ )alkylene-NR ¹ R ² , — O— (C ₂ -C ₆ )alkylene-NR ¹ R ² , — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² R ³ , — (Co-C6)alkylene-S(=0) ₂ NR ¹ R ² , —0—(Ci-C ₆ )alkylene-S(=0) ₂ NR ¹ R ² , —NR ¹ —(Ci- C ₆ )alkylene-S(=O) ₂ NR ² R ³ , —(C ₀ -C6)alkylene-NR ¹ —S(=O) ₂ R ² , —O—(C ₂ -C6)alkylene- NR ¹ —S(=0) ₂ R ² , —NR ¹ —(C ₂ -C6)alkylene-NR ² —S(=0) ₂ R ³ , —(Co-C ₆ )alkylene-C(=0)— NR ^X R ² , — O— (Ci-C ₆ )alkylene-C(=O)— NR ³ R ² , — NR ¹ — (Ci-C ₆ )alkylene-C(=O)— NR ² R ³ , —(Co-C6)alkylene-NR ¹ C(=0)—R ² , —0—(C ₂ -C ₆ )alkylene-NR ¹ C(=0)—R ² , —NR ¹ —(C ₂ - C ₆ )alkylene-NR ² C(=O)— R ³ , — (C ₀ -C ₆ )alkylene-OC(=O)— R ¹ , — O— (C ₂ -C ₆ )alkylene- OC(=O)— R ¹ , — NR ¹ — (C ₂ -C ₆ )alkylene-OC(=O)— R ² , — (Co-C ₆ )alkylene-C(=0)— OR ¹ , — O— (Ci-C ₆ )alkylene-C(=O)— OR ¹ , — NR ¹ — (Ci-C ₆ )alkylene-C(=O)— OR ² , — (Co- C ₆ )alkylene-C(=O)— R ¹ , — O— (Ci-C ₆ )alkylene-C(=O)— R ¹ and — NR ¹ — (Ci-C ₆ )alkylene- C(=O)— R ² ;

R ¹ , R ² and R ³ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C7)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

Any two radicals of R (R ¹ , R ² or R ³ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; n is an integer ranging from 1 to 2;

(B) _n radicals are each independently selected from the group of hydrogen, halogen, — CN, — OH, — NO ₂ , — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C ₂ -Ce)alkynyl, — (C ₂ -Ce)alkenyl, — (C3- C7)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci-Ce)cyano alkyl, — (Ci-C6)alkylene-heteroaryl, — (Ci-Ce)alkylene-aryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkylene-OR ⁴ , — O — (C ₂ - C ₆ )alkylene-OR ⁴ , — NR ⁴ (C ₂ -C ₆ )alkylene-OR ⁵ , — (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C ₃ - C7)cycloalkyl-(Ci-Ce)alkyl, — NR ⁴ — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — O — (Ci-Ce)alkylene- (C3-C7)cyclo alkyl , — NR ⁴ — (Ci-C6)alkylene-(C3-C7)cycloalkyl, — (Ci-Ce)haloalkylene- OR ⁴ , — (Ci-C6)haloalkylene-NR ⁴ R ⁵ , — (C3-Ce)alkynylene-OR ⁴ , — (C3-Ce)alkynylene-NR ⁴ R ⁵ , — (C ₃ -C ₆ )alkenylene-OR ⁴ , — (C ₃ -C ₆ )alkenylene-NR ⁴ R ⁵ , — (Co-C ₆ )alkylene-S— R ⁴ , — O— (C ₂ -C ₆ )alkylene-S— R ⁴ , — NR ⁴ — (C ₂ -C ₆ )alkylene-S— R ⁵ , — (Co-C ₆ )alkylene-S(=0)— R ⁴ , — O— (Ci-C ₆ )alkylene-S(=O)— R ⁴ , — NR ⁴ — (Ci-C ₆ )alkylene-S(=O)— R ⁵ , — (Co-C ₆ )alkylene- S(=O) ₂ — R ⁴ , — O— (Ci-C ₆ )alkylene-S(=O) ₂ — R ⁴ , — NR ⁴ — (Ci-C ₆ )alkylene-S(=O) ₂ — R ⁵ , — (Co-C ₆ )alkylene-NR ⁴ R ⁵ , — O— (C ₂ -C ₆ )alkylene-NR ⁴ R ⁵ , — NR ⁴ — (C ₂ -C ₆ )alkylene-NR ⁵ R ⁶ , — (Co-C6)alkylene-S(=0) ₂ NR ⁴ R ⁵ , —0—(Ci-C ₆ )alkylene-S(=0) ₂ NR ⁴ R ⁵ , —NR ⁴ —(Ci- C ₆ )alkylene-S(=O) ₂ NR ⁵ R ⁶ , —(C ₀ -C6)alkylene-NR ⁴ —S(=O) ₂ R ⁵ , —O—(C ₂ -C6)alkylene- NR ⁴ — S(=O) ₂ R ⁵ , — NR ⁴ — (C ₂ -C ₆ )alkylene-NR ⁵ — S(=O) ₂ R ⁶ , — (Co-C ₆ )alkylene-C(=0)— NR ⁴ R ⁵ , — O— (Ci-C ₆ )alkylene-C(=O)— NR ⁴ R ⁵ , — NR ⁴ — (Ci-C ₆ )alkylene-C(=O)— NR ⁵ R ⁶ , —(Co-C6)alkylene-NR ⁴ C(=0)—R ⁵ , —0—(C ₂ -C ₆ )alkylene-NR ⁴ C(=0)—R ⁵ , —NR ⁴ —(C ₂ - C ₆ )alkylene-NR ⁵ C(=O)— R ⁶ , — (C ₀ -C ₆ )alkylene-OC(=O)— R ⁴ , — O— (C ₂ -C ₆ )alkylene- OC(=O)— R ⁴ , — NR ⁴ — (C ₂ -C ₆ )alkylene-OC(=O)— R ⁵ , — (Co-C ₆ )alkylene-C(=0)— OR ⁴ , — O— (Ci-C ₆ )alkylene-C(=O)— OR ⁴ , — NR ⁴ — (Ci-C ₆ )alkylene-C(=O)— OR ⁵ , — (Co- C ₆ )alkylene-C(=O)— R ⁴ , — O— (Ci-C ₆ )alkylene-C(=O)— R ⁴ and — NR ⁴ — (Ci-C ₆ )alkylene- C(=O)— R ⁵ ;

R ⁴ , R ⁵ and R ⁶ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle and — (Ci-Ce)alkylene-aryl,

Any two radicals of R(R ⁴ , R ⁵ or R ⁶ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;

M is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;

P is selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Co-Ce)alkylene-R ⁷ , — (Co-Ce)haloalkyl, — (C ₂ -Ce)alkylene-NR ⁷ R ⁸ , — (C ₂ - C ₆ )alkylene-OR ⁷ , — (C ₂ -C ₆ )alkylene-SR ⁷ , — (Co-C ₆ )alkylene-C(=0)— R ⁷ , — (C ₂ - C ₆ )alkylene-S(O)— R ⁷ , — (C ₀ -C ₆ )alkylene-C(=O)NR ⁷ R ⁸ , — (Co-C ₆ )alkylene- NR ⁷ C(=O)R ⁸ and — (Co-C ₆ )alkylene-S(0) ₂ — R ⁷ ;

R ⁷ and R ⁸ are selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyano alkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle and — (Ci-Ce)alkylene-aryl.

Formula 439

[001584] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 439. Such compounds are described in WO 2010/088406, published August 5, 2010, corresponding to PCT/US2010/022430, filed January 28, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 439, this reference incorporated by reference herein controls.

[001585] In an embodiment, the glutamate modulator is a compound according to: wherein R is four substituents independently selected from hydrogen, halogen, hydroxyl, methoxy, nitrile, nitro, thiol, optionally substituted amino, alkyl, Ci-6 alkyl, cycloalkyl, C3-10 cycloalkyl, alkoxy, aryl, heteroaryl, and CONR ⁷ R ⁸ , CF3; wherein each R ¹ is one or more substituents independently selected from hydrogen, halogen, hydroxyl, methoxy, alkoxy, nitrile, nitro, thiol, optionally substituted amino, aryl, heteroaryl, CF3, alkyl, C1-6 alkyl, cycloalkyl, C3-10 cycloalkyl, and CONR ⁷ R ⁸ ; wherein each R ² is one or more substituents independently selected from hydrogen, halogen, hydroxyl, methoxy, alkoxy, nitrile, nitro, thiol, optionally substituted amino, aryl, heteroaryl, CF3, NR ⁷ R ⁸ , alkyl, C1-6 alkyl, cycloalkyl, C3-10 cycloalkyl, and CONR ⁷ R ⁸ , SChNR’R ⁸ ; wherein R ³ is hydrogen, NH, alkyl, substituted alkyl, alkoxy, substituted alkoxy, mono or disubstituted amino, and amide; wherein R ⁵ and R ⁶ are independently hydrogen, halogen, carbonyl, thiocarbonyl, CF3, nitrile, alkyl, C1-6 alkyl, cycloalkyl, C3-10 cycloalkyl, or 3-8 membered ring comprising C, O, S, and/or N; wherein R ⁷ and R ⁸ are independently hydrogen, halogen, alkyl, C1-6 alkyl, cycloalkyl, C3- 10 cycloalkyl, alkoxy, aryl, heteroaryl, nitrile, CF3; wherein M is NR ³ , CR ⁵ R ⁶ ; wherein K is NR ³ , CR ⁵ R ⁶ ; wherein Y is C3-C12 cycloalkyl or C3-C12 cycloalkenyl or aryl or heteroaryl or C3-

C 12 heterocycloalkyl or C3-C12 heterocycloalkenyl or 3-8 membered ring comprising C, O, S, and/or N; wherein Z is C3-C12 cycloalkylene or C3-C12 cycloalkenylene or arylene or heteroarylene or C3-C12 heterocycloalkylene or C3-C12 heterocycloalkenylene; wherein k is an integer from 0 to 25; wherein m is an integer from 0 to 24; and wherein each n is independently an integer from 0 to 1; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

[001586] In an embodiment, the glutamate modulator is a compound selected from; including pharmaceutically acceptable salts thereof and substituted variants retaining glutamate modulatory activity.

Formula 440

[001587] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 440. Such compounds are described in WO 2010/079239, published July 15, 2010, corresponding to PCT/EP2010/050305, filed January 12, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 440, this reference incorporated by reference herein controls.

[001588] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein:

A radical is selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH2 and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci- Ce)haloalkyl, — (C3-C?)cycloalkyl, — (Ci-Ce)cyanoalkyl, — (Ci-C6)alkylene-heteroaryl, — (Ci-Ce)alkylene-aryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ¹ , — O — (C2- C ₆ )alkylene-OR ¹ , — NR ¹ (C ₂ -C ₆ )alkylene-OR ² , — (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C ₃ - C7)cycloalkyl-(Ci-Ce)alkyl, — NR ¹ — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — (Ci-Ce)haloalkylene- OR ¹ , — (Ci-C ₆ )haloalkylene-NR ¹ R ² , — (Co-C ₆ )alkyl-S— R ¹ , — O— (C ₂ -C ₆ )alkylene-S— R ¹ , — NR ¹ — (C ₂ -C ₆ )alkylene-S— R ² , — (Co-C ₆ )alkyl-S(=0)— R ¹ , — O— (Ci-C ₆ )alkylene- S(=O)— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-S(=O)— R ² , — (Co-C ₆ )alkyl-S(=0) ₂ — R ¹ , — O— (Ci- C ₆ )alkylene-S(=O) ₂ — R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-S(=O) ₂ — R ² , — (Co-C ₆ )alkyl-NR ¹ R ² , — 0—(C ₂ -C6)alkylene-NR ¹ R ² , —NR ¹ —(C ₂ -C6)alkylene-NR ² R ³ , —(Co-C ₆ )alkyl- S(=O) ₂ NR ¹ R ² , — O— (Ci-C ₆ )alkylene-S(=O) ₂ NR ¹ R ² , — NR ¹ — (Ci-C ₆ )alkylene- S(=O) ₂ NR ² R ³ , — (Co-C ₆ )alkyl-NR ¹ — S(=O) ₂ R ² , — O— (C ₂ -C ₆ )alkylene-NR ¹ — S(=O) ₂ R ² , — NR ¹ —(C ₂ -C6)alkylene-NR ² —S(=O) ₂ R ³ , —(C ₀ -C6)alkyl-C(=O)—NR ¹ R ² , —O—(Ci- C6)alkylene-C(=0)—NR ¹ R ² , —NR ¹ —(Ci-C6)alkylene-C(=0)—NR ² R ³ , —(Co-C ₆ )alkyl- NR ¹ C(=O)— R ² , — O— (C ₂ -C ₆ )alkylene-NR ¹ C(=O)— R ² , — NR ¹ — (C ₂ -C ₆ )alkylene- NR ² C(=O)— R ³ , — (Co-C ₆ )alkyl-C(=0)— R ¹ , — O— (Ci-C ₆ )alkylene-C(=O)— R ¹ , — NR ¹ — (Ci-C ₆ )alkylene-C(=O)— R ² , — (Co-C ₆ )alkyl-NR ¹ — C(=O)— NR ² R ³ , — O— (C ₂ -C ₆ )alkylene- NR ¹ — C(=O)— NR ² R ³ and — NR ¹ — (C ₂ -C ₆ )alkylene-NR ² — C(=O)— NR ³ R ⁴ ;

R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C7)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

Any two radicals of R ¹ , R ² , R ³ or R ⁴ may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; n is an integer ranging from 1 to 2;

B radicals are each independently selected from the group of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C3-C?)cycloalkyl, — (Ci-Ce)cyanoalkyl, — (Ci- C6)alkylene-heteroaryl, — (Ci-Ce)alkylene-aryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl- OR ⁵ , — O— (C ₂ -C ₆ )alkylene-OR ⁵ , — NR ⁵ (C ₂ -C ₆ )alkylene-OR ⁶ , — (C3-C ₇ )cycloalkyl-(Ci- C ₆ )alkyl, — O— (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — NR ⁵ — (C ₃ -C ₇ )cycloalkyl-(Ci-C6)alkyl, — (Ci-C ₆ )haloalkylene-OR ⁵ , — (Ci-C ₆ )haloalkylene-NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-S— R ⁵ , — O— (C ₂ - C ₆ )alkylene-S— R ⁵ , — NR ⁵ — (C ₂ -C ₆ )alkylene-S— R ⁶ , — (Co-C ₆ )alkyl-S(=0)— R ⁵ , — O— (Ci- C ₆ )alkylene-S(=O)— R ⁵ , — NR ⁵ — (Ci-C ₆ )alkylene-S(=O)— R ⁶ , — (Co-C ₆ )alkyl-S(=0) ₂ — R ⁵ , — O— (Ci-C ₆ )alkylene-S(=O) ₂ — R ⁵ , — NR ⁵ — (Ci-C ₆ )alkylene-S(=O) ₂ — R ⁶ , — (Co-C ₆ )alkyl- NR ⁵ R ⁶ , — O— (C ₂ -C ₆ )alkylene-NR ⁵ R ⁶ , — NR ⁵ (C ₂ -C ₆ )alkylene-NR ⁶ R ⁷ , — (Co-C ₆ )alkyl- S(=O) ₂ NR ⁵ R ⁶ , — O— (Ci-C ₆ )alkylene-S(=O) ₂ NR ⁵ R ⁶ , — NR ⁵ — (Ci-C ₆ )alkylene- S(=O) ₂ NR ⁶ R ⁷ , — (Co-C ₆ )alkyl-NR ⁵ — S(=O) ₂ R ⁶ , — O— (C ₂ -C ₆ )alkylene-NR ⁵ — S(=O) ₂ R ⁶ , — NR ⁵ —(C ₂ -C6)alkylene-NR ⁶ —S(=0) ₂ R ⁷ , —(Co-C ₆ )alkyl-C(=0)—NR ⁵ R ⁶ , —0—(Ci- C6)alkylene-C(=0)—NR ⁵ R ⁶ , —NR ⁵ —(Ci-C6)alkylene-C(=0)—NR ⁶ R ⁷ , —(Co-C ₆ )alkyl- NR ⁵ C(=O)— R ⁶ , — O— (C ₂ -C ₆ )alkylene-NR ⁵ C(=O)— R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkylene- NR ⁶ C(=O)— R ⁷ , — (Co-C ₆ )alkyl-C(=0)— R ⁵ , — O— (Ci-C ₆ )alkylene-C(=O)— R ⁵ , —NR ⁵ — (Ci-C ₆ )alkylene-C(=O)— R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ — C(=O)— NR ⁶ R ⁷ , — O— (C ₂ -C ₆ )alkylene- NR ⁵ — C(=O)— NR ⁶ R ⁷ and — NR ⁵ — (C ₂ -C ₆ )alkylene-NR ⁶ — C(=O)— NR ⁷ R ⁸ ;

R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle and — (Ci-Ce)alkylene-aryl;

M is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;

P is selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Co-C ₆ )alkyl-C(=0)— R ⁹ , — (Ci-C ₆ )alkyl-CN, — (C ₂ -C ₆ )alkyl-S(O)— R ⁹ , — (Co-C ₆ )alkyl-C(=0)NR ⁹ R ¹⁰ , — (C ₂ -C ₆ )alkyl-NR ⁹ C(=O)R ¹⁰ and — (Co-C ₆ )alkyl-S(0) ₂ — R ⁹ ; and

R ⁹ and R ¹⁰ are selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cyanoalkyl, — (C3- C?)cycloalkyl, — (C4-Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocycle and — (Ci-Ce)alkylene-aryl. Formula 441

[001589] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 441. Such compounds are described in WO 2009/010455, published January 22, 2009, corresponding to PCT/EP2008/059044, filed July 10, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 441, this reference incorporated by reference herein controls.

[001590] In an embodiment, the glutamate modulator is a compound according to: pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein: X ¹ , X ² and X ³ are each independently selected from the group of C, N, O, S and C=C representing a 5 or 6 membered heteroaryl ring which may further be substituted by 1 to 3 radicals A ^m ; m is an integer ranging from 1 to 3;

A ^m radicals are each independently selected from the group of hydrogen, halogen, — CN, — OH, — NO2, — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)alkylhalo, — (C2-Ce)alkynyl, — (C2-Ce)alkenyl, — (C3- C?)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci-Ce)alkylcyano, — (Ci-Ce)alkylheteroaryl, — (Ci-Ce)alkylaryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ¹ , — O — (C2-Ce)alkyl-OR ¹ , — NR ¹ (C ₂ -C ₆ )alkyl-OR ² , — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C3-C ₇ )cycloalkyl-(Ci- C ₆ )alkyl, — NR ¹ — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — (Ci-C ₆ )alkylhalo-OR ¹ , — (Ci- C ₆ )alkylhalo-NR ¹ R ² , — (C ₃ -C ₆ )alkynyl-OR ¹ , — (C ₃ -C ₆ )alkynyl-NR ¹ R ² , — (C ₃ -C ₆ )alkenyl- OR ¹ , — (C ₃ -C ₆ )alkenyl-NR ¹ R ² , — (Co-C ₆ )alkyl-S— R ¹ , — O— (C ₂ -C ₆ )alkyl-S— R ¹ , — NR ¹ — (C ₂ -C ₆ )alkyl-S— R ² , — (Co-C ₆ )alkyl-S(=0)— R ¹ , — O— (Ci-C ₆ )alkyl-S(=O)— R ¹ , — NR ¹ — (Ci-C ₆ )alkyl-S(=O)— R ² , — (Co-C ₆ )alkyl-S(=0) ₂ — R ¹ , — O— (Ci-C ₆ )alkyl-S(=O) ₂ — R ¹ , — NR ¹ — (Ci-C ₆ )alkyl-S(=O) ₂ — R ² , — (Co-C ₆ )alkyl-NR ¹ R ² , — O— (C ₂ -C ₆ )alkyl-NR ¹ R ² , — NR ¹ — (C ₂ -C ₆ )alkyl-NR ² R ³ , — (Co-C ₆ )alkyl-S(=0) ₂ NR ¹ R ² , — O— (Ci-C ₆ )alkyl- S(=O) ₂ NR ¹ R ² , — NR ¹ — (Ci-C ₆ )alkyl-S(=O) ₂ NR ² R ³ , — (Co-C ₆ )alkyl-NR ¹ — S(=O) ₂ R ² , — O— (C ₂ -C ₆ )alkyl-NR ¹ — S(=O) ₂ R ² , — NR ¹ — (C ₂ -C ₆ )alkyl-NR ² — S(=O) ₂ R ³ , — (Co-C ₆ )alkyl- C(=0)— NBJR ² , — O— (Ci-C ₆ )alkyl-C(=O)— NRjR ² , — NR ¹ — (Ci-C ₆ )alkyl-C(=O)— NR ² R ³ , — (Co-C ₆ )alkyl-NR ¹ C(=0)— R ² , — O— (C ₂ -C ₆ )alkyl-NR ¹ C(=O)— R ² , -NR ¹ —(C ₂ - C ₆ )alkyl-NR ² C(=O)— R ³ , — (C ₀ -C ₆ )alkyl-OC(=O)— R ¹ , — O— (C ₂ -C ₆ )alkyl-OC(=O)— R ¹ , — NR ¹ — (C ₂ -C ₆ )alkyl-OC(=O)— R ² , — (Co-C ₆ )alkyl-C(=0)— OR ¹ , — O— (Ci-C ₆ )alkyl- C(=O)— OR ¹ , — NR ¹ — (Ci-C ₆ )alkyl-C(=O)— OR ² , — (Co-C ₆ )alkyl-C(=0)— R ¹ , — O— (Ci- C ₆ )alkyl-C(=O)— R ¹ , — NR ¹ — (Ci-C ₆ )alkyl-C(=O)— R ² , — (Co-C ₆ )alkyl-NR ¹ — C(=O)— OR ² , — (Co-C ₆ )alkyl-0— C(=O)— NRjR ² , — (Co-Ce)alkyl-NR ¹ — C(=NR ² )— NR ³ R ⁴ , — (Co- C ₆ )alkyl-NR ¹ — C(=O)— NR ² R ³ , — O— (C ₂ -C ₆ )alkyl-NR ¹ — C(=O)— NR ² R ³ , — NR ¹ — (C ₂ - C ₆ )alkyl-NR ² — C(=O)— NR ³ R ⁴ and — (Co-C ₆ )alkyl-NR ¹ — C(=S)— NR ² R ³ ;

Any two radicals of A ^m (A ¹ and A ² ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;

R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)alkylhalo, — (Ci-Ce)alkyl, — (Ci-Ce)alkylcyano, — (C3- C?)cycloalkyl, — (C4-Cio)alkylcycloalkyl, heteroaryl, — (Ci-Ce)alkylheteroaryl, aryl, heterocycle and — (Ci-Ce)alkylaryl;

Any two radicals of R (R ¹ , R ² , R ³ or R ⁴ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring; n is an integer ranging from 1 to 2;

B ⁿ radicals are each independently selected from the group of hydrogen, halogen, — CN, — OH, — NO ₂ , — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)alkylhalo, — (C ₂ -Ce)alkynyl, — (C ₂ -Ce)alkenyl, — (C3- C?)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci-Ce)alkylcyano, — (Ci-Ce)alkylheteroaryl, — (Ci-Ce)alkylaryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ⁵ , — O — (C ₂ -Ce)alkyl-OR ⁵ , — NR ⁵ (C ₂ -C ₆ )alkyl-OR ⁶ , — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C3-C ₇ )cycloalkyl-(Ci- C ₆ )alkyl, — NR ⁵ — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — (Ci-C ₆ )alkylhalo-OR ⁵ , — (Ci- C ₆ )alkylhalo-NR ⁵ R ⁶ , — (C ₃ -C ₆ )alkynyl-OR ⁵ , — (C ₃ -C ₆ )alkynyl-NR ⁵ R ⁶ , — (C ₃ -C ₆ )alkenyl- OR ⁵ , — (C ₃ -C ₆ )alkenyl-NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-S— R ⁵ , — O— (C ₂ -C ₆ )alkyl-S— R ⁵ , — NR ⁵ — (C ₂ -C ₆ )alkyl-S— R ⁶ , — (Co-C ₆ )alkyl-S(=0)— R ⁵ , — O— (Ci-C ₆ )alkyl-S(=O)— R ⁵ , — NR ⁵ — (Ci-C ₆ )alkyl-S(=O)— R ⁶ , — (Co-C ₆ )alkyl-S(=0) ₂ — R ⁵ , — O— (Ci-C ₆ )alkyl-S(=O) ₂ — R ⁵ , — NR ⁵ — (Ci-C ₆ )alkyl-S(=O) ₂ — R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ R ⁶ , — O— (C ₂ -C ₆ )alkyl-NR ⁵ R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkyl-NR ⁶ R ⁷ , — (C ₀ -C ₆ )alkyl-S(=O) ₂ NR ⁵ R ⁶ , — O— (Ci-C ₆ )alkyl- S(=O) ₂ NR ⁵ R ⁶ , — NR ⁵ — (Ci-C ₆ )alkyl-S(=O) ₂ NR ⁶ R ⁷ , — (Co-C ₆ )alkyl-NR ⁵ — S(=O) ₂ R ⁶ , C ₆ )alkyl-NR ⁵ — S(=O) ₂ R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkyl-NR ⁶ — S(=O) ₂ R ⁷ , — (Co-C ₆ )alkyl-C(=0)— NR ⁵ R ⁶ , — O— (Ci-C ₆ )alkyl-C(=O)— NR ⁵ R ⁶ , — NR ⁵ — (Ci-C ₆ )alkyl-C(=O)— NR ⁶ R ⁷ , -(CO- C ₆ )alkyl-NR ⁵ C(=O)— R ⁶ , — O— (C2-C ₆ )alkyl-NR ⁵ C(=O)— R ⁶ , — NR ⁵ — (C2-C ₆ )alkyl- NR ⁶ C(=0)— R ⁷ , — (C ₀ -C ₆ )alkyl-OC(=O)— R ⁵ , — 0— (C ₂ -C ₆ )alkyl-OC(=O)— R ⁵ , —NR ⁵ — (C ₂ -C ₆ )alkyl-OC(=O)— R ⁶ , — (Co-C ₆ )alkyl-C(=0)— OR ⁵ , — O— (Ci-C ₆ )alkyl-C(=O)— OR ⁵ , — NR ⁵ — (Ci-C ₆ )alkyl-C(=O)— OR ⁶ , — (Co-C ₆ )alkyl-C(=0)— R ⁵ , — O— (Ci-C ₆ )alkyl- C(=O)— R ⁵ , — NR ⁵ — (Ci-C ₆ )alkyl-C(=O)— R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ — C(=O)— OR ⁶ , -(Co- C6)alkyl-0—C(=0)—NR ⁵ R ⁶ , —(Co-C6)alkyl-NR ⁵ —C(=NR ⁶ )—NR ⁷ R ⁸ , —(Co-C ₆ )alkyl- NR ⁵ — C(=O)— NR ⁶ R ⁷ , — O— (C ₂ -C ₆ )alkyl-NR ⁵ — C(=O)— NR ⁶ R ⁷ , — NR ⁵ — (C ₂ -C ₆ )alkyl- NR ⁶ — C(=O)— NR ⁷ R ⁸ and — (Co-Ce)alkyl-NR ⁵ — C(=S)— NR ⁶ R ⁷ ;

Any two radicals of B ⁿ (B ¹ and B ² ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;

R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)alkylhalo, — (Ci-Ce)alkyl, — (Ci-Ce)alkylcyano, — (C3- C?)cycloalkyl, — (C4-Cio)alkylcycloalkyl, heteroaryl, — (Ci-Ce)alkylheteroaryl, aryl, heterocycle and — (Ci-Ce)alkylaryl;

Any two radicals of R (R ⁵ , R ⁶ , R ⁷ or R ⁸ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring;

M ¹ is selected from an optionally substituted 3 to 10 membered ring selected from the group of aryl, heteroaryl, heterocyclic and cycloalkyl;

M ² is selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Co-Ce)alkyl-R ⁹ , — (Ci-Ce)alkylhalo, — (C2-C6)alkyl-NR ⁹ R ¹⁰ , — (C2-Ce)alkyl- OR ⁹ , — (C ₂ -C ₆ )alkyl-SR ⁹ , — (Co-C ₆ )alkyl-C(=0)— R ⁹ , — (C ₂ -C ₆ )alkyl-S(O)— R ⁹ , — (Co- C ₆ )alkyl-C(=O)NR ⁹ R ¹⁰ and — (Co-C ₆ )alkyl-S(0)2— R ⁹ ;

M ³ is selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Co-C ₆ )alkyl-C(=0)— R ¹¹ , — (C ₂ -C ₆ )alkyl-S(O)— R ¹¹ , — (Co-C ₆ )alkyl- C(=O)NR ⁿ R ¹² and — (Co-C ₆ )alkyl-S(0)2— R ¹¹ ;

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are selected from the group of a hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)alkylhalo, — (Ci-Ce)alkyl, — (Ci-Ce)alkylcyano, — (C3-C?)cycloalkyl, — (C4-Cio)alkylcycloalkyl, heteroaryl, — (Ci-Ce)alkylheteroaryl, aryl, heterocycle and — (Ci-Ce)alkylaryl.

Formula 442

[001591] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 442. Such compounds are described in WO 2009/010454, published January 22, 2009, corresponding to PCT/EP2008/059043, filed July 10, 2008, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 442, this reference incorporated by reference herein controls.

[001592] In an embodiment, the glutamate modulator is a compound according to: a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof and an N-oxide form thereof, wherein: X ¹ is N and X ² , X ³ and X ⁴ are each independently selected from the group of C, N, O, S and C=C representing a 5 or 6 membered heteroaryl ring which may further be substituted by 1 to 3 radicals A ^m ; m is an integer ranging from 1 to 3;

A ^m radicals are each independently selected from the group of hydrogen, halogen, — CN, — OH, — NO2, — CF3, — SH, — NH ₂ and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)alkylhalo, — (C3-C?)cycloalkyl, — (Ci-Ce)alkylcyano, — (Ci-C6)alkylheteroaryl, — (Ci-Ce)alkylaryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl- OR ¹ , — O— (C ₂ -C ₆ )alkyl-OR ¹ , — (C3-C ₂ )cycloalkyl-(Ci-C ₆ )alkyl, — O— (C ₃ -C ₂ )cycloalkyl- (Ci-C ₆ )alkyl, — (Ci-C ₆ )alkylhalo-OR ¹ , — (Ci-C ₆ )alkylhalo-NR ¹ R ² , — (Co-C ₆ )alkyl-S— R ¹ , — O— (C ₂ -C ₆ )alkyl-S— R ¹ , — (Co-C ₆ )alkyl-S(=0)— R ¹ , — O— (Ci-C ₆ )alkyl-S(=O)— R ¹ , — (Co- C ₆ )alkyl-S(=O) ₂ — R ¹ , — O— (Ci-C ₆ )alkyl-S(=O) ₂ — R ¹ , — O— (C ₂ -C ₆ )alkyl-NR ¹ R ² , — (Co- C ₆ )alkyl-S(=O) ₂ NR ¹ R ² , — O— (Ci-C ₆ )alkyl-S(=O) ₂ NR ¹ R ² , — O— (C ₂ -C ₆ )alkyl-NR ¹ — S(=O) ₂ R ² , — (Co-C ₆ )alkyl-C(=0)— NR ³ R ² , — O— (Ci-C ₆ )alkyl-C(=O)— NR’R ² , — O— (C ₂ - C ₆ )alkyl-NR ¹ C(=O)— R ² , — (Co-C ₆ )alkyl-OC(=0)— R ¹ , — O— (C ₂ -C ₆ )alkyl-OC(=O)— R ¹ , — (Co-C ₆ )alkyl-C(=0)— OR ¹ , — O— (Ci-C ₆ )alkyl-C(=O)— OR ¹ , — (Co-C ₆ )alkyl-C(=0)— R ¹ , — O— (Ci-C ₆ )alkyl-C(=O)— R ¹ , — (Co-C ₆ )alkyl-0— C(=O)— NR ^X R ² , and — O— (C ₂ - C ₆ )alkyl-NR ¹ — C(=O)— NR ² R ³ ;

R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)alkylhalo, — (Ci-Ce)alkyl, — (Ci-Ce)alkylcyano, — (C3- C?)cycloalkyl, — (C4-Cio)alkylcycloalkyl, heteroaryl, — (Ci-Ce)alkylheteroaryl, aryl, heterocycle and — (Ci-Ce)alkylaryl; B ¹ is selected from the group of halogen, — CN, — OH, — NO2, — CF3, — SH, — NH2 and an optionally substituted radical selected from the group of — (Ci-Ce)alkyl, — (Ci-Ce)alkylhalo, — (C3-C?)cycloalkyl, — (Ci-Ce)alkylcyano, — (Ci-Ce)alkylheteroaryl, — (Ci-Ce)alkylaryl, aryl, heteroaryl, heterocycle, — (Co-Ce)alkyl-OR ⁵ , — O — (C2-Ce)alkyl-OR ⁵ , — NR ⁵ (C2- Ce)alkyl-OR ⁶ , — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — O — (C3-C7)cycloalkyl-(Ci-Ce)alkyl, — NR ⁵ — (C3-C7)cycloalkyl-(Ci-C ₆ )alkyl, — (Ci-C ₆ )alkylhalo-OR ⁵ , — (Ci-C ₆ )alkylhalo-NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-S— R ⁵ , — O— (C ₂ -C ₆ )alkyl-S— R ⁵ , — NR ⁵ — (C ₂ -C ₆ )alkyl-S— R ⁶ , — (Co- C ₆ )alkyl-S(=O)— R ⁵ , — O— (Ci-C ₆ )alkyl-S(=O)— R ⁵ , — NR ⁵ — (Ci-C ₆ )alkyl-S(=O)— R ⁶ , — (Co-C ₆ )alkyl-S(=0) ₂ — R ⁵ , — O— (Ci-C ₆ )alkyl-S(=O) ₂ — R ⁵ , — NR ⁵ — (Ci-C ₆ )alkyl-S(=O) ₂ — R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ R ⁶ , — O— (C ₂ -C ₆ )alkyl-NR ⁵ R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkyl-NR ⁶ R ⁷ , — (Co- C ₆ )alkyl-S(=O) ₂ NR ⁵ R ⁶ , — O— (Ci-C ₆ )alkyl-S(=O) ₂ NR ⁵ R ⁶ , — NR ⁵ — (Ci-C ₆ )alkyl- S(=O) ₂ NR ⁶ R ⁷ , — (Co-C ₆ )alkyl-NR ⁵ — S(=O) ₂ R ⁶ , — O— (C ₂ -C ₆ )alkyl-NR ⁵ — S(=O) ₂ R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkyl-NR ⁶ — S(=O) ₂ R ⁷ , — (Co-C ₆ )alkyl-C(=0)— NR ⁵ R ⁶ , — O— (Ci-C ₆ )alkyl- C(=O)— NR ⁵ R ⁶ , — NR ⁵ — (Ci-C ₆ )alkyl-C(=O)— NR ⁶ R ⁷ , — (Co-C ₆ )alkyl-NR ⁵ C(=0)— R ⁶ , — O— (C ₂ -C ₆ )alkyl-NR ⁵ C(=O)— R ⁶ , — NR ⁵ — (C ₂ -C ₆ )alkyl-NR ⁶ C(=O)— R ⁷ , — (Co-C ₆ )alkyl- OC(=O)— R ⁵ , — O— (C ₂ -C ₆ )alkyl-OC(=O)— R ⁵ , — NR ⁵ — (C ₂ -C ₆ )alkyl-OC(=O)— R ⁶ , — (Co-C ₆ )alkyl-C(=0)— OR ⁵ , — O— (Ci-C ₆ )alkyl-C(=O)— OR ⁵ , — NR ⁵ — (Ci-C ₆ )alkyl- C(=O)— OR ⁶ , — (Co-C ₆ )alkyl-C(=0)— R ⁵ , — O— (Ci-C ₆ )alkyl-C(=O)— R ⁵ , — NR ⁵ — (Ci- C ₆ )alkyl-C(=O)— R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ — C(=O)— OR ⁶ , — (Co-C ₆ )alkyl-0— C(=O)— NR ⁵ R ⁶ , — (Co-C ₆ )alkyl-NR ⁵ — C(=NR ⁶ )— NR ⁷ R ⁸ , — (Co-C ₆ )alkyl-NR ⁵ — C(=O)— NR ⁶ R ⁷ , — O— (C ₂ -C ₆ )alkyl-NR ⁵ — C(=O)— NR ⁶ R ⁷ , — NR ⁵ — (C ₂ -C ₆ )alkyl-NR ⁶ — C(=O)— NR ⁷ R ⁸ and — (Co-C ₆ )alkyl-NR ⁵ — C(=S)— NR ⁶ R ⁷ ;

B ² is an optionally substituted aryl or heteroaryl;

R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen or an optionally substituted radical selected from the group of — (Ci-Ce)alkylhalo, — (Ci-Ce)alkyl, — (Ci-Ce)alkylcyano, — (C3- C7)cycloalkyl, — (C4-Cio)alkylcycloalkyl, heteroaryl, — (Ci-Ce)alkylheteroaryl, aryl, heterocycle and — (Ci-Ce)alkylaryl;

Any two radicals of R(R ⁵ , R ⁶ , R ⁷ or R ⁸ ) may be taken together to form an optionally substituted 3 to 10 membered carbocyclic or heterocyclic ring.

[001593] In further embodiments, the glutamate modulator is a compound selected from N-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)picolinamide.

[001594] In further embodiments, the glutamate modulator is a compound selected from:

N-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)-2-methylthiazole -4-carboxamide, N-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)thiazole-2-carboxami de, N-(3-Chloro-4-(pyridin-2-yloxy)phenyl)picolinamide, N-(3-Chloro-4-(2,5-difluorophenoxy)phenyl)picolinamide, N-(3-Chloro-4-(2-chlorophenoxy)phenyl)picolinamide, N-(3-Chloro-4-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)pic olinamide, N-(3-Methoxy-4-(pyrimidin-2-yloxy)phenyl)picolinamide, N-(3-Chloro-4-(3-chlorophenoxy)phenyl)picolinamide, N-(3-Chloro-4-(3-fluorophenoxy)phenyl)picolinamide, N-(3-Chloro-4-(4-fluorophenoxy)phenyl)picolinamide, N-(3-Chloro-4-(4-chlorophenoxy)phenyl)picolinamide, N-(3-Chloro-4-(4-cyanophenoxy)phenyl)picolinamide; and N-(3-Chloro-4-(3-cyanopyridin-2-yloxy)phenyl)picolinamide, including pharmaceutically acceptable salts and substituted variants thereof retaining glutamate modulatory activity. Formula 443 [001595] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 443. Such compounds are described in WO 2015/044358, published April 2, 2015, corresponding to PCT/EP2014/070635, filed September 26, 2014 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 443, this reference incorporated by reference herein controls.

[001596] In an embodiment, the glutamate modulator is a compound according to: wherein

Ri is selected from 2-pyridyl and 3-pyridyl, optionally substituted at the carbon atoms with one, two or three substituents independently selected from the group consisting of -halogen, - OH, -OR ₅ , -OCF ₃ , -SR ₅ , -NR5R6, -NHCORS, -COOR5, -OCOR ₅ ,-NO ₂ , -COR5, -CONR5R6, - SO2NH2, (Ci-Ce) alkyl and (Ce-Cio) aryl;

R2 and R3 are independently selected from -H, halogen, -OR5, -OCF3, -SR5, -NR5R6, - NHCORs, -COOR5, -OCOR5, -NO2, -CN, -COR5, -CONR5R6, -SO2NH2, -NHSO2R5, (Ci-C ₆ ) alkyl, and (Ce-Cio) aryl; R.4 is selected from -NR7CO-R8, -CONR7-R9, -NHSO2-R9, -S-R9, -O-R9, -NR7CONH-R10 and -N-phtalimidyl group;

R5 and Rs are independently selected from H, (Ci-Ce) alkyl and (Ce-Cio) aryl;

R7 is selected from H, -CO-(Ci-C5) alkyl, -CO-(Ce-Cio) aryl, (C4-C6) alkyl, (Ce-Cio) aryl and heterocyclyl; wherein the heterocyclyl group is linked to the -CON- or -NCO- moieties by a ring carbon atom;

Rs is selected from (Cs-Cs) alkyl; (Cs-Cs) cycloalkyl; (Ce-Cio) aryl and o heterocyclyl; wherein the heterocyclyl group is linked to the -NR7CO- moiety by a ring carbon atom;

R9 is selected from (Ci-Cs) alkyl; (Cs-Cs) cycloalkyl; (Ce-Cio) aryl and heterocyclyl; wherein the heterocyclyl group is linked to the -CON-, -NHSO2-, -S-, or -O- moieties by a ring carbon atom;

Rio is selected from (Ci-Cs) alkyl, (Cs-Cs) cycloalkyl, and (Ce-Cio) aryl; wherein the alkyl, aryl, cycloalkyl and heterocyclyl moieties in R2-R3 and R5-R10 defined above are optionally substituted, with one, two or three substituents independently selected from the group consisting of -halogen, -OH, -OR5, -OCF^-SFC, -NR5R6, -NHCOR5, - COOR5, -OCOR5, -NO2, -COR5, -CONR5R6, -SO2NH2, (Ci-C ₆ ) alkyl and (C ₆ -Cio) aryl;

R4 is in meta or para position in respect to the Ri-N=N- moiety; and provided that the compound of formula (1) contains from 2 to 4 ring systems, only 1 -N=N- group and that the compound of formula (1) is not 2-amino-N-[4-[2-(3- pyridinyl)diazenyl]phenyl]benzamide; or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

Formula 444

[001597] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 444. Such compounds are described in WO 2010/114726, published October 7, 2010, corresponding to PCT/US2010/028115, filed March 22, 2010, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 444, this reference incorporated by reference herein controls.

[001598] In an embodiment, the glutamate modulator is a compound according to:

X is selected from halo, methyl and -CM;

Rt f$ selected fem the group consisting of:

(1) Cvgalkyl

(2) Cg-gslkenyl

(3) C2~galkynyL

(4) Cj-ghafoalkyL

(5) C3-^cycloalkyHCH^Jp", wherein p Is 0 _s 1 , 2, 3 or 4. and

(6) 4~(2~methylbenx^mdo)bm^4; each R2 | _s iad.apwdeatly selected fem the -group consisting o£ hafe OB. Q^dkyl, ^tay, CFj rad -CM; each R2 b indtependentiy selected fem the group consisting of: Mo _s Oil Cj^lkyl, C | .

4*1 kmy, CF3 and -CM;

R3 i§ selected fem the gmp eonwtmg of: H, Cj-galkyl, XXO)~Ci-4alkyl and -C(O>phecyl, wherein said phenyl is optionally substituted with 1 to 5 substituents independently selected fem halo and CF3;

Y is selected fem a bond, -8(O)2-- and --{ CfR^sfe--, wherein n is 1 , 2 or 3 ; each R4 is independmdy selected from the group consisting ofc H, halo, OH, C^alkyL C}„ 4alkoxy, CFs, -CN and phenyl, and m iH groups on adjacent atom may be joined together with die atoms to which they am atached to form cyclopropyl, and tw R4 groups on the same atom may be joined together to form carbonyl;

A is selected from aryl* hetercaryl and heterocycle* wherein said aryl, hetaoaryl and heterocycle are optionally substi toted with one or more R$ groups up to the maximum number of substitdable positions; aryl at each occurrence is independently selected from the group consisting of phenyl., naphthyl, anthryl and phenmthryl;

.heteroatyl at each occurrence mdepcntfently means a 5- or b-membtaed monocyclic ammatic or or 10-membered Hcydto ammstic, wherein at one atom in. the aromatic is selected from

N'(R), O and the sulfur optionally oxidized to Mfone or sulfoxide, and the remaining atoms are selected tai C, N(R) _S O and S _s the sulfur optionally oxidized to sulfone or sulfoxide; heterocycle at each occurrence independently means a 5- or 6-membered monocyclic non- aromatic- ring or 9- or 10-membered bicyclic n$m- or partialiy-arom&tic ring, each optionally substituted with ox« _s . wherein at least one atom is selected tai N(R), O and S, the sulfur optionally oxidked to sulfons or sulfoxide, mid the remaining atoms are selected from C, MR}, 0 and S, the sulfur optimally oxidized to sulfone or sulfoxide; sulfur optionally oxidized to sulfone or sulfoxide; each R5 is independently selected from the group consisting of:

(1) halo,

(2) Cl-8alkyl,

(3) C2-6alkenyl,

(4) C2-6alkynyl,

(5) C3-6cycloalkyl,

(6) Cl-6alkoxy,

(7) C3-6cycloalkoxy,

(8) -CN, (9) - OH

(10) -C(O)-O-C l-4alkyl,

(1 1) -C(O)-Cl-4alkyl,

(12) -N(R)2,

(13) -C(O)-N(R)2,

(14) -S(0)k-Cl-4alkyl, wherein k is 0, 1 or 2,

(15) -aryl,

(16) -heteroaryl,

(17) -heterocycle,

(18) -C(O)-aryl,

(19) -N(R)-aryl,

(20) benzyl,

(21) benzyloxy,

(22) phenoxy,

(23) -CO2H,

(24) -SH,

(25) -SO2N(R)R,

(26) -N(R)C(O)N(R)R,

(27) -N(R)C(O)C l-4alkyl,

(28) -N(R)SO2N(R)R,

(29) -B(OH)2 and

(30) heterocycle-CH2- wherein groups (2) to (7), (IS), (16) and (20) to (23) above are optionally substituted from one up to the maximum number of substitotable positions with one or more mbstitueuu indepemietoly selected front the group consisting of: OH, CN _f halo, carboxy, -C(O)d>Cto4aJky1 _} CMalkyh

CMalkoxy, Ci«4alkylammo _s phenyl and hetemyde, and eash R is imfependendy selected from the group consisting of: H and and pharmacmticalty acceptable salts fiwreof.

Formula 445

[001599] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 445. Such compounds are described in WO 2010/079238, published July 15, 2010, corresponding to PCT/EP2010/050304, filed January 12, 2010 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 445, this reference incorporated by reference herein controls.

[001600] In an embodiment, the glutamate modulator is a compound according to: or a pharmaceutically acceptable acid or base addition salt thereof, a sterochemically isomeric form thereof or an N-oxide form thereof, wherein:

M is selected from a 3 to 10 membered ring selected from the group consisting of aryl, heteroaryl, heterocyclyl and cycloalkyl which can be substituted by a substituent selected from the group consisting of — (Ci-Ce)alkyl, halogen and — (Ci-Ce)alkyl-O — (Ci-Ce)alkyl; X ¹ is N;

X ² is S;

Y is — CR ⁴ R ⁵ — CR ⁶ R ⁷ ;

Z ¹ is N; Z ² is N; and Z ³ is C; representing a 5 membered heteroaryl ring which may further be substituted by 1 to 2 radicals (A) _m ; m is 1 or 2;

(A)m radicals are each independently selected from the group consisting of hydrogen, halogen, — CN, — OH, — CF3, — SH, — NH2 and a radical selected from the group consisting of — (Ci-Ce)alkyl, — (Ci-Ce)haloalkyl, — (C2-Ce)alkynyl, — (C2-Ce)alkenyl, — (C3- C?)cycloalkyl, — (C3-C8)cycloalkenyl, — (Ci-Ce)cyanoalkyl, — (Ci -C 6)alkylene-heteroaryl, — (Ci -Ce)alkylene-aryl, aryl, heteroaryl, heterocyclyl, — (Co-C6)alkyl-OR ¹⁰ , — O — (C2- C ₆ )alkylene-OR ¹⁰ , — NR ¹⁰ (C2-C ₆ )alkylene-OR ¹¹ , — (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — O— (C3-C ₇ )cycloalkyl-(Ci -C ₆ )alkyl, — NR ¹⁰ — (C ₃ -C7)cycloalkyl-(Ci-C ₆ )alkyl, — (Ci- C ₆ )haloalkyl-OR ¹⁰ , — (Ci-C ₆ )haloalkyl-NR ¹⁰ R ¹¹ , — (C3-C ₆ )alkynyl-OR ¹⁰ , — (C ₃ -C ₆ )alkynyl- NR ¹⁰ R ⁿ , — (C ₃ -C ₆ )alkenyl-OR ¹⁰ , — (C ₃ -C ₆ )alkenyl -NR ¹⁰ R ⁿ , — (Co-C ₆ )alkyl-S— R ¹⁰ ,— O— (C ₂ -C ₆ )alkylene-S— R ¹⁰ , — NR ¹⁰ — (C2-C ₆ )alkylene-S— R ¹¹ , — (Co-C ₆ )alkyl-S(=0)— R ¹⁰ , — O— (Ci-C ₆ )alkylene-S(=O)— R ¹⁰ , — NR ¹⁰ — (Ci-C ₆ )alkylene-S(=O)— R ¹¹ , — (Co-C ₆ )alkyl- S(=O) ₂ -R ¹⁰ , — O— (Ci-C ₆ )alkylene-S(=O)2— R ¹⁰ , — NR ¹⁰ — (Ci-C ₆ )alkylene-S(=O)2— R ¹¹ , — (Co-C ₆ )alkyl-NR ^1O R ¹¹ , — O— (C2-C ₆ )alkylene-NR ¹⁰ R ¹¹ , — NR ¹⁰ — (C2-C ₆ )alkylene- NR ⁿ R ¹² , — (Co-C ₆ )alkyl-S(=0)2NR ¹ °R ¹¹ , — O— (Ci-C ₆ )alkylene-S(=O)2NR ¹⁰ R ¹¹ , — NR ¹⁰ — (Ci-C ₆ )alkylene -S(=O) ₂ NR ⁿ R ¹² , — (Co-C ₆ )alkyl-NR ¹⁰ — S(=O) ₂ R ⁿ , — 0— (C ₂ -C ₆ )alkylene- NR ¹⁰ — S(=O) ₂ R ¹ \ — NR ¹⁰ — (C ₂ -C ₆ )alkylene-NR ¹ S(=O) ₂ R ¹² , — (Co-C ₆ )alkyl-C(=0)—

NR ¹⁰ R ⁿ — 0— (Ci-C ₆ )alkylene -C(=0)— NR ¹⁰ R ⁿ , — NR ¹⁰ — (Ci-C ₆ )alkylene-C(=O)— NR ⁿ R ¹² , — (C ₀ -C ₆ )alkyl-NR ¹⁰ C(=O)— R ¹¹ , — 0— (C2-C ₆ )alkylene-NR ¹⁰ C(=O)— R ¹¹ , — NR ¹⁰ — (C2-C6)alkylene-NR ⁿ C(=O)— R ¹² , — (Co-C ₆ )alkyl -OC(=O)— R ¹⁰ , -O—(C ₂ - C6)alkylene-OC(=0)—R ¹⁰ , —NR ¹ °—(C2-C6)alkylene-OC(=0)—R ¹¹ , —(Co-C6)alkyl- C(=O)— OR ¹⁰ , — O— (Ci-C ₆ )alkylene-C(=O)— OR ¹⁰ , — NR ¹⁰ — (Ci-C ₆ )alkylene-C(=O)— OR ¹¹ , — (Co-C ₆ )alkyl-C(=0)— R ¹⁰ , — O— (Ci -C ₆ )alkylene-C(=O)— R ¹⁰ , — NR ¹⁰ — (Ci - C ₆ )alkylene -C(=O)— R ¹¹ , — (Co-C ₆ )alkyl-NR ¹⁰ — C(=O)— OR ¹¹ , — (Co-C ₆ )alkyl-0— C(=O)— NR ¹⁰ R ⁿ , — (Co-C ₆ )alkyl-NR ¹⁰ — C(=NR ⁿ )— NR ¹² R ¹³ , — (Co-C ₆ )alkyl-NR ¹⁰ - C(=O)— NR ^{1 X} R ¹² — O— (C2-C ₆ )alkylene-NR ¹⁰ — C(=O)— NR ¹³ R ¹² , — NR ¹⁰ — (C ₂ - C6)alkylene-NR ⁿ — C(=O)— NR ¹² R ¹³ and — (Co-Ce)alkyl-NR ¹⁰ — C(=S)— NR ⁿ R ¹² ;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen and a radical selected from the group consisting of — (Ci- Ce)haloalkyl, — (Ci-Ce)alkyl, — (Ci-Ce)cy anoalkyl, — (C3-C?)cycloalkyl, — (C4- Cio)alkylene-cycloalkyl, heteroaryl, — (Ci-C6)alkylene-heteroaryl, aryl, heterocyclyl and — (C 1 -Ce)alkylene-aryl .

Formula 446

[001601] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 446. Such compounds are described in WO 2007/115077, published October 11, 2007, corresponding to PCT/US2007/065469, filed March 29, 2007, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 446, this reference incorporated by reference herein controls.

[001602] In an embodiment, the glutamate modulator is a compound according to: wherein,

A and B are independently selected from the group consisting of N and C, with the proviso that A and B are not both C; represents a 4- to 8-membered ring;

D is selected from the group consisting of alkylene, alkenylene, and alkynylene;

L is selected from the group consisting of a bond, alkylene, alkenylene, alkynylene, — O — , — X— O— , — O— X— , — X— O— Y, —NR ¹⁰ —, — X— NR ¹⁰ — , — NR ¹⁰ — X— , and — X— NR ¹⁰ — Y — ; wherein X and Y, in each instance, are independently selected from the group consisting of alkylene, alkenylene, and alkynylene, with the proviso that when B is N, L is selected from the group consisting of a bond, alkylene, alkenylene, alkynylene, — X — O — , — X— O— Y— , — X— NR ¹⁰ — , and — X— NR ¹⁰ — Y— ;

R ¹ is selected from the group consisting of hydrogen, alkyl, alkylhalo, alkenyl, alkenylhalo, alkynyl, alkynylhalo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene-cycloalkyl, alkenylene-cycloalkyl, alkynylene-cycloalkyl, alkylene-heterocycloalkyl, alkenylene- heterocycloalkyl, alkynylene-heterocycloalkyl, alkylene-aryl, alkenylene-aryl, alkynylene- aryl, alkylene-heteroaryl, alkenylene-heteroaryl, alkynylene-heteroaryl, alkylene-OR ⁷ , alkenylene-OR ⁷ , alkynylene-OR ⁷ , alkylene-NR ⁸ R ⁹ , alkenylene-NR ⁸ R ⁹ , alkynylene-NR ⁸ R ⁹ , alkylene-cyano, alkenylene-cyano, alkynylene-cyano, alkylene-(CO)R ⁷ , alkenylene-(CO)R ⁷ , and alkynylene-(CO)R ⁷ ; wherein any cyclic group is optionally substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, — O-alkyl, alkylhalo, and — O-alkylhalo;

R ² , in each instance, is independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, — O-alkyl, alkylhalo, — O-alkylhalo, alkenyl, — O-alkenyl, alkynyl, — O-alkynyl, cycloalkyl, heterocyloalkyl, aryl, heteroaryl, alkylene-cycloalkyl, alkenylene- cycloalkyl, alkynylene-cycloalkyl, — O-alkylene-cycloalkyl, — O-alkenylene-cycloalkyl, — O-alkynylene-cycloalkyl, alkylene-heterocycloalkyl, alkenylene-heterocycloalkyl, alkynylene-heterocycloalkyl, — O-alkylene-heterocycloalkyl, — O-alkenylene- heterocycloalkyl, — O-alkynylene-heterocycloalkyl, alkylene-aryl, alkenylene-aryl, alkynylene-aryl, — O-alkylene-aryl, — O-alkenylene-aryl, — O-alkynylene-aryl, alkylene- heteroaryl, alkenylene-heteroaryl, alkynylene-heteroaryl, — O-alkylene-heteroaryl, — O- alkenylene-heteroaryl, and — O-alkynylene-heteroaryl; wherein any cyclic group is optionally substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, — O-alkyl, alkylhalo, and — O-alkylhalo; R ³ is selected from the group consisting of hydrogen, aryl, heteroaryl, and benzo-cycloC . xalkenyl; wherein any carbocyclic group is optionally substituted by one or more independently selected substituents, R ⁵ , and any heterocyclic group is optionally substituted by one or more independently selected substituents, R ⁶ ;

R ⁴ , in each instance, is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, oxo, =CR ⁷ R ⁸ , alkyl, alkylhalo, — O-alkyl, — O-alkylhalo, alkenyl, — O-alkenyl, alkynyl, — O-alkynyl, cycloalkyl, alkylene-cyclcoalkyl, heterocyloalkyl, alkylene-heterocycloalkyl, aryl, alkylene-aryl, heteroaryl, and alkylene-heteroaryl; wherein any cyclic group may be substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, — O-alkyl, alkylhalo, and — O-alkylhalo;

R ⁵ , in each instance, is independently selected from the group consisting of halogen, cyano, alkyl, — O-alkyl, alkylhalo, — O-alkylhalo, alkenyl, — O-alkenyl, alkynyl, — O-alkynyl, cycloalkyl, heterocyloalkyl, aryl, heteroaryl, alkylene-cycloalkyl, alkenylene-cycloalkyl, alkynylene-cycloalkyl, — O-alkylene-cycloalkyl, — O-alkenylene-cycloalkyl, — O- alkynylene-cycloalkyl, alkylene-heterocycloalkyl, alkenylene-heterocycloalkyl, alkynylene- heterocycloalkyl, — O-alkylene-heterocycloalkyl, — O-alkenylene-heterocycloalkyl, — O- alkynylene-heterocycloalkyl, alkylene-aryl, alkenylene-aryl, alkynylene-aryl, — O-alkylene- aryl, — O-alkenylene-aryl, — O-alkynylene-aryl, alkylene-heteroaryl, alkenylene-heteroaryl, alkynylene-heteroaryl, — O-alkylene-heteroaryl, — O-alkenylene-heteroaryl, — O- alkynylene-heteroaryl, alkylene-cyano, — O-alkylene-cyano, alkenylene-cyano, — O- alkenylene-cyano, alkynylene-cyano, and — O-alkynylene-cyano; wherein any cyclic group is optionally substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, — O-alkyl, alkylhalo, and — O-alkylhalo;

R ⁶ , in each instance, is independently selected from the group consisting of halogen, amino, cyano, alkyl, alkylhalo, alkenyl, alkynyl, and aryl; wherein said aryl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, — O-alkyl, alkylhalo, and — O-alkylhalo;

R ⁷ , R ⁸ , and R ⁹ are independently selected from the group consisting of hydrogen, alkyl, alkylhalo, alkenyl, and alkynyl;

R ¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl; m represents an integer selected from the group consisting of 1, 2, 3, and 4; and n represents an integer selected from the group consisting of 1 and 2;

Formula 447 [001603] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 447. Such compounds are described in WO 2007/090840, published August 16, 2007, corresponding to PCT/EP2007/051132, filed February 6, 2007 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 447, this reference incorporated by reference herein controls.

[001604] In an embodiment, the glutamate modulator is a compound according to: wherein:

Ar is selected from the group consisting of phenyl, pyridyl and thienyl, each of which is optionally substituted with one or more groups Y; each Y group is independently selected from the group consisting of: halo, Ci-4alkyl, haloCi- 4alkyl, Ci-4alkoxy, cyano, C(O)Ci-4alkyl, NHSChCi^alkyl, NMeSChCi^alkyl, NHCOCi- 4alkyl, NMeCOCi-4alkyl, SOCi-4alkyl, SChCMalkyl and CChC alkyl, or two Y groups together form a cyclic group — 0(CH2)0 — .

Formula 448

[001605] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 448. Such compounds are described in WO 2007/021308, published February 22, 2007, corresponding to PCT/US2006/005246, filed February 15, 2006, WO 2007/021309, published February 22, 2007 corresponding to PCT/US2006/005247, filed February 15, 2006 , and WO 2006/020879, published February 23, 2006, corresponding to PCT/US2005/028760, filed August 12, 2005, which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 448, these references incorporated by reference herein control.

[001606] In an embodiment, the glutamate modulator is a compound according to: wherein:

R ¹ is a 3- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of N, O and S, wherein said ring may be substituted by one or more A;

R ² and R ³ are independently selected from the group consisting of H, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, aryl, heteroaryl, heterocycloalkyl, Cs-s-cycloalkyl, Ci-6-alkyl-aryl, Ci-6-alkyl- heteroaryl, Ci-6-alkyl-heterocycloalkyl, and Cne-alkyl-Cs-s-cycloalkyl, wherein R ² and R may be substituted by one or more A;

R ⁴ and R ⁶ are independently selected from the group consisting of H, hydroxy, F, Cl, Br, I, nitro, cyano, Ci-6-alkyl, Ci-6-alkylhalo, OCi-ealkyl, OCi-6-alkylhalo, C2-6-alkenyl, OC2-6- alkenyl, C2-6-alkynyl, OC2-6-alkynyl, Cs-s-cycloalkyl, Ci-e-alkyl-Cs-s-cycloalkyl, OCo-6-alkyl- C _3-8 -cycloalkyl, aryl, Ci- ₆ -alkylaryl, OCo-6-alkylaryl, (CO)R ¹⁰ , O(CO)R ⁿ , O(CO)OR ¹⁰ , C(O)OR ⁿ , O(CNR ¹⁰ )OR ⁿ , Ci- ₆ -alkylOR ¹⁰ , OC ₂ -6-alkylOR ¹⁰ , Ci-6-alkyl(CO)R ⁿ , OC1-6- alkyl(CO)R ¹⁰ , C ₀ -6-alkylCO ₂ R ¹⁰ , OCi-6-alkylCO ₂ R ¹⁰ , Ci- ₆ -alkylcyano, OC ₂ -6-alkylcyano, Co- 6-alkylNR ¹⁰ R ⁿ , OC ₂ -6-alkylNR ¹⁰ R ¹¹ , Ci- ₆ -alkyl(CO)NR ¹⁰ R ¹¹ , OCi- ₆ -alkyl(CO)NR ¹⁰ R ¹¹ , Co-6- alkylNR ¹⁰ (CO)R ¹¹ , OC ₂ -6-alkylNR ¹⁰ (CO)R ¹¹ , Co-6-alkylNR ¹⁰ (CO)NR ¹⁰ R ¹⁰ , Co-6-alkylSR ¹⁰ , OC ₂ -6-alkylSR ¹⁰ , Co-6-alkyl(SO)R ¹⁰ , OC ₂ -6-alkyl(SO)R ¹⁰ , C ₀ -6-alkylSO ₂ R ¹⁰ , OC2-6- alkylSO ₂ R ¹⁰ , C ₀ -6-alkyl(SO ₂ )NR ¹⁰ R ¹¹ , OC2-6-alkyl(SO ₂ )NR ¹⁰ R ¹¹ , C ₀ -6-alkylNR ¹⁰ (SO ₂ )R ¹¹ , OC2-6-alkylNR ¹⁰ (SO ₂ )R ¹ \ C ₀ -6-alkylNR(SO ₂ )NR ¹⁰ R ¹ \ OC2-6-alkylNR ¹⁰ (SO ₂ )NR ¹⁰ R ¹ \ (CO)NR ¹⁰ R ⁿ , O(CO)NR ¹⁰ R ⁿ , NR ¹⁰ R ⁿ , Co-e-alkylNR^CC^OR ¹¹ , OC2-6- alkylNR ¹⁰ (CO)OR ⁿ , SO3R ¹⁰ and a 5- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of N, O and S, wherein R ⁴ and R ⁶ may be substituted by one or more A, and wherein any cycloalkyl or aryl is optionally fused to a 5- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of C, N, O and S;

R ⁵ is selected from the group consisting of H, F, Cl, Br, I, nitro, Ci-6-alkyl, Ci-6-alkylhalo, OCi-6-alkylhalo, C2-6-alkenyl, OC2-6-alkenyl, C2-(6-alkynyl, OC2-6-alkynyl, Cs-s-cycloalkyl, Ci-6-alkyl-C3-8-cycloalkyl, OCo-6-alkyl-C3-s-cycloalkyl, aryl, Cnealkylaryl, Cn ealkylheteroaryl, OCi-6-alkylaryl, OCi-6-alkylheteroaryl, Ci-6-alkylheterocycloalkyl, Oheterocycloalkyl, OCi- ₆ -alkylheterocycloalkyl, C(O)H, (CO)R ¹⁰ , O(CO)R ¹⁰ , O(CO)OR ⁿ , C(O)OR ¹⁰ , O(CN)OR ⁿ , Ci-e-alkylOR ¹⁰ , OC ₂ -6-alkylOR ¹⁰ , Ci- ₆ -alkyl(CO)R ¹⁰ , OCi- ₆ - alkyl(CO)R ¹⁰ , C ₀ -6-alkylCO ₂ R ¹⁰ , Ci- ₆ -alkylcyano, OC _2.6 -alkylcyano, Co-e-alkylNR ¹ ^ ¹¹ , OC ₂ . 6-alkylNR ¹⁰ R ⁿ , Ci- ₆ -alkyl(CO)NR ¹⁰ R ¹¹ , OCi- ₆ -alkyl(CO)NR ¹⁰ R ¹¹ , Co- ₆ -alkylNR ¹⁰ (CO)R ¹¹ , OC ₂ -6-alkylNR ¹⁰ (CO)R ¹¹ , C ₀ -6-alkylNR ¹⁰ (CO)NR ¹⁰ R ¹¹ , Co-6-alkylSR ¹⁰ , OC _2.6 -alkylSR ¹⁰ , Co-

6-alkyl(SO)R ¹⁰ , OC _2.6 -alkyl(SO)R ¹⁰ , C ₀ -6-alkylSO ₂ R ¹⁰ , OC _2.6 -alkylSO ₂ R ¹⁰ , Co-6- alkyl(SO ₂ )NR ¹⁰ R ¹¹ , OC _2-6 -alkyl(SO ₂ )NR ¹⁰ R ¹¹ , C ₀ -6-alkylNR ¹⁰ (SO ₂ )R ¹¹ , OC _2.6 - alkylNR ¹⁰ (SO ₂ )R ¹¹ , C ₀ -6-alkylNR ¹⁰ (SO ₂ )NR ¹⁰ R ¹¹ , OC _2-6 -alkylNR ¹⁰ (SO ₂ )NR ¹⁰ R ¹¹ , (CO)NR ¹⁰ R ⁿ , O(CO)NR ¹⁰ R ⁿ , NR ¹⁰ OR ⁿ , Co- ₆ -alkylNR ¹⁰ (CO)OR ¹¹ , OC _2.6 - alkylNR ¹⁰ (CO)OR ⁿ , SO3R ¹⁰ and a 5- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of N, O and S, wherein R ⁵ may be substituted by one or more A, and wherein any cyclic moiety is optionally fused to a 5- to

7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of C, N, O and S;

R ⁷ is selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, OCi-4-alkyl, C1-6- alkyl, Ci-6-alkylhalo, OCi-6-alkylhalo, C ₂ -6-alkenyl, OC ₂ -6-alkenyl, C ₂ -6-alkynyl, OC ₂ -6- alkynyl, and Cs-s-cycloalkyl;

R ⁸ and R ⁹ are independently selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, Ci-6-alkyl, Ci-6-alkylhalo, OCi-ealkyl, OCi-6-alkylhalo, C ₂ -6-alkenyl, OC ₂ -6-alkenyl, C ₂ -6- alkynyl, and OC ₂ -6-alkynyl, or, where n is greater than 1, two or more R ⁸ and/or R ⁹ on adjacent carbon atoms may be absent to form an alkenyl or alkynyl moiety;

R ¹⁰ and R ¹¹ are independently selected from the group consisting of H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, Ci-6-alkyl, Ci-6-alkylhalo, OCi-ealkyl, OCi-6-alkylhalo, C ₂ -6-alkenyl, OC ₂ . 6-alkenyl, C ₂ -6-alkynyl, OC ₂ -6-alkynyl, Cs-s-cycloalkyl, Ci-e-alkyl-Cs-s-cycloalkyl, OC0-6- alkyl-Cs-s-cycloalkyl, aryl, Ci-6-alkylaryl, OCo-6-alkylaryl, Co-6-alkyl-heterocycloalkyl, OC1-6- alkyl-heterocycloalkyl, heteroaryl, and Ci-ealkylheteroaryl, wherein any cyclic moiety is optionally fused to a 5- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of C, N, O and S and any cyclic moiety is optionally substituted with a substituent selected from alkyl, halo, hydroxyl, Oalkyl, haloalkyl and Ohaloalkyl; A is selected from the group consisting of H, hydroxy, F, Cl, Br, I, nitro, cyano, oxo, C1-6- alkyl, Ci-6-alkylhalo, OCi-ealkyl, OCi-6-alkylhalo, C2-6-alkenyl, OC2-6-alkenyl, C2-6-alkynyl, OC2-6-alkynyl, Cs-s-cycloalkyl, Ci-e-alkyl-Cs-s-cycloalkyl, OCo-e-alkyl-Cs-s-cycloalkyl, aryl, Ci-6-alkylaryl, OCo-6-alkylaryl, Ci-6-alkyl-heterocyclyl, Ci-6-alkyl-heterocycloalkyl, OC0-6- alkyl-heterocycloalkyl, (CO)R ¹⁰ , O(CO)R ¹⁰ , O(CO)OR ¹⁰ , O(CNR ¹⁰ )OR ⁿ , Ci- ₆ -alkylOR ¹⁰ , OC ₂ -6-alkylOR ¹⁰ , Ci- ₆ -alkyl(CO)R ¹⁰ , OCi- ₆ -alkyl(CO)R ¹⁰ , C ₀ -6-alkylCO ₂ R ¹⁰ , OC1-6- alkylCO2R ¹⁰ , Ci-6-alkylcyano, OC2-6-alkylcyano, Co-6-alkylNR ^lo R ⁿ , OC2-6-alkylNR ¹⁰ R ⁿ , Co- 6-alkyl(CO)NR ¹⁰ R ⁿ , OCi- ₆ -alkyl(CO)NR ¹⁰ R ¹¹ , Co-6-alkylNR ¹⁰ (CO)R ¹¹ , OC2-6- alkylNR ¹⁰ (CO)R ¹¹ , Co-6-alkylNR ¹⁰ (CO)NR ¹⁰ R ¹¹ , Co-6-alkylSR ¹⁰ , OC ₂ -6-alkylSR ¹⁰ , C1-6- alkyl(SO)R ¹⁰ , OC ₂ -6-alkyl(SO)R ¹⁰ , Ci-6-alkylSO ₂ R ¹⁰ , OC2-6-alkylSO ₂ R ¹⁰ , Co-6- alkyl(SO ₂ )NR ¹⁰ R ¹¹ , OC2-6-alkyl(SO ₂ )NR ¹⁰ R ¹¹ , C ₀ -6-alkylNR ¹⁰ (SO ₂ )R ¹¹ , OC2-6- alkylNR ¹⁰ (SO ₂ )R ¹¹ , Co-6alkylNR ¹⁰ (S0 ₂ )NR ¹⁰ R ¹¹ , OC2-6-alkylNR ¹⁰ (SO ₂ )NR ¹⁰ R ¹¹ , (CO)NR ¹⁰ R ⁿ , O(CO)NR ¹⁰ R ⁿ , NR ¹⁰ R ⁿ , Co-e-alkylNR^CC^OR ¹¹ , OC2-6- alkylNR ¹⁰ (CO)OR ⁿ , SO3R ¹⁰ and a 5- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of N, O and S, wherein said 5- to 7-membered ring is optionally substituted by one or more of R ¹⁰ and R ¹¹ ; and n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8.

Formula 449

[001607] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 449. Such compounds are described in WO 2007/018998, published February 15, 2007, corresponding to PCT/US2006/028165, filed July 21, 2006, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 449, this reference incorporated by reference herein controls.

[001608] In an embodiment, the glutamate modulator is a compound according to: wherein

A is selected from the group consisting of CR ⁸ R ⁹ , NR ⁵ , O, S, SO and SO2; B is selected from the group consisting of CH and N;

D is selected from the group consisting of NH, N — Ci-6-alkyl, and — (CR ⁵ R ⁶ ) _Z — , wherein one of the — CR ⁵ R ⁶ — groups may be replaced by — C(O) — , NH, or NCi-6-alkyl;

L is selected from the group consisting of a direct bond and — (CR ⁵ R ⁶ ) _W — , wherein when L is — (CR ⁵ R ⁶ ) _W — :

(i) B-L may be unsaturated, or two adjacent carbon atoms may form part of a cyclopropyl ring; or

(ii) one or two CR ⁵ R ⁶ groups may be replaced with O, S, or NR ⁵ ; represents a ring selected from the group consisting of azetidine and a 5- to 7-membered ring, which may be unsaturated, wherein the ring may be substituted by one or more R ⁴ ;

R ¹ , in each instance, is selected from the group consisting of H, F, Cl, Br, I, OH, CN, nitro, Ci-6-alkyl, OCi-6-alkyl, Ci-6-alkylhalo, OCi-6-alkylhalo, C2-6-alkenyl, OC2-6-alkenyl, C2-6- alkynyl, OC2-6-alkynyl, Cs-s-cycloalkyl, Ci-e-alkylene-Cs-s-cycloalkyl, OCo-e-alkylene-Cs-s- cycloalkyl, aryl, heteroaryl, Ci-6-alkylenearyl, Ci-6-alkyleneheteroaryl, OCi-6-alkylenearyl, OCi-6-alkyleneheteroaryl, Ci-6-alkyleneheterocycloalkyl, (CO)R ⁵ , (CO)OR ⁵ , C1-6- alkyleneOR ⁵ , OC2-6-alkyleneOR ⁵ , Ci-6-alkylene(CO)R ⁵ , OCi-6-alkylene(CO)R ⁵ , C1-6- alkylenecyano, OC2-6-alkylenecyano, Co-6-alkyleneNR ⁶ R ⁷ , OC2-6-alkyleneNR ⁶ R ⁷ , C1-6- alkylene(CO)NR ⁶ R ⁷ , OCi- ₆ -alkylene(CO)NR ⁶ R ⁷ , Co-6-alkyleneNR ⁶ (CO)R ⁷ , OC2-6- alkyleneNR ⁶ (CO)R ⁷ , Co-6-alkyleneNR ⁶ (CO)NR ⁶ R ⁷ , Co-6-alkyleneS0 ₂ R ⁵ , OC2-6- alkyleneSO2R ⁵ , Co-6-alkylene(S02)NR ⁶ R ⁷ , OC2-6-alkylene(SO2)NR ⁶ R ⁷ , Co-6- alkyleneNR ⁶ (SO ₂ )R ⁷ , OC ₂ -6-alkyleneNR ⁶ (SO ₂ )R ⁷ , Co-6-alkyleneNR ⁶ (S0 ₂ )NR ⁶ R ⁷ , OC2-6- alkyleneNR ⁶ (SO2)NR ⁶ R ⁷ , (CO)NR ⁶ R ⁷ and SO3R ⁵ , wherein any cyclic group may be further substituted with one or more R ² groups;

R ² and R ⁴ , in each instance, are independently selected from the group consisting of H, F, Cl, Br, I, CN, nitro, hydroxy, oxo, Ci-6-alkyl, OCi-6-alkyl, Ci-6-alkylhalo, OCi-6-alkylhalo, and Co-6-alkyleneNR ⁵ R ⁶ ;

R ³ is a 5- to 12-membered ring system that is optionally substituted by up to three R ¹ groups, wherein the ring system may contain one or more heteroatoms independently selected from the group consisting of N, O and S;

R ⁵ is selected from the group consisting of H, Ci-6-alkyl, aryl, Cs-s-cycloalkyl, C1-6- alkylenearyl and Ci-e-alkylene-Cs-s-cycloalkyl, wherein any cyclic group may be further substituted with one or more independently-selected R ² groups; R ⁶ and R ⁷ are independently selected from the group consisting of H and Ci-6-alkyl;

R ⁸ and R ⁹ are independently selected from the group consisting of H, — O — (CH2)2 — O — and — O— (CH ₂ )3— O— ; m and n are integers independently selected from the group consisting of 0, 1, 2, 3 and 4, with the proviso that m and n cannot simultaneously be 0; x and y are integers independently selected from the group consisting of 1, 2, and 3; and w and z are integers independently selected from the group consisting of 1, 2, 3, 4, 5, and 6; or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.

Formula 450

[001609] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 450. Such compounds are described in WO 2006/037996, published April 13, 2006, corresponding to PCT/GB2005/003817, filed October 5, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 450, this reference incorporated by reference herein controls.

[001610] In an embodiment, the glutamate modulator is a compound according to: wherein

R ¹ represents Ci-ealkyl, cycloCs-nalkyl, C2-ealkenyl, aryl, arylCi-ealkyl, arylC2-ealkenyl, heteroaryl, heteroarylCi-6-alkyl, arylCs-ecycloalkyl, heteroarylC2-ealkenyl, 2,3-dihydro-lH- indenyl, cycloCs-nalkyl or cycloCs-nalkyl-Ci-ealkyl, wherein the cycloCs-nalkyl is optionally unsaturated and wherein one or more carbon atoms of the cycloCs-nalkyl moiety may optionally be replaced by an oxygen atom or an NR ⁷ -moiety;

R ² represents hydrogen or Ci-ealkyl;

X represents hydrogen, Ci-ealkyl, halogen, cyano, Ci-ealkoxy, nitro, or di-(Ci-6alkyl)amino;

Y represents hydrogen, halogen, cyano Ci-ealkyl, Ci-ealkoxy, hydroxyCi-ealkyl, or di-Ci- ealkylaminoCi-ealkyl; or X and Y together may form a bivalent radical selected from OCR ⁹ R ¹⁰ , CH2CR ⁹ R ¹⁰ , oxygen, CH ₂ , and N(R ⁸ );

Q represents nitrogen or R ³ — C;

T represents nitrogen or R ⁴ — C;

W represents nitrogen or R ⁵ — C;

Z represents nitrogen or R ⁶ — C; wherein

R ³ , R ⁴ , R ⁵ and R ⁶ each independently represents a hydrogen atom, a halogen atom, or a group selected from hydroxy, cyano, nitro, Ci-ealkyl, hydroxyCi-ealkyl, Ci-ealkoxyCi-ealkyl, aryl, arylCi-ealkyl, heteroaryl, Ci-ealkoxy, cycloC ₃ -i ₂ alkoxy, arylCi-ealkoxy, amino, Ci- ealkylamino, di-(Ci-6alkyl)amino, cycloC ₃ -i ₂ alkylamino, cycloC ₃ -i ₂ alkyl-Ci-6alkylamino, di- (Ci-6alkyl)aminoCi-6alkyl, arylamino, arylCi-ealkylamino, N-aryl-N-Ci-ealkylamino, Ci- ealkylcarbonylamino, N-Ci-ealkyl-N-Ci-ealkylcarbonylamino, pyrrolidino, piperidino, 4-Cn ealkyl-piperazino, morpholino, hexamethyleneimino, pyrrolidinylCi-ealkyl, piperidinylCi- ealkyl, morpholinylCi-ealkyl, Ci-ealkylsulfonyl, Ci-ealkysulfonylamino, Ci-ealkylsulfanyl, Ci- ealkylaminosulfonyl, and di-(Ci-6alkyl)aminosulfonyl;

R ⁴ and R ⁵ together may form a bivalent radical selected from — (CH ₂ ) ₃ — , — (CH ₂ )4 — , — CH=CH— CH=CH— , — (CH ₂ ) ₃ O— , — OCH ₂ O— , — O(CH ₂ ) ₂ O— , and — O(CH ₂ ) ₃ — ;

R ⁷ represents hydrogen, Ci-6-alkyl, aryl, or cycloC ₃ -i ₂ alkylCi-6alkyl;

R ⁸ represents hydrogen, Ci-ealkyl or di-(Ci-6-alkyl)aminocarbonyl;

R ⁹ and R ¹⁰ represent hydrogen or Ci-ealkyl; and optical isomers and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; it being understood that: aryl represents phenyl or naphthyl, or phenyl substituted by one or more substituents, which may be the same or different, selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- ealkyl, C ₂ -6alkenyl, Ci-6-alkoxy, amino, hydroxy, nitro, cyano, Ci-6-alkoxycarbonyl, Ci- ealkylamino, di-(Ci-6alkyl)amino and Ci-6-alkylenedioxy; heteroaryl represents a (hetero)aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substitued by one or more substituents, which may be the same or different, selected from halogen, trifluoromethyl, Ci-6-alkoxy, amino, hydroxy, nitro, cyano, Ci- ealkoxycarbonyl, Ci-6-alkylamino, and di-(Ci-6-alkyl)amino; if Y represents hydrogen or Cnealkyl and R ¹ represents aryl, then the ring formed by the substituents Q, T, W, and Z may not represent phenyl or substituted phenyl; if R ⁸ represents hydrogen, then R ¹ may not represent Ci-6-alkyl, phenyl or phenyl substituted by one or more groups selected from halogen, alkoxy, trifluoromethyl, alkyl, nitro, and amino; naphthyl; isoquinolinyl; 2-pyridyl or 2-thienyl.

Formula 451

[001611] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 451. Such compounds are described in WO 2005/118534, published December 15, 2005, corresponding to PCT/EP2005/005938, filed June 2, 2005, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 451, this reference incorporated by reference herein controls.

[001612] In an embodiment, the glutamate modulator is a compound according to either of: in which:

R i and R 2 are each individually hydrogen or a carboxy-protecting group;

R a is hydrogen or an amino-protecting group;

R 4 to R 8 , identical to or different from each other, represent a hydrogen atom, a halogen atom, an alkyl radical or an aryl radical, a -OH or a -SH, these radicals themselves being substituted where appropriate;

R 4 and R 5 can form a carbonyl bond or a thiocarbonyl bond;

R 9 represents a (R 10 ) n (-R 11 ) m group wherein n represents an integrer of from 0 to 4; m represents an integrer of from 1 to 3;

R 10 is a moiety selected in the group consisting of:

(i) CH ₂

(ii)

(iii) with: a, b and c are, independently from one another, an integer ranging from 0 to 4 ;

A i and A ₂ are, independently from one another, a moiety selected in the group consisting of -CO-, -CS-, -0-, -S-, -SO-, -SO2-, -COO-, -C0N(Cn'H2n'+i)-, -N(C _n ’H _2n ' ₊ i)CO-, - CSN(Cn'H2n' ₊ i)-, -N(Cn'H2n'+i)CS-, -N(C _n 'H ₂ n' ₊ i)-, -(C _n 'H ₂ n' ₊ i)-, aryl, cycloalkyl, -1,4- piperidinyl, 1,4-piperazinyl, with (C _n ,H 2n'+i )- designating a straight or branched chain, or cyclic carbon radical, or combination thereof, which may be fully saturated, mono or polyunsaturated and can include di- and multi-moieties, and having from 1 to 8 carbon atoms, with n' is, independently from one another, an integer ranging from 0 to 8, preferably from 1 to 4, preferably from 1 to 3 and more preferably from 1 to 2,

R 11 is a polar group such as -COOH, -SO3H, -SO2H, -PO3H2, -PO2H, -B(0H)2, tetrazol, -CO (C _m H ₂ m' ₊ i), -C (NOH)(C _m 'H ₂ m' ₊ i), -CS (C _m H ₂ m' ₊ i), -OH, -O(C _m H ₂ m' ₊ i), - OCO(Cm'H ₂ m' ₊ l), -SH, -S(Cm'H ₂ m'+l), -SCO(C _m 'H ₂ m' ₊ l), -NH ₂ , -NHOH, -N(Crn'H2m' ₊ l)2, - N ⁺ (Cm'H2m' ₊ l)3, -NHCO (C _m H ₂ m' ₊ l), -NHSO2(C _m H ₂ m' ₊ l)2, -NHCON (Cm'H ₂ m'+l), - NHCSN(Crn'H2m' ₊ l), -CON(Cm'H2m' ₊ l)2, -CSN(C _m H ₂ m' ₊ l)2, -SO ₂ N(C _m 'H2m' ₊ l)2; with m' is, independently from one another, an integer ranging from 0 to 4, as well as their pharmaceutically acceptable salts, or their metabolically labile esters or amides.

Formula 452

[001613] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 452. Such compounds are described in WO 2001/085669, published November 15, 2001, corresponding to PCT/CA2001/000650, filed May 11, 2001, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 452, this reference incorporated by reference herein controls.

[001614] In an embodiment, the glutamate modulator is a compound according to: stereoisomers thereof, or pharmaceutically acceptable salts or hydrates thereof, wherein:

R1 is (CH2)n(CH) _m XY, where: n is 0-3, m is 0 or 1, X is CO2H and Y is NH2, with the proviso that, when m=0, then n=0 and the groups X and Y are directly attached to the ring, R2 and R3 can be same or different and selected from the group comprising H, halo, alkyl, cycloalkyl, aryl or heterocycle, or when R2 and R3 are present on adjacent carbon atoms and taken together then R2 and R3 can form a cycloalkyl (3-6 carbon atoms), heterocycle, an aromatic ring or heteroaromatic ring,

R4 is selected from the group comprising H, halo, alkyl, cycloalkyl, aryl or heterocycle, R5 is selected from the group comprising carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, — CFfc-carboxyl, — CFfc-phosphono, — CFfc-phosphino, — CH2- sulfono, — CH2-sulfino, — CFh-borono, — CFfc-tetrazol, — CFfc-isoxazol, and higher homologues thereof.

Formula 453

[001615] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 453. Such compounds are described in WO 2001/079185, published October 25, 2001, corresponding to PCT/CA2001/000503, filed April 18, 2001, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 453, this reference incorporated by reference herein controls.

[001616] In an embodiment, the glutamate modulator is a compound according to: or stereoisomers thereof or pharmaceutically acceptable salts or hydrates thereof, wherein:

R1 and R2 can be the same or different and selected from the group comprising H, NH2, COOH and (CH ₂ )nCR5WY, wherein: n=0-5, W is H or COOH, Y is H or NH ₂ , R5 is H, alkyl, aryl, or (CH2)mR6, wherein: m=0-5 and R6 is H, carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, or isoxazol;

R3 and R4 can be the same or different and selected from the group comprising H, alkyl, aryl, acyl, CH2COOH, NH ₂ and — (CH ₂ )n'CHCO ₂ H NH ₂ , wherein: n' is 0-5; and X is O or S.

Formula 454

[001617] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 454. Such compounds are described in WO 99/47490, published September 23, 1999, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 454, this reference incorporated by reference herein controls.

[001618] In an embodiment, the glutamate modulator is a compound according to: wherein n is 0-6; X is CH2, CH2 CH2 or oxygen;

Z is CHR ² or NR ² ;

R ¹ and R ² are selected independently from hydrogen, (Ci -Ce)alkyl, aryl and heteroaryl, wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from 5 and 6 membered aromatic heterocyclic rings that contain from one to four heteroatoms selected, independently, from nitrogen, oxygen and sulfur, and wherein said aryl and heteroaryl moieties can optionally be substituted with one or more substituents that are selected, independently, from halo, — S(Ci -Ce)alkyl, — S(O)(Ci -Ce)alkyl, — S(O)2 (Ci - Ce)alkyl, (Ci -Ce)alkyl optionally substituted with from one to seven fluorine atoms, (Ci - Ce)alkoxy optionally substituted with from one to seven fluorine atoms, amino, nitro, cyano, carboxy, — CO2 (Ci -Ce)alkyl, (Ci -C6)alkylamino, di-[(Ci -C6)alkyl]amino phenoxy, anilino and phenylthio;

Formula 455

[001619] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 455. Such compounds are described in EP 0928792, published July 14, 1999, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 455, this reference incorporated by reference herein controls.

[001620] In an embodiment, the glutamate modulator is a compound according to: wherein n is 0-6;

Z is (C1-C4) alkylene, oxygen, sulfur, NH or N(Ci-Ce)alkyl;

R ¹ is hydrogen, (Ci-Ce)alkyl, aryl or heteroaryl, wherein aryl is selected from phenyl and naphthyl and said heteroaryl is selected from 5 and 6 membered aromatic heterocyclic rings that contain from one to four heteroatoms selected, independently, from nitrogen, oxygen and sulfur, and wherein said aryl and heteraryl moieties can optionally be substituted with one or more substituents, preferably with one or two substituents, that are selected, independently, from halo (e.g., fluoro, chloro, bromo or iodo), -SO(Ci-Ce)alkyl, -SO2R ⁴ , -SO2NR ⁵ R ⁶ , (Ci- Ce)alkyl optionally substituted with from one to seven fluorine atoms, (Ci-Ce)alkoxy optionally substituted with from one to seven fluorine atoms, amino, nitro, cyano, carboxy, - CO2(Ci-Ce)alkyl, (Ci-C6)alkylamino, di-[(Ci-C6)alkyl]amino phenoxy, anilino and phenylthio;

R ⁴ is -O(Ci-Ce)alkyl, phenyl or (Ci-Ce)alkyl; and

R ⁵ and R ⁶ are selected, independently, from hydrogen, (Ci-Ce)alkyl and phenyl; with the optional proviso that R ¹ can not be hydrogen when n is zero, and with the further optional proviso that none of the foregoing heteroaryl moieties may contain more than one ring oxygen atom or more than one ring sulfur atom; or a pharmaceutically acceptable salt thereof.

Formula 456

[001621] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 456. Such compounds are described in WO 96/05818, published February 29, 1996, corresponding to PCT/US95/10745, filed August 21, 1995, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 456, this reference incorporated by reference herein controls.

[001622] In an embodiment, the glutamate modulator is a compound according to: wherein each X independently is selected from the group consisting of H, CHa, CH3O, CH3CH2O, methylene dioxy, Br, Cl, F, CF ₃ , CHF ₂ , CH ₂ F, CF ₃ 0, CH ₃ S, OH, CH ₂ OH, C0NH ₂ , CN, NO 2' CH3CH ₂ , propyl, isopropyl, butyl, isobutyl, t-butyl, and acetoxy; Ar is a hydrophobic entity; each R independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, allyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, indanyl, dihydroindolyl, thiodihydroindolyl, 2-, 3-, or 4- piperid(in)yl;

Y is selected from the group consisting of CH, nitrogen and an unsaturated carbon; and Z is selected from the group consisting of oxygen, nitrogen, sulfur, wherein each n is independently between 1 and 4 inclusive, and each m is independently between 0 and 5 inclusive. Formula 457

[001623] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 457. Such compounds are described in WO 2021/011876, published January 21, 2021, corresponding to PCT/US2020/042543, filed July 17, 2020, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 457, this reference incorporated by reference herein controls.

[001624] In an embodiment, the glutamate modulator is a compound according to: or wherein:

R ¹ is selected from the group consisting of — Ci-Ce alkyl, — Ci-Ce heteroalkyl, — (Co- C3 alkyl)-(C3-Ce cycloalkyl), — (C0-C3 alkyl)-(C4-Cio heterocyclyl), — (C0-C3 alkyl)-(Ce- C10 aryl) and — (C0-C3 alkyl)-(C5-Cio heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are independently optionally substituted;

Ai is N or CR ^2a ;

A ₂ is N or CR ^2b ;

A3 is N or CR ^2c ; each occurrence of R ^2a , R ^2b , R ^2c , R ^2d , and R ^2e is independently selected from the group consisting of H, tritium ( ³ H), — Ci-Ce alkyl, — OH, — Ci-Ce alkoxy, halogen, — NH ₂ , — N(CH ₃ ) ₂ , — C(=O)OH, trifluoromethyl, —ON, — C(=O)O(Ci-C ₄ )alkyl, — C(=O)NH ₂ , — SO ₂ NH ₂ , — C(=NH)NH ₂ , and — NO ₂ ;

R ³ is selected from the group consisting of — (C=0)o-i(Ci-Ce alkyl), — (C=0)o-i(Ci-

C ₆ heteroalkyl), — (C=0)o-i(Co-C ₃ alkyl)-(C ₃ -C ₆ cycloalkyl), — (C=0)o-i(Co-C ₃ alkyl)-(C ₄ - C ₁₀ heterocyclyl), — (C=0)o-i(Co-C ₃ alkyl)-(C ₆ -C ₁₀ aryl), — (C=0)o-i(Co-C ₃ alkyl)-(C ₅ - C 10 heteroaryl), — (S0 ₂ )o-i(Ci-C ₆ alkyl), — (S0 ₂ )o-i(Ci-C ₆ heteroalkyl), — (S0 ₂ )o-i(Co- Cs alkyl)-(C3-Ce cycloalkyl), — (S02)o-i(Co-C3 alkyl)-(C4-Cio heterocyclyl), — (S02)o-i(Co-

C3 alkyl)-(Ce-Cio aryl) and — (S02)o-i(Co-C3 alkyl)-(C5-Cio heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are independently optionally substituted; and

Z is N or CH.

Formula 458

[001625] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 458. Such compounds are described in WO 2003/057661, published July 17, 2003, corresponding to PCT/US02/36145, filed December

5, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 458, this reference incorporated by reference herein controls.

[001626] In an embodiment, the glutamate modulator is a compound according to: wherein

R ¹¹ is C(O)OR ¹⁴ and R ¹² is hydrogen or fluoro; or R ¹¹ is hydrogen or fluoro and R ¹² is C(O)OR ¹⁴ ; and

R ¹³ and R ¹⁴ are, independently, hydrogen, (1-6C) heterocyclylalkyl, aryl or (1-6C) arylalkyl; provided when R ¹³ is hydrogen, R ¹⁴ is not hydrogen; or a pharmaceutically acceptable salt thereof.

Formula 459

[001627] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 459. Such compounds are described in WO 2003/006489, published January 23, 2003, corresponding to PCT/US2002/019825, filed July 2, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 459, this reference incorporated by reference herein controls.

[001628] In an embodiment, the glutamate modulator is a compound according to:

, wherein R11 is C(O)YR14 and R12 is hydrogen or fluoro; or R11 is hydrogen or fluoro and R12 is C(O)YR14;

R13 and R14 are, independently, hydrogen, Cl-10 alkyl, C2-4 alkenyl, C2-4 alkynyl, or aryl; Al is hydrogen or an amino acyl bonded through the carbonyl to form an amine terminus;

X and Y are, independently, I or A2;

A2 is an amino acyl bonded through the amine to form a carboxylate terminus; provided when X is O, Y is not O, or a pharmaceutically acceptable salt thereof.

Formula 460

[001629] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 460. Such compounds are described in WO 02/068380, published September 6, 2002, corresponding to PCT/US02/01247, filed February 12, 2002, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 460, this reference incorporated by reference herein controls.

[001630] In an embodiment, the glutamate modulator is a compound according to: wherein:

X is CH ₂ , O, or NH;

Y is O, S, N or H;

A is a bond, 0, N, (1-10C) alkyl, (2- 10C) alkenyl or (2 -10C) alkynyl;

R is hydrogen, (1-10C) akyl, (2-10C) alkenyl, (3-6C) alkynyl, aryl, heterocyclyl or substituted aryl; or the group XC(Y)AR is where Q is O, S or NH; or a pharmaceutically acceptable metabolically labile ester or amide thereof; or a pharmaceutically acceptable salt thereof.

Formula 461

[001631] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 461. Such compounds are described in WO 02/40002, published May 23, 2002, corresponding to PCT/US2001/048448, filed October 30, 2001 which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 461, this reference incorporated by reference herein controls.

[001632] In an embodiment, the glutamate modulator is a compound according to:

R ¹ , R ² , R ⁵ and R ⁶ are independently

1) Cl-C6-alkyl,

2) C3-C4-alkenyl,

3) C3-C5-cycloalkyl,

4) H, or

5) halogen;

R ³ and R ⁴ are independently

1) H,

2) Cl-C6-alkyl,

3) C3-C4-alkenyl,

4) C3-C5-cycloalkyl,

5) Cl-C6-alkyl-CO—

6) Cl-C6-alkyl-OCO—

7) Cl-C6-alkyl-NHCO—

8) Cl-C6-alkyl-SO ₂ —

9) CF3SO2—

10) PhSO ₂ — 11) HCO— , or

12) C3-C6-alkynyl; and

R ³ and R ⁴ taken together can be — CH2(CH2) _n CH2 — wherein n is 0, 1, 2, or 3.

Formula 462

[001633] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 462. Such compounds are described in WO 00/06083, published February 10, 2000, corresponding to PCT/US99/17018, filed July 28, 1999, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 462, this reference incorporated by reference herein controls.

[001634] In an embodiment, the glutamate modulator is a compound according to: wherein

R ¹ represents a naphthyl group or a phenyl, furyl, thienyl or pyridyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen; nitro; cyano; hydroxyimino; (l-lOC)alkyl; (2-10C)alkenyl; (2-10C)alkynyl; (3- 8C)cycloalkyl; hydroxy(3-8C)cycloalkyl; oxo(3-8C)cycloalkyl; halo(l-10C)alkyl;

(CH ₂ ) _y X ¹ R ⁹ in which y is 0 or an integer of from 1 to 4, X ¹ represents O, S, NR ¹⁰ , CO, COO, OCO, CONR ¹¹ , NR ¹² CO, NR ¹² COCOO or OCONR ¹³ , R ⁹ represents hydrogen, (l-lOC)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3- 8C)cycloalkyl and R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently represents hydrogen or (1- 10C)alkyl, or R ⁹ and R ¹⁰ , R ¹¹ , R ¹² or R ¹³ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N-(l- 4C)alkylpiperazinyl; N-phenyl(l-4C)alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydro-thienyl; dihydrofuryl; dihydmthiopyranyl; dihydropyranyl; dihydrothiazolyl; (1- 4C)alkoxycarbonyldihydrothiazolyl; (l-4C)alkoxycarbonyldimethyldihydrothiazolyl; tetrahydro-thienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R ¹⁴ — (L ^a ) _n — X ² — (L ^b ) _m in which X ² represents a bond, O, NH, S, SO, SO ₂ , CO, CH(OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH or CH=CH, L ^a and L ^b each represent (l-4C)alkylene, one of n and m is 0 or 1 and the other is 0, and R ¹⁴ represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, nitro, cyano, hydroxyimino, (1-10C) alkyl, (2-10C)alkenyl, (2-10C)alkynyl, (3-8C)-cycloalkyl, 4-(l,l-dioxotetrahydro- 1,2-thiazinyl), halo(l-10C)alkyl, cyano(2-10C)alkenyl, phenyl, and (CH2) _Z X ³ R ¹⁵ in which z is 0 or an integer of from 1 to 4, X ³ represents O, S, NR ¹⁶ , CO, CH(OH), COO, OCO, CONR ¹⁷ , NR ¹⁸ CO, NHSO2, NHSO2NR ¹⁷ , NHCONH, OCONR ¹⁹ or NR ¹⁹ COO, R ¹⁵ represents hydrogen, (l-lOC)alkyl, phenyl(l-4C)alkyl, halo(l-10C)alkyl, (l-4C)alkoxycarbonyl(l- 4C)alkyl, (l-4C)alkylsulfonylamino(l-4C)alkyl, (N(l-4C)alkoxy carbonyl) (1- 4C)alkylsulfonylamino-(l-4C)alkyl, (3-10C)alkenyl, (3-10C)alkynyl, (3-8C)-cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (l-4C)alkyl, halo(l-4C)alkyl, di(l-4C)alkylamino and (l-4C)alkoxy and R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ each independently represents hydrogen or (l-lOC)alkyl, or R ¹⁵ and R ¹⁶ , R ¹⁷ , R ¹⁸ or R ¹⁹ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group;

R ² represents (l-6C)alkyl, (3-6C)cycloalkyl, fluoro(l-6C)alkyl, chloro(l-6C)alkyl, (2- 6C)alkenyl, or (l-4C)alkoxy(l-4C)alkyl, or a group of formula R ³ R ⁴ N in which R ³ and R ⁴ each independently represents (l-4C)alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group;

R ⁶ represents methyl; and

R ⁷ represents hydrogen; or a pharmaceutically acceptable salt thereof.

Formula 463

[001635] In an embodiment, the glutamate modulator may be selected from the following compounds according to Formula 203. Such compounds are described in WO 2015/197079, published December 30, 2015, corresponding to PCT/DK2015/050186, which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 203, this reference incorporated by reference herein controls.

[001636] In an embodiment the glutamate receptor modulator is an mGluR modulator, such as a Group 2/3 mGluR modulator. In one embodiment the Group 2/3 mGluR modulator is selected from the group consisting of a mGluR2 modulator, a mGluR3 modulator, a mGluR4 modulator, a mGluR6 modulator, a mGluR7 modulator and a mGluR8 modulator. In an embodiment, the Group 2 mGluR modulator is selected from the group consisting of LY 379268, DCG-IV, APICA (1 -amino-5-phosphonoindan-l - carboxylic acid) and EGLU ((2S)-a-ethylglutamic acid), and derivatives thereof. In an embodiment, the Group 3 mGluR agonist (mGluR4 agonist) is selected from the group consisting of eglumegad (LY354740); LY544344; LSP-13081 ; LSP-121 1 1 ; LuAF- 21934; VU-400195 and VU-0354770, and derivatives thereof

[001637] In an embodiment, the glutamate receptor modulator according to the present invention is a mGluR modulator, such as a Group 1 mGluR modulator. In one embodiment the Group 1 mGluR modulator is an mGluRI modulator or an mGluR5 modulator. In one embodiment the Group 1 mGluR modulator is selected from the group consisting of mavoglurant (AFQ056), dipraglurant, 2-methyl-6- (phenylethynyl)pyridine (MPEP); 3-((2- methyl-4-thiazolyl)ethynyl)pyridine (MTEP); fenobam (1 -(3-chlorophenyl)-3-(3-methyl-5- oxo-4H-imidazol-2-yl)urea); and derivatives thereof.

[001638] The glutamate modulator may be present as isotopically labeled forms of compounds detailed herein. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to ² H (deuterium, D), ³ H (tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, CI and I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C are incorporated, are provided. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of subjects (e.g. humans). Also provided for isotopically labeled compounds described herein are any pharmaceutically acceptable salts, or hydrates, as the case may be.

[001639] In some variations, the compounds disclosed herein may be varied such that from 1 to “n” hydrogens attached to a carbon atom is/are replaced by deuterium, in which “n” is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and are thus useful for increasing the half-life of the compound when administered to a subject. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. [001640] Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved drug metabolism and pharmacokinetics (DMPK) properties, relating to absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ¹⁸ F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure can generally be prepared by carrying out the procedures known to those skilled in the art by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compounds provided herein.

[001641] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as 'H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition.

[001642] The glutamate modulators of the present invention may be given orally, sublingually, intranasally, buccally, subcutaneously or in any other suitable means of delivery. The glutamate modulators may be in the form of a prodrug, which releases the agent in the body, a sustained release vehicle, a delayed release vehicle, or any other suitable delivery form. The glutamate modulator and the metal channel activator may be delivered simultaneously or sequentially. If the agents are delivered sequentially, either agent may be dosed first, and the separation of time may include finishing the dosing of one agent completely before commencing the dosage of the other or they may be intermingled in time. Typically, the glutamate modulator is administered at a time proximate to the administration of the metal channel activator, e.g., within 1 week, 1 day, 1 hour, 1 minute before or after the metal channel activator or simultaneously with the metal channel activator.

[001643] The dose of the glutamate modulator for use with the metal channel activator to be administered may depend on the subject to be treated inclusive of the age, sex, weight and general health condition thereof. In this regard, precise amounts of the agent(s) for administration will depend on the judgment of the practitioner. In determining the effective amount of the glutamate modulator and metal channel activator to be administered in the treatment or reducing of the conditions associated with the symptoms and disorders, the physician may evaluate clinical factors including symptoms severity or progression of the disorder. In some conditions, a rapid absorption of the glutamate modulator or metal channel activator may be desirable. The effective amount of the treatment will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of administration, and may be determined routinely by one of ordinary skill in the art.

[001644] The glutamate modulator as part of the formulation for treating cancer or symptoms may be dosed at or below about 400 mg/day, at or below about 300 mg/day, at or below about 150 mg/day, at or below about 100 mg/day, at or below about 70 mg/day, at or below about 60 mg/day, at or below about 50 mg/day, at or below about 42.5 mg/day, at or below about 37.5 mg/day at or below about 35 mg/day, at or below about 20 mg/day, at or below about 17.5 mg/day, at or below about 15 mg/day, at or below about 10 mg/day, at or below about 5 mg/day, or at or below about 1 mg/day.

[001645] The pharmaceutical compositions of the present invention comprising the glutamate modulator typically also include other pharmaceutically acceptable carriers and/or excipients such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents and mixtures thereof. A skilled artisan in the art would know what other pharmaceutically acceptable carriers and/or excipients could be included in the formulations according to the invention. The choice of excipients would depend on the characteristics of the compositions and on the nature of other pharmacologically active compounds in the formulation. Appropriate excipients are known to those skilled in the art (see Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., McGraw Hill) and have been utilized to yield a novel sublingual formulation with unexpected properties.

[001646] Examples of pharmaceutically acceptable carriers that may be used in preparing the pharmaceutical compositions of the present invention may include, but are not limited to, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methyl-cellulose, sodium carboxymethylcellulose, polyvinyl-pyrrolidone (PVP), talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen-free water and combinations thereof. If desired, disintegrating agents may be combined as well, and exemplary disintegrating agents may be, but not limited to, crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more chemical agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention may be manufactured in conventional methods known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes and the like. Glutamate modulators such as riluzole and the pharmaceutically acceptable salts thereof can be formulated using pharmaceutically acceptable carriers well known in the art into dosages suitable for sublingual, intranasal or buccal administration. Such carriers enable the glutamate modulators to be formulated in dosage forms such as tablets, powders, pills, capsules, liquids, gels, films, syrups, slurries, suspensions, and the like.

[001647] Some of the glutamate modulators can be administered sublingually. PCT Application No. PCT/US2015/061106 and PCT Application No. PCT/US2015/061114 describe a sublingual formulation of riluzole, a preferred glutamate modulator. The sublingual formulation may be administered in an effective amount to a subject in need thereof. The subject may be an animal or human. When the glutamate modulator is prepared as a sublingual formulation, the sublingually administered chemical agent or the drug can diffuse into capillaries through mucous membrane under the tongue, and then enter venous circulation of the subject. As such, sublingual administration may have advantages over oral administration as allowing for direct or faster entry to venous circulation, without risks of degradation in gastrointestinal tract, alteration by drug metabolism in liver and the like. [001648] A sublingual formulation useful in the present invention comprises an effective amount of riluzole or pharmaceutically acceptable salts, solvates, anomers, enantiomers, hydrates or prodrugs thereof. The formulation provides sufficient solubility for riluzole to be incorporated into the sublingual formulation at relatively large doses and sublingually delivered. The formulation is preferably a modified oral disintegrating formulation of riluzole. The excipients, including mannitol and gelatin, are blended, solubilized with water and deaerated before being mixed with the active pharmaceutical ingredient (or “API”), riluzole, which has been milled separately. Particle size of the API (D50) is less than about 2 microns. The mixture is lyophilized by flash freezing and then freeze-dried. The formulation has good oral palatability. The effective amount of a glutamate modulator for the sublingual formulation useful in the present invention to achieve a lower therapeutic dose may be less than that of orally administered agent. Moreover, effective dose of the sublingual formulation of the glutamate modulator may be about 1 to 95 % of that of the orally administered agent. To the extent that a sublingual formulation of the metal channel activator can be made, it may also have improved properties.

[001649] In one aspect of the invention, the glutamate modulator is provided in a sublingual formulation in a form of an orally dissolving or disintegrating tablet (ODT). The ODT as used herein may be prepared by mixing the glutamate modulator and/or the metal channel activator with water-soluble diluents and compressed in a tablet. A suspension comprising the active product may be prepared with appropriate excipients and the suspension may be dispensed into blister packs and freeze-dried. An exemplary freeze-dried preparation platform that could be used for the ODT is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation. In particular, the excipients, including water, are blended and the glutamate modulator is separately milled to size and mixed with the excipients. The suspension then undergoes lyophilization by flash freezing and freeze drying. Other methods of preparing ODTs may be used without limitation, and detailed description of general methods thereof have been disclosed, for example, in U.S. Patent Nos 5,631,023; 5,837,287; 6,149,938; 6,212,791; 6,284,270; 6,316,029; 6,465,010; 6,471,992; 6,471,992; 6,509,040; 6,814,978; 6,908,626; 6,908,626; 6,982,251; 7,282,217; 7,425,341; 7,939,105; 7,993,674; 8,048,449; 8,127,516; 8,158,152; 8,221,480; 8,256,233; and 8,313,768, each of which is incorporated herein by reference in its entirety. Some of the glutamate modulators can be administered sublingually. PCT Application No. PCT/US2015/061106 and PCT Application No. PCT/US2015/061114 describe a sublingual formulation of riluzole, a preferred glutamate modulator. The sublingual formulation may be administered in an effective amount to a subject in need thereof. The subject may be an animal or human.

[001650] The clinical or therapeutic effect of the glutamate modulator sublingually formulated may have an improved pharmacokinetic profile for the pharmaceutical agent as measured by standard testing parameters. When the glutamate modulator is administered sublingually, the T _ma x, Cmax and AUC of the drug may be improved compared to the same dose of the orally administered version of the same compound. For example, the sublingual formulation of the glutamate modulator may have a greater Cmax than the orally administered glutamate modulator to provide a therapeutically beneficial effect. The sublingual formulation of the glutamate modulator may have an earlier or lesser T _ma x than the orally administered glutamate modulator to provide a therapeutically beneficial effect and in some instances, a more rapid therapeutic effect. Alternatively, the sublingual formulation of the glutamate modulator may have a greater AUC per milligram of the agent than the orally administered glutamate modulator. In addition, as the glutamate modulator may make the metal channel activator more effective, lesser amounts of the metal channel activator may be needed to achieve the same results, with a lessening of the inherent side effects.

[001651] In an embodiment, provided is a pharmaceutical composition including the following Compound A or a pharmaceutically acceptable salt thereof and a glutamate modulator or a pharmaceutically acceptable salt thereof:

1. C'uffip£>i,uKi A:

A

[001652] The glutamate modulator may be selected from riluzole, memantine, n- acetlcysteine, amantadine, topiramate, pregabalin, lamotrigine, ketamine, s-ketamine, AZD8108, AZD6765 (lanicemine), BHV-4157 (troriluzole), dextromethorphan, AV-101, CERC-301, GLY-13, and pharmaceutically acceptable salts, prodrugs or analogs thereof.

[001653] In another embodiment, provided is a pharmaceutical composition including the following compound (ezogabine) or a pharmaceutically acceptable salt thereof and a glutamate modulator or a pharmaceutically acceptable salt thereof:

[001654] The glutamate modulator may be selected from ketamine, lanicemine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (N ₂ O). PHARMACEUTICAL COMPOSITIONS

[001655] In an embodiment, provided is a pharmaceutical composition comprising a metal channel activator and a glutamate modulator.

[001656] In another embodiment, the metal channel activator in said pharmaceutical composition is a potassium channel activator.

[001657] In another embodiment, the potassium channel activator in said pharmaceutical composition is a Kv7 channel activator.

[001658] In another embodiment, the Kv7 channel activator in said pharmaceutical composition is selected from the group consisting of a Kv7.1 channel activator, a Kv7.2 channel activator, a Kv7.3 channel activator, a Kv7.4 channel activator, a Kv7.5 channel activator, or any combination thereof.

[001659] In another embodiment, the Kv7 channel activator in said pharmaceutical composition is a Kv7.2/7.3 channel activator.

[001660] In another embodiment, the metal channel activator in said pharmaceutical composition is selected from one or more of the disclosed compounds according to any one or more of formulas 1 to 171 and the compounds disclosed in the “further embodiments” under the “METAL CHANNEL ACTIVATORS” subheading.

[001661] In another embodiment, the glutamate modulator in said pharmaceutical composition is selected from one or more of the disclosed compounds according to any one or more of formulas 200 to 463.

[001662] In another embodiment, the glutamate modulator in said pharmaceutical composition is selected from one or more of the disclosed compounds according to any one or more of formulas 200 to 463, and the metal channel activator in said pharmaceutical composition is selected from one or more of the disclosed compounds according to any one or more of formulas 1 to 171 and the compounds disclosed in the “further embodiments” under the “METAL CHANNEL ACTIVATORS” subheading.

[001663] In another embodiment, one or more of the Kv7 activator and the glutamate modulator or a pharmaceutically acceptable salt thereof in said pharmaceutical composition is in a form of a prodrug.

[001664] Where Formulas are referred to in a range (e.g. Formula 1 to 171), the range is inclusive of each referenced formula between Formula 1 and Formula 171 (i.e. the range is inclusive of Formula 1, Formula 2, Formula 3, . . . Formula 169, Formula 170, and Formula 171). Likewise, the range Formula 200 - 463 is inclusive of all Formulas in the range (i.e. Formula 200, Formula 201, Formula 202, . . . Formula 460, Formula 461, Formula 462, Formula 463). Any sub-ranges within these ranges (e.g. Formulas 200 to 202; or Formulas 3 - 5) are also contemplated and inclusive of all Formulas encompassed in the ranges. The use of a dash (-) or the word “to” within the range (i.e. Formulas 200 to 202 vs. 200 - 202) have the same meaning, and ranges repeating the term “Formula(s)” after the dash (-) or word “to” have the same meaning as ranges which do not repeat the term “Formula(s)” (i.e. Formulas 200 to 202 vs. Formula 200 to Formula 202) have the same meaning.

[001665] In another embodiment, the glutamate modulator is a compound according to Formula 200, Formula 201, or Formula 202, and the metal channel activator is a compound according to one of Formula 1 to 171.

[001666] In another embodiment, the glutamate modulator is a compound according to Formula 201, and the metal channel activator is a compound according to one of Formula 1 to 171.

[001667] In another embodiment the glutamate modulator is riluzole or a prodrug thereof, and the metal channel activator is a compound according to one of Formula 1 to 171.

[001668] In another embodiment, the glutamate modulator is troriluzole and the metal channel activator is a compound according to one of Formula 1 to 171.

[001669] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 463 and the metal channel activator is a compound according to one of Formula 1 to 9.

[001670] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 463 and the metal channel activator is a compound according to one of Formula 1 to 5.

[001671] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 463 and the metal channel activator is a compound according to Formula 2. [001672] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 463 and the metal channel activator is a compound according to Formula 2-1, Formula 2-2, Formula 2-3, Formula 2-4, Formula 2-5, Formula 2-6, Formula 2-7, Formula 2- 8, Formula 2-9, or Formula 2-10.

[001673]In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 463 and the metal channel activator is a compound according to Formula 3. [001674] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 463 and the metal channel activator is a compound according to Formula 4. [001675] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 463 and the metal channel activator is a compound according to Formula 5. [001676] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 202 and the metal channel activator is a compound according to one of Formula 1 to 5.

[001677] In another embodiment, the glutamate modulator is a compound according to Formula 200 and the metal channel activator is a compound according to one of Formula 1 to 5.

[001678] In another embodiment, the glutamate modulator is a compound according to Formula 201 and the metal channel activator is a compound according to one of Formula 1 to 5.

[001679] In another embodiment, the glutamate modulator is a compound according to Formula 202 and the metal channel activator is a compound according to one of Formula 1 to 5.

[001680] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 202 and the metal channel activator is a compound according to Formula 2.

[001681] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 202 and the metal channel activator is a compound according to Formula 2-1, Formula 2-2, Formula 2-3, Formula 2-4, Formula 2-5, Formula 2-6, Formula 2-7, Formula 2-

8, Formula 2-9, or Formula 2-10.

[001682] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 202 and the metal channel activator is a compound according to Formula 3. [001683]In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 202 and the metal channel activator is a compound according to Formula 4.

[001684] In another embodiment, the glutamate modulator is a compound according to one of Formula 200 to 202 and the metal channel activator is a compound according to Formula 5. [001685]In an embodiment, the glutamate modulator is a compound according to Formula 200 and the metal channel activator is a compound according to Formula 2.

[001686]In an embodiment, the glutamate modulator is a compound according to Formula 200 and the metal channel activator is a compound according to Formula 2-1, Formula 2-2, Formula 2-3, Formula 2-4, Formula 2-5, Formula 2-6, Formula 2-7, Formula 2-8, Formula 2-

9, or Formula 2-10. [001687] In an embodiment, the glutamate modulator is a compound according to Formula 200 and the metal channel activator is a compound according to Formula 4.

[001688] In an embodiment, the glutamate modulator is a compound according to Formula 200 and the metal channel activator is a compound according to Formula 5.

[001689]In an embodiment, the glutamate modulator is a compound according to Formula 200 and the metal channel activator is a compound selected from:

[001690] In an embodiment, the glutamate modulator is a compound according to: , wherein R23 is selected from the group consisting of H, CH ₃ , CH2CH3, CH2CH2CH3, CH2CCH, CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ )2,

CH(CH ₃ )CH ₂ CH3, CH2OH, CH2OCH2PI1, CH2CH2OCH2PI1, CH(OH)CH ₃ , CH2PI1,

CH ₂ (cyclohexyl), CH ₂ (4-OH-Ph), (CH ₂ ) ₄ NH2, (CH ₂ )3NHC(NH ₂ )NH, CH ₂ (3 -indole), CH ₂ (5- imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and the metal channel activator is a compound selected from: including pharmaceutically acceptable salts thereof.

[001691] In an embodiment, the metal channel activator is metal channel activator is a compound selected from:

the glutamate modulator is selected from riluzole and troriluzole, including pharmaceutically acceptable salts thereof.

[001692]In an embodiment, the metal channel activator is a compound selected from:

the glutamate modulator is the compound: troriluzole), including pharmaceutically acceptable salts thereof.

[001693]In an embodiment, the glutamate modulator is a compound according to Formula

200 and the metal channel activator is the compound:

[001694] In an embodiment, the glutamate modulator is a compound according to: , wherein R23 is selected from the group consisting of H, CH ₃ , CH2CH3, CH2CH2CH3, CH2CCH, CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ )2, CH(CH ₃ )CH ₂ CH3, CH2OH, CH ₂ OCH ₂ Ph, CH2CH ₂ OCH ₂ Ph, CH(OH)CH ₃ , CH ₂ Ph, CH ₂ (cyclohexyl), CH ₂ (4-OH-Ph), (CH ₂ ) ₄ NH2, (CH ₂ )3NHC(NH ₂ )NH, CH ₂ (3 -indole), CH ₂ (5- imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and the metal channel activator is the compound:

, including pharmaceutically acceptable salts thereof.

[001695] In an embodiment, the metal channel activator is the compound:

, including pharmaceutically acceptable salts thereof, and the glutamate modulator is selected from riluzole and troriluzole, including pharmaceutically acceptable salts thereof.

[001696] In an embodiment, the metal channel activator is the compound: including pharmaceutically acceptable salts thereof, and the glutamate modulator is the compound: troriluzole), including pharmaceutically acceptable salts thereof. METHODS OF TREATING DISEASES

[001697] The combination therapies (i.e. including one or more metal channel activators and one or more glutamate modulators) disclosed herein are useful for treating various neurological and neurodegenerative disorders. These disorders include amyotrophic lateral sclerosis, bipolar disorder, treatment resistant and major depression, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorders, Rett syndrome, eating disorders, conduct disorder, neurodegenerative disorders, pain disorders, post-traumatic stress disorder (PTSD), supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer’s disease, drug addiction, tinnitus, mental retardation, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, spinocerebellar ataxia (SCA), cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, Huntington’s disease, or any combination thereof.

[001698] The combination therapies disclosed herein are useful for treating various depressive disorders. The depressive disorder include major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof.

[001699] The combination therapies disclosed herein are useful for treating various pain disorders. The pain disorders include acute pain, chronic pain, neuropathic pain, nociceptive pain, radicular pain. The pain disorders may also include migraine, inflammatory pain, persistent pain, cancer pain, and postoperative pain.

[001700] The metal channel activator and the glutamate modulator may be given orally, sublingually, subcutaneously or in any other means of delivery. The agents may be delivered simultaneously or sequentially. If the agents are delivered sequentially, either agent may be dosed first, and the separation of time may include finishing the dosing of one agent completely before commencing the dosage of the other or they may be intermingled in time.

[001701] In an embodiment, provided is a kit for treating a patient afflicted with at least one of the aforementioned disorders, said kit including:

(a) a metal channel activator; and

(b) instructions for administering said metal channel activator in combination with a glutamate modulator by one of the aforementioned methods.

[001702] In another embodiment, provided is a kit for treating a patient afflicted with at least one of the aforementioned disorders, said kit including:

(a) a glutamate modulator; and

(b) instructions for administering said glutamate modulator with a metal channel activator by one of the aforementioned methods.

[001703] As used herein, the term “metal channel activator” is construed to include both metal channel activator and pharmaceutically acceptable salt thereof.

[001704] As used herein, the term “glutamate modulator” is construed to include both glutamate modulator and pharmaceutically acceptable salt thereof.

[001705] Throughout this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention.

[001706] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and Examples herein can be employed. Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination.

PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATMENT

[001707] Compounds are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of one or more of a compound of any one of Formulas 1 - 171, Formulas 200 - 463, those listed in “Further Embodiments” under the “METAL CHANNEL ACTIVATORS” subsection, or pharmaceutically acceptable salt(s) thereof, and a pharmaceutically acceptable carrier, further optionally containing conventional excipients. A therapeutically effective amount is the amount needed to provide a meaningful patient benefit as determined by practitioners in that art. Pharmaceutically acceptable carriers are those having acceptable safety profiles which are conventionally known. Compositions encompass common solid and liquid forms including but not limited to capsules, tablets, lozenges, liquid suspensions, syrups, elixirs, and solutions. Solid compositions may by formulated to timed or sustained release. Compositions are made using common formulation techniques, such as the aforementioned solid and liquid forms, conventional excipients, such as binding and wetting agents, and vehicles, such as water and alcohols.

[001708] The glutamate modulators of the present invention may be given orally, sublingually, intranasally, buccally, subcutaneously or in any other suitable means of delivery in table 1. The glutamate modulators may be in the form of a prodrug, which releases the agent in the body, a sustained release vehicle, a delayed release vehicle, or any other suitable delivery form. The glutamate modulator and the metal channel activator may be delivered simultaneously or sequentially. If the agents are delivered sequentially, either agent may be dosed first, and the separation of time may include finishing the dosing of one agent completely before commencing the dosage of the other or they may be intermingled in time. Typically, the glutamate modulator is administered at a time proximate to the administration of the metal channel activator, e.g., within 1 week, 1 day, 1 hour, 1 minute before or after the metal channel activator or simultaneously with the metal channel activator.

[001709] The metal channel activators of the present invention may be given orally, sublingually, intranasally, buccally, subcutaneously or in any other suitable means of delivery in table 1. Metal channel activators may be given in the form of a prodrug, which will release the active compound in the body, a delayed release formulation, which will release the active compound after a time delay, a sustained release formulation, which will release the active compound slowly over time, or any other suitable formulation to deliver the active ingredient. The metal channel activator may be delivered simultaneously or sequentially with the glutamate modulator. If the agents are delivered sequentially, either agent may be dosed first, and the separation of time may include finishing the dosing of one agent completely before commencing the dosage of the other or they may be intermingled in time. Typically, the metal channel activator will be administered at a time nearing the administration of the glutamate modulator e.g., within 1 week, 1 day, 1 hour, 1 minute before or after the glutamate modulator or simultaneously with the metal channel activator.

[001710] The dose of the glutamate modulator and metal channel activator for use together may depend on the subject to be treated inclusive of the age, sex, weight, and general health condition thereof. In this regard, precise amounts of the agent(s) for administration will depend on the judgment of the practitioner. In determining the effective amount of the glutamate modulator and metal channel activator to be administered in the treatment or reducing of the conditions associated with the symptoms and disorders, the physician may evaluate clinical factors including symptoms severity or progression of the disorder. In some conditions, a rapid absorption of the glutamate modulator or metal channel activator may be desirable. The effective amount of the treatment will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of administration, and may be determined routinely by one of ordinary skill in the art.

[001711] Some of the glutamate modulators and metal channel activators can be administered sublingually. The sublingual formulation may be administered in an effective amount to a subject in need thereof. The subject may be an animal or human. When the glutamate modulator or metal channel activator is prepared as a sublingual formulation, the sublingually administered chemical agent or the drug can diffuse into capillaries through mucous membrane under the tongue, and then enter venous circulation of the subject. As such, sublingual administration may have advantages over oral administration as allowing for direct or faster entry to venous circulation, without risks of degradation in gastrointestinal tract, alteration by drug metabolism in liver and the like.

[001712] A sublingual formulation useful in the present invention comprises an effective amount of an glutamate modulator, metal channel activator, or pharmaceutically acceptable salts, solvates, anomers, enantiomers, hydrates, or prodrugs thereof. The formulation provides sufficient solubility for a glutamate modulator and/or metal channel activator to be incorporated into the sublingual formulation at relatively large doses and sublingually delivered. The formulation is preferably a modified oral disintegrating formulation of a glutamate modulator and/or metal channel activator. The excipients, including mannitol and gelatin, are blended, solubilized with water and deaerated before being mixed with the active pharmaceutical ingredient (or “API”), a glutamate modulator and/or a metal channel activator, which have been milled separately. Particle size of the API (D50) may be less than about 2 microns. The mixture is lyophilized by flash freezing and then freeze-dried. The formulation has good oral palatability. The effective amount of a glutamate modulator and/or metal channel activator for the sublingual formulation useful in the present invention to achieve a lower therapeutic dose may be less than that of orally administered agent. Moreover, effective dose of the sublingual formulation of the glutamate modulator and/or metal channel activator may be about 1 to 95 % of that of the orally administered agent. Sublingual formulations of the metal channel activator and/or glutamate modulator may also have improved properties.

[001713] In one aspect of the invention, the glutamate modulator and/or metal channel activator is provided in a sublingual formulation in a form of an orally dissolving or disintegrating tablet (ODT). The ODT as used herein may be prepared by mixing the glutamate modulator and/or the metal channel activator with water-soluble diluents and compressed in a tablet. A suspension comprising the active product may be prepared with appropriate excipients and the suspension may be dispensed into blister packs and freeze- dried. An exemplary freeze-dried preparation platform that could be used for the ODT is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation. In particular, the excipients, including water, are blended and the glutamate modulator and/or metal channel activator are separately milled to size and mixed with the excipients. The suspension then undergoes lyophilization by flash freezing and freeze drying. Other methods of preparing ODTs may be used without limitation, and detailed description of general methods thereof have been disclosed, for example, in US Patent Nos 5,631,023; 5,837,287; 6,149,938; 6,212,791; 6,284,270;

6,316,029; 6,465,010; 6,471,992; 6,471,992; 6,509,040; 6,814,978; 6,908,626; 6,908,626; 6,982,251; 7,282,217; 7,425,341; 7,939,105; 7,993,674; 8,048,449; 8,127,516; 8,158,152; 8,221,480; 8,256,233; and 8,313,768, each of which is incorporated herein by reference in its entirety.

[001714] The clinical or therapeutic effect of the sublingually formulated glutamate modulator may have an improved pharmacokinetic profile for the pharmaceutical agent as measured by standard testing parameters. When the glutamate modulator is administered sublingually, the T _ma x, Cmax and AUC of the drug may be improved compared to the same dose of the orally administered version of the same compound. For example, the sublingual formulation of the glutamate modulator may have a greater Cmax than the orally administered glutamate modulator to provide a therapeutically beneficial effect. The sublingual formulation of the glutamate modulator may have an earlier or lesser T _ma x than the orally administered glutamate modulator to provide a therapeutically beneficial effect and in some instances, a more rapid therapeutic effect. Alternatively, the sublingual formulation of the glutamate modulator may have a greater AUC per milligram of the agent than the orally administered glutamate modulator. In addition, as the glutamate modulator may make the metal channel activator more effective, lesser amounts of the metal channel activator may be needed to achieve the same results, lessening the inherent side effects.

[001715] The clinical or therapeutic effect of the sublingually formulated metal channel activator may have an improved pharmacokinetic profile for the pharmaceutical agent as measured by standard testing parameters. When the metal channel activator is administered sublingually, the T _ma x, Cmax and AUC of the drug may be improved compared to the same dose of the orally administered version of the same compound. For example, the sublingual formulation of the metal channel activator may have a greater Cmax than the orally administered metal channel activator to provide a therapeutically beneficial effect. The sublingual formulation of the metal modulator may have an earlier or lesser Tmax than the orally administered metal channel activator to provide a therapeutically beneficial effect and in some instances, a more rapid therapeutic effect. Alternatively, the sublingual formulation of the metal channel activator may have a greater AUC per milligram of the agent than the orally administered metal channel activator. In addition, as the metal channel activator may make the glutamate modulator more effective, lesser amounts of the glutamate modulator may be needed to achieve the same results, lessening the inherent side effects.

[001716] The disclosure and methods encompass all conventional modes of administration including oral, parenteral, intranasal, sublingual, topical, and transdermal methods. Among other routes of administration, the standard routes of administration described by the FDA are contemplated herein as shown in Table 1 below (FDA Routes of Administration; retrieved from www.fda.gov; content current as of 11/1/2022).

Table 1 : FDA Routes of Administration

[001717] In some embodiments, the route of administration may be oral, intranasal, inhalation, intravenous, sublingual, topical, injectable and/or transdermal.

[001718] The pharmaceutical compositions of the present invention comprising the glutamate modulator and/or metal channel activator may also include other pharmaceutically acceptable carriers and/or excipients such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents and mixtures thereof. A skilled artisan in the art would know what other pharmaceutically acceptable carriers and/or excipients could be included in the formulations according to the invention. The choice of excipients would depend on the characteristics of the compositions and on the nature of other pharmacologically active compounds in the formulation.

[001719] The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical. Excipients may also serve as part of the overall vehicle for delivery. Excipients may also be used to achieve effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating. Excipients herein may also serve an antimicrobial function or improve pharmaceutical composition characteristics such as lubricity, flowability, disintegration and taste.

[001720] Pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Pharmaceutically acceptable carriers are biologically acceptable and compatible with the other ingredients in the formulation. Appropriate excipients are known to those skilled in the art (see Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., McGraw Hill) and have been utilized to yield a novel sublingual formulation with unexpected properties. Pharmaceutical compositions herein are not limited to a single active ingredient, and supplementary active ingredients can also be incorporated. [001721] Examples of pharmaceutically acceptable carriers that may be used in preparing the pharmaceutical compositions of the present invention may include, but are not limited to, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methyl-cellulose, sodium carboxymethylcellulose; other carriers such as, polyvinylpyrrolidone (PVP), talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen-free water and combinations thereof. If desired, disintegrating agents may be combined as well, and exemplary disintegrating agents may be, but not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more chemical agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention may be manufactured in conventional methods known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes, and the like. Glutamate modulators, metal channel activator, and/or the pharmaceutically acceptable salts thereof can be formulated using pharmaceutically acceptable carriers well known in the art into dosages suitable for sublingual, intranasal or buccal administration. Such carriers enable the glutamate modulator and/or metal channel activator to be formulated in dosage forms such as tablets, powders, pills, capsules, liquids, gels, films, syrups, slurries, suspensions, and the like.

[001722] The glutamate modulator and/or metal channel activator compounds disclosed can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. Oral formulations containing a compound disclosed can be any conventionally used oral form, including but not limited to tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions, or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99% of the compound.

[001723] Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., com, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

[001724] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, ion exchange resins, benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, methyl acetate, sucralose, and vanillin. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[001725] Liquid carriers can be used in preparing solutions for oral, parenteral (such as intravenous, intramuscular, or other injections), or inhalation administration including but not limited to suspensions, emulsions, syrups, and elixirs. An glutamate modulator and/or metal channel activator compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

[001726] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal, or subcutaneous injection. Sterile injectable solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[001727] Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be further sub-divided to contain appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes, or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal, and subcutaneous injections), rectally, vaginally, and transdermally.

[001728] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the pharmaceutical composition formulated, the mode of administration, physical factors related to the individual being treated, and severity of the condition being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition, stage of said condition, and the characteristics of the patient including their size, age and response pattern to the compound utilized.

[001729] In some cases, it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath- operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

[001730] Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

[001731] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can be sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[001732] Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[001733] Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water- in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

[001734] Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[001735] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

Pharmacokinetics and Dosing

[001736] In some embodiments, a method of treating a neurological disease may be characterized by one or more pharmacokinetic parameters such as AUC, Cmax, T _ma x, and others known and understood to persons of skill in the art. The term “pharmacokinetic” (PK) as used herein is used in its ordinary sense to mean the pharmacokinetic aspects of drug delivery. By definition pharmacokinetics (PK) is the study of how an organism affect a drug, e.g., how, and how fast it metabolizes the drug. The pharmacokinetics typically vary based upon the dosage amount of one or more of the disclosed glutamate modulators and/or metal channel activators. The pharmacokinetics may or may not vary as a function of administration route, and, if any, the binders, excipients, and dilutants in the pharmaceutical composition.

[001737] In some embodiments, a method of treating a neurological disease may be characterized by an AUC for a glutamate modulator and/or metal channel activator compound according to Formulas 1 - 171, Formulas 200 - 463, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof. In some embodiments, the AUCo-t and/or AUCo-inf (collectively referred to in the alternative as, simply, AUC) may be from about 80 - 125% of a given AUC value. In some embodiments, the AUC may be within 80 - 125 % of about 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 hr*ng/mL. In some embodiments, a systemic treatment may have a larger AUC than a localized (such as topical or subdermal) treatment.

[001738] In some embodiments, a method of treating a neurological disease may be characterized by a Cmax for a glutamate modulator and/or metal channel activator compound according to Formulas 1 - 171, Formulas 200 - 463, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof. In some embodiments, the Cmax may be from about 80 - 125% of a given Cmax value. In some embodiments, the Cmax may be within 80 - 125 % of about 1, 2, 3, 4, 5, 8, 10, 20, 35, 50, 80,100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1600, 1900, 2500, 3500, 5000, 7500, 10,000, 15,000, 20,000, 30,000, 50,000, and/or 100,000 ng/mL. In some embodiments, a systemic treatment may have a larger Cmax than a localized (such as topical or subdermal) treatment.

[001739] In some embodiments, a ratio Cmax/ AUC may be used to characterize a method of treating a neurological disease wherein one or more of a glutamate modulator and/or metal channel activator compound according to Formulas 1 - 171, Formulas 200 - 463, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof are administered to a subject. In some embodiments, the Cmax/ AUC ratio may be from about 80 - 125 % of a given Cmax/ AUC ratio. In some embodiments, the Cmax/ AUC ratio may be from about 80 - 125 % of about 0.01, 0.03, 0.05, 0.08, 0.1, 0.13, 0.17, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, and 0.9.

[001740] In some embodiments, the Tmaxmay range from about 0.1 - 16 hours, or from about 0.3 - 8 hours, or from about 0.5 - 4 hours, or from 0.5 - 2 hours, or from about 1 - 2 hours. In some embodiments, the route of administration, which may be any route described herein or known to a person of skill in the art, may affect the T _ma x of a compound according to Formulas 1 - 171, Formulas 200 - 463, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof. Excipients or other pharmaceutically acceptable carriers in pharmaceutical compositions of one or more compounds according to Formulas 1 - 171, Formulas 200 - 463, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof may alter the T _ma x value by making it larger or smaller than a pharmaceutical composition having the excipient or carrier excluded.

[001741] Solid compositions are normally formulated in dosage units providing from about 0.1 to about 1000 mg of the active ingredient per dose. Some examples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 100 mg, 500 mg, and 1000 mg. Liquid compositions are generally in a unit dosage range of 0.1-100 mg/mL. Some examples of liquid dosage units are 0.1 mg/mL, 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.

[001742] In some embodiments, a dose is daily. In some embodiments, a dose is twice daily. In some embodiments, a does is one, two, three, four, or five times daily. In some embodiments, a dose is once every other day, once every second day, once every third day, once every fourth day, once every fifth day, once every sixth day, weekly, bi-weekly, or monthly. Typically, a dose may be from 0.01-100 mg/kg body weight, or from .05 - 50 mg/kg body weight, or from 0.1 - 10 mg/kg body weight, or from 0.15 - 5 mg/kg body weight, or from 0.2 - 2 mg/kg body weight, or from 0.5 - 1.5 mg/kg body weight, or from 1 - 1.5 mg/kg body weight. In some embodiments, the dosing regimen may comprise one or more optional loading doses and a subsequent maintenance dose regimen. A loading dose may be larger than the doses given in a subsequent maintenance dose regimen.

[001743] In some embodiments, the dosage is adjusted based upon neurological disease symptoms observed in the patient. A symptom-dependent regimen may have a larger treatment dose while symptoms are present and a smaller preventative dose while symptoms are lessened, in remission, controlled, etc. In some embodiments, a treatment dose may comprise a unit dosage of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, or 200 mg of a glutamate modulator according to any one of Formulas 200 - 463, and/or a metal channel activator according to any one of Formulas 1 - 171, or a compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof . In some embodiments, a preventative dose may comprise a unit dosage of about 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 100 mg, 120 mg, or 140 mg of a glutamate modulator according to any one of Formulas 200 - 463, and/or a metal channel activator according to any one of Formulas 1 - 171, or a compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof . In some embodiments, the preventative dose is an amount that is about 7/8, 3/4, 5/8, 1/2, 3/8, 1/4, or about 1/8 of the amount of the treatment dose. In some embodiments, if a patient receiving a preventative dosing regimen experiences recurrence or onset of symptoms, a treatment dosing regimen may replace the preventative dosing regimen until symptoms have lessened or subsided. Each of the treatment and/or preventative doses may be adjusted during the regimen based upon the severity of neurological disorder symptoms.

EXAMPLES

[001744] Combination therapies including a metal (e.g. potassium) channel activator and a glutamate modulator were evaluated for synergism in neurological conditions. A maximal electroshock seizure threshold (MEST) study was applied to evaluate a combination of a Kv7 metal channel activator according to Formula 2 and a glutamate modulator according to Formula 200. In the MEST study, an alternating current is applied bilaterally for a short period of time (0.1-0.3s) through corneal electrodes in rodents to produce tonic hindlimb extensor seizure. An increase in seizure threshold is indicative of an anticonvulsive effect whereas a reduction in seizure threshold is indicative of a proconvulsive effect. See, for further background, Lbscher W, Fassbender CP, Nolting B (1991) The role of technical, biological, and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res. 8: 79-84. Lbscher W (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure. 20:359-68. Additionally, MEST studies can provide insights for pathway-targeting drugs more broadly in neurological and neurodegenerative diseases, depressive or mood disorders, pain, or other conditions associated with the brain and central nervous system (CNS).

[001745] The study involved 2 phases to evaluate the additivity or synergism of the glutamate modulator (troriluzole; Formula 201) and Kv7 metal channel activator (Formula 2- 2) in rats, and results of this study are shown in the isobologram of FIG. 3. In the first phase, the median effective dose (ED50) of each drug was determined, where the ED50 is the dosage where an anticonvulsant effect was observed in 50% of the study population. See, FIG. 1 and FIG. 2. The vehicles were 0.5% methyl cellulose and 0.25% sodium laurel sulfate for the metal channel activator and saline for the glutamate modulator, which were administered by PO (oral; gavage) route. The values derived in phase 1 were then used to determine where the line of additivity lies as shown in FIG. 3. The line of additivity is where a combination therapy would be expected to lie if the drugs only had an additive effect. A greater-than-additive effect would indicate synergism while a lesser-than-additive effect would indicate antagonism. Additionally, the confidence intervals from the ED50 regression were used to approximate the confidence limits for each dose ratio tested, which is represented by the shaded area in the isobolograph.

[001746] Prior to testing the different combinations, it was verified that the calculated ED50s indeed provided -50% protection to test animals using the formulation prepared for phase 2. The metal channel activator and the glutamate modulator were delivered sequentially by PO (oral; gavage) route. Initially, the ratios 1 :3, 1 : 1 and 3: 1 were investigated as per protocol. Because the results showed synergy at 3: 1 outside of the confidence interval, an additional 10: 1 ratio was tested with remaining animals to assess whether this additional ratio could provide additional information.

[001747] Table 1. Combination ratio doses of Kv7 activator and glutamate modulator .

[001748] The final results showed supra-additivity at the 3 : 1 ratio (1.4 mg/kg Kv7 channel activator + 5.5mg/kg glutamate modulator, i.e. three parts of the Kv7 channel activator ED50 to 1 part of the glutamate modulator ED50, or 75% of the Kv7 channel activator ED50 and 25% of the glutamate modulator ED50). The isobologram of FIG. 3 and percent protection of FIG. 4 show an additive interaction between the Kv7 activator and glutamate modulatorat all dose ratios tested, indicating that the Kv7 activator and glutamate modulator advantageously do not have an antagonistic effect at any dose ratio tested. Surprisingly, the 3: 1 ratio produced a supra-additive (i.e. synergistic) interaction indicating that the combination of the Kv7 activator and glutamate modulator has a greater-than- additive effect.

[001749] These results support multiple favorable conclusions for the combination therapies described herein. First, despite acting upon different but related physiological targets, it was discovered that the Kv7 activator and glutamate modulator did not have an antagonistic effect at any dosage ratio. This is significant because combination therapies may be applied to provide an effective treatment at lower doses of each drug, providing a new option to avoid dose-dependent side effects associated with the drugs given alone, to achieve a similarly effective treatment. Additionally, for patients having particular sensitivity to a given drug, the dosage ratios may be adjusted to reduce or eliminate side effects.

[001750] The unexpected supra-additivity observed indicates that Kv7 activators and glutamate modulators in specific ratio combination may have greater-than-additive effects. In addition to lowering the required dose of each drug, this indicates that the underlying physiological pathways may be synergistically targeted to provide enhanced patient responses. These results support that the Kv7 activator and glutamate modulator combination therapies of the present disclosure can provide effective treatment for depressive disorders, pain, and neurological and neurodegenerative disorders. Even further, the Kv7 activator and glutamate modulator combination therapies herein may act upon Kv7 and glutamate- associated targets synergistically to provide treatment efficacy greater than therapies directed to each target alone.

[001751] Throughout this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention. [001752] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and Examples herein can be employed.

Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination.