WO2024054807A1 - Combination therapies including metal channel activators and tdp-43 modulators - Google Patents

Combination therapies including metal channel activators and tdp-43 modulators Download PDF

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WO2024054807A1
WO2024054807A1 PCT/US2023/073491 US2023073491W WO2024054807A1 WO 2024054807 A1 WO2024054807 A1 WO 2024054807A1 US 2023073491 W US2023073491 W US 2023073491W WO 2024054807 A1 WO2024054807 A1 WO 2024054807A1
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alk
cycloalk
phenyl
methyl
amino
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PCT/US2023/073491
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French (fr)
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Vladimir Coric
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Biohaven Therapeutics Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a combination of a metal channel activator and a modulator of the trans-activation response element (TAR) DNA-binding protein 43 (TDP-43) for treatment of neurological and neurodegenerative disorders.
  • the metal channel activator may target the Kv7 family of voltage- gated potassium (K + ) channels.
  • Metal channel activators openers
  • Metal channels 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.
  • K + Potassium
  • Na + Sodium
  • 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. [0004] 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.
  • 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.
  • TDP-43 (also known as TARBP and more formally known as transactive response DNA binding protein 43 kDa) is a multifaceted regulator of transcription and translation. TDP-43 enacts this function through both RNA and DNA binding domains. Although only a subset of patients with ALS have a genetic mutation related to TDP-43, aggregates of TDP-43 have been identified in 97% of ALS cases. These aggregates may be due to post translational modifications including ubiquitination, phosphorylation, acetylation, PARylation, and methylation, or due to mislocalization away from the nucleus. Counteracting these multifaceted aggregates is a major therapeutic objective for ALS.
  • TDP-43 a pathological form of the transactive response (TAR) DNA binding protein (TDP-43) is known to bind to RNA in stress granules to form membraneless, amyloid-like TDP-43 aggregates in the cytoplasm of ALS motor neurons. Such aggregates cause RNA dysregulation, which contributes to disease pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurologic or neurodegenerative diseases.
  • TDP-43 binders are known to prevent binding of TDP-43 to RNA, so they may be potentially useful to stop or at least slow down progression of ALS or another neurologic or neurodegenerative disease in a patient.
  • Current treatment options for ALS and other neurological or neurodegenerative disorders are limited.
  • Riluzole is an approved treatment for ALS.
  • Riluzole is believed to have anti-excitotoxic method of action, in part, through an anti- glutaminergic/Na+ blocking pathway.
  • hyperexcitability may be a consequence of increased Na+ or decreased K+ conductance depending on age and disease stage.
  • Analysis of K+ channels in sporadic ALS postmortem spinal cords suggests hypermethylation, down-regulation, and decreased K+ channel expression, suggesting a dysregulated potassium current in ALS pathology.
  • hyperexcitability is intrinsic or synaptic, and how long it persists.
  • a K+ channel activator and TDP-43 modulator will allow for use of lower doses of one or more of the K+ channel activator or TDP-43 modulator, to achieve improved treatment efficacy while reducing adverse effects, if any. It is disclosed that a Kv7 activator in combination with a TDP-43 modulator will more effectively treat, prevent, and/or slow the progression of ALS or other neurologic or neurodegenerative diseases compared to current available treatments. [0009] Described herein are compositions and methods for combination therapies of Kv7 openers with TDP-43 modulators. The combination therapies have treatment capabilities greater than Kv7 openers or TDP-43 modulators alone, and may be particularly useful for neurological diseases.
  • compositions combining these agents may also be useful for treatment of a pain or depressive disorder. These two agents target distinct molecular targets associated with neurological diseases and neurodegenerative disorders such as ALS. Specifically, the Kv7 channel opener reduces excitability, and TDP-43 modulators reduce aggregation of TDP-43. We have found that combining Kv7 opener and a TDP-43 modulator will yield improved treatment outcomes as described herein.
  • the present invention is directed to combination therapies including a metal channel activator and a TDP-43 modulator.
  • a pharmaceutical composition including a metal channel activator and a TDP-43 modulator.
  • a method for treating or preventing a disease that involves TDP-43 including administering to a subject the pharmaceutical composition.
  • a method for treating or preventing a disease associated with TDP-43 proteinopathies including administering to a subject the pharmaceutical composition.
  • a method for treating or preventing diseases that involve excess amounts of TDP-43 in the cytosol including administering to a subject the pharmaceutical composition.
  • substituted refers to a group substituted with deuterium, a halogen (-F, -Cl, -Br, -I), a hydroxy group (-OH), an amino group (-NH 2 ), a carboxyl group (-CO 2 H), a substituted or unsubstituted C1-C10 amine group, a nitro group (-NO 2 ), a C1-C10 alkyl group, a C3- C10 cycloalkyl group, a C6-C12 aryl group, a C1-C10 alkoxy group, a C1 to C10 trifluoroalkyl group such as a trifluoromethyl group (-CF 3 ) and the like, or a cyano group (-CN) instead of at least one hydrogen of a substituting group or compound.
  • modulator 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.
  • TDP-43 modulator may target TAR DNA binding protein 43 (TDP-43), or other human proteins known in the art to modulate TDP-43, including but not limited to mitochondrial permeability transition pore (mPTP), phosphatidylinositol-3- phosphate 5-kinase type III (PIKfyve), Cytochrome P450 Family 51 Subfamily A Member 1 (CYP51A1), and Forkhead Box O (FOXO) family proteins.
  • mPTP mitochondrial permeability transition pore
  • PIKfyve phosphatidylinositol-3- phosphate 5-kinase type III
  • CYP51A1 Cytochrome P450 Family 51 Subfamily A Member 1
  • FOXO Forkhead Box O
  • TDP-43 modulators may target any other human protein modulating or effecting modulation of TDP-43, as appreciated by a person of skill in the art.
  • 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, Binswang
  • the term “metal channel activator” is construed to include both metal channel activator and pharmaceutically acceptable salt thereof.
  • TDP-43 modulator is construed to include both TDP- 43 modulator and pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • ALS Amyotrophic lateral sclerosis
  • ALS Frontotemporal Lobar Degeneration
  • Lewy Body Dementia 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.
  • substituents and definitions are numbered (e.g., R 1 , R 2 , Y, etc.) and are intended to apply within a given formula.
  • ALS Amyotrophic lateral sclerosis
  • motor neurons Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ.
  • Kv7 channel activator may be selected from one of the following compounds according to Formula 1.
  • the Kv7 channel activator is a compound according to formula 1: rmula 1 wherein D is optionally substituted C 3-6 carbocyclyl, optionally substituted C 2-5 heterocyclyl, isopropyl, or t-butyl; Bz is optionally substituted benzoimidazol-1,2-diyl; A is C 1-8 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.
  • D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl.
  • 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.
  • the Kv7 channel activator is a compound according to formula 1 wherein, D is optionally substituted C 3-6 carbocyclyl, optionally substituted C 2-5 heterocyclyl, isopropyl, or t-butyl; Bz is optionally substituted benzoimidazol-1,2-diyl; A is C 1-8 alkyl; X is H, F, CF 3 , 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.
  • D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl.
  • each substituent of D, X, and Y 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.
  • R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1- 4 alkyl, or C 1-4 hydroxyalkyl.
  • X is optionally substituted phenyl.
  • X is CF 3 .
  • X is optionally substituted pyridinyl.
  • X is H.
  • Y is H.
  • Y is OH.
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • 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.
  • 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 C 2-8 alkyl; X is H, F, CF 3 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, OCH 3 , CHF 2 , CF 3 , C 1-4 —CO 2 -alkyl, C 1-4 alkyl, — CH 2 CO 2 H, —CH 2 CO 2 CH
  • Y is H, F, CF 3 , OH, C 1-5 O-alkyl, C 0-6 alkylamino, optionally substituted tetrahydropyranyl, or C 0-6 fluoroalkylamino.
  • R 1 is Cl, Br, —OCH 3 , —CN, —CF 3 , —CH 2 OH, — COOCH 2 CH 3 , —C(CH 3 ) 2 OH, —CHOHCH 2 CH 3 , —CHOHCH 3 , —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 .
  • R 2 is H, F, —CH 2 OH, —CO 2 Me, or —C(CH 3 ) 2 OH.
  • R 3 is H.
  • R 4 is H, —CH 3 , or —CF 3 .
  • R 1 is Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl.
  • X is optionally substituted phenyl.
  • X is CF 3 .
  • X is optionally substituted pyridinyl.
  • X is H.
  • Y is H.
  • Y is OH.
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator is a compound according to formula 2 wherein, D is optionally substituted cyclobutyl, or t-butyl; A is C 2-8 alkyl; X is H, CF 3 , or optionally substituted phenyl; Y is H or OH; R 1 is CN or C 1-4 hydroxyalkyl; and R 2 , R 3 , and R 4 are independently H, or F. [0067] In further embodiments, R 1 is CN, —C(CH 3 ) 2 OH, or —CH 2 C(CH 3 ) 2 OH. [0068] In further embodiments, R 2 is F. [0069] In further embodiments, R 3 is H.
  • R 4 is H.
  • R 1 is CN.
  • R 1 is C 1-4 hydroxyalkyl.
  • X is optionally substituted phenyl.
  • X is CF 3 .
  • X is H.
  • Y is H.
  • Y is OH.
  • the Kv7 channel activator is a compound according to formula 2 wherein, D is cyclobutyl; A is C 1-8 alkyl; X is CF 3 ; Y is H; R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl; R 2 is H, F, —CH 2 OH, — CO 2 Me, or —C(CH 3 ) 2 OH; 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, —CH 3 , or —CF 3 ; or D is optionally substituted cyclobutyl; A is C 1-8 alkyl; X is CF 3 ;
  • 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.
  • Y is H, F, CF 3 , OH, C 1-5 O-alkyl, C 0-6 alkylamino, optionally substituted tetrahydropyranyl, or C 0-6 fluoroalkylamino.
  • R 1 is H, Cl, Br, —OCH 3 , —CN, —CF 3 , —CH 2 OH, — COOCH 2 CH 3 , —C(CH 3 ) 2 OH, —CHOHCH 2 CH 3 , —CHOHCH 3 , —CHF 2 , —CH(CH 3 ) 2 , — C(CH 2 CH 3 )OH, —CH 2 COOCH 2 CH 3 , —CH 2 C(CH 3 ) 2 OH, —CH 2 COOH, or — CH 2 CON(CH 3 ) 2 .
  • R 2 is H, F, —CH 2 OH, —CO 2 Me, or —C(CH 3 ) 2 OH.
  • R 3 is H.
  • R 4 is H, —CH 3 , or —CF 3 .
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator is a compound selected from the group consisting of:
  • the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is:
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator is a compound selected from the group consisting of: [0102] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof. [0103] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof. [0104] In further embodiments, the compound is: or a pharmaceutically acceptable salt thereof. [0105] In further embodiments, the compound is:
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is:
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • D is optionally substituted cyclobutyl, or t-butyl; A is C 2-8 alkyl, X is H, CF 3 , or optionally substituted phenyl, Y is H or OH, R 1 is CN or C 1-4 hydroxyalkyl; and R 2 , R 3 , and R 4 are independently H, or F.
  • R 1 is CN, -C(CH 3 ) 2 OH, or -CH 2 C(CH 3 ) 2 OH.
  • R 2 is F.
  • R 3 is H.
  • R 4 is H.
  • R 1 is CN.
  • R 1 is C 1-4 hydroxyalkyl.
  • X is optionally substituted phenyl.
  • X is CF 3 .
  • X is H.
  • Y is H. In a further embodiment, Y is OH.
  • D is cyclobutyl;
  • A is C 1-8 alkyl, X is CF 3 , Y is H,
  • R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl;
  • R 2 is H, F, -CH 2 OH, -CO 2 Me, or -C(CH 3 ) 2 OH;
  • 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, -CH 3 , or -CF 3 .
  • D is optionally substituted cyclobutyl
  • A is C 1-8 alkyl
  • X is CH 3
  • Y is H
  • R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl
  • R 2 is H, F, -CH2OH, -CO2Me, or -C(CH3)2OH
  • R 3 is H
  • R 4 is H, -CH3, or -CF 3 .
  • D is t-butyl;
  • A is C 1-8 alkyl;
  • X is H;
  • Y is H;
  • R 1 is Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl;
  • R 2 is H, F, - CH 2 OH, -CO 2 Me, or -C(CH 3 ) 2 OH;
  • 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, -CH 3 , or -CF 3 .
  • D is t-butyl;
  • A is C 1-8 alkyl;
  • X is CF 3 ;
  • Y is H;
  • R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 hydroxyalkyl;
  • R 2 is H, F, - CH 2 OH, -CO 2 Me, or -C(CH 3 ) 2 OH;
  • 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, CH 3 , or CF 3 .
  • D is cyclobutyl; A is C 1-8 alkyl; X is H; Y is methyl(2,2,2-trifluoroethyl)amino; R 1 is H, Cl, Br, CN, OCH 3 , CF 3 , -CO 2 CH 2 CH 3 , C 1-4 alkyl, or C 1-4 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 .
  • D is optionally substituted cyclobutyl, optionally substituted phenyl, or optionally substituted C 2-5 alkyl, wherein the optional substituents are selected from -CH 3 and F;
  • A is C 1 alkyl, X is substituted cyclobutyl, wherein the substituent is F;
  • Y is H;
  • R 1 is selected from H, C 3 hydroxyalkyl, CN, F, or Cl;
  • R 2 is selected from H, CN, F, Br, or -OCF 3 ;
  • R 3 is selected from H, F, or -OCH 3 ;
  • 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.
  • 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.
  • the Kv7 channel activator is a compound according to formula 3: Formula 3 , wherein, R 1 and R 2 , 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 , C 1 -C 6 alkyl, C( ⁇ O)C 1 -C 6 alkyl; NH—C 1 -C 6 alkyl; N(C 1 -C 6 alkyl)-C 1 -C 6 alkyl, NHC( ⁇ O)C 1 -C 6 alkyl, C( ⁇ O)N(CH 3 ) 2 , C( ⁇ O)N(Et) 2 , C( ⁇ O)NH 2 , C( ⁇ O)NH—C 1 -C 6 alkyl, SO 2 NH 2 , NHSO 2 —C 1 -C 6 alkyl; C( ⁇ O)OC 1 -C 6 alkyl
  • R 1 and R 2 vary independently, and are selected from the group consisting of H, halogen, CF 3 , C 1 -C 6 alkyl, C( ⁇ O)C 1 -C 6 alkyl, C( ⁇ O)OC 1 - C 6 alkyl, OC( ⁇ O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SCH 3 , C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 - C 6 cycloalkyl, phenyl, pyridyl, pyrrolyl, thienyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, and (CH 2 ) 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 groups optionally contain one or two heteroatoms
  • R 1 and R 2 vary independently, and are selected from the group consisting of H, halogen, CF 3 , C 1 -C 6 alkyl, C( ⁇ O)C 1 -C 6 alkyl, C( ⁇ O)OC 1 - C 6 alkyl, OC( ⁇ O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SCH 3 , (CH 2 ) m cyclopropyl, (CH 2 ) m cyclobutyl, (CH 2 ) m cyclopentyl, (CH 2 ) m cyclohexyl, (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
  • R 1 and R 2 vary independently, and are selected from the group consisting of H, halogen, CF 3 , OC 1 -C 3 alkyl, C 1 -C 6 alkyl, C( ⁇ O)OC 1 -C 3 alkyl, OC( ⁇ O)C 1 -C 3 alkyl, and C( ⁇ O)C 1 -C 3 alkyl;
  • R′ is selected from the group consisting of H, F, CH 3 , and ethyl;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OC 1 -C 3 alkyl, and C 1 -C 3 alkyl; and
  • R 5 is C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w
  • R 2 is H or F;
  • R′ is H;
  • R 3 is selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , OCF 3 , and Cl;
  • R 4 is selected from the group consisting of CH 3 , OCH 3 , CF 3 , OCF 3 , and Cl;
  • R 5 is C 3 -C 6 alkyl or (CH 2 ) w C 3 -C 6 cycloalkyl.
  • R 1 is halogen or CF 3 ;
  • R 2 is H or F;
  • R′ is H;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , OCF 3 , or Cl;
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 - C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ⁇ CH—C 3 - C 6 cycloalkyl, CH ⁇ CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 - C 6 cycloalkenyl, C 2 -C 6 alken
  • R 1 is halogen or CF 3 ;
  • R 2 is H or F;
  • R′ is H;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , OCF 3 , or Cl;
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 - C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ⁇ CH—C 3 - C 6 cycloalkyl, CH ⁇ CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 - C 6 cycloalkenyl, C 2 -C 6 alken
  • 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.
  • the Kv7 channel activator is a compound according to formula 4: Formula 4 , wherein, R 1 is selected from the group consisting of H, halogen, CN, CH 2 CN, CF 3 , C 1 - C 6 alkyl, OCH 3 , (C ⁇ O)OCH 3 , O(C ⁇ O)CH 3 , OCF 3 , (CH 2 ) m C 3 -C 6 cycloalkyl, phenyl, and pyridyl; R 2 is selected from the group consisting of H, F, OCH 3 , CH 3 , and CF 3 ; R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OC 1 -C 3 alkyl, or C 1 -C 3 alkyl; and R 5 is selected from the group consisting of C 1 - C 6 alkyl, (CHR 6 ) w C 3 -C 6 cyclo
  • R 1 is selected from the group consisting of H, F, Cl, Br, CF 3 , C 1 -C 6 alkyl, OCH 3 , CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 OCH 2 CH 3 , and OCH 2 CH 3 ;
  • R′ is selected from the group consisting of H, CH 3 , CH 2 CH 3 , or halogen;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OCH 3 , and CH 3 ;
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, CH 2 C 3 - C 6 cycloalkyl, CH 2 CH 2 C 3 -C 6 cycloalkyl, CH ⁇ CH—C 3 -C 6 cycloalkyl, CH ⁇ CH—C 5 - C 6 cycloalkenyl, CH 2 C 5 -C 6 cycloalkenyl, CH 2 C 5
  • R 1 is selected from the group consisting of H, F, Cl, Br, CF 3 , C 1 -C 6 alkyl, OCH 3 , CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 OCH 2 CH 3 , and OCH 2 CH 3 ;
  • R′ is selected from the group consisting of H, CH 3 , CH 2 CH 3 , or halogen;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OCH 3 , and CH 3 ;
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, CH 2 C 3 - C 6 cycloalkyl, CH 2 CH 2 C 3 -C 6 cycloalkyl, CH ⁇ CH—C 3 -C 6 cycloalkyl, CH ⁇ CH—C 5 - C 6 cycloalkenyl, CH 2 C 5 -C 6 cycloalkenyl, CH 2 C 5
  • R 1 is selected from the group consisting of F, CF 3 , Cl, CH 3 , CH 2 CH 3 , SCH 3 , OCH 3 , CH 2 OCH 3 , CH 2 OCH 2 CH 3 , OCF 3 , phenyl, thienyl, and H;
  • R 2 is selected from the group consisting of H, F, Cl, and OCH 3 ;
  • R′ is selected from the group consisting of H, F, CH 2 CH 3 , and CH 3 ;
  • R 3 and R 4 vary independently, and are selected from the group consisting of H, Cl, CH 3 , CF 3 , OCH 3 , and OCF 3 ;
  • R 5 is selected from the group consisting of C 4 -C 6 alkyl, (CH 2 ) w Ar, and (CH 2 ) w C 5 -C 6 cycloalkyl; wherein w is 1, 2, or 3.
  • R 1 is selected from the group consisting of F, CF 3 , Cl, CH 3 , OCH 3 , CH 2 OCH 3 , and H;
  • R 2 is selected from the group consisting of H, F, CH 3 , and Cl;
  • R′ is H;
  • R 3 is selected from the group consisting of H, Cl, CH 3 , CF 3 , OCH 3 , and OCF 3 ;
  • R 4 is selected from the group consisting of Cl, OCH 3 , and CH 3 ; and
  • R 5 is C 4 - C 6 alkyl or 2-cyclopentyl ethyl.
  • R 3 and R 4 are both CH 3 or both OCH 3 ; and R 5 is C 5 - C 6 alkyl.
  • R′ and R 2 are H; R 3 and R 4 are both methyl; and R 5 is C 5 - C 6 alkyl or (CH2)wC5-C6 cycloalkyl; wherein w is 1, 2, or 3.
  • the compound is selected from the group consisting of: N- (2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3- dimethylbutanamide; N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide; N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6- (trifluoromethyl)phenyl)-3-cyclopentylpropanamide; N-(2-chloro-4-(6-fluoro-3,4- dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethylphenyl)-3,3-dimethylbutanamide; N-[2- chloro-4-(3,4-dihydro-1H-
  • 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. [0136]
  • the Kv7 channel activator is a compound according to formula 5: Formula 5 , optionally wherein the compound is substituted at any position.
  • 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. ula 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.
  • the Kv7 channel activator is a compound according to formula 7: mula 7 , wherein, L is CH2; R 1 is optionally substituted cyclic C3H5, wherein the optional substituent of R 1 is CF 3 ; R 2 is optionally substituted cyclobutyl; R 3 is optionally substituted C 3 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 CF 3 or CH 3 ; R 2 is optionally substituted cyclobutyl; R 3 is optionally substituted C 3 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 , CHCH 3 , CH 2 CH 2 , C 3 H 6 , CH 2 O, C 2 H 4 O
  • R 2 is optionally substituted C 4 H 9 , optionally substituted cyclobutyl, optionally substituted C 6-10 aryl, or optionally substituted C 2-9 heterocyclyl.
  • R 2 is optionally substituted C 4 H 9 , or optionally substituted cyclobutyl.
  • R 2 is optionally substituted phenyl, or optionally substituted C 2-9 heterocyclyl.
  • R 1 is optionally substituted phenyl.
  • R 1 is optionally substituted phenyl.
  • R 1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl. [0145] In further embodiments, R 1 is C 2-4 —O-alkyl. [0146] In further embodiments, R 1 is optionally substituted tetrahydrofuranyl or optionally substituted tetrahydro-2H-pyranyl. [0147] In further embodiments, R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of: [0149] In further embodiments, R 3 is CF 3 , Cl, CN, OCH 3 , or H. [0150] In further embodiments, R 1 is selected from the group consisting of:
  • R 4 is CH 3 , CF 3 , Cl, or H.
  • R 2 is selected from the group consisting of:
  • the Kv7 channel activator is selected from the group consisting of:
  • the Kv7 channel activator is selected from the group consisting of:
  • 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.
  • 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 H 6 O bonded with R 1 ; wherein R 1 is optionally substituted C 1-2 alkyl, optionally substituted C 5-10 cycloalkyl, optionally substituted C 1-12 —O-alkyl, optionally substituted C 6-10 aryl, optionally substituted C 6-10 —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 ,
  • R 2 is optionally substituted C 4 H 9 , optionally substituted cyclobutyl, optionally substituted C 6-10 aryl, or optionally substituted C 2-9 heterocyclyl. [0157] In further embodiments, R 2 is optionally substituted C 4 H 9 , or optionally substituted cyclobutyl. [0158] In further embodiments, R 2 is optionally substituted phenyl, or optionally substituted C 2-9 heterocyclyl. [0159] In further embodiments, R 1 is optionally substituted phenyl. [0160] In further embodiments, R 1 is optionally substituted phenyl.
  • R 1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl.
  • R 1 is C 2-4 —O-alkyl.
  • R 1 is optionally substituted tetrahydrofuranyl or optionally substituted tetrahydro-2H-pyranyl.
  • R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of: [0166]
  • R 3 is CF 3 , Cl, CN, OCH 3 , or H.
  • R 1 is selected from the group consisting of:
  • R 4 is CH 3 , CF 3 , Cl, or H.
  • R 2 is selected from the group consisting of: Formula 9
  • 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.
  • the Kv7 channel activator is a compound according to formula 9: Formula 9 wherein, R1 is selected from the group consisting of C 1 -C 6 alkyl, CF 3 , CH 2 CF 3 , CF 2 CHF 2 , C 3 -C 8 cycloalkyl, wherein said C 3 -C 8 cycloalkyl may be substituted with 1 or 2 substituents selected from the group consisting of C 1 -C 3 alkyl, F, CHF 2 and CF 3 ; and R2 is H, C 1 -C 6 alkyl or CF 3 ; or R1 and R2 combine to form C 3 -C 5 cycloalkyl optionally substituted with 1 or 2 F, CHF2 or CF3; and R3 is C1-C3 alkyl or CH2O—C1-3 alkyl, said C 1 -C 3 alkyl or CH 2 O—C 1 -C 3 is alkyl substituted with C ⁇ N, 3 F or C
  • R3 is selected from the group consisting of CH 2 —O— CF 3 , CH 2 —O— cyclopropyl, CH 2 —C ⁇ N.
  • R1 is C 3 -C 4 cycloalkyl optionally substituted with 1 or 2 C 1 -C 3 alkyl, F, CHF 2 or CF 3 .
  • R1 and R2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R4 is OCF 3 or OCHF 2 .
  • the Kv7 channel activator is selected from the group consisting of: (S)—N—((R)-2-cyclopropoxy-1-(3-(difluoromethoxy) phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-1-(3-(difluoromethoxy)phenyl)-2- (trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-1-(3- (trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4- dimethylpentanamide; (S)—N—((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide; (S)—N—((S)—N—((S
  • the Kv7 channel activator is selected from the group consisting of (R)—N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4- dimethylpentanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-3-hydroxy-4,4- dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl) pentanamide; (R)-3-hydroxy- 4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy) phenyl)ethyl)pentanamide; (R)—N— ((R)-2-(difluoromethoxy
  • the Kv7 channel activator is a compound according to formula 8 wherein R 1 is selected from the group consisting of C 1 -C 6 alkyl, CF 3 , CH 2 CF 3 , CF 2 CHF 2 , C 3 -C 8 cycloalkyl, wherein said C 3 -C 8 cycloalkyl may be substituted with 1 or 2 F, CHF2 or CF3, and R 2 is H, C1-C6 alkyl or CF3; or R 1 and R 2 combine to form C3- C 5 cycloalkyl optionally substituted with 1 or 2 F, CHF 2 or CF 3 ; R 3 is C 1 -C 3 alkyl or CH 2 O—C 1-3 alkyl, said C 1 -C 3 alkyl or CH 2 O—C 1-3 alkyl may optionally be substituted with 1 or 2 F; and R 4 is selected from the group consisting of OCF 3 , OCH 2 CF 3 or OCHF 2 .
  • R 4 is OCF 3 or OCHF 2 .
  • R 2 is H or CH 3 .
  • R 3 is CH 2 O—C 1-3 alkyl.
  • R 1 is C 3 -C 4 cycloalkyl optionally substituted with 1 or 2 F, CHF 2 or CF 3 .
  • R 1 is t-butyl and R 2 is H and R 4 is OCF 3 , OCH 2 CF 3 , OCHF 2 or CF 3 .
  • R 1 and R 2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R 4 is OCF 3 , OCH 2 CF 3 , OCHF 2 or CF 3 .
  • the Kv7 channel activator is selected from the group consisting of: (S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3- (trifluoromethoxy)phenyl]ethyl]pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3- (trifluoromethoxy)phenyl]ethyl]pentanamide, (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3- (2,2,2- trifluoroethoxy)phenyl) ethyl)pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-((S)-1- (3-(2,2- trifluoroethoxy)phenyl
  • 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. WO2009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2004058739A1, 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.
  • the Kv7 channel activator is a compound according to formula 10: ormula 10 wherein R 1 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl and hydroxy-C 3-8 -Cycloalk(en)yl; R 2 and R 2′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, aryl, C 3-8 -cycloalk(en)yl-C 1- 6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl, acyl,
  • 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 C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, aryl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl, acyl, halogen, halo-C 1-6 -alk(en/yn)yl, alk(en/yn)yloxy, —CO—NR 6 R 6′ , cyano, nitro, —NR 7 R 4′ , —S—R 8 , —SO 2 R 8 , and SO 2 OR 8 ; wherein: R 6 and R 6′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en
  • the Kv7 channel activator is selected from the group consisting of: ⁇ 2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-methyl-amino]-phenyl ⁇ - 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- yl
  • the Kv7 channel activator is a compound according to the formula: or a pharmaceutically acceptable salt thereof.
  • the Kv7 channel activator is selected from the group consisting of: 2-Cyclopentyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide; 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-
  • the Kv7 channel activator is a compound according to formula 10 wherein: R 1 is selected from the group consisting of hydrogen, C 1-6 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, acyl, hydroxy-C 1-6 - alk(en/yn)yl and hydroxy-C 3-8 -cycloalk(en)yl; R 2 and R 2′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, aryl, C 3-8 - cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(
  • R 1 is selected from the group consisting of hydrogen and C 1-6 -alk(en/yn)yl.
  • at least one of the substituents R 2 and R 2′ is a hydrogen atom.
  • both R 2 and R 2′ are hydrogen atoms.
  • X is CO.
  • q is 0.
  • q is 1 and Z is an oxygen atom.
  • R 3 is selected from the group consisting of C 1-6 - alk(en/yn)yl and aryl-C 1-6 -alk(en/yn)yl.
  • R 3 is C 1-6 -alk(en/yn)yl. [0200] In further embodiments, R 3 is aryl-C 1-6 -alk(en/yn)yl. [0201] In further embodiments, W is a sulfur atom.
  • 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 C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, aryl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl, acyl, halogen, halo-C 1-6 -alk(en/yn)yl, C 1-6 -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
  • 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 C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, aryl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, aryl-C 1-6 -alk(en/yn)yl, acyl, halogen, halo-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, —CO—NR 6 R 6′ , cyano, nitro, — NR 7 R 7′ , —S—R 8 , —SO 2 R 8 , and SO 2 OR 8 , wherein: R 6 and R 6′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(
  • 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. WO2009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2004058739A1, 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.
  • the Kv7 channel activator is a compound according to formula 11: Formula 11 wherein: s is 0 or 1; U is O, S, SO 2 , SO 2 NR 11 , CO—O or CONR 11 ; wherein: R 11 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, and C 3-8 -cycloalk(en)yl-C 1-6 -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 SO 2 ; with the proviso when X is SO 2 , then q is 0; Z is O or S; R 1 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)
  • 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 ⁇ -carbamic acid ethyl ester; ⁇ 4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl ⁇ -carbamic acid ethyl ester; ⁇ 2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl ⁇ -carbamic acid ethyl ester; [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid ethyl ester; [4-(4- Fluoro-benzy
  • the Kv7 channel activator is a compound according to formula 11, wherein: s is 0 or 1; U is O, S, SO 2 , SONR 11 , or CONR 11 ; wherein: R 11 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6 -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 SO 2 ; with the proviso that q is 0 when X is SO 2 ; Z is O or S; R 1 is hydrogen, C 1-6 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)
  • R 1 is C 1-6 -alk(en/yn)yl or a hydrogen atom.
  • s is 0.
  • s is 1.
  • U is an oxygen atom.
  • R 2 is hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, Ar, Ar—C 1-6 -alk(en/yn)yl, halogen, halo-C 1-6 -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.
  • Z is an oxygen atom.
  • Z is a sulfur atom.
  • q is 0.
  • R 3 is C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, heterocycloalk (en)yl-C 1 -6 -alk(en/yn)yl, heterocycloalk(en)yl, Ar, Ar—C 1-6 -alk(en/yn)yl, Ar-oxy-C 1-6 -alk (en/yn)yl, Ar—C 1-6 - alk(en/yn)yloxy-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy-carbonyl-C 1-6 -alk(en/yn)yl, hal
  • R 12 and R 12′ are each independently hydrogen, C 1-6 - alk(en/yn)yl or Ar.
  • V is CH.
  • each R 5 is independently C 1-6 -alk(en/yn)yl, C 1-6 - alk(en/yn)yl-heterocycloalk(en)yl, Ar, C 1-6 -alk(en/yn)yloxy, Ar-oxy, C 1-6 -alk(en/yn)yloxy- carbonyl, halogen, halo-C 1-6 -alk(en/yn)yl, NR 7 R 7′ , S—R 8 or SO 2 R 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.
  • both R 7 and R 7′ are C 1-6 -alk(en/yn)yl.
  • R 8 is C 1-6 -alk(en/yn)yl or Ar.
  • the Kv7 channel activator is selected from the group consisting of: 2-(4-Fluorophenyl)-N- ⁇ 2-methyl-4-[(6-p-tolyloxypyridin-3-ylmethyl)-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-Di
  • 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 SO 2 ; Z is O, S or NR 4 ; wherein R 4 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl and hydroxy-C 3-8 -cycloalk(en)yl; q is 0 or 1; R 1 and R 1′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl- C 1-6 -alk(
  • 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 C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, Ar, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Ar—C 1-6 -alk(en/yn)yl, acyl, C 1-6 - alk(an/en/yn)yloxy, halogen, halo-C 1-6 -alk(en/yn)yl, —CO—NR 6 R
  • R 1 and R 1 ' are independently selected from the group consisting of hydrogen and C 1-6 -alk(en/yn)yl. [0226] In further embodiments, at least one of R 1 and R 1 ' is a hydrogen atom. In further embodiments, s is 1. [0227] In further embodiments, s is 0. [0228] In further embodiments, R 2 is selected from the group consisting of hydrogen, C 1- 6 -alk(en/yn)yl, Ar and halogen, provided that when R is halogen, then s is 0. [0229] In further embodiments, U is NR 2 ' and at least one of R and R 2 ' is a hydrogen atom.
  • both R 2 and R 2 are hydrogen atoms.
  • X is CO.
  • q is 0.
  • q is 1.
  • Z is an oxygen atom.
  • R 3 is C 1-6 - alk(en/yn)yl.
  • each R 5 is independently selected from the group consisting of a C 1-6 -alk(en yn)yl, C 3-8 - cycloalk(en)yl, Ar, cyano, halogen, halo-C ⁇ -6 - alk(en/yn)yl and C 1-6 - 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.
  • 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 ethy
  • 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 SO 2 ; Z is O, S or NR. , wherein R 4 is selected from the group consisting of hydrogen, C ⁇ -6-alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en yn)yl and hydroxy-C 3-8 -cycloalk(en)yl; q is O or 1; R 1 and R 1 ' are independently selected from the group consisting of hydrogen, C ⁇ .
  • R is selected from the group consisting of hydrogen, halogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C ⁇ -6 - alk(en/yn)yl, Ar, Ar-C 1-6 - alk(en/yn)yl, Ar-C 3-8 -cycloalk(en)yl
  • R 3 is selected from the group consisting of C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C ⁇ -6 -alk(en/yn)yl, Ar, Ar-C 1-6 -alk(en/yn)yl, Ar-C 3-8 - cycloalk(en)yl, hydroxy- C ⁇ -6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo
  • R 7 and R 7 ' are independently selected from the group consisting of hydrogen, C ⁇ .
  • R 8 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C ⁇ -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, C 3-8 -cycloalk(en)yl and C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl; with the provisos that when R 5 is SO 2 OR 8 then R 8 is not
  • 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 SO 2 ; Z is O, S or NR , wherein R is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3- 8 -cycloalk(en)yl, C 3 -s-cycloaUc(en)yl-C ⁇ -6 -alk(en/yn)yl, hydroxy-C ⁇ -6 -alk(en/yn)yl and hydroxy-C 3-8 -cycloalk(en)yl; q is O or 1; 11 ' R and R are independently selected from the group consisting of hydrogen, C ⁇ _ 6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1;
  • R is selected from the group consisting of hydrogen, halogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C ⁇ -6 -alk(en yn)yl, Ar, Ar-C ⁇ -6 - alk(en yn)yl, Ar-C 3-8 -cycloalk(en)yl, acyl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy- C 3-8 -cycloalk(en)yl, halo-C ⁇ -6 -alk(en/yn)yl, halo-C 3-8 - 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, halogen or cyan
  • R 3 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en yn)yl, Ar, Ar-C 1-6 - alk(en/yn)yl, Ar-C 3 . 8 -cycloalk(en)yl, acyl, hydroxy-C ⁇ 6 -alk(en/yn)yl, hydroxy-C 3-8 - cycloalk(en)yl, halo-C 1-6 -alk(en/yn)yl and halo-C 3-8 - 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 C1-6-alk(en/yn)yl, C3-8- cycloalk(
  • R 7 and R 7 ' are independently selected from the group consisting of hydrogen, Cj.
  • R 8 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 - 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.
  • 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.
  • 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, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 - cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yl, halo-C
  • the compound of formula I is not: N-[1-(phenylmethyl)-1H-indol-5-yl]-Methanesulfonamide; N-[1-[(4-fluorophenyl)methyl]-1H-indol-5-yl]-Methanesulfonamide; N-[2,3-dihydro-1- (phenylmethyl)-1H-indol-5-yl]-Methanesulfonamide; N-[1-(phenylmethyl)-1H-indol-5-yl]- N′-4-quinolinyl-Urea; N-[1-(phenylmethyl)-1H-indol-5-yl]-N′-4-quinolinyl-Urea; or 1-(1- benzyl-5-indolinyl)-3-phenyl-Urea; or salts thereof.
  • R 1 or R 1′ is a hydrogen atom.
  • R 1 and R 1′ are hydrogen atoms.
  • s is 0.
  • s is 1.
  • R 2 is a hydrogen atom.
  • R 2 is NO 2 or a halogen atom.
  • U is NR 11 .
  • R 11 is a hydrogen atom.
  • X is CO.
  • X is SO 2 .
  • q is 0.
  • R 3 is selected from the group consisting of C 1-6 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl, Ar, Ar—C 1-6 -alk(en/yn)yl, Ar-oxy-C 1-6 -alk(en/yn)yl, Ar— C 1-6 -alk(en/yn)yloxy-C 1-6 -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.
  • 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, C 1-6 -alk(en/yn)yl, Ar and Ar—C 1-6 - 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.
  • each R 5 is independently selected from the group consisting of C 1-6 -alk(en/yn)yl, Ar, Ar-thio, Ar-oxy, halogen and halo-C 1-6 -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.
  • the Kv7 channel activator is selected from the group consisting of: N-[4-Chloro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3- dimethylbutyramide; N-[4-Chloro-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol- 5-yl]-3,3-dimethylbutyramide; [1-(4-Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid propyl ester; N-[1-(4-Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl- methanesulfonamide; 4-Fluoro-N-[1-(4-fluorobenzyl
  • 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. WO2009015667A1, 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. [0261] In an embodiment, the Kv7 channel activator is a compound according to formula 13.
  • R1 is selected from the group consisting of halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl- C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy and C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy; R2 is selected from the group consisting of halogen, cyano, C 1-6 -alk(en/yn)yl
  • the Kv7 channel activator is selected from the group consisting of: N-(2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenyl)-2-(4-fluoro-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-cyclopentyl- propionamide; N-(2-Chloro-6-cyano-4-morpholin-4-yl-phenyl)-3-cyclohexyl- propionamide; 2-Cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-acetamide; 2-Cyclopentyl-N-[2,6-dimethyl-4-(2-phenyl-morpholin
  • 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. WO2009015667A1, published February 5, 2008 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2006029623A1, 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.
  • 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, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 3-8 -heterocycloalk(en)yl, Aryl, Heteroaryl, halo-C 1-6 - alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 - alk(en/yn)yloxy, C3-8-cycl
  • 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)
  • 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, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl, halo-C 1-6 -alk(en/yn)yl, halo-C 3- 8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 - cycloalk(en)yloxy, and C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy; R 3
  • R 1 and R 2 are each independently selected from the group consisting of halogen, amino, C 1-6 -alk(en/yn)yl, Aryl, and halo-C 1-6 -alk(en/yn)yl.
  • R 3 is selected from the group consisting of C 1-8 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl-C 1-6 - alk(en/yn)yl, Aryl-C 3-8 -cycloalk(en)yl, and amino-C 1-6 -alk(en/yn)yl.
  • R 4 is selected from the group consisting of halogen, C 1-6 - alk(en/yn)yl, NR 5 R 6 and R 7 NH—C 1-6 -alk(en/yn)yl, wherein R 5 , R 6 and R 7 are as previously defined.
  • R 4 is NR 5 R 6 , wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, Aryl-C 1-6 -alk(en/yn)yl, and C 1-6 - alk(en/yn)yl, with the proviso that R 5 and R 6 cannot both be hydrogen.
  • R 4 is R 7 NH—C 1-6 -alk(en/yn)yl, wherein R 7 is Aryl.
  • any Aryl is optionally substituted with one or more substituents independently selected from the group consisting of amino, halogen, cyano, C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, hydroxy, C 1-6 -alk(en/yn)yloxy, halo-C 1-6 - alk(en/yn)yloxy, di-(C 1-6 -alk(en/yn)yl)amino, C 1-6 -alk(en/yn)yl-CO—NH— and C 1-6 - 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,
  • 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, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Aryl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy, and C 3-8 -cycloalk(en)yl-C 1-6
  • 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. WO2009015667A1, published February 5, 2009 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2006092143A1, 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.
  • 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, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl- C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy and C 3-8 - cycloalk(en)yl-C 1-6 -alk(
  • 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-pyridin-3-yl)-carbamic acid 2-chloro-benzyl ester; 2-(4- Chloro-phenyl)-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-acetamide; 2-Phenyl- cyclopropanecarboxylic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-amide; N-(2,4- Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-2-thiophen-2-yl-acetamide; 3-Cyclohexyl-N-(2,4- dimethyl-6-morpholin-4-yl-pyridin
  • R 1 and R 2 each is independently selected from the group consisting of halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, halo-C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 -cycloalk(en)yloxy and C 3-8 - cycloalk(en)yl-C 1-6 -alk(en/yn)yloxy; and R 3 is selected from the group consisting of C
  • 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. WO2009015667A1, 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.
  • 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-C 1-6 -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, C 1-6 -alk(en/yn)yl, C 3-8 - cycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yloxy, C3-8- cycloalk(en)yloxy, C 3-8 -cycloalk(en)yloxy, C
  • the Kv7 channel activator is selected from the group consisting of: N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin-5-yl]-2- cyclopentylacetamide; N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin- 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-
  • 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. WO2007065449A1, 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.
  • 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-C 1-6 -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, C 1-6 - alk(en/yn)yl, C 3-8 - cycloalk(en)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 -cycloalk(en)yl, C 1-6 -alk(en/yn)yloxy, C 3-8 - cycloalk(en)yloxy, C 3-8 - cycloal
  • R 1 and R 2 are independently selected from hydrogen and optionally substituted aryl-C 1-6 -alk(en/yn)yl, provided that R 1 and R 2 are not both hydrogen.
  • 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.
  • said further hetero atom is oxygen.
  • said ring is a 6 membered ring.
  • said ring is a morpholine ring.
  • R 3 and R 4 are independently selected from amino and C 1-6 -alk(en/yn)yl, preferably methyl.
  • R 5 is selected from the group consisting of C 1-10 - alk(en/yn)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, optionally substituted aryl-C 1-6 - alk(en/yn)yl and optionally substituted aryl.
  • the Kv7 Channel activator is selected from the group consisting of: N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin-5-yl]-2- cyclopentylacetamide, N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin- 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-
  • 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. WO2004096767A1, 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.
  • the Kv7 channel activator is a compound according to formula 18: mula 18 wherein, the dotted line represents an optional bond; R 1 and R 1′ are independently selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3- 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, hydroxy-C 1-6 -alk(en/yn)yl, hydroxy-C 3-8 -cycloalk(en)yl, hydroxy-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)yl, halo-C 3-8 - cycloalk(en)yl, halo-C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)
  • 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.
  • 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(CH 3 ), 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(CH 3 ), 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 C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted;
  • a 1 , A 2 and A 3 independently of each other represent CR 4 , N, O, S or N(CH 3 ), 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(CH 3 ), 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 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(C 1-4 -aliphatic residue), N(C 1-4 -aliphatic residue) 2 , OH, ⁇ O, O—
  • n denotes 1 and A 1 represents N
  • a 2 represents CR 4
  • a 3 represents CR 4 and A 4 represents CR 4
  • n denotes 1 and A 1 represents CR 4
  • a 2 represents N
  • a 3 represents CR 4 and A 4 represents CR 4
  • n denotes 1 and A 1 represents CR 4
  • a 2 represents CR 4
  • a 3 represents N and A 4 represents CR 4
  • n denotes 1 and A 1 represents CR 4
  • a 2 represents CR 4
  • a 3 represents N and A 4 represents CR 4
  • 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
  • n denotes 1 and A 1 represents N
  • a 2 represents CR 4
  • a 3 represents N and A 4 represents CR 4
  • n denotes 1 and A 1 represents N
  • a 2 represents CR 4
  • a 3 represents N and A 4 represents CR 4
  • n denotes 1
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; C 1-4 -aliphatic residue, S—C 1-4 -aliphatic residue or O—C 1-4 -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, ⁇ O, OH and O—C 1-4 -aliphatic residue.
  • R 2 represents C 1-4 -aliphatic residue.
  • each R 4 independently represents H; F; Cl; Br; CN; CF 3 ; OCF 3 ; CH 3 , OCH 3 or S( ⁇ O) 2 CH 3 .
  • R 1 represents the partial structure: wherein, m denotes 0, 1, or 2, R 1a and R 1b each independently of one another represent H, F, Cl, Br, I, O—C 1-4 -aliphatic residue or C 1-4 -aliphatic residue, R 1c denotes C 1-4 - aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1- 4 -aliphatic residue, wherein the C 1-4 -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
  • m denotes 1 or 2
  • R 1a and R 1b represent H
  • R 1c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue
  • denotes C 3-10 -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, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue
  • m denotes 0 and R 1c denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consist
  • R 3 denotes 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, OH, ⁇ O, O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , S—C 1-4 - aliphatic residue, CF 3 , CN and C 1-4 -aliphatic residue wherein the C 1-4 -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, CF 3 and O—C 1-4 - 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
  • R 3 denotes C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ⁇ O, O—C 1-4 -aliphatic residue, OCF 3 , SCF 3 , CF 3 and C 1-4 - aliphatic residue, or denotes C 3-6 -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, ⁇ O, O— C 1-4 -aliphatic residue, OCF 3 , SCF 3 , CF 3 and C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or O—C 1-4 -
  • a 1 , A 2 and A 3 independently of each other represent CR 4 , N, O, S or N(CH 3 ), 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(CH 3 ), 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 1a and R 1b each independently of one another represent H, F, Cl, O—C 1-4 -aliphatic residue or C 1-4 -aliphatic residue, R 1c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at
  • the Kv7 channel activator is selected from the group consisting of:12-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-[1,5]naphthyridine- 3-carboxylic acid amide; 22-Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl- [1,5]naphthyridine-3-carboxylic acid amide; 3-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]- 4-methyl-[1,6]naphthyridine-3-carboxylic acid amide; 42-Ethylsulfanyl-N-[(4- fluorophenyl)-methyl]-4-methyl-[1,6]naphthyridine-3-carboxylic acid amide; 52- Ethylsulfanyl-N-[[(4- fluorophen
  • 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. PCT/EP2013/003572 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.
  • the Kv7 channel activator is a compound according to formula 20: Formula 20 wherein: A 1 represents CR 10 R 11 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 C1-10-aliphatic residue, unsubstituted or mono- or polysub
  • a 1 represents CR 10 R 11 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
  • 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 C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consist
  • R 8 represents H or C 1-4 -aliphatic residue, wherein the C 1-4 -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, OCF 3 , CF 3 and O—C 1-4 -aliphatic residue.
  • 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.
  • 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 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
  • R 1 represents the partial structure: wherein: R 14a and R 14b each independently of the other represent H; F; Cl; Br; CF 3 ; CN; OH; OCF 3 ; NH 2 ; C 1-4 -aliphatic residue, O—C 1-4 -aliphatic residue, NH(C 1-4 -aliphatic residue), N(C 1-4 -aliphatic residue) 2 , 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—C 1-4 -aliphatic residue, OH and OCF 3 ; or independently represent C 3-10 -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
  • 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 ; (CH 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 represents 0 and B represents CH 3 ; CH 2 CH 3 ; (CH 2 ) 2 CH 3 ; CH(CH 3 ) 2 ; (CH 2 ) 3 CH 3 ; CH(CH 3 )CH 2 CH 3 ; C(CH 3 ) 3 ; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl; adamantyl; bicyclo[2.2.1]heptyl; bicycl
  • 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 ; CH 2 CH 3 ; (CH 2 ) 2 CH 3 ; CH(CH 3 ) 2 ; (CH 2 ) 3 CH 3 ; CH(CH) 3 CH 2 CH 3 ; C(CH 3 ) 3 ; OCH 3 ; OCH 2 CH 3 ; O(CH 2 ) 2 OCH 3 ; O(CH 2 ) 2 OH; SCH 3 ; SCH 2 CH 3 ; 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
  • each R 7 represents H, F; Cl; CN; CF 3 ; CHF 2 ; CH 2 F; OCF 3 ; OCHF 2 ; OCH 2 F; SCF 3 ; CH 3 ; CH 2 CH 3 ; CH 2 CH 2 CH 3 ; CH(CH 3 ) 2 ; OH 2 CH 2 CH 2 CH 3 ; 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 .
  • R 6 represents a C 3-10 -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, ⁇ O, O—C 1-4 -aliphatic residue, OCF 3 , C 1-4 -aliphatic residue, CF 3 , SH, S—C 1-4 -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—C 1-4 -aliphatic residue, OCF 3 , C 1-4 -aliphatic residue
  • 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—C 1-4 - aliphatic residue, OCF 3 , C 1-4 -aliphatic residue, CF 3 and SCF 3 .
  • the Kv7 channel activator is selected from the group consisting of: 12-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-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-methyl-butyl)-pyridine-2- carboxylic acid amide; 43-[2-(Benzenesulfonyl)-ethylsulfanyl]-N-(thiophen-2-yl-methyl)- pyridine-2-carboxylic acid amide; 54-[[3,3-Difluoro-3-(4-fluoropheny
  • 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.
  • 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, CH3, CF3, CHF2, CH2F, OCH3, C2H5, SCH3, OCF3, OCHF2 or OCH2F; 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 C 1-4 -aliphatic residue or C 3-5 -
  • 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
  • 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
  • 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 C 1-4 -aliphatic residue or C 3-5 - cycloaliphatic
  • 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.
  • 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.
  • R 5 denotes F, Cl, CH 3 , OCH 3 or CH 2 CH 3 ; and/or R 6 denotes H; and/or R 7 denotes CH 3 , CH 2 CH 3 or cyclopropyl; and/or R 8 denotes H.
  • R 1 represents the partial structure: wherein: m denotes 0, 1, or 2, R 1a and R 1b each independently of one another represent H, F, Cl, Br, I, O—C 1-4 -aliphatic residue or C 1-4 -aliphatic residue, R 1c denotes C 1-4 - aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1- 4 -aliphatic residue, wherein the C 1-4 -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, CF 3 and O—C 1-4 -aliphatic residue, or denotes C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycloaliphatic residue, in each case unsubsti
  • m denotes 1 or 2
  • R 1a and R 1b represent H
  • R 1c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue
  • denotes C 3-10 -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, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue
  • m denotes 0 and R 1c denotes aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consist
  • R 2 is selected from the group consisting of CH 3 , C 2 H 5 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , C(CH 3 ) 3 , CH 2 -cyclopropyl, OCH 3 , OC 2 H 5 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , O-cyclopropyl, SCH 3 , SC 2 H 5 , SCH 2 CH 2 CH 3 , SCH(CH 3 ) 2 , S-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N(CH 3 ) 2 , N(CH 3 )C 2 H 5 , N(CH 3 )CH 2 CH 2 CH 3 , N(CH 3 )CH(CH 3 ) 2 , N
  • 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—C1-4-aliphatic residue or C1-4-aliphatic residue or together denote ⁇ O, and R 3c denotes C 1-4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, O—C 1-4 -aliphatic residue, CF 3 and C 1-4 -aliphatic residue, wherein the C 1-4 - 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, CF 3 and O—C 1-4 - aliphatic residue, or denotes C 3-10 -cycloaliphatic residue or 3 to 10 membered heterocycloali
  • 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 ⁇ O, R 3c 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, O—C 1-4 -aliphatic residue, and CF 3 , 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—C 1-4 - aliphatic residue,
  • 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, CH 3 , OCH 3 or CH 2 CH 3 ; and/or R 6 denotes H; and/or R 7 denotes CH 3 , CH 2 CH 3 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 if
  • the Kv7 channel activator is selected from the group consisting of: N-[(4-Chlorophenyl)-methyl]-4-ethylsulfanyl-6-methyl-2-morpholin-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-carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-methyl-6-morpholin-4-yl-4-propyl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-ethoxy-2-methyl-6-morpholin-4-yl-pyr
  • 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.
  • the Kv7 channel activator is a compound according to formula 22: Formula 22 , wherein, R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -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 C 1-8 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 C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF
  • R 1 denotes a 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, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -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
  • 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, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, and R 12c denotes a C 1-4 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue)
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue or together denote ⁇ O, and R 12c denotes a C 1-4 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—C 1-4 aliphatic residue, CN, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -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, CF 3 and an unsubsti
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, or a O—C 1-4 -aliphatic residue, wherein the C 1-4 -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, ⁇ O, OH, and an unsubstituted O—C 1-4 -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
  • R 3 represents H; F; Cl; Br; I; CN; CF 3 ; SCF 3 ; NO 2 ; OCF 3 ; a C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, or a S—C 1-4 -aliphatic residue, wherein the C 1-4 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, ⁇ O, OH, and an unsubstituted O—C 1-4 aliphatic residue.
  • 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, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S— C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -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, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 - cycloaliphatic residue or a 3 to 10 membered heterocycl
  • R 6 denotes 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, OH, ⁇ O, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 - aliphatic residue, OCF 3 , SH, SCF 3 , a S aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case is unsubstituted, or denotes a C 3-10 -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, ⁇ O, an O—C 1-4 ali
  • 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, CH 3 or OCH 3 , or together denote ⁇ O, R 12c denotes a C 1-4 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 —CH 3 , an unsubstituted O—C 1- 4 aliphatic residue, and CF 3 , or denotes a C 3-10 -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, an unsubstituted O—C 1-4 aliphatic residue, CF 3
  • the Kv7 channel activator is selected from the group consisting of: N-[(3,5-Difluoro-phenyl)-methyl]-2-methoxy-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; 9 N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4- yl-2-[(E)-prop-1-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-pyridine-3-carboxylic acid amide; N-[3-Fluorophenyl)-methyl]-2-(2-methoxy-ethoxy
  • 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. PCT/EP2011/005265 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.
  • the Kv7 channel activator is a compound according to formula 23: Formula 23 wherein, R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -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 C 1-8 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 C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF 3
  • R 1 denotes a 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, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -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
  • 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, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF3, CN, a C1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, and R 12c denotes a C 1-4 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 ,
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue or together denote ⁇ O, and R 12c denotes a C 1-4 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—C 1-4 aliphatic residue, CN, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -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, CF 3 and an unsubsti
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, or a O—C 1-4 -aliphatic residue, wherein the C 1-4 -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, ⁇ O, 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
  • R 3 represents H; F; Cl; Br; I; CN; CF 3 ; SCF 3 ; NO 2 ; OCF 3 ; a C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, or a S—C 1-4 -aliphatic residue, wherein the C 1-4 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, ⁇ O, OH, and an unsubstituted O—C 1-4 -aliphatic residue.
  • 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, NO 2 , NH 2 , a NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, and R 13c denotes a C 1-4 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue or together denote ⁇ O, and R 13c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, ⁇ O, an O—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1- 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, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -
  • 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, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S— C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -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, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 - cycloaliphatic residue or a 3 to 10 membered heterocycl
  • 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 C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 - aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , CF 3 , a C( ⁇ O)—O—C 1-4 -aliphatic residue, and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be
  • R 6 denotes 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, OH, ⁇ O, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 - aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case is unsubstituted, or denotes a C 3-10 -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, ⁇ O, an O—
  • C 3-10 -cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a unsubstituted C 1-4 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 C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C1-4-aliphatic residue, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a C( ⁇
  • 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, CH 3 or OCH 3 , or together denote ⁇ O, R 12c denotes a C 1-4 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 —CH 3 , an unsubstituted O—C 1- 4 aliphatic residue, and CF 3 , or denotes a C 3-10 -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, an unsubstituted O—C 1-4 aliphatic residue, CF 3
  • 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-fluorophenyl)-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
  • 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.
  • the Kv7 channel activator is a compound according to formula 24: Formula 24 wherein, X 1 represents a C 2-6 -aliphatic residue, unsubstituted or mono- or polysubstituted; or 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 C 1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or represents OX 6 , wherein X 6 represents a C 1-6 -aliphatic residue, unsubstituted or mono- or polysubstituted; or a C 3-6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted; X 2 and X 3 independently of one another represent H; F; Cl; Br; I; CN; CH
  • 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCH 2 F, OCHF 2 , OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O)—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CN, and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting
  • 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCH 2 F, OCHF 2 , OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a S( ⁇ O)—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CN, and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting
  • 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue)2, OH, ⁇ O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C 1-4 -aliphatic residue, a S( ⁇ O)—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, CN, and a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue is in each case unsubstituted, or represents a C 3-6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted
  • 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, OH, and an unsubstituted O—C 1-4 -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, OH, and an unsubstituted O—C 1-4 -aliphatic residue, or represents OX 6 , wherein X 6 represents a C 1- 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—C 1-4 -aliphatic residue.
  • X 1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH 2 —CH(CH 3 )(C 2 H 5 ), 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.-
  • 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 C 1-4 -aliphatic residue, or an O—C 1-4 aliphatic residue, wherein the C 1-4 -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—C 1-4 -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—C 1-4 -aliphatic residue, CH
  • X 2 and X 3 independently of one another represent H; F; Cl; Br; I; CH 2 F; CHF 2 ; CF 3 ; OH; a C 1-4 -aliphatic residue, or an O—C 1-4 aliphatic residue, wherein the C 1-4 -aliphatic residue is in each case unsubstituted, or represent a C 3-6 - 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; CH 2 F; CHF 2 ; CF 3 ; a C 1-4 -aliphatic residue, wherein the C 1-4 -aliphatic residue is unsubstituted, or represent a C 3-6 -cycloaliphatic residue or a 3 to 6 membered hetero
  • X 2 and X 3 independently of one another represent H; OH; an unsubstituted C 1-4 -aliphatic residue, or an unsubstituted O—C 1-4 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; CH 2 F; CHF 2 ; CF 3 ; an unsubstituted C 1-4 -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 C 3-10 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, CH 2 F, CHF 2 , CF 3 , an unsubstituted O—C 1-4
  • 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, CH 2 —CH(CH 3 )(C 2 H 5 ), C(CH 3 ) 2 (C 2 H 5 ), OCH 3 or OCH 2 CH 3 , 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,
  • 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
  • the Kv7 cannel activator is selected from the group consisting of: 2-Cyclopropyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4- yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-[[(1S,2R)-2-hydroxy-cyclohexyl]- methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N- [[(1R,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
  • 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. [0366] In an embodiment, the Kv7 channel activator is a compound according to formula 25.
  • R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -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 C 1-8 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 C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents H; F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a C(
  • R 1 denotes a 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, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -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 an unsubstituted O—C 1-4 -aliphatic residue
  • R 2 represents H; F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 -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, ⁇ O, 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, ⁇ O, OH, a C 1-4 -aliphatic residue and a O—C 1-4 -
  • 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 C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)— O—C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group
  • 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)—C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S— C 1-4 aliphatic residue, wherein the C 1-4 -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 .
  • 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 ,
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1- 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—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -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, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 denotes a 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, NO 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , CN, and a C 1-4 - aliphatic residue wherein the C 1-4 -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 an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic
  • R 7 denotes a C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 - aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -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,
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 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—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -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, an unsubstituted O—C 1-4 aliphatic residue,
  • 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-(trifluoromethyl)- 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
  • 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.
  • the Kv7 channel activator is a compound according to formula 26: Formula 26 wherein, R 1 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -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 C 1-8 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 C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents H; F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF 3
  • R 1 denotes a 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, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -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 an unsubstituted O—C 1-4 -aliphatic residue
  • R 2 represents H; F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 -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, ⁇ O, OH, and an unsubstituted O—C 1-4 -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, ⁇ O, OH, a C 1-4 -aliphatic residue and
  • 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 C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)— O—C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group
  • 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)—C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S— C 1-4 aliphatic residue, wherein the C 1-4 -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 .
  • 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 ,
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1- 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—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -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, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 denotes a 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, NO 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , CN, and a C 1-4 - aliphatic residue wherein the C 1-4 -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 an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic
  • R 7 denotes a C 1-8 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ⁇ O, an O—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 - aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, and a C1-4-aliphatic residue wherein the C 1-4 -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, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 - cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 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—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -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, an unsubstituted O—C 1-4 aliphatic residue,
  • the Kv7 channel activator may be selected from the group consisting of: [0391] 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-(trifluoromethyl)-quinoline- 3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2-methyl]-2-isopropoxy
  • 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. PCT/EP2011/004279 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. [0393] In an embodiment, the Kv7 channel activator is a compound according to formula 27:
  • R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -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 C 1-8 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 C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents H; F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a C( ⁇ O)
  • R 1 denotes a 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, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -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 an unsubstituted O—C 1-4 -aliphatic residue
  • R 2 represents H; F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 -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, ⁇ O, OH, and an unsubstituted 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, ⁇ O, OH, a C 1-4 -aliphatic residue and a O—C 1-4
  • R 2 is ⁇ H.
  • 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 C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)— O—C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or
  • 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)—C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S— C 1-4 aliphatic residue, wherein the C 1-4 -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 ⁇ H.
  • R 1 represents the partial structure: [0400] 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(C 1-4 aliphatic residue), an N(C 1- 4 aliphatic residue) 2 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1- 4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, R 8c denotes a C 1-4 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(C 1-4 aliphatic residue), an N(C 1-4 aliphatic residue) 2
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1- 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—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -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, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 denotes a C 2-10 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, ⁇ O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , CN, and a C 1-4 - aliphatic residue wherein the C 1-4 -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 an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 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, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S— C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -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, CF
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 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—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -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, an unsubstituted O—C 1-4 aliphatic residue,
  • the Kv7 channel activator is selected from the group consisting of: 4-methyl-2-propyl-N-(thiophene-2-yl-methyl)-7-(trifluoromethyl)-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-[(
  • 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. WO2012028300A1, 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. [0407] In an embodiment, the Kv7 channel activator is a compound according to formula 28:
  • R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted and optionally bridged via a C 1-8 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 C 1-8 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—C 1-4 aliphatic residue,
  • R 1 denotes a 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, NO 2 , OH, ⁇ O, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -aliphatic residue and C( ⁇ O)—OH, wherein the C 1-4 -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 an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 - cycloaliphatic residue, unsubstituted or mono- or
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 -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, ⁇ O, OH, and an unsubstituted O—C 1-4 -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, ⁇ O, OH, a C 1-4 -aliphatic residue and a O
  • 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 C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)— O—C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group
  • 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)—C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S— C 1-4 aliphatic residue, wherein the C 1-4 -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 .
  • 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 , OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S— C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, or together denote ⁇ O, R 8c denotes a C 1-4 aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO 2 , ⁇ O, OH, an O—C 1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1- 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—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -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—C1-4-aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue, unsubstituted or mono-
  • R 7 denotes a 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, NO 2 , ⁇ O, OH, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, CF 3 , CN, and a C 1-4 - aliphatic residue wherein the C 1-4 -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, ⁇ O, OH, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycl
  • R 7 denotes a C 1-8 -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—C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -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, CF 3 and an un
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 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—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -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—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue;
  • the Kv7 channel activator is selected from the group consisting of: N-(3-fluorobenzyl)-2,4-dimethyl-1-oxo-7-(trifluoromethyl)-1,2- dihydroisoquinoline-3-carboxamide; N-(3-fluorobenzyl)-4-methyl-1-oxo-2-propyl-7- (trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide; 2-ethyl-N-(3-fluorobenzyl)-4- methyl-1-oxo-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide; N-(3- fluorobenzyl)-2-isopropyl-4-methyl-1-oxo-7-(trifluoromethyl)-1,2 dihydroisoquinoline-3- carboxamide; andN-(3-fluorobenzyl)-2-(2-methoxyethyl)
  • 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. WO2012025239A1filed 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.
  • the Kv7 channel activator is a compound according to formula 29: wherein: X denotes O or S, R 1 represents a C 1-10 -aliphatic residue, unsubstituted or mono- or polysubstituted; a C 3-10 -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 C 1-8 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 C 1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R 2 represents F; Cl; Br; I; CN; CF 3 ; C( ⁇ O)H; NO
  • R 1 denotes a 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, NO 2 , NH 2 , an NH(C 1-4 aliphatic residue), OH, an O—C 1-4 - aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , CN, a C 1-4 -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, OCF 3 , CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic
  • R 2 represents F; Cl; Br; I; CN; CF 3 ; NO 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a O—C 1-4 -aliphatic residue, wherein the C 1-4 -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 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, ⁇ O, OH, a C 1-4 -aliphatic residue and a O—C 1-4 -aliphatic residue
  • 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 C 1-4 -aliphatic residue, a C( ⁇ O)—C 1-4 aliphatic residue, a C( ⁇ O)— O—C 1-4 aliphatic residue, a O—C 1-4 -aliphatic residue, a O—C( ⁇ O)—C 1-4 -aliphatic residue, a S—C 1-4 -aliphatic residue, a S( ⁇ O) 2 —C 1-4 -aliphatic residue, wherein the C 1-4 - aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group
  • 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)—C 1-4 aliphatic residue, a C 1-4 aliphatic residue, O—C 1-4 aliphatic residue, a S— C 1-4 aliphatic residue, wherein the C 1-4 -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 .
  • 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(C1-4 aliphatic residue), OH, an O—C1-4 aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 aliphatic residue, CF 3 , CN, a C 1-4 aliphatic residue or C( ⁇ O)—OH, R 8c denotes a C 1-4 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(C 1-4 aliphatic residue), OH, an O—C 1-4 aliphatic residue
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue, R 8c denotes a C 1- 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—C 1-4 aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue, wherein the C 1-4 -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, CF 3 and an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue or a 3 to 10 member
  • R 7 denotes a 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, NO 2 , OH, an O—C 1-4 -aliphatic residue, OCF 3 , SH, SCF 3 , a S— C 1-4 -aliphatic residue, a C( ⁇ O)—O—C 1-4 -aliphatic residue, COOH, CF 3 , CN, and a C 1-4 - aliphatic residue wherein the C 1-4 -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 an unsubstituted O—C 1-4 -aliphatic residue, or denotes a C 3-10 -cycloaliphatic residue
  • R 7 denotes a C 1-8 -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—C1-4-aliphatic residue, COOH, a C( ⁇ O)—O—C1-4- aliphatic residue, OCF 3 , SH, SCF 3 , a S—C 1-4 -aliphatic residue, CF 3 , and a C 1-4 -aliphatic residue wherein the C 1-4 -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, CF 3 and an un
  • 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—C 1-4 aliphatic residue or a C 1-4 aliphatic residue; R 8c denotes a C 1-4 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—C 1-4 aliphatic residue, CF 3 , and an unsubstituted C 1-4 -aliphatic residue, or denotes a C 3-10 -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, an unsubstituted O—C1-4 aliphatic residue,
  • the Kv7 channel activator is selected from the group consisting of: N-[(3-Fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-7-(trifluoromethyl)-1H- quinoline-3-carboxylic acid amide; 1-Butyl-N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1,4- dimethyl-2-thioxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-1-(2-methoxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H- quinoline-3-carboxylic acid amide; 1-Ethyl-
  • 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. WO2010075973A1, 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.
  • the Kv7 channel activator is a compound according to formula 30: , wherein, R 0 stands for C 1-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-7 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged C 3- 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 C 1-8 alkyl-bridged aryl or heteroaryl,
  • R 1 stands for C 1-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C 1- 8 alkyl-bridged C 3-7 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; C 1-8 alkyl-bridged heteroaryl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted, mono-
  • R 3 , R 4 , R 5 and R 6 each mutually independently denote H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; R 0 ; C( ⁇ O)(R 0 or H); C( ⁇ O)O(R 0 or H); C( ⁇ O)N(R 0 or H) 2 ; OH; OR 0 ; —O—(C 1-8 alkyl)-O—; O—(C 1-8 alkyl)-O—C 1-8 alkyl; OCF 3 ; N(R 0 or H) 2 ; N(R 0 or H)—C( ⁇ O)—R 0 ; N(R 0 or H)—C( ⁇ O)—N(R 0 or H) 2 ; SH; SCF 3 ; SR 0 ; S( ⁇ O) 2 R 0 ; S( ⁇ O) 2 O(R 0 or H); S( ⁇ O) 2 —N(R 0 or H
  • R 7 , R 8 , R 9 , R 10 mutually independently stand for H; or C 1- 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.
  • R 11 stands for H; F; Cl; Br; CN; C 1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; phenyl or heteroaryl, each unsubstituted or mono- or polysubstituted; or C 1-4 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; C 1-10 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 alky
  • R 12 and R 14 each mutually independently stand for H; or C 1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.
  • R 15 stands for C 3-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, unsubstituted or mono- or polysubstituted; C 1-8 alkyl- bridged C 3-7 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, wherein the alkyl
  • 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. WO2010075973A1, 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.
  • the Kv7 channel activator is a compound according to formula 31: wherein, R 1 stands for C 1-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl or thienyl, each unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged C 3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; C 1-8 alkyl-bridged phenyl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted; or C 1-8 alkyl-bridged thi
  • 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 0 ; C( ⁇ O)(R 0 or H); C( ⁇ O)O(R 0 or H); C( ⁇ O)N(R 0 or H) 2 ; OH; OR 0 ; O—(C 1-8 alkyl)-O; O—(C 1-8 alkyl)-O—C 1-8 alkyl; N(R 0 or H) 2 ; N(R 0 or H)— C( ⁇ O)—R 0 ; N(R 0 or H)— C( ⁇ O)—R 0 ; N(R 0 or H)— C( ⁇ O)—R
  • the Kv7 channel activator is selected from the group consisting of: 4-Oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3- (trifluoromethyl)benzyl)butyric acid amide; 4-(1-Methyl-3,4-dihydro-1H-isoquinolin-2-yl)- 4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide; 4-Oxo-4-(1-thien-2-yl-3,4- dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric acid amide; 4-Oxo-4-[1- (4-pyridyl)-3,4-dihydro-1H-isoquinolin-2-yl]-N-[[3-(trifluoromethyl
  • 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. WO2010037863A1, 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.
  • the Kv7 channel activator is a compound according to formula 32: 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-1H-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
  • 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.
  • R 3 represents furanyl which is optionally substituted with C 1-6 -alkyl.
  • R 4 represents C 1-6 -alkyl.
  • R 5 and R 6 together with the nitrogen to which they are attached, represents morpholinyl.
  • the compound is 3-Methyl-furan-2-carboxylic acid [2- ((R)-3-fluoro-pyrrolidin-1-yl)-4-methyl-6-[1,4]oxazepan-4-yl-pyridin-3-yl]-amide. [0451] In further embodiments, the compound is 3-Methyl-furan-2-carboxylic acid [2- ((R)-3-fluoro-pyrrolidin-1-yl)-4-methyl-6-morpholin-4-yl-pyridin-3-yl]-amide; Formula 33 [0452] 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.
  • the Kv7 channel activator is a compound according to 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 C 1-6 -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 C 1-6 - alkyl, C 1 -6 -alkoxy, halo and trifluoromethyl; R 4 represents C 1-6 -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.
  • R 1 represents metyl or iso-propyl.
  • R 3 represents furanyl which is optionally substituted with C 1-6 -alkyl.
  • R 4 represents C 1-6 -alkyl.
  • R 5 and R 6 together with the nitrogen to which they are attached, represents 1,4-oxazepanyl.
  • the compound is 3-Methyl-furan-2-carboxylic acid(2- isopropyl-4-methyl-6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide; or 3-Methyl-furan-2- carboxylic acid(2,4-dimethyl-6-[1,4]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.
  • 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.
  • the Kv7 channel activator is a compound according to formula 34:
  • R 1 and R 2 together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-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, C 1- 6 -alkyl, trifluoromethyl, C 1-6 -alkoxy, hydroxy-C 1-6 -alkyl and C 1-6 -alkoxy-C 1 -C 6 -alkyl; L represents a linker selected from —CR′R′′—, —CH2—CR′R′′
  • 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.
  • 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.
  • L represents —CH 2 —.
  • R 3 represents C 1-6 -alkyl.
  • R 3 represents phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or C 3-6 -cycloalkyl, which phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl is optionally substituted one or more times with substituents selected from C 1-6 -alkyl and halo.
  • R 4 represents C 1-6 -alkyl.
  • R 5 represents hydrogen.
  • the Kv7 channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N-[6-(7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-4- methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-acetamide N-[6-(7,8-Dihydro-5H-[1,6]naphthyridin- 6-yl)-4-methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-3,3-dimethyl-butyramide; N-[6-(7,8-Dihydro- 5H-[1,6]naphthyridin-6-yl)-4-methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-3-fluoro-benzamide; N- [6-(7,8-dihydro-5H-1,
  • 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. WO2010105960A1, 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.
  • the Kv7 channel activator is a compound according to 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, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl or C 1-6 -alkoxy-C 1-6 -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-1H-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 halogen, hydroxy, amino, C 1-6 -
  • 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.
  • L represents —CH 2 —, and n is 1.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with halogen.
  • R 3 represents C 1-6 -alkyl.
  • R 4 represents halogen.
  • R 4 represents hydrogen.
  • the Kv7 Channel activator is selected from the group consisting of: N- ⁇ 6-[(6-Chloro-pyridin-3-ylmethyl)-amino]-2-pyrrolidin-1-yl-pyridin-3-yl ⁇ -2- (3,5-difluoro-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N- ⁇ 6-[(pyridin-3-ylmethyl)- amino]-2-pyrrolidin-1-yl-pyridin-3-yl ⁇ -acetamide; N- ⁇ 6-[(6-Chloro-pyridin-3-ylmethyl)- amino]-2-pyrrolidin-1yl-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.
  • 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.
  • the Kv7 channel activator is a compound according to 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- ⁇ -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-1 H-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 halogen, hydroxy, amino, Ci -6 -alkyl
  • R 1 and R 2 independently of each other, represent Ci- 6 - alkyl.
  • L represents -CH 2 -.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with halogen.
  • R 4 represents methyl.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N- ⁇ 4-methyl-6-morpholin-4-yl-2-[(tetrahydro-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.
  • 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. WO2010094644A1, 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.
  • the Kv7 channel activator is a compound according to 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-1 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, C 1-6 -alkyl, trifluoromethyl, Ci- 6 -alkoxy, hydroxy-d- 6 -alkyl and Ci- 6 -alkoxy- Ci- 6 -alkyl; L represents a linker
  • 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.
  • R' and R independently of each other, represents hydrogen or methyl.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with halogen.
  • R 3 represents d-e-alkyl.
  • R 4 represents methyl.
  • the Kv7 Channel activator is selected from the group consisting of: 3,3-Dimethyl-N-(5-methyl-6-morpholin-4-yl-2-pyrrolidin-1-yl-pyridin-3-yl)- butyramide; 2-(3,5-Difluoro-phenyl)-N-(5-methyl-6-morpholin-4-yl-2-pyrrolidin-1-yl- pyridin-3-yl)-acetamide; N-[2-((R)-3-Fluoro-pyrrolidin-1-yl)-5-methyl-6-morpholin-4-yl- pyridin-3-yl]-3,3-dimethylbutyramide; (S)-N-[2-((R)-3-Fluoro-pyrrolidin-1-yl)-5-methyl-6- morpholin-4-yl-pyridin-3-yl]-2-phenylpropionamide;[2-((R)-3-Fluor
  • 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. WO2010094645A1, 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.
  • the Kv7 channel activator is a compound according to 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-1 H-pyrrol-1-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 -
  • 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.
  • R 1 and R 2 together with the nitrogen to which they are attached is 1 ,4-oxazepanyl.
  • L is -CH 2 - and n is 1.
  • n is 0.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with halogen.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,4-Difluoro-phenyl)-N-[2-((R)-3-fluoro-pyrrolidin-1-yl)-5-methyl-6- [1 ,4]oxazepan-4-yl-pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-/V-(5-methyl-2,6-bis-[1 ,4]oxazepan-4-yl-pyridin-3-yl)- acetamide; 3-Fluoro-/V-(5-methyl-6-[1 ,4]oxazepan-4-yl- 2-pyrrolidin-1-yl-pyridin-3-yl)- benzamide; 3-methyl-N-[5-methyl-6-(1 ,4-oxazepan-4-yl)- 2-pyrrolidin-1-yl-3-pyridy
  • 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. WO2008142140A2, 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.
  • the reference incorporated by reference herein controls.
  • 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 —(CH 2 ) n — bridge, wherein n is 1, 2 or 3; R 3 , R 4 and R 5
  • R 1 represents hydrogen or alkyl
  • R 2 represents hydrogen or alkyl
  • 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.
  • R 6 and R 7 independently of each other, represent hydrogen, halo, haloalkyl, hydroxy, alkoxy, or amino.
  • R′ and R′′ independently of each other, represent alkyl, hydroxy-alkyl, cycloalkyl, or phenyl-alkyl.
  • 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.
  • the Kv7 Channel activator is selected from the group consisting 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-quinazolin-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-quinazolin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-(2-dimethylamino
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3-Fluoro-4-trifluoromethyl-phenyl)-N-(4-oxo-2-pyrrolidin-1-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-Difluoro-phenyl)-N-(2- morpholin-4-yl-4-oxo-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluor
  • 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. WO2010060955A1, published June 3, 2010 and corresponding to International Application No. PCT/EP2009/065890 filed November 26, 2009; US Publication No.
  • the Kv7 channel activator is a compound according to 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 —(CH 2 ) n —, — (CH 2 ) n —O— or —(CH 2 ) n —S— wherein n is 0 or 1;
  • R 1 represents C 1-6 -alkyl, benzo[1,3]dioxolyl, phenyl or pyridyl, which phenyl and pyridyl are optionally substituted one or more times with substituents selected from the group consisting of C 1-6 -alkyl, halogen, trifluoromethyl, hydroxy, C 1-6 -alkoxy and trifluoromethoxy;
  • R 2 and R 3 independently of each other, represent hydrogen or C 1-6 -alkyl; and
  • R 4 and R 5 independently of
  • Y represents —(CH 2 ) n —, wherein n is 0 or 1;
  • R 1 represents C 1-6 -alkyl, benzo[1,3]dioxolyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of C 1-6 -alkyl, halogen, trifluoromethyl, hydroxy, C 1-6 -alkoxy and trifluoromethoxy;
  • R 2 and R 3 independently of each other, represent hydrogen or C 1-6 -alkyl;
  • R 4 and R 5 independently of each other, represent hydrogen, C 1-6 -alkyl, halogen, trifluoromethyl, hydroxy, C 1-6 -alkoxy or trifluoromethoxy.
  • n is 1.
  • R 1 represents phenyl optionally substituted one or more times with substituents selected from the group consisting of C 1-6 -alkyl, halogen, trifluoromethyl and C 1-6 -alkoxy.
  • R 2 and R 3 represent hydrogen.
  • R 2 and R 3 represent C 1-6 -alkyl.
  • R 4 and R 5 independently of each other, represent hydrogen or halogen.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluoro-phenyl)-N-[6-(4-fluoro-benzylamino)-2-morpholin-4-yl- pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N- ⁇ 6-[1-(4-fluoro-phenyl)-1-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[1,3]dioxol-5-yl-N-[6-(4-fluoro- benzylamino)-2-morpholin-4-yl-pyridin-3-yl]-acetamide;
  • 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. WO2010051819A1, 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.
  • the Kv7 channel activator is a compound according to Formula 41: A stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein L represents a linker selected from —(CR′R′′) 2 —, —CR′R′′—S—, —CR′R′′—O— or wherein R′ and R′′, independently of each other, represent hydrogen, C 1-6 -alkyl or halogen; R 1 and R 2 , independently of each other, represent C 1-6 -alkyl, hydroxy-C 1-6 -alkyl-, C 1-6 -alkoxy-C 1-6 - alkyl-, phenyl, phenyl-C 1-6 -alkyl-, which phenyl is optionally substituted with one or two times with a substituent selected from the group consisting of C 1-6 -alkoxy, halogen and cyano; or R 1 and R 2 ,
  • R 1 and R 2 independently of each other, represent C 1-6 - alkyl, alkoxy-C 1-6 -alkyl- or phenyl-C 1-6 -alkyl-.
  • R 1 and R 2 together with the nitrogen to which they are attached, form a pyrrolidinyl ring.
  • R 3 , R 4 and R 5 independently of each other, represent hydrogen, C 1-6 -alkyl or halogen.
  • R 6 and R 7 independently of each other, represent hydrogen or halogen.
  • the Kv7 Channel activator is selected from the group consisting of: N-(7-Fluoro-4-oxo-2-pyrrolidin-1-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
  • the compound is of formula: wherein: X represents —CR′R′′—, —S—, or —O—, wherein R′ and R′′, independently of each other, represent hydrogen, C 1-6 -alkyl or halogen, and R′, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above. [0529] 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.
  • the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in International Publication No.
  • the Kv7 channel activator is a compound according to 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-1H-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
  • 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.
  • R 3 represents furanyl which is optionally substituted with C 1-6 -alkyl.
  • R 4 represents C 1-6 -alkyl.
  • R 5 and R 6 together with the nitrogen to which they are attached, represents morpholinyl.
  • the Kv7 Channel activator is selected from the group consisting of: 3-Methyl-furan-2-carboxylic acid [2-((R)-3-fluoro-pyrrolidin-1-yl)-4-methyl- 6-[1,4]oxazepan-4-yl-pyridin-3-yl]-amide; 3-Methyl-furan-2-carboxylic acid [2-((R)-3- fluoro-pyrrolidin-1-yl)-4-methyl-6-morpholin-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.
  • 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. WO2010026104A1, 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.
  • the Kv7 channel activator is a compound according to 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
  • R 1 and R 2 independently of each other, represent Ci-6- alkyl.
  • 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.
  • 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 trifluoromethyl.
  • 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 trifluoromethyl.
  • R 3 represents te/t-butyl.
  • 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.
  • L represents -CH 2 -.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluorophenyl)-N- ⁇ 2-pyrrolidin-1-yl-6-[(tetrahydro-pyran-4- ylmethyl)-amino]- pyridin-3-yll-acetamide; 3,3-Dimethyl-N- ⁇ 2-pyrrolidin-1-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]- pyridin-3-yll-acetamide; 2- (3,5-Difluoro-phenyl)-N- ⁇ 2-dimethylamino-6-[(tetrahydro-pyran-4-ylmethyl)-amino]- pyridin
  • 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. WO2010105960A1, 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.
  • the Kv7 channel activator is a compound according to 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 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′′—, — CH 2 —CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • R 1 represents alkyl or phenyl, which phenyl is optionally substituted one or
  • R 1 represents alkyl.
  • R 1 represents phenyl optionally substituted one or more times with substituents selected from alkyl and halo.
  • R 3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.
  • R 3 represents alkyl.
  • L represents a linker selected from —CR′R′′—, —CH 2 — CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen or alkyl.
  • 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-(
  • 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. WO2009074593A1, 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. [0556] In an embodiment, the Kv7 channel activator is a compound according to Formula 45:
  • R 1 represents alkyl, phenyl, benzo[1,3]dioxolyl or benzo[1,4]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
  • L represents a linker selected from —CR′R′′—, — CH 2 —CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • 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
  • L represents a linker selected from —CR′R′′—, —CH 2 —CR′R′′—, — CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • R 1 represents alkyl.
  • R 1 represents phenyl, benzo[1,3]dioxolyl or benzo[1,4]dioxinyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, trifluoromethyl, alkoxy, cyano and difluoromethoxy.
  • R 3 represents alkyl.
  • R 3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.
  • L represents a linker selected from —CR′R′′—, —CH 2 — CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen or alkyl.
  • the Kv7 Channel activator is selected from the group consisting of: N-[6-(4-Fluoro-benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-2-(3-fluoro-4- trifluoromethyl-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(4-fluoro-benzylamino)- 2-pyrrolidin-1-yl-pyridin-3-yl]-acetamide; 2-(3,4-Difluoro-phenyl)-N-[6-(4-fluoro- benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-acetamide; (S)-N-[6-(4-Fluoro-benzylamino)- 2-pyrrolidin-1-yl-pyridin-3-yl]-2-phenyl-
  • 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. WO2009074591A1, 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.
  • the Kv7 channel activator is a compound according to 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′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • R 1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl
  • R 1 represents alkyl.
  • R 1 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl.
  • R 3 represents alkyl.
  • R 3 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.
  • L represents a linker selected from —CR′R′′—, — CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • 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-
  • 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. WO2009074594A1, 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.
  • the Kv7 channel activator is a compound according to 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 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′′—, — CH 2 —CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • R 1 represents alkyl or phenyl, which phenyl is optionally substituted one or
  • R 1 represents alkyl.
  • R 1 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl.
  • R 3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl.
  • R 3 represents alkyl.
  • L represents a linker selected from —CR′R′′—, —CH 2 — CR′R′′—, —CR′R′′—CH 2 — and cycloalkyl, wherein R′ and R′′, independently of each other, represent hydrogen, alkyl or halo.
  • 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; (
  • 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. WO2007104717A1, 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.
  • 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.
  • R 1 and R 2 independently of each other, represent hydrogen, alkyl, cycloalky
  • 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.
  • R 3 represents alkyl, cycloalkyl or alkoxy.
  • 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.
  • 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
  • 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. WO2007057447A1, 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.
  • the Kv7 channel activator is a compound according to 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 —(CH 2 ) n — bridge, wherein n is 1, 2 or 3; R 3 and R 4 , independently of each other, represent hydrogen, alkyl, cycloalkyl, hal
  • R 1 represents hydrogen or alkyl.
  • R 2 represents alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenylalkyl, amino, alkyl-carbonyl-amino, cyano or nitro.
  • R 1 represents hydrogen or methyl; and R 2 represents methyl, ethyl, isopropyl, cyclohexyl, fluoro or benzyl.
  • R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl group.
  • R 1 represents hydrogen; and R 2 together with R 3 attached in ortho-position on the aromatic ring form a —(CH 2 ) 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 methylenedioxy group.
  • R 3 attached in ortho-position on the aromatic ring and together with R 2 form a —(CH 2 ) n — bridge, wherein n is 1, 2 or 3; and R 4 is as defined in claim 7.
  • R 5 represents alkyl, cycloalkyl, alkoxy, alkylthio or phenyl.
  • 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.
  • the Kv7 Channel activator is selected from the group consisting of: N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-3-methyl-2-phenyl-butyramide; 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-trifluoromethyl-4H-quinazolin-3-yl)- propionamide; N-(2-Ethyl-7-fluoro-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionamide; (S)-N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionamide; (S
  • 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. WO2004080377A2, 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.
  • the Kv7 channel activator is a compound according to 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′′CH 2 (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 OCH 2 , with the proviso that when
  • R 4 represents benzyl which is substituted one or two times with halo or one time with methylenedioxy. [0601] In further embodiments, R 4 represents 4-fluoro-benzyl, 3,4-dichloro-benzyl or benzo[1,3]dioxol-5-ylmethyl.
  • 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[1,3]dioxol-5-ylmethyl)-amino]-2- hydroxy-benzonitrile; or a pharmaceutically-acceptable addition salt thereof.
  • 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 .
  • R 4 represents 3-phenoxy-phenyl, 3-benzyloxy-phenyl, or biphenyl-4-yl.
  • 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 [0606]
  • 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.
  • the Kv7 channel activator is a compound according to 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.
  • 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.
  • R 1 , R 3 and R 4 represent hydrogen, and R 2 represents halogen, trihalogenmethyl or phenyl.
  • 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 is hydrogen or methyl.
  • R 6 is chlorine.
  • the Kv7 Channel activator is selected from the group consisting of: (+)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol- 2-one; ( ⁇ )-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one; ( ⁇ )-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6(4-methylphenyl)-2H-indol-2-one; ( ⁇ )-3- (5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-one; ( ⁇ )-3-(5-chloro-2-hydroxyphenyl)- 4,6-dichloro-1,3-dihydro-2H-indol-one; ( ⁇ )-3-(5-(5-chloro-2-
  • 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
  • R 6 represents halogen or trihalogenmethyl, or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent.
  • 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. CN114380731A, 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.
  • the Kv7 channel activator is a compound according to Formula 52: wherein, R 1 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; R 2 is optionally selected from H, alkyl, alkenyl or alkynyl; R 3 and R 4 each independently selected from H or alkyl; y is selected from O or S; R 5 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.
  • R 1 is selected from H,
  • R 2 is selected from H, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkenyl or C 1 -C 3 Alkynyl.
  • R 3 and R 4 are each independently selected from H or C 1 -C 6 An alkyl group.
  • R 5 is selected from substituted or unsubstituted C 1 - C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy or furyl, the substituents of the alkyl or the alkoxy being selected from C 1 -C 6 Alkoxy, di (C) 1 -C 4 Alkyl) amino or C 1 -C 6 Alkoxycarbonyl, the substituents of cycloalkyl being selected from halogen.
  • the formula is one of formulas II – IV: wherein, n is more than or equal to 0;R 11 and R 12 each independently selected from H, halogen or halomethyl; R 2 is selected from H, C 1 -C 3 Alkyl radical, C 2 -C 3 Alkenyl or C 2 - C 3 An alkynyl group; R 3 and R 4 are independently selected from H or C 1 -C 6 alkyl group; y is selected from O or S; R 5 is selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C3-C6Cycloalkyl radical, C1-C6Alkoxy or furyl, the substituents of the alkyl being selected from C 1 -C 6 Alkoxy, di (C) 1 -C 4 Alkyl) amino or C 1 - C 6 Alkoxycarbonyl, the substituents of cycloalkyl being selected from halogen
  • n is 0 to 3
  • R 11 is selected from H, F or trifluoromethyl
  • R 12 is selected from H, F, Cl or methyl.
  • R 3 is one of H or methyl
  • R 4 is other of H or methyl.
  • R 5 is selected from methyl, ethyl, isopropyl, isobutyl, neopentyl, cyclobutyl, ethoxy, isopropoxy, tert-butoxy or tetrahydrofuranyl.
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 53.
  • the Kv7 channel activator is a compound according to Formula 53:
  • 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 (C 1-4 )alkyl; R 2A represents hydrogen; (C 1-4 )alkyl; (C 1-4 )fluoroalkyl; (C 1-4 )hydroxyalkyl; or (C 1-4 )alkoxy-(C 1- 2 )alkyl; R 2B represents hydrogen; L represents a direct bond, -CH 2 -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 (C 1-4 )alkyl; R 5 represents hydrogen, fluoro, or hydroxy; and R 6 represents fluoro or (C 1 )fluoroalkyl; or • R 4 and R 5 together represent a bridge selected
  • R 2A represents hydrogen, (C 1-4 )alkyl, (C 1-4 )fluoroalkyl, (C 1-4 )hydroxyalkyl, or methoxymethyl; and R 2B represents hydrogen; or a salt thereof.
  • L represents a direct bond; or a salt thereof.
  • R 3 represents fluoro; or a salt thereof.
  • R X4 represents hydrogen; or a salt thereof.
  • each of X 1 , X 2 , and X 3 represents CH; or a salt thereof.
  • the fragment represents: ; wherein R X4 represents hydrogen or halogen; R 3 represents hydrogen or fluoro; and L represents a direct bond, -CH 2 -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 (C 1-4 )alkyl; R 3 represents hydrogen or fluoro; and L represents -CH 2 -O-*, or-O-; wherein the asterisk indicates the bond which is linked to the aromatic carbon atom; or a salt thereof.
  • R 4 represents hydrogen; R 5 represents hydrogen or fluoro; and R 6 represents fluoro, difluoromethyl or trifluoromethyl; or a salt thereof.
  • R 4 and R 5 together represent a -CH 2 - bridge; and R 6 represents hydrogen, fluoro, difluoromethyl, or trifluoromethyl; or a salt thereof.
  • the Kv7 Channel activator is selected from the group consisting of: 1-(3,3-Difluoro-cyclobutyl)-3-(3-trifluoromethyl-benzyl)-urea; 1- Bicyclo[1.1.1]pent-1-yl-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl- cyclobutyl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Fluoro-bicyclo[1.1.1]pent-1- yl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl-bicyclo[1.1.1]pent-1- yl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Diflu
  • 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.
  • the Kv7 channel activator is a compound according to Formula 54: wherein, X 1 represents nitrogen or CR x1 ; wherein R X1 represents hydrogen, halogen, (C 1-4 )alkyl, or (C 1- 4 )alkoxy;X 2 represents nitrogen or CR X2 ; wherein R X2 represents hydrogen, halogen, (C 1-4 )alkyl, or (C 1- 4 )alkoxy; X 3 represents nitrogen or CR X3 ; wherein R X3 represents hydrogen, halogen, (C 1-4 )alkyl, (C 1- 4 )alkoxy, or hydroxy;• R 1 represents hydrogen, or methyl; or• R 1 and R X1 together represent a -CH 2 CH 2 - bridge; Y represents -C(R Y1 )(R Y2 )-, or *-CH 2 -C(R Y3 )(R Y4 )-, wherein the asterisk
  • R 1 represents hydrogen; or a salt thereof (meaning a salt of compound of Formula 54).
  • R Y1 , R Y2 , R Y3 and R Y4 all represent hydrogen; or a salt thereof.
  • R 2A represents hydrogen, (C 1-4 )alkyl, (C 3-6 )cycloalkyl, (C 1-4 )fluoroalkyl, (C 1-4 )hydroxyalkyl, (C 1-4 )alkoxy-(C 1-2 )alkyl, (C 1-2 )alkyl-S-(C 1-2 )alkyl, (C 1- 2 )alkyl-(SO 2 )-(C 1-2 )alkyl, cyano, (C 1- 2 )cyanoalkyl, H 2 N-C(O)-(C 1-2 )alkyl, (R N1 ) 2 N-(C 1- 2)alkyl, or (R N1 )2N-C(O)-, wherein R N1 independently represents hydrogen or (C1-2)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
  • R 2A represents hydrogen, methyl, or hydroxymethyl; and R 2B represents hydrogen; or a salt thereof.
  • R 3 represents a fragment whereinR 31 represents hydrogen, or fluoro; and L represents a direct bond, -CHR L -O- * , - O-CH 2 - * , -CH 2 -NH- * , -CH 2 -N(CH 3 )- * , or -O-; wherein R L represents hydrogen, methyl, CH 3 -O-CH 2 -, or (CH 3 ) 2 NCH 2 -; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; or a salt thereof.
  • R 4 represents hydrogen; or a salt thereof.
  • the fragment 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- * , -CH 2 -NH- * , -CH 2 -N(CH 3 )- * , -O-, or ; wherein R L represents hydrogen, or methyl; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; or 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,
  • 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 -CH 2 -, or -CH 2 -CH 2 -; 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.
  • the Kv7 Channel activator is selected from the group consisting of: 1-Spiro[3.3]hept-2-yl-3-(3-trifluoromethyl-benzyl)-urea;1-Spiro[2.3]hex-5- yl-3-(3-trifluoromethyl-benzyl)-urea;1 -(1 , 1 -Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-((3r,5r)-1,1-Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-((3s,5s)-1 , 1 -Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-(6,6-Difluoro-s
  • 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.
  • the Kv7 channel activator is a compound according to Formula 55: or a tautomer, salt, solvate, stereoisomer or isotope thereof, wherein: Y is selected from: C1-C10 alkylamino, C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, Cl- C10 alkylcarbonyl, Cl -CIO alkylaminocarbonyl, Cl -CIO alkylthio, aryl, heterocycle, Cl -CIO carbonyl, C1-C10 amide and C1-C10 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, C
  • b is 1.
  • Y is Cl -CIO alkylamino, Cl -CIO alkyl or Cl -CIO alkoxy.
  • 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.
  • Ri, R3, R4 and R5 are each independently: H, C1-C6 alkyl, C3- C6 cycloalkyl, NH 2 , NH(C1-C6 alkyl), N(C1-C6 alkyl)2 , azepane, pirrolidine, piperidine, aziridine or halogen.
  • 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. WO2020016297A1, published January 23, 2020, and corresponding to International Application No. PCT/EP2019/069240 filed July 17, 2019; Patent Cooperation Treaty application No. PCT/EP2019/069240 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.
  • the Kv7 channel activator is a compound according to Formula 56: wherein, R 1 is selected from a branched or unbranched C1 to C5 alkyl group and – NR 1a R 1b group, where R 1a and R 1b are selected independently of one another from hydrogen atom and branched or unbranched C1 to C5 alkyl group or with one another and with the nitrogen atom the NR 1a R 1b 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 C1 to C3 alkyl group and optionally in addition to the nitrogen atom of the NR 1a R 1b - Group has at least one further heteroatom in the cycle; R 2 is selected from the group consisting of branched or unbranched C1 to C10 alkyl group, C3 to C10 cycloalkyl group, C3 to C10 heterocycloalkyl group, at least one further heteroatom in the
  • R 1 is selected from the group consisting of branched or unbranched C1- to C3-alkyl group and - NR 1a R 1b group, wherein R 1a and R 1b are independently selected from hydrogen atom and branched or unbranched C1- to C3-alkyl group or with one another and form a C4 to C6 heterocycloalkyl group with the nitrogen atom of the NR 1a R 1b group, the C4 to C6 heterocycloalkyl group each having at least one substituent selected from the hydrogen atom and C1 to C3 alkyl group and optionally in addition to the nitrogen atom of the NR 1a R 1b 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;
  • the Kv7 channel activator is selected from the group consisting of: Formulas 57 – 139
  • 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. WO2018204765A1, 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.
  • the Kv7 channel activator is a compound according to any one of formulas 57 – 139:
  • 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. [0665] In an embodiment, the Kv7 channel activator is a compound according to Formula 140:
  • 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
  • R 30 , R 31 and R 32 are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy.
  • R 1 is H.
  • R 2 is C 1 -C 6 alkyl.
  • R 2 is carbocyclic-substituted alkyl or heterocyclic- substituted alkyl.
  • R 3 and R 4 are each H.
  • R 5 is H.
  • 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.
  • R 8 is selected from: w erein R 9 -R 25 are each independently H, halogen, optionally-substituted sulfanyl, or optionally-substituted alkyl. [0673] In further embodiments, R 8 is: eein at least one of R 9 or R 10 is halogen. [0674] In further embodiments, R 8 is: wherein at least one of R 19 or R 20 is halogen. [0675] 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.
  • R 14 -R 18 is —SF 5 or CF 3 .
  • R 8 is: wherein at least one of R 11 -R 13 or R 23 -R 25 is substituted sulfanyl.
  • R 8 is: wherein at least one of R 14 -R 18 is halo-substituted sulfanyl, haloalkyl or halogen.
  • at least one of R 14 -R 18 is —SF5 or —CF3.
  • R 15 , R 16 , or R 17 is —SF 5 or —CF 3 .
  • R 32 is —F
  • R 30 and R 31 are each H.
  • the Kv7 Channel activator is selected from the group consisting of:
  • 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
  • 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
  • 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;R 8 is in 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.
  • R 32 is halogen. [0687] In further embodiments, R 32 is —F. [0688] In further embodiments, at least one of R 14 -R 18 is halo-substituted sulfanyl. [0689] In further embodiments, at least one of R 14 -R 18 is haloalkyl. [0690] In further embodiments, at least one of R 14 -R 18 is —SF 5 . [0691] In further embodiments, at least one of R 14 -R 18 is —CF 3 . [0692] In further embodiments, R 16 is —SF 5 . [0693] In further embodiments, R 16 is —CF 3 .
  • R 2 is alkyl.
  • R 2 is C 1 -C 6 alkyl.
  • R 2 is ethyl.
  • R 3 , R 4 , R 5 , R 6 , and R 7 are each H.
  • R 32 is —F and R 16 is —CF 3 .
  • R 2 is alkyl.
  • R 3 and R 31 are each H.
  • R 15 , R 16 , or R 17 is —SF 5 or —CF 3 .
  • 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 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.
  • the Kv7 channel activator is a compound 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; andR 8 is optionally-substituted thiazolyl.
  • 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.
  • 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.
  • the Kv7 channel activator is a compound according to Formula 142: wherein, X is selected from a group consisting of oxygen and sulfur; n is 1, 2 or 3;R 1 is H or halogen;R 2 and R 3 are each independently selected from a group consisting of H, D and C 1 -C 3 alkyl; or R 2 and R 3 together with the carbon atom to which they attached form C 3 -C 6 saturated ring;R 4 and R 5 are each independently selected from a group consisting of H; halogen; C 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; cyano; alkoxyl; C 1 -C 6 alkyl substituted by hydroxy, amino, C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl, or halogen; C 1 -C 4 alkoxy substituted by halogen; C 1 -C 6 alkylcarbonyl; C 1 -C 6 alkoxycarbon
  • R 1 is H or fluorine
  • R 2 and R 3 are each independently selected from a group consisting of H and D, or R 2 and R 3 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 C 1 -C 4 alkyl.
  • one of R 4 and R 5 is methyl, and the other is H or methyl.
  • Formula 143 [0710]
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 143.
  • the Kv7 channel activator is a compound according to Formula 143: wherein, X: is selected from a group consisting of oxygen and sulfur;R 1 is H or halogen;R 2 and R 3 are each independently selected from a group consisting of H, D and C 1 -C 3 alkyl; or R 2 and R 3 together with the carbon atom to which they attached form C 3 - C 6 saturated ring;R 4 and R 5 are each independently selected from a group consisting of H; halogen; C 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; cyano; C 1 -C 4 alkoxyl; C 1 -C 6 alkyl substituted by hydroxy, amino, C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyl, or halogen; C 1 -C 4 alkoxy substituted by halogen; C 1 -C 6 alkylcarbonyl; C 1 -C 6 alkoxycarbony
  • R 1 is H or fluorine
  • R 2 and R 3 are each independently selected from a group consisting of H and D, or R 2 and R 3 together with the carbon atom to which they attached form cyclopropyl
  • one of R 4 and R 5 is C 1 -C 4 alkyl, and the other is H or C 1 -C 4 alkyl.
  • Formula 144 - 146 [0713]
  • the Kv7 channel activator may be selected from one of the following compounds according to any one of Formulas 144 - 146.
  • the Kv7 channel activator is a compound according to a formula from the group consisting of 144, 145, and 146:
  • R 2 and R 3 are each independently selected from a group consisting of H, D and C1-C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3- C 6 saturated ring;
  • R 4 and R 5 are each independently selected from a group consisting of H; C 1 -C 6 alkyl; C 1 -C 4 alkoxyl; C 1 -C 6 alkyl substituted by halogen; C 1 -C 4 alkoxy substituted by halogen; provided that R 4 and R 5 are not simultaneously hydrogen;
  • R 9 is selected from a group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;
  • R 10 is selected from a group consisting of C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted by halogen, cyano, hydroxy, C 1 -C 6 alkoxyl, di(C 1 -C 4 alkyl)amino, C 1 -C
  • R 2 and R 3 are each independently selected from a group consisting of H and D, or R 2 and R 3 together with the carbon atom to which they attached form cyclopropyl; one of R 4 and R 5 is C 1 -C 1 alkyl, and the other is H or C 1 - C 4 alkyl;R 9 is selected from a group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;R 10 is selected from a group consisting of C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted by halogen, cyano, hydroxy, C 1 -C 6 alkoxyl, di(C 1 -C 4 alkyl)amino, C 1 -C 6 alkylcarbonyl, C 1 - C 6 alkylamido, or C 1 -C 6 alkoxycarbonyl; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl; C 3 -C 6
  • R 9 is selected from a group consisting of methyl, ethyl and propyl;R 10 is selected from a group consisting of C 1 -C 3 alkyl; C 1 -C 3 alkyl substituted by halogen, cyano, hydroxy, C 1 -C 3 alkoxyl, di(C 1 -C 3 alkyl)amino, C 1 -C 3 alkylcarbonyl, C 1 - C 3 alkylamido, or C 1 -C 3 alkoxycarbonyl; C 3 -C 6 cycloakyl; C 3 -C 6 cycloakyl substituted by halogen; tetrahydrofuranyl; and wherein, R 7 and R 8 are each independently selected from a group consisting of C 1 -C 3 alkyl.
  • the Kv7 Channel activator is selected from the group consisting of:
  • 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.
  • the Kv7 channel activator is a compound according to Formula 147: or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X7, and X8 are each independently selected from hydrogen, deuterium, and F; X9 and X 10 are each independently selected from hydrogen and deuterium; and n is 1, 2, or 3, wherein at least one of X 1 , X 2 , and X 3 is F.
  • the Kv7 channel activator is: wherein, A is N or C—X 3 ; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are each independently selected from hydrogen, 19F and 18F; and n is 2 or 3, provided that one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is 18F. [0721] In further embodiments, two of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are F.
  • the Kv7 channel activator is: wherein, X 1 , X 2 , X 3 , and X 6 are each independently selected from hydrogen, 18F, and 19F, provided that one of X 1 , X 2 , X 3 , and X 6 is 18F.
  • X 6 is fluorine and one of X 1 , X 2 , and X 3 is fluorine.
  • one of X 1 , X 2 , X 3 , and X 6 is 18F.
  • at least one of X 1 , X 2 , and X 3 is 19F.
  • X6 is 19F or 18F.
  • the compound is selected from the group consisting of: Formula 148
  • 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.
  • the Kv7 channel activator is a compound according to 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, C 1-6 alkyl, C 3-6 cycloalkyl, or —C 1-6 alkyl-C 3- 6 cycloalkyl, 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
  • R 1 is C 5-6 alkyl
  • R 2 is NR 4 R 5 , wherein one of R 4 or R 5 is H and the other is C 3-6 alkyl, C 3-6 cycloalkyl, or —C 1-3 alkyl-C 3-6 cycloalkyl
  • 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 —CH 2 —CH 2 —; or a pharmaceutically acceptable salt thereof.
  • R 1 is —CH 2 C(CH 3 ) 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 —CH 2 —CH 2 —; or a pharmaceutically acceptable salt thereof.
  • R 1 is C 5-6 alkyl
  • R 2 is C 3-6 cycloalkyl
  • R 3 is halogen, or alkyl, wherein alkyl may be substituted with one or more halogen atoms
  • —X—Y— is ⁇ CH—CH ⁇ or —CH 2 —CH 2 —; or a pharmaceutically acceptable salt thereof.
  • R 1 is —CH 2 C(CH 3 ) 3 ;
  • R 2 is cyclopropyl;
  • R 3 is chloro, methyl, trifluoromethyl or 1,1-difluoroethoxy;
  • —X—Y— is ⁇ CH—CH ⁇ or —CH 2 —CH 2 — ; or a pharmaceutically acceptable salt thereof.
  • Formula 149 [0735]
  • 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.
  • the Kv7 channel activator is a compound 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, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R 1 may be
  • 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 an integer of from 0 to 4.
  • 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.
  • R 4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups.
  • V is selected from the group consisting of (CR 3a R 3b ) p SO 2 N(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 ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the
  • V is a group of formula of (CR 3a R 3b ) p SO 2 N(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 ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 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 atom
  • V is a group of formula of (CR 3a R 3b ) p SO 2 N(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 ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 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.
  • 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, alkylsulphony
  • 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 an integer of from 0 to 3;R 2 is
  • 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
  • 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, alkylsulphony
  • the Kv7 Channel activator is selected from the group consisting of: 1-[2-(2,6-Dichlorophenylamino)phenyl]-N-[2-(2-hydroxyethoxy)ethyl]- methanesulfonamide,N-[2-(2-hydroxyethoxy)ethyl]-C-[2-(2,4,6- trichlorophenylamino)phenyl]-methanesulfonamide,1-[2-(2,6-dichloro-4- trifluoromethylphenylamino)phenyl]-N- ⁇ 2-(2-hydroxyethoxy)ethyl]methanesulfonamide,1- [2-(2,6-dichloro-3-methylphenylamino)phenyl]-N- ⁇ 2-(2-hydroxyethoxy)- ethyl]methanesulfonamide,N-(2-hydroxyethyl)-1-[3-(2,4,6- trich
  • 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, alkoxycarbonylamino groups, alkylsulphonyl 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,
  • 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.
  • 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.
  • Ar 1 and Ar 2 are each phenyl.
  • 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.
  • 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 ) n1 wherein each n1 is 0.
  • 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
  • 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 ) c1 — O—(CR 6c R 6d ) c2 ] c3 — wherein c1 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
  • 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.
  • 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, 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, alkylsulphonyl groups having from 1 to 4 carbon atoms, alkylsulphonylamino groups having from 1 to 4 carbon atoms and cyano groups and, wherein: Ar 1 and Ar 2 are each
  • the Kv7 Channel activator is selected from the group consisting of: N-(2-hydroxyethyl)-2-[3-(2,4,6-trichlorophenylamino)phenyl]acetamide; ⁇ 2- [5-(3,5-dichlorophenylamino)-2-fluorophenyl]-acetylamino ⁇ acetic acid; 2-[4-(2,6-dichloro- 4-trifluoromethyl-phenylamino)-phenyl]-N-(2-hydroxyethyl)-acetamide; ⁇ 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-
  • 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, alkoxycarbonylamino groups, alkylsulphonyl 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, alkoxycarbonyl groups, carb
  • 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
  • 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.
  • 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-phenyl]-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-phenyl]-N- (2-hydroxy-2-methyl-propyl)acetamide; and 2-[4-(2,6-dichloro-4-trifluoromethoxy- phenylamino)-2-fluoro-phen
  • 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, alkoxycarbonylamino groups, alkylsulphonyl 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,
  • 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 an integer of from 0 to 4.
  • 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.
  • R 4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups.
  • V is selected from the group consisting of (CR 3a R 3b ) p SO 2 N(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 ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 and c2 are the
  • V is a group of formula of (CR 3a R 3b ) p SO 2 N(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 ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 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 atom
  • V is a group of formula of (CR 3a R 3b ) p SO 2 N(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 ) c1 —O—(CR 6c R 6d ) c2 ] c3 — wherein c1 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.
  • 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
  • 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 an
  • 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
  • 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
  • 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. WO2012004698A1, 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.
  • the Kv7 channel activator is a compound according to Formula 150: wherein, n is an integer of 1 or 2; t is 0 or 1; each R 1 is independently selected from C 1- 3 alkoxy, C 1-3 alkyl, C 1-3 alkyl-O—C 1-3 alkyl; R 2 and R 3 are independently C 1-3 alkyl, C 1- 3 alkoxy, or C 3-6 cyloalkyl provided that at least one is C 1-3 alkoxy; R 4 is C 1-6 alkyl, C 1- 3 alkyl-C 3-6 cyloalkyl, C 3-6 heterocycloalkyl; or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , and R 3 are each C 1-3 alkoxy; wherein R 4 is C 4- 6 alkyl, and wherein n and t are each 1, or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , and R 3 are each methoxy; R 4 is —CH 2 -t-butyl, and n and t are each 1, or a pharmaceutically acceptable salt thereof.
  • the compound is N-(4,6-dimethoxy-2-(4- methoxypiperidin-1-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide, or a pharmaceutically acceptable salt thereof.
  • 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. WO2013060097A1, 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.
  • these references incorporated by reference herein control 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. WO2013060097A1, 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.
  • these references incorporated by reference herein control are described in US Patent No.9,353,048 issued May 31, 2016, and corresponding to US Application No. 14/353,842 filed
  • the Kv7 channel activator may be selected from one of the following compounds according to Formula 152.
  • 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.
  • 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 heteroaryl;R 1 is an optional substituent wherein each occurrence of R 1 is independently G a , 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
  • Z 1 is benzo, heteroaryl, or cycloalkyl.
  • R 3 is alkyl, halogen, haloalkyl, G 3a , or -(CR 3a R 3b ) m -G 3a .
  • R 4 is unsubstituted alkyl, haloalkyl, -C(R 4a R 4b ) n -G 4a , or alkyl substituted with a -S(R la ) group.
  • 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.
  • Z 1 is benzo, cycloalkyl, or heteroaryl; and R 4 is -C(R 4a R 4b ) n -G 4a .
  • 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 .
  • 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 ; and
  • G 3a is aryl or cycloalkyl.
  • Z 1 is benzo, cycloalkyl, or heteroaryl; andR 4 is unsubstituted alkyl or haloalkyl.
  • 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 .
  • 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.
  • Z 1 is benzo, cycloalkyl, or heteroaryl; and R 4 is alkyl substituted with a -S(R la ) group.
  • 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 .
  • 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.
  • the Kv7 Channel activator is selected from the group consisting of: 2-(4-chlorophenyl)-N-(4-isopropyl-l-oxophthalazin-2(lH)-yl)acetamide; 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)acetamide; 2-(4- chlorophenyl)-N-( 1 -oxo-4-phenylphthalazin-2( 1 H)-yl)acetamide; 2-(3,5- difluorophenyl)-N-(4-isopropyl-l-oxophthalazin-2(lH)-yl)acetamide;
  • 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.
  • 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 G a , 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 )CO
  • 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.
  • the Kv7 channel activator is a compound according to 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 a , 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
  • 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.
  • 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 G a , 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
  • 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. [0809] In an embodiment, the Kv7 channel activator is a compound according to Formula 156:
  • R 1 is an optional substituent wherein each occurrence of R 1 is independently G a , 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 )COOR b , -N(R a )CONR a R b ,
  • 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. WO2007087424A2, 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.
  • the Kv7 channel activator is a compound according to Formula 157: [0812] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-5,7-Diiodo-8-hydroxyquinoline and zinc-8-Hydroxyquinoline. [0813] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-pyrrolidine dithiocarbamate, zinc-diethyldithiocarbamate, zinc- disulfiram and zinc-dimethyldithiocarbamate. [0814] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-vitamin E and zinc-vitamin A.
  • 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. WO2007087424A2, 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.
  • the Kv7 channel activator is a compound according to Formula 158: wherein, A is a bond, CH 2 , CHR b , CH 2 S, CHR b S, CH 2 O, CH 2 NR c , or NH; Rb is alkyl; R c is H or S(O) m -aryl; R 1 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, R 3 is H or alkyl; each R d and R e is independently an optionally substituted alkyl, an optionally substituted aryl, or R d and R e together
  • 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. WO2007087424A2, 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.
  • the Kv7 channel activator is a compound according to Formula 159: wherein, R 4 is H, an optionally substituted alkyl, an optionally substituted alkenyl, alkynyl, allyl, or an optionally substituted aryl; R 5 is H, hal, or hydroxyl; R 6 is H, hal, hydroxyl, NH 2 , a mono- or di-substituted amine, or an optionally substituted alkoxy; R 7 is H, hal, hydroxyl, an optionally substituted alkoxy, or nitro; X is S or NR a ; Y is O, S, or NR a ; and each R a is independently H or an optionally substituted aryl.
  • the Kv7 Channel activator is selected from the group consisting of: N-Benzo[g]quinolin-4-yl-N′-(2-diethylamino-ethyl)-benzene-1,4-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- ethylsulfanyl)-nicotinonitrile; 2-(2-Oxo-2-thiophen-2-yl-ethyls
  • 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. WO2004060880A1, 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.
  • the Kv7 channel activator is a compound according to Formula 160: wherein, R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, —(CH 2 ) 1-4 C 3-7 cycloalkyl, —(CH 2 ) 2-4 N(C 1-6 alkyl) 2 , —(CH 2 ) 2-4 OC 1-6 alkyl, hydrogen, C 1-6 alkyl, or — (CH 2 ) 2-4 OC 1-6 alkyl; or where R 1 and R 2 taken together are —CH 2 CH 2 XCH 2 CH 2 —, where X is a chemical bond, CH 2 , CHOH, NH, NCH 3 , NCOCH 3 , O, or S; R 3 is hydrogen or hydroxy, provided that where R 3 is hydroxy, m is not 0; R 4 is hydrogen, C 1-6 alkyl, hydroxymethyl, or trifluoromethyl; R 5 is halogen, C 1-6 alkyl, C 1-2
  • the Kv7 Channel activator is selected from the group consisting of: 2-[2-(4-morpholinyl)ethyl]-N-[1-[3-(3-pyridinyl)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; N-[1-[3-(dimethylamino)phenyl]ethyl]-2-[2-(1- pyrrolidinyl)ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(1-pyrrolidinyl)ethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-[(2- furanylmethyl)methyl
  • the Kv7 Channel activator is selected from the group consisting of: 2-[1-hydroxy-2-(1-piperidinyl)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]- 4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[1-hydroxy-2-(1-pyrrolidinyl)ethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-[(2- furanylmethyl)methylamino]-1-hydroxyethyl]-4-(trifluoromethyl)-N-[1-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide
  • the compound has a stereochemical configuration according to the formula: [0829]
  • the compound is according to the formula: [0830]
  • R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, —(CH 2 ) 1-4 C 3-7 cycloalkyl, —(CH 2 ) 2-4 N(C 1- 6 alkyl) 2 , —(CH 2 ) 2-4 OC 1-6 alkyl, s hydrogen C 1-6 alkyl, or —(CH 2 ) 2-4 OC 1-6 alkyl; or where R 1 and R 2 taken together are —CH 2 CH 2 XCH 2 CH 2 —, where X is a chemical bond, CH 2 , CHOH, NH, NCH 3 , NCOCH 3 , O, or S; R 3 is hydrogen or hydroxy, provided that where R 3 is hydroxy, m is not 0; R 4 is hydrogen, C 1-6 alkyl, hydroxymethyl, or trifluor
  • 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. WO2004047738A2, 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.
  • the Kv7 channel activator is a compound according to Formula 161: wherein, R is C 1-4 alkyl, CF 3 or hydroxymethyl; R 1 and R 2 are each independently hydrogen, C 1-4 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 C 1- 4 alkyl, 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 —CH 2 CH 2 O—; and R 3 , R 6 and R 7 are each independently selected from hydrogen or fluoro.
  • 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. WO2004047738A2, 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.
  • the Kv7 channel activator is a compound according to Formula 162: , wherein, R is methyl or hydroxymethyl; R 1 and R 2 are each independently hydrogen, C 1- 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 C1-4alkyl, 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 —CH 2 CH 2 O—; and R 3 , R 6 and R 7 are each independently selected from hydrogen or fluoro.
  • R is methyl or hydroxymethyl
  • R 1 and R 2 are each independently hydrogen, C 1- 4 alkyl, halogen or morpholin-4-yl
  • R 4 is selected from the
  • the Kv7 Channel activator is selected from the group consisting of: 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3-dihydro- benzofuran-5-yl)-ethyl]-amide; 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3- dihydro-benzofuran-5-yl)-ethyl]-amide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide; 2-(2-fluoro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide; 2-(3-fluoro- phenyl)-cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2-y
  • 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. WO2004047743A2, 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.
  • 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, C 3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; A is —CH ⁇ CH— or —(CH 2 ) 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(C 1-4 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 substitu
  • 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. WO2004047743A2, 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. [0839] In an embodiment, the Kv7 channel activator is a compound according to Formula 164:
  • R 1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, furanyl, C 3-6 cycloalkyl and phenyl optionally substituted with substituent independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro;
  • A is —CH ⁇ CH— or —(CH 2 ) n —;
  • R 2 is hydrogen;
  • n is an integer of 0, 1 or 2;
  • R 4 is selected from the group consisting of di(C 1-4 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 C 1-4 alkyl, aminomethyl, hydroxymethyl
  • the Kv7 Channel activator is selected from the group consisting of: (R)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl- propionamide; (R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]- acrylamide; (R)-3-(3-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]- acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]- acrylamide; (R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(
  • 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. WO2004047744A2, 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.
  • 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. WO2004047744A2, 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.
  • the Kv7 channel activator is a compound according to Formula 166: wherein, R 1 is selected from the group consisting of straight or branched chain C 1-6 alkyl optionally substituted with amino, C 1-4 alkylamino or di(C 1-4 alkyl) amino, pyridinyl, pyrrodidinyl, piperidinyl, 2-thienyl, furanyl, imidazolyl, indenyl, benzofuran, C 3-6 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 —(CH 2 ) 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
  • 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-[1-(3-thiazol-2-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro- phenyl)-N-[1-(3-pyrazol-1-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro-phenyl)-N-[1-(3- imidazol-1-yl-phenyl)-ethyl]-acrylamide; (S)-4-phenyl-N-[1-(3-pyridin-3-yl-phenyl)-ethyl]-butyr
  • 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. WO2002096858A1, 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.
  • the Kv7 channel activator is a compound according to Formula 167: , wherein, R is C 1-4 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, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and halogen; R 4 is selected from the group consisting of di(C 1-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4
  • 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. WO2002096858A1, 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.
  • the Kv7 channel activator is a compound according to Formula 168: , wherein, R 1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, benzodioxanyl, 1,3-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, C 1-4 alkyl, C -4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R 4 is selected from the group consisting of optionally substituted di(C 1-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substitu
  • R 1 is substituted phenyl or 1,3-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(CH 2 ) m Y— in which X and Y are each O, and m is 1.
  • R 1 is selected from the group consisting of substituted phenyl, 1,3-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, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy and trifluoromethyl; and R 4 and R 5 taken together are —X(CH 2 ) m Y— in which X is CH 2 , Y is O, and m is 1.
  • 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, C 1-4 alkyl, C 1-4 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 C 1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; and
  • R 5 is hydrogen or fluoro.
  • R 1 is phenyl, fluorophenyl or difluorophenyl.
  • R 1 is substituted phenyl or 1,3-benzodioxol-5-yl in which said substituted phenyl is substituted with one or two substituents each independently selected from halogen or C 1-4 alkyl; and R 4 and R 5 taken together are —X(CH 2 ) m Y— in which X and Y are O, and m is 2.
  • 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 C 1-4 alkyl;
  • R 4 and R 5 taken together are —X(CH 2 ) m Y— in which X is (CH 2 ) n N(R 9 )—; Y is CH 2 , and m and n are 1; and
  • R 9 is CO 2 (C 1-4 alkyl).
  • 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(CH 2 ) m Y— in which X is (CH 2 ) n N(R 9 )— and Y is O wherein m is 2 and n is 0; and R 9 is hydrogen, cyclopropylmethyl or C 1-4 alkyl.
  • R 1 is 3-quinolinyl or pyridinyl; R 4 is trifluoromethoxy; and R 5 is hydrogen.
  • R 1 is substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen or C 1-4 alkyl;
  • R 4 and R 5 taken together are —X(CH 2 ) m Y—, in which X is CH 2 and Y is (CH 2 ) n N(R 9 )— wherein m is 1 and n is 0; and R 9 is CO2(C1-4alkyl).
  • 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(CH 2 ) m Y—, in which X is (CH 2 ) n N(R 9 )— and Y is CH 2 wherein m is 2 and n is 0; and
  • R 9 is hydrogen, C 1-4 alkyl, acetyl, hydroxyethyl or methoxyethyl.
  • 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(CH 2 ) n Y—, in which X is CH 2 and Y is (CH 2 ) n N(R 9 )— wherein m is 2 and n is 0; and
  • R 9 is hydrogen, C 1-4 alkyl, acetyl, hydroxyethyl or methoxyethyl.
  • 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 C 1-4 alkyl and halogen; and R 5 is hydrogen or fluoro.
  • R 1 is 1,3-benzodioxol-5-yl; R 4 is di(C 1-4 alkyl)amino; and R 5 is hydrogen or fluoro.
  • 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.
  • 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.
  • R 1 is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from C 1-4 alkyl and halogen;
  • R 4 is piperazinyl or 4-methylpiperazinyl; and
  • R 5 is hydrogen or fluoro.
  • the Kv7 Channel activator is selected from the group consisting of: 2-Methyl-3-phenyl-but-2-enoic acid (1-naphthalen-2-ylethyl)-amide; N-(1- Benzo[1,3]dioxol-5-yl-ethyl)-3-(3-methoxy-phenyl)-acrylamide; N-[1-(2,3- Dihydrobenzofuran-5-yl)ethyl]-3-(3-methoxyphenyl)-acrylamide; (S)-3-Phenyl-N-[1-(3- morpholin-4-yl-phenyl)ethyl]acrylamide; 3-(3-Fluorophenyl)-N-[1-(2,3- dihydrobenzo[1,4]dioxin-6-yl)-ethyl]acrylamide; ( ⁇ )-7- ⁇ 1-[3-(4- Fluorophenyl
  • 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. WO2002096858A1, 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.
  • the Kv7 channel activator is a compound according to Formula 169: wherein, R 1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, benzodioxanyl, 1,3-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, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R 4 is selected from the group consisting of optionally substituted di(C 1-4 alkyl)amino, trifluoromethoxy and optionally substituted morpholin-4-yl, pyridinyl, pyrimidinyl, piperazinyl, and pyrazinyl with one or two substituents
  • 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, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethoxy and nitro; and R 4 and R 5 taken together are —CH ⁇ CH—CH ⁇ CH—.
  • 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, C 1-4 alkyl, C 1-4 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 C 1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; and
  • R 5 is hydrogen or fluoro.
  • R 1 is phenyl, fluorophenyl or difluorophenyl.
  • 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 C 1-4 alkyl and halogen; and R 5 is hydrogen or fluoro.
  • R 1 is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from C 1-4 alkyl and halogen; R 4 is piperazinyl or 4-methylpiperazinyl; and R 5 is hydrogen or fluoro.
  • 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. WO2001010381A2, 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.
  • the Kv7 channel activator is a compound according to 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, (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C 1 -C 4 )alkyl, substituted aryl(C 1 - C 4 )alkyl, CN, —C(O)R 2 , —OR 3 , —C(O)NR 3 R 4 , and —S(O) 2 NR 3 R 4 ; wherein R 2 is a member selected from the group consisting of (C 1 -C 8
  • 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.
  • Ar 1 is substituted phenyl, substituted or unsubstituted 2- indolyl and substituted or unsubstituted 2-thienyl.
  • X is O.
  • the Ar 1 substituents are selected from the group consisting of halogen, alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, nitro, cyano, —NHC(O)R 7 , —NHR 7 , phenyl and substituted phenyl, wherein R 7 is a member selected from hydrogen, (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heterocyclyl, substituted hcterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C 1 -C 4 )alkyl and substituted aryl(C 1 -C 4 )alkyl, or R 7 can
  • Ar 2 is selected from the group consisting of heteroaryl and substituted heteroaryl.
  • Ar 1 is substituted aryl;
  • Ar 2 is heteroaryl or substituted heteroaryl; and
  • X is O.
  • Ar 2 is pyridyl or substituted pyridyl.
  • Ar 2 is selected from the group consisting of 6-methyl-3- pyridyl and 2-chloro-5-pyridyl.
  • Ar 1 is substituted phenyl.
  • the compound is according to the formula: [0886] wherein, Y is a member selected from the group consisting of halogen, C1- C 4 alkyl, C 1 -C 4 substituted alkyl, —OCH 3 and —OCF 3 , and R 5 and R 6 are members independently selected from the group consisting of H, halogen, alkyl, halo(C 1 -C 4 )alkyl, nitro, cyano and phenyl, with the proviso that both R 5 and R 6 are not H.
  • 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 TDP-43 Modulators section.)
  • 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.
  • 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 cycl
  • the Kv7 channel activator is selected from the group consisting of N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 10.36, 12.67, 28.64 and 29.98 (°2 ⁇ ) using CuK ⁇ 1 radiation.; N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 8.68, 18.09, 22.60 and 30.62 (°2 ⁇ ) using CuK ⁇ 1 radiation.; N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 8.63, 22.26, 23.40 and 30.49 (°2 ⁇ ) using CuK ⁇ 1 radiation.
  • 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.
  • 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.
  • the Kv7 Channel activator is selected from the group consisting of: NS15370, P-Retigabine, SF0034 or RL648_81 or any combination thereof.
  • the Kv7 channel activator is selected from the group consisting of: linopirdine, (1,3-Dihydro-1-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-1-yl)phenyl)butanamide (ML252)) and UCL2077.
  • XE991 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone
  • DMP-543 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anth
  • the Kv7 channel activator is an analog of flupirtine.
  • 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[2.2.1]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-(l -adamantyl)-N-(2,6-difluorophenyl)acetamide; N-(2-bromo-4-methylphenyl)-2- cyclopentylacetamide; N-(2,3-dimethylpheny
  • 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.
  • TDP-43 MODULATORS [0899] Amyotrophic lateral sclerosis (ALS) is a neurological disorder in which the upper and lower motor neurons progressively degenerate (Asakawa K, Handa H, Kawakami K. Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons.
  • TDP-43 Trans-activation response element
  • TDP-43 modulators are disclosed in Formulas 200 – 220, and in the corresponding references applications. Such TDP-43 modulators are advantageously useful in combination therapies with Kv7 modulators as described herein.
  • Formula 200 [0901]
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 200. Such compounds are described in International Publication No. WO2021035101A1, published February 25, 2021, and corresponding to International Application No. PCT/US2020/047287 filed August 21, 2020; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 200, these references incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to Formula 200:
  • X 1 is selected from the group consisting of nitrogen and CH;
  • R 1a is selected from the group consisting of hydrogen, halogen, C 1-20 linear alkyl, C 3-20 branched alkyl, C 1-20 linear heteroalkyl, C 3-20 branched heteroalkyl, each of which except hydrogen and halogen are optionally substituted;
  • R 1b is selected from the group consisting of hydrogen, halogen, C 1-20 linear alkyl, C 3-20 branched alkyl, C 1-20 linear heteroalkyl, C 3-20 branched heteroalkyl, each of which except hydrogen and halogen are optionally substituted;
  • R 1c is selected from the group consisting of hydrogen, halogen, C1-20 linear alkyl, C3-20 branched alkyl, C 1-20 linear heteroalkyl, C 3-20
  • X 1 is selected from the group consisting of nitrogen and CH;
  • R la is selected from the group consisting of hydrogen, halogen, CF 3 , OCF 3 , C 1- 4 linear alkyl, C3-4 branched alkyl, (C2-8 dialkylamino)(C2-4 alkyl), (C3-6 alkyleneamino)(C2-4 alkyl), C 1-4 linear alkoxy, and C 3-4 branched alkoxy;
  • R lb is selected from the group consisting of hydrogen, halogen, CF 3 , OCF 3 , C 1-4 linear alkyl, C3-4 branched alkyl, (C2-8 dialkylamino)(C2-4 alkyl), (C3-6 alkyleneamino)(C2-4 alkyl), C 1- 4 linear alkoxy, and C 3-4 branched alkoxy;
  • R lc is selected from the group consisting of hydrogen, halogen, CF 3 , OCF 3 , C 1-4 linear alkyl, C
  • R 3a is at each occurrence independently selected from the group consisting of C 1-4 linear alkyl and C 3-4 branched alkyl
  • R 3b is at each occurrence independently selected from the group consisting of C 1-4 linear alkyl and C 3-4 branched alkyl
  • R 5 is selected from the group consisting of hydrogen, C 1-4 linear alkyl, C3-4 branched alkyl, - CH2-(C1-6 cycloalkyl), C(0)C 1-6 linear alkyl, C(0)C 3 - 6 branched alkyl
  • R 6 is selected from the group consisting of C 1-4 linear alkyl, C3-4 branched alkyl, and an optionally substituted benzyl group wherein the optionally substituted benzyl group is substituted with 0 to 2 groups selected from the group consisting of halogen, - CN, -NO 2 , -OH, -NH 2 , Ci-6 alkyl, C 3-7 branched alkyl, Ci-6 linear haloal
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , R 5 , and R 6 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , R 5 , and R 6 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , R 6 , and R 7 are defined as above.
  • the compound is:
  • R 1a , R 1b , R 1c , R 1d , R 4 , R 6 , and R 7 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein q, R 1a , R 1b , R 1c , R 1d , R 4 , R 6 , and R 7 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein q, R 1a , R 1b , R 1c , R 1d , R 4 , R 6 , and R 7 are defined as above.
  • the compound is:
  • R 1a , R 1b , R 1c , R 1d , R 4 , R 6 , and R 7 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein y, R 1a , R 1b , R 1c , R 1d , R 4 , R 6 , and R 7 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein z, R 1a , R 1b , R 1c , R 1d , R 4 , and R 6 are defined as above.
  • the compound is:
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein z, R 1a , R 1b , R 1c , R 1d , R 4 , and R 6 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein r, R 1a , R 1b , R 1c , R 1d , R 4 , and R 7 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein r, R 1a , R 1b , R 1c , R 1d , R 4 , and R 7 are defined as above.
  • the compound is:
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and R 6 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and R 6 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , R 5 , and R 6 are defined as above.
  • the compound is:
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , R 5 , and R 6 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , R 5 , and R 6 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and R 6 are defined as above.
  • the compound is:
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and u are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and u are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and x are defined as above.
  • the compound is:
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and x are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , v, X 2 , and n 1 are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , v, X 2 , and n 1 are defined as above.
  • the compound is:
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and w are defined as above.
  • the compound is: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R 1a , R 1b , R 1c , R 1d , R 4 , and w are defined as above.
  • the TDP-43 modulator is selected from the group consisting of: N 1 -(3-((2-(4-Methoxyphenyl)quinolin-4-yl)amino)propyl)-N 1 ,N 3 ,N 3 - trimethylpropane-1,3-diamine; 2-(4-Methoxyphenyl)-N-(3- ⁇ methyl[3- (methylamino)propyl]-amino ⁇ propyl)quinolin-4-amine; N 1 -(3-Aminopropyl)-N 3 -(2-(4- methoxyphenyl)quinolin-4-yl)-N 1 -methylpropane-l,3-diamine; N 1 -(2-(4- Methoxyphenyl)quinolin-4-yl)-N 3 -(3-(piperidin-1-yl)propyl)propane-1,3-diamine; N 1 -(2-(2-(4- Methoxyphen
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 201.
  • Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022, and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 201, these references incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to Formula 201: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, X, Y, and Z are each independently N or CH;
  • R 2 is an amino(C 3 -Cv)cycloalkyl group or a (Ci- C 5 alkyl) 2 amino(C 3 -Cv)cycloalkyl group, wherein the (C i-C alkyl) attached to “amino” are optionally connected to form a ring;
  • R 3 is a substituted or unsubstituted phenyl group; and
  • R 4 is an amino(C 3 -Cv)cycloalkyl group, a (Ci-C 5 alkyl) 2 amino(C 3 -Cv)cycloalkyl group wherein the (C i-C alkyl)
  • X is CH, Y is CH, and Z is CH.
  • X is N, Y is CH, and Z is CH.
  • X is CH, Y is N, and Z is CH.
  • X is CH, Y is CH, and Z is N.
  • X is N, Y is N, and Z is CH.
  • X is CH, Y is N, and Z is N.
  • X is CH, Y is N, and Z is N.
  • X is N, Y is CH, and Z is N.
  • X is N, Y is CH, and Z is N.
  • X is N, Y is CH, and Z is N.
  • X is N, Y is N, and Z is N.
  • R 2 is an amino(C 3 -C 7 )cycloalkyl group selected from an aminocyclopropyl group, an aminocyclobutyl group, an aminocyclopentyl group, an aminocyclohexyl group, or an aminocycloheptyl group, each of which has either cis- configuration or trans-configuration.
  • R 2 is a (C 1 -C 5 alkyl)2amino(C 3 -C 7 )cycloalkyl group selected from a (C 1 -C 5 alkyl) 2 aminocyclopropyl group, a (C 1 -C 5 alkyl) 2 aminocyclobutyl group, a (C 1 -C 5 alkyl)2aminocyclopentyl group, a (C 1 -C 5 alkyl) 2 aminocyclohexyl group, or a (C 1 - C 5 alkyl)2aminocycloheptyl group, each of which has either cis-configuration or trans configuration.
  • R 3 is a substituted or unsubstituted phenyl group.
  • R 3 is a phenyl group, a chlorophenyl group, or a methoxyphenyl group.
  • R 4 is a (C 0 -C 5 alkyl)2amino(C 2 -C 5 )alkyloxy group selected from a (C 1 -C 5 alkyl)2 a minoethyloxy group, a (C 1 -C 5 alkyl) 2 aminopropyloxy group, a (C 1 - C 5 alkyl)2aminobutyloxy group, and a (C 1 -C 5 alkyl) 2 aminopentyloxy group, wherein two “(C 1 - C 5 alkyl)” are optionally connected to form a ring.
  • the ring is a substituted or unsubstituted azetidine, a substituted or unsubstituted pyrrolidine, or a substituted or unsubstituted piperidine.
  • R 4 is a (C 0 -C 5 alkyl)2amino(C 2 -C 5 )alkyl group selected from a (C 1 -C 5 alkyl) 2 aminoethyl group, a (C 1 -C 5 alkyl) 2 aminopentyl group, a (C 1 - C 5 alkyl) 2 aminobutyl group, and a (C 1 -C 5 alkyl) 2 aminopentyl group, wherein two “(Ci- Csalkyl)” are optionally connected to form a ring.
  • the ring is a substituted or unsubstituted azetidine, a substituted or unsubstituted pyrrolidine, or a substituted or unsubstituted piperidine.
  • R 4 is a heterocyclyl(C2-C5)alkyloxy group or a heteroaryl(C 2 -C 5 )alkyloxy group, wherein “heterocyclyl” is a substituted or unsubstituted nitrogen-containing non-aromatic mono-heterocycle and wherein “heteroaryl” is a substituted or substituted nitrogen-containing aromatic mono-heterocycle.
  • heterocyclyl and the “heteroaryl” are connected to the “(C 2 -C 5 )alkyloxy” through a nitrogen atom.
  • R 4 is a substituted or unsubstituted pyrrolidinoethyloxy group or substituted or unsubstituted pyrrolidinopropyloxy group.
  • the compound is according to formula 201, an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, X, Y, and Z are each independently N or CH; R 2 is a substituted or unsubstituted C 1 -C 20 linear, branched, or cyclic organic group including at least one nitrogen; and R 3 and R 4 are each independently hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted C 0 -C 10 amino group, a substituted or unsubstituted Ci- C10 alkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C 2 -C 10 alkynyl group, and a substituted or unsubstit
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 202.
  • Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022 and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 202, these references incorporated by reference herein control.
  • Formula 203 - 204 [0957]
  • the TDP-43 modulator may be selected from one of the following compounds according to any one of Formula 203 - 204. Such compounds are described in International Publication No.
  • the TDP-43 modulator is a compound according to any one of Formula 203 - 204: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, R 2 is a substituted or unsubstituted C 1 -C 20 linear, branched, or cyclic organic group including at least one nitrogen; and R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted C 0 -C 10 amino group, a substituted or unsubstituted Ci- C 10 alkyl group, a substituted or unsubstituted C 2 - C 10 alkenyl group, a substituted or unsubstituted C 2 -C 10 alkynyl group
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 205.
  • Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022, and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 205, these references incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to Formula 205: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, R 2 is a substituted or unsubstituted C 1 -C 20 linear, branched, or cyclic organic group including at least one nitrogen; and R 1a , R 1b , R 1c , and R ld are each independently hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted C 0 - C 10 amino group, a substituted or unsubstituted C 1 -C 10 alkyl group, a substituted or unsubstituted C 2 -C 10 alkenyl group, a substituted or unsubstituted C 2 -C 10 alkynyl group
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 206.
  • Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022, and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 206, these references incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to Formula 206: an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, R 2 is a substituted or unsubstituted C 1 -C 20 linear, branched, or cyclic organic group including at least one nitrogen; and R 1a , R 1b , 1 lc , R 1d , and R 1e are each independently hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted Co-Cio amino group, a substituted or unsubstituted Ci-Cio alkyl group, a substituted or unsubstituted C 2 -C 10 alkenyl group, a substituted or unsubstituted C 2 -C 10 alkyny
  • the TDP-43 modulator may be selected from one of the following compounds according to any one of Formulas 207 - 210.
  • Such compounds are described in International Publication No. WO2022015997A2, published January 20, 2022, and corresponding to International Application No. PCT/US2021/041852 filed July 15, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of any one of Formulas 207 - 210, this reference incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to Formula 207: N-(2-(3-hydroxypiperidin-1-yl)ethyl)-5-((3-(trifluoromethyl)phenoxy)methyl)isoxazole-3- carboxamide, or a pharmaceutically acceptable salt thereof and/or a structurally similar compound.
  • the TDP-43 modulator is a compound according to Formula 208:
  • the TDP-43 modulator is a compound according to Formula 209: , 6-(benzo[d][1,3]dioxol-5-yl)-N-((1-isobutylpyrrolidin-3-yl)methyl)nicotinamide or a pharmaceutically acceptable salt thereof and/or a structurally similar compound.
  • the TDP-43 modulator is a compound according to Formula 210: 3-(5-(1H-indol-3-yl)-1,3,4-oxadiazol-2-yl)-N-(1,2,3,4-tetrahydronaphthalen-1- yl)propenamide or a pharmaceutically acceptable salt thereof and/or a structurally similar compound.
  • Formula 211 - 212 [0968] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to one of Formulas 211 - 212.
  • the TDP-43 modulator is a compound according to one of Formulas 211 - 212:
  • each of R and R 3a is independently hydrogen or alkyl;
  • R a is — CF 3 , —OR a1 , or —NR b1 R b2 ;
  • R a1 is H or alkyl;
  • each of R b1 and R b2 is independently H or alkyl;
  • R 1a is hydrogen, alkyl, or a nitrogen protecting group;
  • each of R 1 , R 2 and R 3 is independently hydrogen, alkyl, haloalkyl, halide, vinyl, alkynyl, —CHO, — C( ⁇ O)R 1b (ketone), —CO 2 R 1c (ester), —OR 1d , OSO 2 R 1e , aryl and heteroaryl, wherein each of R 1b , R 1c , R 1d , and R 1e is independently alkyl or aryl;
  • R 2a is hydrogen, alkyl,
  • R 1a , R 1 , and R 3 are H, R 2 is halide, and R is alkyl.
  • * is an (R)- or (S)-configuration and R 2b is alkyl, Z is an ester, and R 2a is alkenyl or heteroaryl.
  • diastereomeric excess of said compound is at least 90% d.e.
  • the TDP-43 modulator of formula 212 is selected from the group consisting of:
  • the TDP-43 modulator is selected from the group consisting of: or a pharmacologically acceptable salt thereof.
  • Formula 213 the TDP-43 modulator may be selected from one of the following compounds according to Formula 213. Such compounds are described in International Publication No. WO2021025723A1, published February 11, 2021, and corresponding to International Application No. PCT/US2020/000030 filed July 312020; US Publication No. US20210052519A1, published February 25, 2021, and corresponding to US Application No.16/873,866 filed July 31, 2020; which are incorporated by reference in their entirety herein.
  • the TDP-43 modulator is a compound according to Formula 213: , wherein, R 1 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 3 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl,
  • R 1 is hydrogen, alkyl or acyl.
  • R 3 -R 6 are independently hydrogen or alkyl.
  • R 20 -R 24 are independently hydrogen, alkyl or halogen.
  • R 25 -R 29 are independently hydrogen, alkyl or halogen.
  • Formula 214 [0981] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 214. Such compounds are described in International Publication No. WO2021025723A1, published February 11, 2021, and corresponding to International Application No. PCT/US2020/000030 filed July 312020; US Publication No.
  • the TDP-43 modulator is a compound according to Formula 214: wherein, R 1 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R 3 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, hal
  • R 1 is hydrogen, alkyl or acyl.
  • R 3 -R 6 are independently hydrogen or alkyl.
  • R 20 -R 24 are independently hydrogen, alkyl or halogen.
  • R 25 -R 29 are independently hydrogen, alkyl or halogen.
  • Formula 215 the TDP-43 modulator may be selected from one of the following compounds according to Formula 215. Such compounds are described in US Publication No. US20170369474A1, published December 28, 2017, and corresponding to US Application No.15/533,339 filed December 4, 2015; International Publication No.
  • the TDP-43 modulator is a compound according to Formula 215: , wherein, Ring A is heteroaryl; R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —OR A , —NR B R C , —NR B C(O)R D , or —SR E , each of which is optionally substituted with 1-5 R 7 ; R 2 is H, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl
  • R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, cycloalkyl, —OR A , or — NR B R C , and R B and R C , together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R 7 .
  • R 1 is —NR B R C , and R B and R C , together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R 7 .
  • R 1 is selected from the group consisting of [0992]
  • R 2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R 8 .
  • each of R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR A , —NR B R C , —C(O)R D , —C(O)OR A , —C(O)NR B R C , or —NR B C(O)R D , each of which is optionally substituted with 1-5 R 9 .
  • R 5 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R 9 .
  • Ring A is a monocyclic or bicyclic heteroaryl.
  • Ring A is a 5- or 6-membered monocyclic heteroaryl.
  • R 6 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano, hydroxy, halo, —OR A , —NR B R C , —C(O)R D , —C(O)OR A , —C(O)NR B R C , —S(O) 2 R E , — NR B S(O) 2 R E , or —S(O) 2 NR B R C , each of which is optionally substituted with 1-5 R 9 .
  • R 6 is C 1 -C 6 alkyl, cyano, hydroxy, halo, —OR A , or — NR B R C .
  • n is 0, 1, or 2.
  • the TDP-43 modulator is a compound of formula 215 or a pharmaceutically acceptable salt thereof, wherein, Ring A is aryl; R 1 is C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —OR A , —NR B R C , —NR B C(O)R D , or —SR E , each of which is optionally substituted with 1-5 R 7 ; R 2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl
  • R 1 is —NR B R C , and R B and R C , together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R 7 .
  • R 1 is selected from the group consisting of [1004]
  • R 2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R 8 .
  • each of R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR A , —NR B R C , —C(O)R D , —C(O)OR A , —C(O)NR B R C , or —NR B C(O)R D , each of which is optionally substituted with 1-5 R 9 .
  • R 5 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R 9 .
  • Ring A is a monocyclic fused aryl.
  • R 6 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano, hydroxy, halo, —OR A , —NR B R C , —C(O)R D , —C(O)OR A , —C(O)NR B R C , —S(O)2R E , — NR B S(O) 2 R E , or —S(O) 2 NR B R C , each of which is optionally substituted with 1-5 R 9 .
  • R 6 is C 1 -C 6 alkyl, cyano, hydroxy, halo, —OR A , or — NR B R C .
  • n is 0, 1, or 2.
  • Ring A is selected from the group consisting of: [1012] In further embodiments, Ring A is [1013] In further embodiments, the compound is or a pharmaceutically acceptable salt thereof. [1014] In further embodiments, the compound is or a pharmaceutically acceptable salt thereof.
  • Formula 216 [1015] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 216. Such compounds are described in US Publication No.
  • the TDP-43 modulator is a compound according to Formula 216: or a pharmaceutically acceptable salt thereof, wherein, Ring A is aryl or heteroaryl; Ring B is 6-membered aryl or 5- or 6-membered heteroaryl; R′′ is H or C(O)R 1 ; R 1 is C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 - C 6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —OR A , —NR B R C , —NR B C(O)R D , or —SR E , each of which is optionally substituted with 1-5 R
  • R′′ is H or C(O)R 1 .
  • R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, cycloalkyl, —OR A , or — NR B R C , and R B and R C , together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4R 7 .
  • R 1 is —NR B R C , and R B and R C , together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R 7 .
  • R 1 is selected from the group consisting of [1021]
  • each R is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR A , —NR B R C , —C(O)R D , —C(O)OR A , —C(O)NR B R C , or — NR B C(O)R D , each of which is optionally substituted with 1-5 R 8 .
  • each R is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halo, each of which is optionally substituted with 1-5 R 8 .
  • R is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R 8 .
  • R 5 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R 9 .
  • Ring A is a monocyclic or bicyclic aryl or heteroaryl.
  • Ring A is phenyl or a 5- or 6-membered heteroaryl.
  • R 6 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 - C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano, hydroxy, halo, —OR A , —NR B R C , —C(O)R D , —C(O)OR A , —C(O)NR B R C , —S(O) 2 R E , — NR B S(O) 2 R E , or —S(O) 2 NR B R C , each of which is optionally substituted with 1-5 R 9 .
  • Ring A is selected from the group consisting of: [1029] In further embodiments, Ring A is and R 6 is C 1 -C 6 alkyl or halo. [1030] In further embodiments, Ring B is phenyl. [1031] In further embodiments, Ring B is selected from: [1032] In further embodiments, Ring B is a 5- or 6-membered heteroaryl. [1033] In further embodiments, Ring B is selected from: wherein the connectivity to —S(O) 2 is indicated by a wavy line and the connectivity to R′′ is as shown. [1034] In further embodiments, n is 0, 1, or 2 and p is 0 or 1.
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 217.
  • Such compounds are described in US Publication No. US20170360726A1, published December 21, 2017, and corresponding to US Application No.15/533,354 filed December 4, 2015; International Publication No. WO2016090317A1, published June 9, 2016, and corresponding to International Application No. PCT/US2015/064107 filed December 4, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 217, these references incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to Formula 217: , or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or C(R D )2, and Ring A, R, R′′, R 5 , R 6 , R D , n, p and subvariables thereof are defined as for Formula 216.
  • the TDP-43 modulator is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • Formula 218 [1038] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 218. Such compounds are described in International Publication No.
  • the TDP-43 modulator is a compound according to Formula 218: and analogs, derivatives, isomers, prodrugs, and pharmaceutically acceptable salts thereof wherein, R 11 and R 12 are independently H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, C(O)R 17 , or C(O)OR 17 , each of which can be optionally substituted.
  • R 11 is an optionally substituted aryl or heteroaryl
  • R 13 and R 14 are independently H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, OR 17 , C(O)R 17 , or C(O)OR 17 , N(R 17 )2, each of which can be optionally substituted
  • R15 is independently, halo, alkyl, alkenyl, cyclyl, heterocyclyl, aryl, heteroaryl, NO 2 , OR 17 , OC(O)R 17 , OC(O)OR 17 , N(R 17 ) 2 , NHC(O)R 17 , NHC(O)OR 17 , C(O)R 17 , C(O)OR 17 , SR 17 , or SO 2 R 17 , each of which can be optionally substituted; b is 0, 1, 2, 3, or 4; c is 0, 1, 2, 3, 4, or 5; and when present a R 17
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 219.
  • Such compounds are described in US Publication No. US20220160699A1, published May 26, 2022 and corresponding to US Application No.17/310,971 filed March 16, 2020; International Publication No. WO2020190866A1, published September 24, 2020 and corresponding to International Application No. PCT/US2020/022972 filed March, 16, 2020; which are incorporated by reference in their entirety herein.
  • these references incorporated by reference herein control are described in US Publication No. US20220160699A1, published May 26, 2022 and corresponding to US Application No.17/310,971 filed March 16, 2020; International Publication No. WO2020190866A1, published September 24, 2020 and corresponding to International Application No. PCT/US2020/022972 filed March, 16, 2020; which are incorporated by reference in their entirety herein.
  • these references incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to Formula 219: wherein, R 1 is H, OH, or lower alkyl; R 2 is an optionally substituted aromatic ring of four, five, or six carbons, wherein the aromatic ring is carbocyclic or heterocyclic, and wherein each position on the aromatic ring is independently H, halo, lower alkyl, OH, lower alkoxy, NH 2 , lower alkylamino, di(lower alkyl)amino, SH, lower alkylthio, NO 2 , or two residues together form a heterocyclic ring; R 3 and R 8 are each independently H, lower alkyl, ⁇ O, ⁇ S, OH, NH 2 , aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH 2 , lower alkyl, lower alkoxy, SH, lower
  • the compound is according to Formula 219 wherein the compound is according to any one of the subformulas: , wherein, R 1 is H, OH, or lower alkyl; R 2 , is an optionally substituted aromatic ring of four, five, or six carbons, wherein the aromatic ring is carbocyclic or heterocyclic, and wherein each position on the aromatic ring is independently H, halo, lower alkyl, OH, lower alkoxy, NH 2 , lower alkylamino, di(lower alkyl)amino, SH, lower alkylthio, NO 2 , or two residues together form a heterocyclic ring; R 3 and R 8 are each independently H, lower alkyl, ⁇ O, ⁇ S, OH, NH 2 , aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of
  • the compound is according to Formula 219 wherein the compound is according to the subformulas: wherein, R 1 is H, OH, or lower alkyl; R 2 is an optionally substituted aromatic ring of four, five, or six carbons, wherein the aromatic ring is carbocyclic or heterocyclic, and wherein each position on the aromatic ring is independently H, halo, lower alkyl, OH, lower alkoxy, NH 2 , lower alkylamino, di(lower alkyl)amino, SH, lower alkylthio, NO 2 , or two residues together form a heterocyclic ring; R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, lower alkyl, OH, NH 2 , aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH 2 , lower
  • the compound is according to Formula 219 wherein the compound is according to any one of the subformulas: wherein, R 1 is H, OH, or lower alkyl; R 2 is an optionally substituted aromatic ring of four, five, or six carbons, wherein the aromatic ring is carbocyclic or heterocyclic, and wherein each position on the aromatic ring is independently H, halo, lower alkyl, OH, lower alkoxy, NH 2 , lower alkylamino, di(lower alkyl)amino, SH, lower alkylthio, NO 2 , or two residues together form a heterocyclic ring; R 3 , R 4 , R 5 , R 6 , and R 7 are each independently H, lower alkyl, OH, NH 2 , aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH 2
  • the TDP-43 modulator is AIM4, a compound according to formula 220 described in Prasad, A., Raju, G., Sivalingam, V. et al.
  • An acridine derivative, [4,5-bis ⁇ (N-carboxy methyl imidazolium)methyl ⁇ acridine] dibromide shows anti-TDP-43 aggregation effect in ALS disease models. Sci Rep 6, 39490 (2016), which is incorporated by reference in its entirety herein:
  • Formula 221 [1048]
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 221. Such compounds are described in International Publication No.
  • the TDP-43 modulator is a compound according to Formula 221: wherein, R 1a is H or methyl; R 1b is H or fluoro; A is group (Aa), (Ab), (Ac) or (Ad): wherein group (Aa) is: Aa); wherein: R 2 is H, C 1-4 alkyl, C 1- 4 alkylene(aryl), C 1-4 alkylene(OH), C 1-4 alkylene(C 3-6 cycloalkyl), C 1- 4 alkylene(4-7 membered heterocycloalkyl), C 1-4 alkoxy, OC 1-4 alkylene(aryl), C 1- 4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 3-6 cycloalkyl, C 1-4 alkyleneO(4-7 membered heterocycloalkyl), C 1- 4 alkyleneO(aryl), C 3-6 alkynyl and C 1-4 alkyleneO(C 3-6 alkynyl); wherein
  • R 1a is H or methyl; R 1b is H or fluoro; A is group (Aa), (Ab), (Ac) or (Ad): wherein group (Aa) is: (Aa); wherein: R 2 is H, C 1- 4 alkyl, C 1-4 alkylene(aryl), C 1-4 alkylene(OH), C 1-4 alkylene(C 3-6 cycloalkyl), C 1- 4 alkylene(4- 7 membered heterocycloalkyl), C 1-4 alkoxy, OC 1-4 alkylene(aryl), C 1- 4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 3-6 cycloalkyl, C 1-4 alkyleneO(4-7 membered heterocycloalkyl), C 1- 4 alkyleneO(aryl), C 3-6 alkynyl or C 1-4 alkyleneO(C 3-6 alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl
  • R 2 is C 1-4 alkyl, C 1- 4 alkylene(aryl), C 1-4 alkylene(OH), C 1- 4 alkyleneOC 1-4 alkyl, C 1-4 alkyleneOC 3-6 cycloalkyl, C 1- 4 alkyleneO(aryl), C 1-4 alkylene(4-7 membered heterocycloalkyl), C 1-4 alkyleneO(4-7 membered heterocycloalkyl) and C 1- 4 alkyleneO(C 3-6 alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl may be optionally substituted by up to 3 substituents each independently selected from C 1- 4 alkyl, C 3-6 cycloalkyl; C 1-4 alkoxy, C 1-4 haloalkyl, halo and CN.
  • the aryl is unsubstituted.
  • the aryl is substituted by 1, 2 or 3 substituents independently selected from methyl, chloro and fluoro.
  • the heterocycloalkyl is unsubstituted.
  • the heterocycloalkyl is substituted by 1, 2 or 3 substituents independently selected from CH 2 CH 2 F and fluoro.
  • each R 3 is independently fluoro or methyl.
  • m is 1 or 2.
  • m is 1 and R 3 is in the 3- position.
  • m is 1 and R 3 is in the 6- position.
  • m is 2, one R 3 is in the 3-position, and the other R 3 is in the 6-position.
  • R 4 is H, methyl or benzyl.
  • R 5 is H.
  • each R 6 is independently fluoro or methyl.
  • n is 0.
  • R 7 is methyl, CH 2 OH or CH 2 OMe.
  • o is 2.
  • X is a bond or O.
  • R 8 is independently methyl, OMe or fluoro.
  • p is 0 or 1.
  • each R 9 is independently fluoro.
  • q is 1 or 2.
  • D, E and F are C(R 10 ).
  • D is N, and E and F are C(R 10 ).
  • E is N, and D and F are C(R 10 ).
  • F is N, and D and E are C(R 10 ).
  • each R 10 is independently H, fluoro, chloro or methyl.
  • the TDP-43 modulator is selected from the group consisting of: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro- 1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2- methylcyclohexyl) acrylamide (racemic mixture); (E) 3 (1H indazol 6 yl) N ((1R2R) 2 methylcyclohexyl) acrylamide (enantiomer 1); (E)-3-(1H-inda
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 222.
  • Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control.
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 223. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1082] In an embodiment, the TDP-43 modulator is a compound according to Formula 223:
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 224. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1085] In an embodiment, the TDP-43 modulator is a compound according to Formula 224:
  • R 1 is optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C1-9 heterocyclyl, optionally substituted C6-10 aryl, or optionally substituted C1-9 heteroaryl
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 225.
  • Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control.
  • the TDP-43 modulator is a compound according to Formula 225: or a pharmaceutically acceptable salt thereof, wherein each bond denoted as is either a single bond or a double bond, provided that the bonds denoted as are not both simultaneously double bonds;
  • X 1 is selected from N and CR A ;
  • X 2 is selected from N and CR A ;
  • X 3 is selected from N and CR A ;
  • each R A is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
  • Ar is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 7 ;
  • each R 7 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OR a1
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 226.
  • Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control.
  • the TDP-43 modulator is a compound according to Formula 226: or a pharmaceutically acceptable salt thereof, wherein R 1 is hydroxy, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; each occurrence of R 2 is independently optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; R 3 is a nitrogen- or oxygen-containing moiety; Ring A is (i) a 5 or 6-membere
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 227.
  • Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control.
  • the TDP-43 modulator is a compound according to Formula 227 , or a pharmaceutically acceptable salt thereof, wherein Q 1 and Q 2 are each independently CH or N, wherein Q 1 and Q 2 are not both N; each R 1 is independently hydroxy, C1-4 alkyl, or C1-4 alkoxy; n is 0, 1, or 2; each R 2 is independently C1-4 alkyl or C1-4 alkoxy; and m is 0 or 1.
  • the TDP-43 modulator compound is or a pharmaceutically acceptable salt thereof.
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 228. Such compounds are described in International Publication No.
  • the TDP-43 modulator is a compound according to Formula 228: or a pharmaceutically acceptable salt thereof, wherein Ar 1 is phenyl or pyridyl, with each optionally independently substituted with 1 or 2 C1-4 alkoxy; Ar 2 is phenyl, pyridyl, or pyrimidyl with each optionally independently substituted with halo, C1-4 alkyl, C1-4 alkoxy, or C(O)NR 2a R 2b ; and R 2a and R 2 are each independently H or C1-4 alkyl.
  • the TDP-43 modulator compound is selected from the group consisting of:
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 229. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 229, this reference incorporated by reference herein control. [1100] In an embodiment, the TDP-43 modulator is a compound according to Formula 229:
  • the TDP-43 modulator compound is selected from the group consisting of: Formula 230
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 230. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control.
  • the TDP-43 modulator is a compound according to Formula 230:
  • the TDP-43 modulator compound is selected from the group consisting of: Formula 231 [1105] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 231. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No.
  • the TDP-43 modulator is a compound according to Formula 231: or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen or C1-4 alkyl; R 3 is hydrogen or C1-3 alkyl substituted with morpholinyl.
  • the TDP-43 modulator compound is selected from the group consisting of:
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 232. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1109] In an embodiment, the TDP-43 modulator is a compound according to Formula 232:
  • the TDP-43 modulator compound is Formulas 233 - 237 [1111]
  • the TDP-43 modulator may be selected from one of the following compounds according to any one of Formulas 233 - 237. Such compounds are described in International Publication No. WO2021247921A1, published December 9, 2021, and corresponding to International Application No. PCT/US2021/035778 filed June 3, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of any one of Formulas 233 - 237, this reference incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to any one of Formulas 233 - 237: wherein n is 0, 1, 2, 3, or 4; X is S or O; each R 1 is, independently, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, - SO2-optionally substituted C1-C6 alkyl, or -CO2-optionally substituted C1-C6 alkyl; R 2 is optionally substituted C2-C9 heteroaryl; and R 3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocyclyl, optionally substituted C1-C6 alkyl C3-C8 cycloalkyl, optionally substituted C1-C6 heteroalkyl C3-C8 cycloalkyl, optionally substituted C1-C6 alkyl C2-
  • X is S. [1114] In further embodiments, X is O. [1115] In further embodiments, n is 0. [1116] In further embodiments, n is 1. [1117] In further embodiments, R 1 is halo. [1118] In further embodiments, halo is fluoro. [1119] In further embodiments, R 1 is cyano. [1120] In further embodiments, R 1 is hydroxy. [1121] In further embodiments, R 1 is optionally substituted C1-C6 alkyl. [1122] In further embodiments, optionally substituted C1-C6 alkyl is methyl, ethyl, trifluoromethyl, or hydroxymethyl.
  • R 1 is optionally substituted C1-C6 heteroalkyl.
  • optionally substituted C1-C6 heteroalkyl is ethoxy or trifluoromethoxy.
  • R 1 is -SO2-optionally substituted C1-C6 alkyl.
  • -SO2-optionally substituted C1-C6 alkyl is -SO2-methyl.
  • R 1 is -CO2-optionally substituted C1-C6 alkyl.
  • -CO2-optionally substituted C1-C6 alkyl is -CO2-methyl or -CO2-ethyl.
  • R 2 is a 5-membered optionally substituted C2-C9 heteroaryl.
  • R 2 is [1131] In further embodiments, R 2 is a 6-membered optionally substituted C2-C9 heteroaryl.25.
  • R 3 is wherein R 4 is -C(O)R 5 ; R 5 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C1-C6 alkyl C3-C8 cycloalkyl, or optionally substituted C1-C6 heteroalkyl C3-C8 cycloalkyl. [1136] In further embodiments, R 3 is optionally substituted C6-C10 aryl.
  • R 3 is phenyl, 4-cyano-phenyl, or 4-fluoro-phenyl.
  • the TDP-43 modulator compound is selected from the group consisting of (where the structure numbers are independent from the Formula numbers utilized herein):
  • the TDP-43 modulator may be selected from one of the following compounds according to Formula 238.
  • Such compounds are described in International Publication No. WO2021239915A1, published December 2, 2021, and corresponding to International Application No. PCT/EP2021/064274 filed May 27, 2021; US Patent No.8,133,882, issued March 13, 2012 and corresponding to US Application No.12/293,055 filed March 14, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 238, these references incorporated by reference herein control.
  • the TDP-43 modulator is a compound according to Formula 238: Formula 238 or a pharmaceutically acceptable salt thereof: wherein R 1 : a cycloalkyl or lower alkylene-cycloalkyl, wherein the cycloalkyl in R 1 may be substituted; R 2 : — H or a halogen; R 3 : — H, a halogen, — OR 0 or — O-lower alkylene-aryl; R°: the same or different from each other and each represents — H or a lower alkyl R 4 : a lower alkyl, halogeno-lower alkyl, lower alkylene-cycloalkyl, cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic group in R 4 may respectively be substituted; R 5 : — NO2, — CN, a lower alkyl, lower alkenyl, halogeno-lower alkenyl
  • the TDP-43 modulator compound is selected from the group consisting of: Further TDP-43 modulator embodiments [1142]
  • the TDP-43 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.
  • isotopes that can be incorporated into compounds of the disclosure at levels higher than natural abundance 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.
  • 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).
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • any pharmaceutically acceptable salts, or hydrates as the case may be.
  • 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. [1144] 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).
  • DMPK drug metabolism and pharmacokinetics
  • 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. [1145]
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as ⁇ " or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition.
  • PHARMACEUTICAL COMPOSITIONS [1146]
  • the metal channel activator in said pharmaceutical composition is a potassium channel activator.
  • the potassium channel activator in said pharmaceutical composition is a Kv7 channel activator.
  • 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.
  • the Kv7 channel activator in said pharmaceutical composition is a Kv7.2/7.3 channel activator.
  • 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 170 and the compounds disclosed in the “further embodiments” under the “METAL CHANNEL ACTIVATORS” subheading.
  • the TDP-43 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 238.
  • the TDP-43 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 238, 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 170 and the compounds disclosed in the “further embodiments” under the “METAL CHANNEL ACTIVATORS” subheading.
  • the TDP-43 modulator or a pharmaceutically acceptable salt thereof in said pharmaceutical composition is in a form of a prodrug.
  • the combination therapies disclosed herein are useful for treating or preventing various neurological and neurodegenerative disorders.
  • a method for treating or preventing a disease that involves TDP-43 including administering to a subject any of the above pharmaceutical compositions.
  • the disease may be selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), chronic traumatic encephalopathy (CTE), hippocampal sclerosis of aging (CARTS), inclusion body myositis (IBM), Alzheimer’s disease (AD), Alzheimer’s disease (AD) related disorders, or any combination thereof.
  • a method for treating or preventing a disease associated with TDP-43 proteinopathies including administering to a subject any of the above pharmaceutical compositions.
  • a method for treating or preventing a disease associated with TDP-43 proteinopathies and/or that can benefit from Kv7 channel activation including administering to a subject any of the above pharmaceutical compositions.
  • a method for treating or preventing a disease that can benefit from Kv7 channel activation including administering to a subject any of the above pharmaceutical compositions.
  • TDP-43 modulators of the present invention as positron emission tomography (PET) imaging agents, including administering to a subject any of the pharmaceutical compositions.
  • PET positron emission tomography
  • TDP-43 modulators of the present invention as single-photon emission computed tomography (SPECT) imaging agents, wherein the method includes administering to a subject any of the above pharmaceutical compositions including an isotopically labeled metal channel activator, an isotopically labeled TDP-43 modulator, or any combination thereof.
  • SPECT single-photon emission computed tomography
  • the pharmaceutical composition may be administered in a combination with at least one other agent known to treat amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), chronic traumatic encephalopathy (CTE), hippocampal sclerosis of aging (CARTS), inclusion body myositis (IBM), Alzheimer’s disease (AD), Alzheimer’s disease (AD) related disorders, or any combination thereof.
  • ALS amyotrophic lateral sclerosis
  • FTLD frontotemporal lobar degeneration
  • CTE chronic traumatic encephalopathy
  • CARTS hippocampal sclerosis of aging
  • IBM inclusion body myositis
  • AD Alzheimer’s disease
  • AD Alzheimer’s disease
  • AD Alzheimer’s disease
  • AD Alzheimer’s disease
  • AD Alzheimer’s disease
  • AD Alzheimer’s disease
  • the combination of Kv7 opener and TDP-43 modulator further includes at least one other agent.
  • the at least one other agent is riluzole, troriluzol
  • kits for treating a patient afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the metal channel activator; and (b) instructions for administering said metal channel activator in combination with [1164]
  • a kit is provided for treating a patient wherein the patient is afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the metal channel activator; and (b) instructions for administering said metal channel activator in combination with a TDP-43 modulator by one of the aforementioned methods.
  • kits for treating a patient wherein the patient is afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the TDP-43 modulator; and (b) instructions for administering said TDP-43 modulator with a metal channel activator by one of the aforementioned methods.
  • 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 – 180, Formulas 200 – 238, 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. [1169]
  • the TDP-43 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 TDP-43 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 TDP-43 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.
  • the TDP-43 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.
  • 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 TDP-43 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.
  • the metal channel activator will be administered at a time nearing the administration of the TDP-43 modulator e.g., within 1 week, 1 day, 1 hour, 1 minute before or after the TDP-43 modulator or simultaneously with the metal channel activator.
  • the dose of the TDP-43 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 TDP-43 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.
  • TDP-43 modulator or metal channel activator may 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.
  • 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.
  • a sublingual formulation useful in the present invention comprises an effective amount of a TDP-43 modulator, metal channel activator, or pharmaceutically acceptable salts, solvates, anomers, enantiomers, hydrates, or prodrugs thereof.
  • the formulation provides sufficient solubility for a TDP-43 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 TDP-43 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 TDP-43 modulator and/or a metal channel activator, which have 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 TDP-43 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.
  • the TDP-43 modulator and/or metal channel activator is provided in a sublingual formulation in a form of an orally dissolving or disintegrating tablet (ODT).
  • ODT as used herein may be prepared by mixing the TDP-43 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.
  • the excipients, including water are blended and the TDP-43 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.
  • the clinical or therapeutic effect of the sublingually formulated TDP-43 modulator may have an improved pharmacokinetic profile for the pharmaceutical agent as measured by standard testing parameters.
  • the T max , C max and AUC of the drug may be improved compared to the same dose of the orally administered version of the same compound.
  • the sublingual formulation of the TDP-43 modulator may have a greater C max than the orally administered TDP-43 modulator to provide a therapeutically beneficial effect.
  • the sublingual formulation of the TDP-43 modulator may have an earlier or lesser T max than the orally administered TDP-43 modulator to provide a therapeutically beneficial effect and in some instances, a more rapid therapeutic effect.
  • the sublingual formulation of the TDP-43 modulator may have a greater AUC per milligram of the agent than the orally administered TDP-43 modulator.
  • the TDP-43 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 of the inherent side effects.
  • 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 max , C max and AUC of the drug may be improved compared to the same dose of the orally administered version of the same compound.
  • the sublingual formulation of the metal channel activator may have a greater C max 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 T max than the orally administered metal channel activator to provide a therapeutically beneficial effect and in some instances, a more rapid therapeutic effect.
  • 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.
  • the metal channel activator may make the TDP-43 modulator more effective, lesser amounts of the TDP-43 modulator may be needed to achieve the same results lessening of the inherent side effects.
  • the disclosure and methods encompass all conventional modes of administration including oral, parenteral, intranasal, sublingual, topical, and transdermal methods.
  • 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
  • the route of administration may be oral, intranasal, inhalation, intravenous, sublingual, topical, injectable and/or transdermal.
  • the pharmaceutical compositions of the present invention comprising the TDP- 43 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.
  • 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.
  • compositions may comprise one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • pharmaceutically acceptable 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.
  • 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.
  • Examples of pharmaceutically acceptable carriers 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.
  • 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
  • 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.
  • 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.
  • TDP-43 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 TDP-43 modulators 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.
  • the TDP-43 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.
  • the carrier in powders, can be a finely divided solid, which is an admixture with a finely divided compound.
  • 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.
  • 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., corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • 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, e
  • 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.
  • 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.
  • a TDP-43 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.
  • suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents
  • 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.
  • 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.
  • the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • 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.
  • 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.
  • parenterally including intravenous, intraperitoneal, and subcutaneous injections
  • rectally vaginally
  • transdermally transdermally.
  • 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.
  • 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.
  • 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.
  • compositions 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. [1192]
  • 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.
  • 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.
  • 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.
  • 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. [1195]
  • 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.
  • 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.
  • a method of treating a neurological disease may be characterized by one or more pharmacokinetic parameters such as AUC, C max , T max , and others known and understood to persons of skill in the art.
  • pharmacokinetic as used herein is used in its ordinary sense to mean the pharmacokinetic aspects of drug delivery.
  • pharmacokinetics 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 TDP-43 modulators and/or metal channel activators.
  • a method of treating a neurological disease may be characterized by an AUC for a TDP-43 and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 238, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof.
  • the AUC 0-t and/or AUC 0-inf may be from about 80 – 125% of a given AUC value.
  • 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.
  • a systemic treatment may have a larger AUC than a localized (such as topical or subdermal) treatment.
  • a method of treating a neurological disease may be characterized by a C max for a TDP-43 and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 238, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof.
  • the C max may be from about 80 – 125% of a given C max value.
  • the C max 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.
  • a systemic treatment may have a larger C max than a localized (such as topical or subdermal) treatment.
  • a ratio C max /AUC may be used to characterize a method of treating a neurological disease wherein one or more of a TDP-43 and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 238, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof are administered to a subject.
  • the C max /AUC ratio may be from about 80 – 125 % of a given C max /AUC ratio.
  • the C max /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.
  • the T max may 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.
  • 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 max of a compound according to Formulas 1 – 180, Formulas 200 – 238, 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 – 180, Formulas 200 – 238, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof may alter the T max value by making it larger or smaller than a pharmaceutical composition having the excipient or carrier excluded.
  • 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.
  • liquid dosage units are 0.1 mg/mL, 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
  • a dose is daily.
  • a dose is twice daily.
  • a does is one, two, three, four, or five times daily.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 TDP- 43 modulator according to any one of Formulas 1 – 180, and/or a metal channel activator according to any one of Formulas 200 – 238, or a compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof .
  • 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 TDP-43 modulator according to any one of Formulas 1 – 180, and/or a metal channel activator according to any one of Formulas 200 – 238, or a compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof .
  • 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.
  • 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.

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Abstract

Provided is a pharmaceutical composition including a metal channel activator and a TDP-43 modulator. Also provided is a method of treating a depressive disorder, including administering the pharmaceutical composition. Also provided is a method of treating a neurological or neurodegenerative disorder, including administering the pharmaceutical composition. Also provided is a method of treating a pain disorder, including administering the pharmaceutical composition.

Description

COMBINATION THERAPIES INCLUDING METAL CHANNEL ACTIVATORS AND TDP-43 MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS This International Patent Application claims priority to United States Provisional Patent Application No.63/403,988, filed September 6, 2022 and United States Provisional Patent Application No.63/492,547, filed March 28, 2023, the contents of which applications are incorporated by reference in their entireties herein. TECHNICAL FIELD [0001] The present invention relates to combination therapies for treatment of various medical conditions. Specifically, the present invention relates to a combination of a metal channel activator and a modulator of the trans-activation response element (TAR) DNA-binding protein 43 (TDP-43) for treatment of neurological and neurodegenerative disorders. In particular, the metal channel activator may target the Kv7 family of voltage- gated potassium (K+) channels. BACKGROUND [0002] 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. [0003] 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. [0004] 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. [0005] TDP-43 (also known as TARBP and more formally known as transactive response DNA binding protein 43 kDa) is a multifaceted regulator of transcription and translation. TDP-43 enacts this function through both RNA and DNA binding domains. Although only a subset of patients with ALS have a genetic mutation related to TDP-43, aggregates of TDP-43 have been identified in 97% of ALS cases. These aggregates may be due to post translational modifications including ubiquitination, phosphorylation, acetylation, PARylation, and methylation, or due to mislocalization away from the nucleus. Counteracting these multifaceted aggregates is a major therapeutic objective for ALS. [0006] More generally, a pathological form of the transactive response (TAR) DNA binding protein (TDP-43) is known to bind to RNA in stress granules to form membraneless, amyloid-like TDP-43 aggregates in the cytoplasm of ALS motor neurons. Such aggregates cause RNA dysregulation, which contributes to disease pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurologic or neurodegenerative diseases. TDP-43 binders are known to prevent binding of TDP-43 to RNA, so they may be potentially useful to stop or at least slow down progression of ALS or another neurologic or neurodegenerative disease in a patient. [0007] Current treatment options for ALS and other neurological or neurodegenerative disorders are limited. For example, Riluzole is an approved treatment for ALS. Riluzole is believed to have anti-excitotoxic method of action, in part, through an anti- glutaminergic/Na+ blocking pathway. However, hyperexcitability may be a consequence of increased Na+ or decreased K+ conductance depending on age and disease stage. Analysis of K+ channels in sporadic ALS postmortem spinal cords suggests hypermethylation, down-regulation, and decreased K+ channel expression, suggesting a dysregulated potassium current in ALS pathology. Several aspects are not clear, such as whether hyperexcitability is intrinsic or synaptic, and how long it persists. [0008] It is disclosed that both modulating K+ channels and preventing binding of TDP- 43 to RNA as a result of a treatment regimen will more effectively treat ALS or other neurologic or neurodegenerative diseases. Therefore, administering a K+ channel modulator (or other metal ion channel modulator) in combination with a TDP-43 modulator will have a greater benefit than either therapy administered alone. As an alternative to a TDP-43 modulator, modulators of protein targets other than TDP-43 may be utilized which are effective to disaggregate TDP-43 or treat TDP-43 proteinopathies. Additionally, one or more K+ channel activators or TDP-43 modulators may have a dose-dependent adverse effect limiting their therapeutic window. However, the combination of a K+ channel activator and TDP-43 modulator will allow for use of lower doses of one or more of the K+ channel activator or TDP-43 modulator, to achieve improved treatment efficacy while reducing adverse effects, if any. It is disclosed that a Kv7 activator in combination with a TDP-43 modulator will more effectively treat, prevent, and/or slow the progression of ALS or other neurologic or neurodegenerative diseases compared to current available treatments. [0009] Described herein are compositions and methods for combination therapies of Kv7 openers with TDP-43 modulators. The combination therapies have treatment capabilities greater than Kv7 openers or TDP-43 modulators alone, and may be particularly useful for neurological diseases. Pharmaceutical compositions combining these agents may also be useful for treatment of a pain or depressive disorder. These two agents target distinct molecular targets associated with neurological diseases and neurodegenerative disorders such as ALS. Specifically, the Kv7 channel opener reduces excitability, and TDP-43 modulators reduce aggregation of TDP-43. We have found that combining Kv7 opener and a TDP-43 modulator will yield improved treatment outcomes as described herein. SUMMARY [0010] The present invention is directed to combination therapies including a metal channel activator and a TDP-43 modulator. [0011] In an embodiment, provided is a pharmaceutical composition including a metal channel activator and a TDP-43 modulator. [0012] In another embodiment, disclosed is a method for treating or preventing a disease that involves TDP-43, including administering to a subject the pharmaceutical composition. [0013] In another embodiment, disclosed is a method for treating or preventing a disease associated with TDP-43 proteinopathies, including administering to a subject the pharmaceutical composition. [0014] In another embodiment, disclosed is a method for treating or preventing diseases that involve excess amounts of TDP-43 in the cytosol, including administering to a subject the pharmaceutical composition. DETAILED DESCRIPTION [0015] 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. [0016] 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. [0017] 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. [0018] 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. [0019] 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. [0020] 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. [0021] The articles "a" and "an" refer to one or to more than one (i.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. [0022] 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 C1-C10 alkoxy group, a C1 to C10 trifluoroalkyl group such as a trifluoromethyl group (-CF3) and the like, or a cyano group (-CN) instead of at least one hydrogen of a substituting group or compound. [0023] 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 TDP-43) may each or both be small molecule compounds, proteins, antibody fragments or antibodies, or any other construct effecting modulation. [0024] As used herein, “TDP-43 modulator” may target TAR DNA binding protein 43 (TDP-43), or other human proteins known in the art to modulate TDP-43, including but not limited to mitochondrial permeability transition pore (mPTP), phosphatidylinositol-3- phosphate 5-kinase type III (PIKfyve), Cytochrome P450 Family 51 Subfamily A Member 1 (CYP51A1), and Forkhead Box O (FOXO) family proteins. TDP-43 modulators may target any other human protein modulating or effecting modulation of TDP-43, as appreciated by a person of skill in the art. [0025] 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-Barré 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), Klüver-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, Sjögren'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. [0026] As used herein, the term “metal channel activator” is construed to include both metal channel activator and pharmaceutically acceptable salt thereof. [0027] As used herein, the term “TDP-43 modulator” is construed to include both TDP- 43 modulator and pharmaceutically acceptable salt thereof. [0028] 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. [0029] 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. [0030] 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. [0031] 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. [0032] Additional aspects will be set forth in part of the description which follows and, in part, will be apparent from the description. [0033] 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., R1, 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 ACTIVATORS [0034] Amyotrophic lateral sclerosis (ALS) is a neurological disorder characterized by progressive upper and lower motor neuron degeneration, leading to muscular atrophy and eventually fatal paralysis. A now appreciated characteristic of ALS is hyperexcitability of motor neurons (Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep.2014 Apr 10;7(1):1-11. doi: 10.1016/j.celrep.2014.03.019. Epub 2014 Apr 3. PMID: 24703839; PMCID: PMC4023477). Mutations in metal channels, and in particular mutations in the Kv7 family of voltage-gated potassium (K+) channels have been implicated in hyperexcitability disorders (Jepps TA, Barrese V, Miceli F. Editorial: Kv7 Channels: Structure, Physiology, and Pharmacology. Front Physiol.2021 Apr 16;12:679317. doi: 10.3389/fphys.2021.679317. PMID: 33935812; PMCID: PMC8085343). The Kv7 family includes Kv7.1-7.5 corresponding to the KCNQ1-5 genes. Kv7 channel activators, a subset of metal channel activators, can reduce hyperexcitability of neurons. This suggests that treatment of ALS patients with Kv7 channel activators may reduce ALS symptomology. Thus, in combination with TDP-43 as described herein, effective treatment outcomes are obtained for ALS. [0035] Examples of metal channel activators including Kv7 channel activators are disclosed in Formulas 1 – 170, the “Further embodiments” section, and in the corresponding referenced applications. Formula 1 [0036] 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. [0037] In an embodiment, the Kv7 channel activator is a compound according to formula 1: rmula 1
Figure imgf000012_0001
wherein D is optionally substituted C3-6 carbocyclyl, optionally substituted C2-5 heterocyclyl, isopropyl, or t-butyl; Bz is optionally substituted benzoimidazol-1,2-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. [0038] In further embodiments, D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl. [0039] 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. [0040] 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-1,2-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. [0041] In further embodiments, D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl. [0042] 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. [0043] In further embodiments, R1 is H, Cl, Br, CN, OCH3, CF3, —CO2CH2CH3, C1- 4 alkyl, or C1-4 hydroxyalkyl. [0044] In further embodiments, X is optionally substituted phenyl. [0045] In further embodiments, X is CF3. [0046] In further embodiments, X is optionally substituted pyridinyl. [0047] In further embodiments, X is H. [0048] In further embodiments, Y is H. [0049] In further embodiments, Y is OH. [0050] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Formula 2 [0051] 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. [0052] In an embodiment, the Kv7 channel activator is a compound according to formula 2: Formula 2
Figure imgf000024_0001
, 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; R1 is F, Cl, Br, CN, OCH3, CHF2, CF3, C1-4 —CO2-alkyl, C1-4 alkyl, — CH2CO2H, —CH2CO2CH2CH3 or —CH2CON(CH3)2, or C1-5 hydroxyalkyl; and R2, R3, and R4 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. [0053] In further embodiments, Y is H, F, CF3, OH, C1-5 O-alkyl, C0-6 alkylamino, optionally substituted tetrahydropyranyl, or C0-6 fluoroalkylamino. [0054] In further embodiments R1 is Cl, Br, —OCH3, —CN, —CF3, —CH2OH, — COOCH2CH3, —C(CH3)2OH, —CHOHCH2CH3, —CHOHCH3, —CHF2, —CH(CH3)2, — C(CH2CH3)2OH, —CH2COOCH2CH3, —CH2C(CH3)2OH, —CH2COOH, or — CH2CON(CH3)2. [0055] In further embodiments, R2 is H, F, —CH2OH, —CO2Me, or —C(CH3)2OH. [0056] In further embodiments, R3 is H. [0057] In further embodiments, R4 is H, —CH3, or —CF3. [0058] In further embodiments, R1 is Cl, Br, CN, OCH3, CF3, —CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl. [0059] In further embodiments, X is optionally substituted phenyl. [0060] In further embodiments, X is CF3. [0061] In further embodiments, X is optionally substituted pyridinyl. [0062] In further embodiments, X is H. [0063] In further embodiments, Y is H. [0064] In further embodiments, Y is OH. [0065] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
[0066] 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; R1 is CN or C1-4 hydroxyalkyl; and R2, R3, and R4 are independently H, or F. [0067] In further embodiments, R1 is CN, —C(CH3)2OH, or —CH2C(CH3)2OH. [0068] In further embodiments, R2 is F. [0069] In further embodiments, R3 is H. [0070] In further embodiments, R4 is H. [0071] In further embodiments, R1 is CN. [0072] In further embodiments, R1 is C1-4 hydroxyalkyl. [0073] In further embodiments, X is optionally substituted phenyl. [0074] In further embodiments, X is CF3. [0075] In further embodiments, X is H. [0076] In further embodiments, Y is H. [0077] In further embodiments, Y is OH. [0078] 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; R1 is H, Cl, Br, CN, OCH3, CF3, —CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, —CH2OH, — CO2Me, or —C(CH3)2OH; R3 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 R4 is H, —CH3, or —CF3; or D is optionally substituted cyclobutyl; A is C1-8 alkyl; X is CF3; Y is H; R1 is H, Cl, Br, CN, OCH3, CF3, —CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, —CH2OH, —CO2Me, or —C(CH3)2OH; R3 is H; and R4 is H, —CH3, or —CF3; or D is t-butyl; A is C1-8 alkyl; X is H; Y is H; R1 is Cl, Br, CN, OCH3, CF3, — CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, —CH2OH, —CO2Me, or — C(CH3)2OH; R3 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 R4 is H, —CH3, or —CF3 ; or D is t-butyl; A is C1-8 alkyl; X is CF3; Y is H; R1 is H, Cl, Br, CN, OCH3, CF3, — CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, —CH2OH, —CO2Me, or — C(CH3)2OH; R3 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 R4 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; R1 is H, Cl, Br, CN, OCH3, CF3, —CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, — CH2OH, —CO2Me, or —C(CH3)2OH; R3 is H; and R4 is H, —CH3, or —CF3; or D is cyclobutyl; A is C1-8 alkyl; X is CF3; Y is dimethylamino; R1 is H, Cl, Br, CN, OCH3, CF3, —CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, —CH2OH, — CO2Me, or —C(CH3)2OH; R3 is H; and R4 is H, —CH3, or —CF3; 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 C1 alkyl; X is substituted cyclobutyl, wherein the substituent is F;Y is H; R1 is selected from H, C3 hydroxyalkyl, CN, F, or Cl; R2 is selected from H, CN, F, Br, or — OCF3; R3 is selected from H, F, or —OCH3; R4 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; [0079] In an embodiment, the Kv7 channel activator is a compound according to formula 2. Wherein, R1, R2, R3, and R4 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. [0080] In further embodiments, Y is H, F, CF3, OH, C1-5 O-alkyl, C0-6 alkylamino, optionally substituted tetrahydropyranyl, or C0-6 fluoroalkylamino. [0081] In further embodiments, R1 is H, Cl, Br, —OCH3, —CN, —CF3, —CH2OH, — COOCH2CH3, —C(CH3)2OH, —CHOHCH2CH3, —CHOHCH3, —CHF2, —CH(CH3)2, — C(CH2CH3)OH, —CH2COOCH2CH3, —CH2C(CH3)2OH, —CH2COOH, or — CH2CON(CH3)2. [0082] In further embodiments, R2 is H, F, —CH2OH, —CO2Me, or —C(CH3)2OH. [0083] In further embodiments, R3 is H. [0084] In further embodiments, R4 is H, —CH3, or —CF3. [0085] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000037_0001
Figure imgf000038_0001
or a pharmaceutically acceptable salt thereof. [0086] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof. [0087] In further embodiments the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof. [0088] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000041_0001
or a pharmaceutically acceptable salt thereof. [0089] In further embodiments, the compound is:
Figure imgf000041_0002
or a pharmaceutically acceptable salt thereof. [0090] In further embodiments, the compound is:
Figure imgf000042_0002
or a pharmaceutically acceptable salt thereof. [0091] In further embodiments, the compound is:
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof. [0092] In further embodiments, the compound is:
Figure imgf000042_0003
or a pharmaceutically acceptable salt thereof. [0093] In further embodiments, the compound is:
Figure imgf000042_0004
or a pharmaceutically acceptable salt thereof. [0094] In further embodiments, the compound is:
or a pharmaceutically acceptable salt thereof. [0095] In further embodiments, the compound is: 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: or a pharmaceutically acceptable salt thereof. [0098] In further embodiments, the compound is:
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof. [0099] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000044_0002
or a pharmaceutically acceptable salt thereof. [0100] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000045_0001
or a pharmaceutically acceptable salt thereof. [0101] In further embodiments, the Kv7 channel activator is a compound selected from the group consisting of:
Figure imgf000046_0001
Figure imgf000047_0001
[0102] In further embodiments, the compound is:
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof. [0103] In further embodiments, the compound is:
Figure imgf000048_0002
or a pharmaceutically acceptable salt thereof. [0104] In further embodiments, the compound is:
Figure imgf000048_0003
or a pharmaceutically acceptable salt thereof. [0105] In further embodiments, the compound is:
Figure imgf000049_0001
or a pharmaceutically acceptable salt thereof. [0106] In further embodiments, the compound is:
Figure imgf000049_0002
or a pharmaceutically acceptable salt thereof. [0107] In further embodiments, the compound is:
Figure imgf000049_0003
or a pharmaceutically acceptable salt thereof. [0108] In further embodiments, the compound is:
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof. [0109] In further embodiments, the compound is:
Figure imgf000050_0002
or a pharmaceutically acceptable salt thereof. [0110] In further embodiments, the compound is:
Figure imgf000050_0003
or a pharmaceutically acceptable salt thereof. [0111] In further embodiments, the compound is:
Figure imgf000051_0001
or a pharmaceutically acceptable salt thereof. [0112] In further embodiments, the compound is:
Figure imgf000051_0002
or a pharmaceutically acceptable salt thereof. [0113] In further embodiments the compound is:
Figure imgf000051_0003
or a pharmaceutically acceptable salt thereof. [0114] 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, R1 is CN or C1-4 hydroxyalkyl; and R2, R3, and R4 are independently H, or F. In a further embodiment, R1 is CN, -C(CH3)2OH, or -CH2C(CH3)2OH. In a further embodiment, R2 is F. In a further embodiment, R3 is H. In a further embodiment, R4 is H. In a further embodiment, R1 is CN. In a further embodiment, R1 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. [0115] In an embodiment of Formula 2, D is cyclobutyl; A is C1-8 alkyl, X is CF3, Y is H, R1 is H, Cl, Br, CN, OCH3, CF3, -CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, -CH2OH, -CO2Me, or -C(CH3)2OH; R3 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 R4 is H, -CH3, or -CF3. [0116] In an embodiment of Formula 2, D is optionally substituted cyclobutyl, A is C1-8 alkyl, X is CH3, Y is H, R1 is H, Cl, Br, CN, OCH3, CF3, -CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, -CH2OH, -CO2Me, or -C(CH3)2OH; R3 is H; and R4 is H, -CH3, or -CF3. [0117] In an embodiment of Formula 2, D is t-butyl; A is C1-8 alkyl; X is H; Y is H; R1 is Cl, Br, CN, OCH3, CF3, -CO2CH2CH3, C1-4alkyl, or C1-4 hydroxyalkyl; R2 is H, F, - CH2OH, -CO2Me, or -C(CH3)2OH; R3 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 R4 is H, -CH3, or -CF3. [0118] In an embodiment of Formula 2, D is t-butyl; A is C1-8 alkyl; X is CF3; Y is H; R1 is H, Cl, Br, CN, OCH3, CF3, -CO2CH2CH3, C1-4alkyl, or C1-4 hydroxyalkyl; R2 is H, F, - CH2OH, -CO2Me, or -C(CH3)2OH; R3 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 R4 is H, CH3, or CF3. [0119] 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; R1 is H, Cl, Br, CN, OCH3, CF3, -CO2CH2CH3, C1-4 alkyl, or C1-4 hydroxyalkyl; R2 is H, F, -CH2OH, -CO2Me, or -CH(CH3)2OH; R3 is H; and R4 is H, -CH3, or -CF3. [0120] 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 C1 alkyl, X is substituted cyclobutyl, wherein the substituent is F; Y is H; R1 is selected from H, C3 hydroxyalkyl, CN, F, or Cl; R2 is selected from H, CN, F, Br, or -OCF3; R3 is selected from H, F, or -OCH3; R4 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. [0121] In an embodiment, the Kv7 channel activator is a compound according to formula 3: Formula 3 , wherein, R1 and R2, vary independently, and are selected from the group consisting of H, CN, halogen, CH2CN, OH, CH2F, CHF2, CF3, CF2CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl; NH—C1-C6 alkyl; N(C1-C6 alkyl)-C1-C6 alkyl, NHC(═O)C1-C6 alkyl, C(═O)N(CH3)2, C(═O)N(Et)2, C(═O)NH2, C(═O)NH—C1-C6alkyl, SO2NH2, NHSO2—C1-C6 alkyl; C(═O)OC1-C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SC1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl, C2- C6 alkynyl, Ar, (CH2)mthienyl, (CH2)mimidazolyl, (CH2)mpyrazyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, and (CH2)mpyrimidyl, 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 R1 and R2, 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, CF3, OC1-C3 alkyl and C1-C3 alkyl; R3 and R4 vary independently, and are selected from the group consisting of H, CN, halogen, CF3, OCF3, OC1-C3 alkyl, and C1-C3 alkyl; X is O or S; Y is O or S; q=1 or zero; and R5 is selected from the group consisting of C1- C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3- C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5- C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar, 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 R6 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 R1, R2, R′, R3, R4, R5, R6, 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. [0122] In further embodiments, R1 and R2, vary independently, and are selected from the group consisting of H, halogen, CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, C(═O)OC1- C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SCH3, C3-C6 cycloalkyl, (CH2)mC3- C6 cycloalkyl, phenyl, pyridyl, pyrrolyl, thienyl, (CH2)mphenyl, (CH2)mpyrrolyl, and (CH2)mpyridyl; 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 R4 vary 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=1 or 0; R5 is selected from the group consisting of C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR7)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 R6 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 R1, R2, R3, R4, R5, R6, 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. [0123] In further embodiments, R1 and R2, vary independently, and are selected from the group consisting of H, halogen, CF3, C1-C6 alkyl, C(═O)C1-C6 alkyl, C(═O)OC1- C6 alkyl, OC(═O)C1-C6 alkyl, OC1-C6 alkyl, SCH3, (CH2)m cyclopropyl, (CH2)mcyclobutyl, (CH2)m cyclopentyl, (CH2)m cyclohexyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolyl, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl, and (CH2)mpyrimidyl; 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 R4 vary 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=1 or 0; R5 is selected from the group consisting of C1- C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3- C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5- C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar; 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; R6 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 R1, R2, R3, R4, R5, R6, 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. [0124] In further embodiments, R1 and R2, vary independently, and are selected from the group consisting of H, halogen, CF3, OC1-C3 alkyl, C1-C6 alkyl, C(═O)OC1-C3 alkyl, OC(═O)C1-C3 alkyl, and C(═O)C1-C3 alkyl; R′ is selected from the group consisting of H, F, CH3, and ethyl; R3 and R4 vary independently, and are selected from the group consisting of H, F, Cl, CF3, OCF3, OC1-C3 alkyl, and C1-C3 alkyl; and R5 is C1-C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, or (CHR6)wAr, CH2(CHR6)wAr, or (CHR6)wCH2Ar. [0125] In further embodiments, R2 is H or F; R′ is H; R3 is selected from the group consisting of H, CH3, OCH3, CF3, OCF3, and Cl; R4 is selected from the group consisting of CH3, OCH3, CF3, OCF3, and Cl; and R5 is C3-C6 alkyl or (CH2)wC3-C6 cycloalkyl. [0126] In further embodiments, R1 is halogen or CF3; R2 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 C1-C6 alkyl, (CHR6)wC3- C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3- C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5- C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar. [0127] In further embodiments, R1 is halogen or CF3; R2 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 C1-C6 alkyl, (CHR6)wC3- C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3-C6 cycloalkyl, CR6═CH—C3- C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5-C6 cycloalkenyl, CH2(CHR6)wC5- C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar. Formula 4 [0128] 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. [0129] In an embodiment, the Kv7 channel activator is a compound according to formula 4: Formula 4
Figure imgf000057_0001
, wherein, R1 is selected from the group consisting of H, halogen, CN, CH2CN, CF3, C1- C6 alkyl, OCH3, (C═O)OCH3, O(C═O)CH3, OCF3, (CH2)mC3-C6 cycloalkyl, phenyl, and pyridyl; R2 is selected from the group consisting of H, F, OCH3, CH3, and CF3; R3 and R4 vary 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 C1- C6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, CH2(CHR6)wC3- C6 cycloalkyl, CR6═CH—C3-C6 cycloalkyl, CH═CR6—C3-C6 cycloalkyl, (CHR6)wC5- C6 cycloalkenyl, CH2(CHR6)wC5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6)wAr, CH2(CHR6)wAr, and (CHR6)wCH2Ar, wherein w=0-3; Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl; and R6 is C1-C3 alkyl; wherein all alkyl, cycloalkyl, aryl, and heteroaryl groups in R1, R2, R3, R4, R5, R6, 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 CF3. [0130] In other embodiments, R1 is selected from the group consisting of H, F, Cl, Br, CF3, C1-C6 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 R5 is selected from the group consisting of C1-C6 alkyl, CH2C3- C6 cycloalkyl, CH2CH2C3-C6 cycloalkyl, CH═CH—C3-C6 cycloalkyl, CH═CH—C5- C6 cycloalkenyl, CH2C5-C6 cycloalkenyl, CH2CH2C5-C6 cycloalkenyl, C2-C6 alkenyl, and (CH2)wAr; wherein w=1 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 R1, R2, R3, R4, R5, R6, and Ar are optionally substituted with one or two substituents selected independently from the group consisting of CH3, halogen, OCH3, OCH2CH3, CN, and CF3. [0131] In other embodiments, R1 is selected from the group consisting of H, F, Cl, Br, CF3, C1-C6 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 R5 is selected from the group consisting of C1-C6 alkyl, CH2C3- C6 cycloalkyl, CH2CH2C3-C6 cycloalkyl, CH═CH—C3-C6 cycloalkyl, CH═CH—C5- C6 cycloalkenyl, CH2C5-C6 cycloalkenyl, CH2CH2C5-C6 cycloalkenyl, C2-C6 alkenyl, and (CH2)wAr; wherein w=1 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 R1, R2, R3, R4, R5, R6, 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, R1 is selected from the group consisting of F, CF3, Cl, CH3, CH2CH3, SCH3, OCH3, CH2OCH3, CH2OCH2CH3, OCF3, phenyl, thienyl, and H; R2 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)wAr, and (CH2)wC5-C6 cycloalkyl; wherein w is 1, 2, or 3. [0132] In other embodiments, R1 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. [0133] In other embodiments, R3 and R4 are both CH3 or both OCH3; and R5 is C5- C6 alkyl. [0134] In other embodiments, R′ and R2 are H; R3 and R4 are both methyl; and R5 is C5- C6 alkyl or (CH2)wC5-C6 cycloalkyl; wherein w is 1, 2, or 3. [0135] In other embodiments, the compound is selected from the group consisting of: N- (2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3- dimethylbutanamide; N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3- dimethylbutanamide; N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6- (trifluoromethyl)phenyl)-3-cyclopentylpropanamide; N-(2-chloro-4-(6-fluoro-3,4- dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethylphenyl)-3,3-dimethylbutanamide; N-[2- chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl phenyl]-3,3-dimethylbutanamide; N- [2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl phenyl]-3- cyclopentylpropionamide; N-[2,6-dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H- isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide; N-[2-chloro-6-trifluoromethyl-4-(6- trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide; N-[2- chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl phenyl]-3,3- dimethylbutanamide; N-[4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl- phenyl]-3,3-dimethylbutanamide; N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6- dimethyl phenyl]-3,3-dimethylbutanamide; N-[2-chloro-4-(7-fluoro-3,4-dihydro-1H- isoquinolin-2-yl)-6-trifluoromethyl-phenyl]-3,3-dimethylbutanamide; N-[4-(7-fluoro-3,4- dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide; N-[2-chloro- 4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide; N- [2-chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3- dimethylbutanamide; N-[2-chloro-6-methyl-4-(6-trifluoromethyl-3,4-dihydro-1H- isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide; N-[2-chloro-4-(6-chloro-3,4-dihydro- 1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethylbutanamide; N-[2-chloro-4-(6-fluoro- 3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide; N-[4-(6-fluoro-3,4- dihydro-1H-isoquinolin-2-yl)-2-methyl-phenyl]-3,3-dimethylbutanamide; N-[4-(6-fluoro- 3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethylphenyl]-3,3-dimethylbutanamide; N-[2- chloro-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3- dimethylbutanamide; N-[4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethyl- phenyl]-3,3-dimethylbutanamide; 3,3-dimethyl-N-[2-trifluoromethyl-4-(7-trifluoromethyl- 3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]butanamide; N-[4-(6-methoxy-3,4-dihydro-1H- isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide; N-[4-(3,4-dihydro-1H- isoquinolin-2-yl)-2-methoxy-6-methyl-phenyl]-3,3-dimethylbutanamide; N-[2-chloro-4- (3,4-dihydro-1H-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-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl butanamide; N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)- phenyl]-3,3-dimethyl-thiobutanamide; [2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H- isoquinolin-2-yl)-phenyl]-carbamic acid ethyl ester; and N-[2,6-Dimethyl-4-(7- trifluoromethyl-3,4-dihydro-1H-isoquinolin-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. [0136] In an embodiment, the Kv7 channel activator is a compound according to formula 5: Formula 5 ,
Figure imgf000061_0001
optionally wherein the compound is substituted at any position. Formula 6 [0137] 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. ula 6
Figure imgf000061_0002
, 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. [0138] In an embodiment, the Kv7 channel activator is a compound according to formula 7: mula 7
Figure imgf000062_0001
, wherein, L is CH2; R1 is optionally substituted cyclic C3H5, wherein the optional substituent of R1 is CF3; R2 is optionally substituted cyclobutyl; R3 is optionally substituted C3 alkyl, wherein the optional substituent of R3 is OH; R4 is H; and R5 is H; or wherein, L is CH2; R1 is optionally substituted C2 alkyl, wherein the optional substituents of R1 are independently CF3 or CH3; R2 is optionally substituted cyclobutyl; R3 is optionally substituted C3 alkyl, wherein the optional substituent of R3 is OH; R4 is H; and R5 is H; or wherein, wherein L is CH2, CF2, CHCH3, CH2CH2, C3H6, CH2O, C2H4O, or C3H6O with the O of CH2O, C2H4O, or C3H6O bonded with R1; wherein R1 is optionally substituted C1-2 alkyl, optionally substituted C5-10 cycloalkyl, optionally substituted C1- 12 —O-alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 —O-aryl, or optionally substituted C2-9 heterocyclyl, wherein the optional substituents of R1 are independently RA, F, Cl, CN, ORA, CF3, NRARB, CORA, CO2RA, OCORA, NRACORB, CONRARB, wherein RA and RB are independently H or C1-12 alkyl; wherein R2 is optionally substituted C2-4 acyclic alkyl, optionally substituted cyclobutyl, optionally substituted C6-10 aryl, or optionally substituted C2-9 heterocyclyl, wherein the optional substituents of R2 are independently F, Cl, Br, I, CN, C1-6 alkyl, C1-6 —O-alkyl, C1- 6 alkylamine, C1-6 aminoalkyl, C1-6 aminoacyl, C1-6 alkylthio, or C1-6 alkylsulfonyl; wherein R3, R4, and R5 are independently H, F, Cl, Br, I, CN, optionally substituted C1-12 alkyl, optionally substituted C1-12 —O-alkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C6-10 aryl, optionally substituted C2-9 —O-heterocyclyl, optionally substituted C6-10 O-aryl, optionally substituted C1-12 acylamino, optionally substituted C1- 12 aminoacyl, or optionally substituted C1-12 aminoalkyl, wherein the optional substituents of R3, R4, or R5 are independently F, Cl, Br, I, CN, C1-6 alkyl, C1-6 —O-alkyl, C1- 6 alkylamine, C1-6 aminoalkyl, C1-6 aminoacyl, C1-6 acylamino, C1-6 alkylthio, or C1- 6 alkylsulfonyl. [0139] In further embodiments, R2 is optionally substituted C4H9, optionally substituted cyclobutyl, optionally substituted C6-10 aryl, or optionally substituted C2-9 heterocyclyl. [0140] In further embodiments, R2 is optionally substituted C4H9, or optionally substituted cyclobutyl. [0141] In further embodiments, R2 is optionally substituted phenyl, or optionally substituted C2-9 heterocyclyl. [0142] In further embodiments, R1 is optionally substituted phenyl. [0143] In further embodiments, R1 is optionally substituted phenyl. [0144] In further embodiments, R1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl. [0145] In further embodiments, R1 is C2-4 —O-alkyl. [0146] In further embodiments, R1 is optionally substituted tetrahydrofuranyl or optionally substituted tetrahydro-2H-pyranyl. [0147] In further embodiments, R1 is selected from the group consisting of:
Figure imgf000064_0001
[0148] In further embodiments, R2 is selected from the group consisting of:
Figure imgf000065_0001
[0149] In further embodiments, R3 is CF3, Cl, CN, OCH3, or H. [0150] In further embodiments, R1 is selected from the group consisting of:
Figure imgf000066_0001
[0151] In further embodiments, R4 is CH3, CF3, Cl, or H. [0152] In further embodiments, R2 is selected from the group consisting of:
Figure imgf000067_0001
[0153] In further embodiments, the Kv7 channel activator is selected from the group consisting of:
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
[0154] In further embodiments, the Kv7 channel activator is selected from the group consisting of:
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
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. [0155] In an embodiment, the Kv7 channel activator is a compound according to formula 8: Formula 8
Figure imgf000084_0002
, wherein, L is CH2, CF2, CHCH3, CH2CH2, C3H6, CH2O, C2H4O, or C3H6O with the O of CH2O, C2H4O, or C3H6O bonded with R1; wherein R1 is optionally substituted C1-2 alkyl, optionally substituted C5-10 cycloalkyl, optionally substituted C1-12 —O-alkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 —O-aryl, or optionally substituted C2- 9 heterocyclyl, wherein the optional substituents of R1 are independently RA, F, Cl, CN, ORA, CF3, NRARB, CORA, CO2RA, OCORA, NRACORB, CONRARB, wherein RA and RB are independently H or C1-12 alkyl; wherein R2 is optionally substituted C2-4 acyclic alkyl, optionally substituted cyclobutyl, optionally substituted C6-10 aryl, or optionally substituted C2-9 heterocyclyl, wherein the optional substituents of R2 are independently F, Cl, Br, I, CN, C1-6 alkyl, C1-6 —O-alkyl, C1-6 alkylamine, C1-6 aminoalkyl, C1-6 aminoacyl, C1-6 alkylthio, or C1-6 alkylsulfonyl; wherein R3, R4, and R5 are independently H, F, Cl, Br, I, CN, optionally substituted C1-12 alkyl, optionally substituted C1-12 —O-alkyl, optionally substituted C2-9 heterocyclyl, optionally substituted C6-10 aryl, optionally substituted C2- 9 —O-heterocyclyl, optionally substituted C6-10 O-aryl, optionally substituted C1- 12 acylamino, optionally substituted C1-12 aminoacyl, or optionally substituted C1- 12 aminoalkyl, wherein the optional substituents of R3, R4, or R5 are independently F, Cl, Br, I, CN, C1-6 alkyl, C1-6 —O-alkyl, C1-6 alkylamine, C1-6 aminoalkyl, C1-6 aminoacyl, C1- 6 acylamino, C1-6 alkylthio, or C1-6 alkylsulfonyl. [0156] In further embodiments, R2 is optionally substituted C4H9, optionally substituted cyclobutyl, optionally substituted C6-10 aryl, or optionally substituted C2-9 heterocyclyl. [0157] In further embodiments, R2 is optionally substituted C4H9, or optionally substituted cyclobutyl. [0158] In further embodiments, R2 is optionally substituted phenyl, or optionally substituted C2-9 heterocyclyl. [0159] In further embodiments, R1 is optionally substituted phenyl. [0160] In further embodiments, R1 is optionally substituted phenyl. [0161] In further embodiments, R1 is optionally substituted cyclopentyl or optionally substituted cyclohexyl. [0162] In further embodiments, R1 is C2-4 —O-alkyl. [0163] In further embodiments, R1 is optionally substituted tetrahydrofuranyl or optionally substituted tetrahydro-2H-pyranyl. [0164] In further embodiments, R1 is selected from the group consisting of:
Figure imgf000086_0001
[0165] In further embodiments, R2 is selected from the group consisting of:
Figure imgf000086_0002
[0166] In further embodiments, R3 is CF3, Cl, CN, OCH3, or H. [0167] In further embodiments, R1 is selected from the group consisting of:
Figure imgf000087_0001
[0168] In further embodiments, R4 is CH3, CF3, Cl, or H.
[0169] In further embodiments, R2 is selected from the group consisting of:
Figure imgf000088_0001
Formula 9 [0170] 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. [0171] In an embodiment, the Kv7 channel activator is a compound according to formula 9: Formula 9
Figure imgf000089_0001
wherein, R1 is selected from the group consisting of C1-C6 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, C1-C6 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 CH2O—C1-3 alkyl, said C1-C3 alkyl or CH2O—C1-C3 is alkyl substituted with C≡N, 3 F or C3-C5 cycloalkyl; R4 is selected from the group consisting of OCF3, or OCHF2 [0172] In further embodiments, R4 is OCF3 or OCHF2. [0173] In further embodiments, R3 is selected from the group consisting of CH2—O— CF3, CH2—O— cyclopropyl, CH2—C≡N. [0174] In further embodiments R1 is C3-C4 cycloalkyl optionally substituted with 1 or 2 C1-C3 alkyl, F, CHF2 or CF3. [0175] In further embodiments, R1 and R2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R4 is OCF3 or OCHF2. [0176] In further embodiments, the Kv7 channel activator is selected from the group consisting of: (S)—N—((R)-2-cyclopropoxy-1-(3-(difluoromethoxy) phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-1-(3-(difluoromethoxy)phenyl)-2- (trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-1-(3- (trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4- dimethylpentanamide; (S)—N—((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide; (S)—N—((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl) propyl)-3-hydroxy-4,4-dimethylpentanamide; (R)—N-(2-cyclopropoxy-1-(3- (trifluoromethoxy) phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)—N- (2-cyclopropoxy-1-(3-(difluoromethoxy) phenyl)ethyl)-2-(3,3-difluoro-1- hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3- (difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetamide; and (S)—N-(2-cyano-1- (3-(trifluoromethoxy) phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide or a pharmaceutically acceptable salt of any of these compounds. [0177] In further embodiments, the Kv7 channel activator is selected from the group consisting of (R)—N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4- dimethylpentanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-3-hydroxy-4,4- dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl) pentanamide; (R)-3-hydroxy- 4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy) phenyl)ethyl)pentanamide; (R)—N— ((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro- methyl)cyclopropyl)propanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro- methyl)cyclopropyl)propanamide; (R)—N—((R)-2-(difluoromethoxy)-1-(3- (trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1- (trifluoromethyl)cyclopropyl)propanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3- (trifluoromethoxy)phenyl) ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl) propanamide; (R)-3-(3,3-difluorocyclobutyl)-N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)- N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3- hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N—((R)-2-(difluoromethoxy)-1-(3- (trifluoromethoxy)phenyl) ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)- N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3- hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N—((S)-1-(3- (difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)- N—((S)-1-(3-(difluoromethoxy) phenyl)butyl)-3-hydroxypropanamide; (S)—N—((R)-2- (difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3- hydroxypropanamide; (R)—N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (S)—N—((S)-1-(3- (difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N—((S)-1-(3- (difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide; (S)— N—((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4- dimethylpentanamide; (S)—N—((S)-1-(3-(difluoromethoxy) phenyl)ethyl)-3-hydroxy-4,4- dimethylpentanamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)- 1-(3-(difluoromethoxy)phenyl) ethyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)- N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(3,3- difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)butyl)acetamide; (S)-2- (3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4- difluorobutyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(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-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4- dimethylpentanamide; (R)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)—N— ((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) ethyl)-3-(1-fluorocyclopropyl)-3- hydroxybutanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3- (trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)—N— ((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl) ethyl)-3-(1-fluorocyclopropyl)-3- hydroxybutanamide; (R)-3-cyclopropyl-N—((R)-2-(difluoromethoxy)-1-(3- (trifluoromethoxy)phenyl) ethyl)-3-hydroxybutanamide; (S)-3-cyclopropyl-N—((R)-2- (difluoromethoxy)-1-(3-(trifluoromethoxy) phenyl)ethyl)-3-hydroxybutanamide; (R)—N— ((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3- methylpentanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (R)— N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5- dimethylhexanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide; (S)—N—((R)-2- (difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4- dimethylpentanamide; (R)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide; (S)—N—((R)-2- (difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3- hydroxypropanamide; (R)—N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide; (S)-3- cyclopentyl-N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3- hydroxypropanamide; (R)-3-cyclopentyl-N—((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(1-fluorocyclopropyl)-3- hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide; and (S)-3- (1-fluorocyclopropyl)-3-hydroxy-N—((R)-2-methoxy-1-(3- (trifluoromethoxy)phenyl)ethyl)butanamide; or a pharmaceutically acceptable salt of any of these compounds. [0178] In further embodiments, the Kv7 channel activator is a compound according to formula 8 wherein R1 is selected from the group consisting of C1-C6 alkyl, CF3, CH2CF3, CF2CHF2, C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl may be substituted with 1 or 2 F, CHF2 or CF3, and R2 is H, C1-C6 alkyl or CF3; or R1 and R2 combine to form C3- C5 cycloalkyl optionally substituted with 1 or 2 F, CHF2 or CF3; R3 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 R4 is selected from the group consisting of OCF3, OCH2CF3 or OCHF2. [0179] In further embodiments, R4 is OCF3 or OCHF2. [0180] In further embodiments, R2 is H or CH3. [0181] In further embodiments, R3 is CH2O—C1-3 alkyl. [0182] In further embodiments, R1 is C3-C4 cycloalkyl optionally substituted with 1 or 2 F, CHF2 or CF3. [0183] In further embodiments, R1 is t-butyl and R2 is H and R4 is OCF3, OCH2CF3, OCHF2 or CF3. [0184] In further embodiments, R1 and R2 combine to form cyclobutyl optionally substituted with 1 or 2 F and R4 is OCF3, OCH2CF3, OCHF2 or CF3. [0185] In further embodiments, the Kv7 channel activator is selected from the group consisting of: (S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3- (trifluoromethoxy)phenyl]ethyl]pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3- (trifluoromethoxy)phenyl]ethyl]pentanamide, (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3- (2,2,2- trifluoroethoxy)phenyl) ethyl)pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-((S)-1- (3-(2,2,2- trifluoroethoxy)phenyl) ethyl)pentanamide, (S)-N-((S)-1-(3- (difluoromethoxy)phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide, (R)-N-((S)-1-(3- (difluoromethoxy)phenyl)ethyl)-3- hydroxy-4,4-dimethylpentanamide, (S)-3-hydroxy-4,4- dimthyl-N-((S)-1-(3- (trifluoromethyl)phenyl)ethyl)pentanamide (R)-3-hydroxy-4,4- dimethyl-N-((S)-1-(3- (trifluoromethyl)phenyl)ethyl)pentanamide, (S)-3-hydroxy-4,4- dimethyl-N-((S)-1-(3- (trifluoromethoxy)phenyl)propyl)pentanamide, (R)-3-hydroxy-4,4- dimethyl-N-((S)-1-(3- (trifluoromethoxy)phenyl)propyl)pentanamide, (S)-3-(3,3- difluorocyclobutyl)-3-hydroxy-N-((S)- 1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide, (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)- 1-(3- (trifluoromethoxy)phenyl)ethyl)propanamide, (S)-3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2- trifluoroethoxy)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2- trifluoroethoxy)phenyl)ethyl)pentanamide, (S)-3-(1-(difluoromethyl)cyclopropyl)-3- hydroxy- N-((S)-1-(3-(trifluoro- methoxy)phenyl)ethyl)propanamide, (R)-3-(1- (difluoromethyl)cyclopropyl)-3-hydroxy- N-((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)propanamide, (R)-3-hydroxy-N-((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)-3-(1- (trifluoromethyl)cyclopropyl)propanamide, (S)-3- hydroxy-N-((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)-3-(1- (trifluoromethyl)cyclopropyl)propanamide, (S)- 3-hydroxy-4-methyl-N-((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4-methyl-N-((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)pentanamide, N-((R)-2-(difluoromethoxy)-1-(3- (trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy- 4,4-dimethylpentanamide, N-((R)-2- (difluoromethoxy)-1-(3- (trifluoromethoxy) phenyl)ethyl)-3-(S)-hydroxy- 4,4- dimethylpentanamide, (S)-3-hydroxy-N-((R)-2-methoxy-1-(3- (trifluoromethoxy)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-1-hydroxycyclobutyl)-N-(1-(3- (trifluoromethoxy)phenyl)ethyl)acetamide, (S)-2- (1-hydroxycyclobutyl)-N-(1-(3-(2,2,2- trifluoroethoxy)phenyl)ethyl)acetamide, (3R)-3- hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2- trifluoroethoxy)phenyl]ethyl]-3- (trifluoromethyl)pentanamide, (3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2- trifluoroethoxy)phenyl]ethyl]-3- (trifluoromethyl)pentanamide, 4,4,4-Trifluoro-3-hydroxy- N-[(1S)-1-[3- (trifluoromethoxy)phenyl]ethyl]-3- (trifluoromethyl)butanamide, (R)-4,4,5,5- tetrafluoro-3-hydroxy-3-methyl-N- ((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)pentanamide, (S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl- N- ((S)-1-(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-(1- fluorocyclopropyl)-3-hydroxy-N-((S)-1- (3-(trifluoromethoxy)phenyl)ethyl)butanamide, (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1- (3-(trifluoro- methoxy)phenyl)ethyl)butanamide, (R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1-(3- (trifluoromethoxy)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)-1- (3-(2,2,2- trifluoroethoxy)phenyl)ethyl)butanamide, and (S)-4,4,4- trifluoro-3-hydroxy-3-methyl-N-((S)-1- (3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide or a pharmaceutically acceptable salt of any of these compounds. Formula 10 [0186] 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. WO2009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2004058739A1, 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. [0187] In an embodiment, the Kv7 channel activator is a compound according to formula 10: ormula 10
Figure imgf000095_0001
wherein R1 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl and hydroxy-C3-8-Cycloalk(en)yl; R2 and R2′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-C1- 6-alk(en/yn)yl, aryl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl and hydroxy-C3-8- cycloalk(en)yl; R3 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl-C3-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, aryl-C3-8-cycloalk(en)yl, NR10R10′—C1-4-alk(en/yn)yl, NR10R10′—C3-8-Cycloalk(en)yl and hydroxy-C3-8-cycloalk(en)yl; wherein: R10 and R10′ 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-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy- C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6- alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R10 and R10′ 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 NR4, wherein: R4 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; or R3 and R4 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 R3 and R4 and the nitrogen atom is optionally substituted with one or more substituents independently selected from C1-6-alk(en/yn)yl, aryl and aryl-C1-6- alk(en/yn)yl; q is 0 or 1; and Y represents a heteroaryl of one of the following formulas:
Figure imgf000096_0001
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 R5 is independently selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl-C1-6-alk(en/yn)yl, acyl, halogen, halo-C1-6-alk(en/yn)yl, alk(en/yn)yloxy, —CO—NR6R6′, cyano, nitro, —NR7R4′, —S—R8, —SO2R8, and SO2OR8; wherein: R6 and R6′ 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-C1-6-alk(en/yn)yl and aryl; R7 and R7′ 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- C1-6-alk(en/yn)yl, aryl and acyl; and R8 is selected from the group consisting of C1-6- alk(en/yn)yl, C1-6-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl and NR9R9′; wherein: R9 and R9′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or a pharmaceutically acceptable salt thereof. [0188] In further embodiments, the Kv7 channel activator is selected from the group consisting of: {2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-methyl-amino]-phenyl}- 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}-carbamic acid ethyl ester; {2-Amino-4-[(5-fluoro-benzofuran-3-ylmethyl)-amino]phenyl}-carbamic 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-ylmethyl)- 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. [0189] In further embodiments, the Kv7 channel activator is a compound according to the formula:
Figure imgf000097_0001
or a pharmaceutically acceptable salt thereof. [0190] 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)-acetamide; 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. [0191] In further embodiments, the Kv7 channel activator is a compound according to formula 10 wherein: R1 is selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6- alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; R2 and R2′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, aryl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; R3 is selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl-C1-6- alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, aryl-C3-8-cycloalk(en)yl, NR10R10′—C1-6- alk(en/yn)yl, NR10R10′—C3-8-cycloalk(en)yl and hydroxy-C3-8-cycloalk(en)yl, wherein: R10 and R10′ 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-C1-6-alk(en/yn)yl, hydroxy-C1-6- alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, or R10 and R10′ 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 NR4, wherein: R4 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; or R3 and R4 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 R3 and R4 and the nitrogen atom is optionally substituted with one or more substituents independently selected from C1-6-alk(en/yn)yl, aryl and aryl-C1-6- alk(en/yn)yl; q is 0 or 1; and Y represents a heteroaryl of formula:
Figure imgf000099_0001
, 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 R5 is independently selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl-C1-6-alk(en/yn)yl, acyl, halogen, halo-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, —CO—NR6R6′, cyano, nitro, — NR7R7′, —S—R8, —SO2R8, and SO2OR8, wherein: R6 and R6′ 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-C1-6-alk(en/yn)yl and aryl; R7 and R7′ 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-C1-6-alk(en/yn)yl, aryl and acyl; and R8 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl and —NR9R9′, wherein: R9 and R9′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl; or a pharmaceutically acceptable salt thereof. [0192] In further embodiments, R1 is selected from the group consisting of hydrogen and C1-6-alk(en/yn)yl. [0193] In further embodiments, at least one of the substituents R2 and R2′ is a hydrogen atom. [0194] In further embodiments both R2 and R2′ are hydrogen atoms. [0195] In further embodiments, X is CO. [0196] In further embodiments, q is 0. [0197] In further embodiments, q is 1 and Z is an oxygen atom. [0198] In further embodiments, R3 is selected from the group consisting of C1-6- alk(en/yn)yl and aryl-C1-6-alk(en/yn)yl. [0199] In further embodiments, R3 is C1-6-alk(en/yn)yl. [0200] In further embodiments, R3 is aryl-C1-6-alk(en/yn)yl. [0201] In further embodiments, W is a sulfur atom. [0202] In further embodiments, Y is of formula:
Figure imgf000100_0001
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 R5 is independently selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl-C1-6-alk(en/yn)yl, acyl, halogen, halo-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, —CO—NR6R6′, cyano, nitro, — NR7R7′, —S—R8, —SO2R8, and SO2OR8, wherein: R6 and R6′ 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-C1-6-alk(en/yn)yl and aryl; R7 and R7′ 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-C1-6-alk(en/yn)yl, aryl and acyl; and R8 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl and —NR9R9′, wherein: R9 and R9′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl. [0203] In further embodiments, Y is of formula:
Figure imgf000101_0001
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 R5 is independently selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, aryl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl-C1-6-alk(en/yn)yl, acyl, halogen, halo-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, —CO—NR6R6′, cyano, nitro, — NR7R7′, —S—R8, —SO2R8, and SO2OR8, wherein: R6 and R6′ 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-C1-6-alk(en/yn)yl and aryl; R7 and R7′ 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-C1-6-alk(en/yn)yl, aryl and acyl; and R8 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, aryl and —NR9R9′, wherein: R9 and R9′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6- 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. WO2009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2004058739A1, 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. WO2004082677A1, published September 30, 2004 and corresponding to International Application No. PCT/DK2004/000186 filed March 18, 2004; International Publication No. WO2004080950A1, 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. [0204] In an embodiment, the Kv7 channel activator is a compound according to formula 11: Formula 11
Figure imgf000102_0001
wherein: s is 0 or 1; U is O, S, SO2, SO2NR11, CO—O or CONR11; wherein: R11 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R2 and R11 together with the nitrogen atom to which R11 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; R1 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; R2 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8- cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR10R10′—C1-6-alk(en/yn)yl, NR10R10′—C3-8-cycloalk(en)yl and NR10R10′—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; wherein: R10 and R10′ 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-C1-6-alk(en/yn)yl, hydroxy-C1-6- alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6- alk(en/yl; or R10 and R10′ 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 R2 is halogen or cyano, then s is 0; and when s is l and R2 is a hydrogen atom or acyl, then U is O or S; R3 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, heterocycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yl- heterocycloalk(en)yl, heterocycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar-heterocycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, Ar—C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ar—C1-6-alk(en/yn)yl- heterocycloalk(en)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6- alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yloxy- heterocycloalk(en)yl, Ar-oxy-C1-6-alk(en/yn)yl, Ar—C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-carbonyl-C1-6- alk(en/yn)yl, C3-8-cycl oal k(en)yl-C1-6-alk(en/yn)yl oxy-carbonyl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl-C3-8- cycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, halo-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl- heterocycloalk(en)yl, halo-C1-6-alk(en/yn)yl-Ar, halo-C3-8-cycloalk(en)yl-Ar, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl-Ar, halo-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl-Ar, cyano- C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano-C1-6- alk(en/yn)yl-heterocycloalk(en)yl, acyl-C1-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl- heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl-C1-6-alk(en/yn)yl-C3- 8-cycloalk(en)yl, acyl-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, NR12R12′, optionally substituted NR12R12′—C1-6-alk(en/yn)yl, optionally substituted NR12R12′—C3-8- cycloalk(en)yl, and optionally substituted NR12R12′—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; wherein: R12 and R12′ 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-C1-6-alk(en/yn)yl, Ar, Ar—C1-6- alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar- heterocycloalk(en)yl, Ar-oxy-C1-6-alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, Ar-oxy-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar-oxy-heterocycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6- alk(en/yr)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1- 6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R12 and R12′ 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 R3 is NR12R12′, then q is 0; and Y represents a group of the following formulas:
Figure imgf000104_0001
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 R5 is independently selected from the group consisting of a C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl, Ar-oxy, Ar-oxy-C1-6-alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, C1-6- alk(en/yn)yl-heterocycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, C1-6- alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, C1-6- alk(en/yn)yloxy-carbonyl, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo- C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, —CO—NR6R6′, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR7R7′, S—R8 and SO2R8; or two adjacent R5 together with the aromatic group form a 5-8 membered ring that optionally contains one or two heteroatoms; wherein: R6 and R6′ 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-C1-6-alk(en/yn)yl and Ar; R7 and R7′ 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- C1-6-alk(en/yn)yl, Ar, heterocycloalk(en)yl-C1-6-alk(en/yn)yl, heterocycloalk(en)yl-C3-8- cycloalk(en)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, heterocycloalk(en)yl-Ar and acyl; or R7 and R7′ 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 R8 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycl oal k(en)yl, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, Ar and —NR9R9′; wherein R9 and R9′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl; or a pharmaceutically acceptable salt thereof. [0205] 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}-carbamic acid ethyl ester; {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic acid ethyl ester; {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic 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-methylphenyl)-carbamic acid propyl ester; {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic acid propyl ester; {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic acid propyl ester; {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-methylphenyl}-carbamic acid propyl ester; {2-Methyl-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid propyl ester; [4-(4-Isopropyl-benzylamino)-2-methylphenyl]-carbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic 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}-carbamic 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-thiophen-2-ylmethyl]-amino)-phenyl}-carbamic acid propyl ester; {4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic acid propyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic acid propyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid propyl ester; {4-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-chlorophenyl}-carbamic 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}-carbamic acid methyl ester; {4-[(5-Bromo-thiophen-2-ylmethyl)-amino]-2-methoxyphenyl}-carbamic acid isopropyl ester; {4-[(4-Fluoro-benzyl)-(methyl)amino]-2-methoxyphenyl}-carbamic 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-phenyl}-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-isopropoxyphenyl}-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}-carbamic 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]-carbamic 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]-carbamic acid ethyl ester; [2-Benzyloxy-4-(3- methoxybenzylamino)-phenyl]-carbamic acid ethyl ester; {4-[(Benzo[1,3]dioxol-5- ylmethyl)-amino]-2-isopropoxyphenyl}-carbamic 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]-phenyl}-carbamic acid propyl ester; {4-[(4-tert-Butyl-benzyl)-(methyl)amino]-2-chlorophenyl}-carbamic 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-trifluoromethyl- phenyl}-carbamic acid ethyl ester; {4-[(5-Chloro-thiophen-2-ylmethyl)-(methyl)amino]-2- trifluoromethyl-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}- carbamic 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-phenyl}-carbamic acid propyl ester; {4-[(4-tert-Butyl- benzyl)-(methyl)amino]-2-trifluoromethyl-phenyl}-carbamic acid propyl ester; {4-[Methyl- (4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-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-1-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- methoxyphenyl}-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-thiophen- 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]-phenyl}-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-thiophen-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-phenyl)-acetamide, N-{2-Chloro-4-[(5-chloro-thiophen-2- ylmethyl)-(methyl)amino]-phenyl)-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;Cyclopropanecarboxylic 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}-amide; N-{2-Chloro-4- [(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-thiophen-2-yl-acetamide; N-{2-Chloro- 4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2-(3-methoxyphenyl)-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[1,4]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}-amide; N-{2-Chloro-4- [(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-3-cyclohexylpropionamide; 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-methylphenyl}-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-thiophen-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- methyl phenyl}-malonamic acid methyl ester; 2-(4-Chlorophenyl)-N-{4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)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-cyclohexylpropionamide; {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}-carbamic acid benzyl ester; {2-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic acid isobutyl ester; {2-Chloro-4- [(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic acid butyl ester; {2- Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-carbamic acid hexyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-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]-phenyl}-carbamic acid 2-chlorobenzyl ester; {2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-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-Chloro-4-[(5-chloro- thiophen-2-ylmethyl)-(methyl)amino]-phenyl}-3-(2-fluorophenyl)-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-biphenyl-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}-butyramide; [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-chlorophenyl)-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-phenyl}-carbamic acid ethyl ester; {4-[(5-Dimethylamino-3-methyl-benzo[b]thiophen-2-ylmethyl)-amino]-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-fluorophenyl)-acetamide; {4-[(7-Dimethylamino-benzo[b]thiophen-2- ylmethyl)-amino]-2-methylphenyl}-carbamic acid propyl ester; 1-{2-Cyclopentyloxy-4-[(4- fluorobenzyl)-(methyl)amino]-phenyl}-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-methylphenyl}-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-Amino-cyclopropanecarboxylic acid [2-methyl-4-(4- trifluoromethyl-benzylamino)-phenyl]-amide; {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]- 2-pyridin-4-yl-phenyl}-carbamic acid ethyl ester; N-[2-Methyl-4-(4-trifluoromethyl- benzylamino)-phenyl]-2-piperidin-1-yl-acetamide; N-(4-{[5-(4-Chlorophenoxy)-1,3- dimethyl-1H-pyrazol-4-ylmethyl]-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-1-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-acetamide; 2,2-Dimethyl-N-{2-methyl-4-[(3-methyl-5-phenylisoxazol-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-fluorophenyl)-acetamide; {4-[(5-Chloro-thiophen-2-ylmethyl)-amino]-2- quinolin-5-yl-phenyl}-carbamic acid ethyl ester; and pharmaceutically acceptable salts thereof. [0206] 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, SONR11, or CONR11; wherein: R11 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, or C3-8-cycloalk(en)yl-C1-6 -alk(en/yn)yl; or R2 and R11 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; R1 is hydrogen, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6 -alk(en/yn)yl, acyl, hydroxy-C1-6- alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo -C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en) yl or cyano-C3-8 - cycloalk(en)yl-C1-6-alk(en/yn)yl; R2 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3- 8-cycloalk(en)yl-C1-6 -alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar— C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk (en)yl, hydroxy-C3-8 -cycloalk(en)yl-C1-6-alk(en/yn)yl, halogen, halo-C1-6- alk(en/yn)yl, halo-C3-8-cycloalk (en)yl, halo -C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, NR10R10′—C1-6-alk(en/yn)yl, NR10R10′—C3-8 -cycloalk(en)yl or NR10R10′—C3- 8-cycloalk(en)yl-C1-6-alk(en/yn)yl; wherein: R10 and R10′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1- 6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl or cyano-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl; or R10 and R10′ 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 R2 is halogen or cyano, then s is 0; and when s is 1 and R2 is a hydrogen atom or acyl, then U is O or S; R3 is C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, heterocycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6- alk(en/yn)yl-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yl-heterocycloalk(en)yl, heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yloxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, C1-6- alk(en/yn)yloxy-heterocycloalk(en)yl, C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3- 8-cycloalk(en)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy - carbonyl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy -heterocycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1- 6-alk(en/yn)yl -C3-8-cycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, halo - C3-8-cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo -C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano- C3-8-cycloalk(en)yl -C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano- C1-6-alk(en/yn)yl -heterocycloalk(en)yl, acyl-C1-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl-C1-6- alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, NR12R12′, optionally substituted NR12R12′-C1-6-alk(en/yn)yl, optionally substituted NR12R12′-C3-8- alk(en/yn)yl, or optionally substituted NR12R12′-C3-8-alk(en/yn)yl-C1-6-alk(en/yn)yl; wherein: R12 and R12′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8- cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar-heterocycloalk(en)yl, Ar-oxy- C1-6-alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, Ar-oxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar-oxy -heterocycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano- C3-8-cycloalk(en)yl, or cyano -C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R12 and R12′ 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 R3 is NR12R12′ then q is 0; and Y is a group of formula:
Figure imgf000115_0001
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 R5 is independently C1-6-alk(en/yn)yl, C3-8- cycloalk (en)yl, C3-8-cycloalk(en) yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8- cycloalk(en)yl, Ar—C3-8-cycloalk (en)yl-C1-6-alk(en/yn)yl , Ar-oxy, Ar-oxy-C1- 6alk(en/yn)yl, Ar-oxy-C3-8-cycloalk(en)yl, C1-6-alk (en/yn)yl -heterocycloalk(en)yl, Ar-oxy- C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, C1-6-alk (en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, C1-6-alk(en/yn)yloxy-carbonyl, halogen, halo-C1- 6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, — CO—NR6R6′, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk (en)yl, cyano-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, NR7R7′, S—R8 or SO2R8; or two adjacent R5 groups taken together with the aromatic group form a 5-8 membered ring, which optionally contains one or two heteroatoms; wherein: R6 and R6′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl or Ar; R7 and R7′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, heterocycloalk(en)yl-C1-6-alk (en/yn)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl, heterocycloalk(en)yl-C3-8-cycloalk(en)yl-C1-6-alk (en/yn)yl, heterocycloalk(en)yl-Ar or acyl; or R7 and R7′ 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 R8 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar or —NR9R9′; wherein: R9 and R9′ are each independently hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl or C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl; or salts thereof. [0207] In further embodiments, R1 is C1-6-alk(en/yn)yl or a hydrogen atom. [0208] In further embodiments, s is 0. [0209] In further embodiments, s is 1. [0210] In further embodiments, U is an oxygen atom. [0211] In further embodiments, R2 is hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, Ar, Ar—C1-6-alk(en/yn)yl, halogen, halo-C1-6-alk(en/yn)yl or cyano; with the provisos that when R2 is halogen or cyano, then s is 0; and when s is 1 and R2 is a hydrogen atom, then U is O or S. [0212] In further embodiments, Z is an oxygen atom. [0213] In further embodiments, Z is a sulfur atom. [0214] In further embodiments, q is 0. [0215] In further embodiments, q is 1. [0216] In further embodiments, X is CO. [0217] In further embodiments, R3 is C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, heterocycloalk (en)yl-C1 -6-alk(en/yn)yl, heterocycloalk(en)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar-oxy-C1-6-alk (en/yn)yl, Ar—C1-6- alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, halo- C1-6 -alk(en/yn)yl, NR12R12′, optionally substituted NR12R12′—C1-6-alk(en/yn)yl, or optionally substituted NR12R12′—C3-8-cycloalk(en)yl. [0218] In further embodiments, R12 and R12′ are each independently hydrogen, C1-6- alk(en/yn)yl or Ar. [0219] In further embodiments, V is CH. [0220] In further embodiments, each R5 is independently C1-6-alk(en/yn)yl, C1-6- alk(en/yn)yl-heterocycloalk(en)yl, Ar, C1-6-alk(en/yn)yloxy, Ar-oxy, C1-6-alk(en/yn)yloxy- carbonyl, halogen, halo-C1-6-alk(en/yn)yl, NR7R7′, S—R8 or SO2R8; or two adjacent R5 groups taken together with the aromatic group form a 5-8 membered ring, which optionally contains one or two heteroatoms. [0221] In further embodiments, both R7 and R7′ are C1-6-alk(en/yn)yl. [0222] In further embodiments, R8 is C1-6-alk(en/yn)yl or Ar. [0223] 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-ylmethyl)-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- fluorophenyl)-acetamide; or 2,2-Dimethyl-N-{2-methyl-4-[(6-phenoxypyridin-3-ylmethyl)- amino]-phenyl }-proprionamide; or a salt thereof. [0224] In further embodiments, the Kv7 channel activator is a compound according to formula 11 wherein: U is O, S or NR2′; s is 0 or 1; X is CO or SO2; Z is O, S or NR4; wherein R4 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; q is 0 or 1; R1 and R1′ 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- C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-C1-6- alk(en/yn)yl and halo-C3-8-cycloalk(en)yl; R2 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-C1-6- alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, acyl, hydroxy-C1-6- alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and cyano; provided that: when R2 is halogen or cyano, then s is 0; and when s is 1 and U is NR2′, then R2′ is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar— C3-8-cycloalk(en)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-C1- 6-alk(en/yn)yl and halo-C3-8-cycloalk(en)yl; or R2 and R2′ together form a 5-8 membered saturated or unsaturated ring that optionally contains one further heteroatom; R3 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl and halo- C3-8-cycloalk(en)yl; and Y represents a group of the following formulas:
Figure imgf000118_0001
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 R5 is independently selected from the group consisting of a C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, Ar, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar—C1-6-alk(en/yn)yl, acyl, C1-6- alk(an/en/yn)yloxy, halogen, halo-C1-6-alk(en/yn)yl, —CO—NR6R6′, cyano, nitro, — NR7R7′, —S—R8 and SO2OR8; or two adjacent R5 substituents together with the aromatic group form a 5-8 membered saturated or unsaturated ring that optionally contains one or two heteroatoms; wherein: R6 and R6′ 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-C1-6-alk(en/yn)yl and Ar; R7 and R7′ 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- C1-6-alk(en/yn)yl, Ar and acyl; and R8 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar and — NR9R9′; wherein R9 and R9′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; with the provisos that; when R5 is SO2OR8 then R8 is not —NR9R9′; and when R5 is SO2R8, then R8 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. [0225] In further embodiments, R1 and R1' are independently selected from the group consisting of hydrogen and C1-6-alk(en/yn)yl. [0226] In further embodiments, at least one of R1 and R1' is a hydrogen atom. In further embodiments, s is 1. [0227] In further embodiments, s is 0. [0228] In further embodiments, R2 is selected from the group consisting of hydrogen, C1- 6-alk(en/yn)yl, Ar and halogen, provided that when R is halogen, then s is 0. [0229] In further embodiments, U is NR2' and at least one of R and R2' is a hydrogen atom. [0230] In further embodiments, both R2 and R2 are hydrogen atoms. [0231] In further embodiments, X is CO. [0232] In further embodiments, q is 0. [0233] In further embodiments, q is 1. [0234] In further embodiments, Z is an oxygen atom. [0235] In further embodiments, R3 is C1-6- alk(en/yn)yl. [0236] In further embodiments, each R5 is independently selected from the group consisting of a C1-6-alk(en yn)yl, C3-8- cycloalk(en)yl, Ar, cyano, halogen, halo-Cι-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. [0237] 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- 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-dichlorophenylamino)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-[1-(4- chlorophenylamino)ethyl]phenyl}carbamic acid ethyl ester; {2-Amino-4-[1-(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}carbamic 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-chloro-3- fluorophenylamino)methyl]phenyl}butyramide; N-{4-[(4-fluoro-phenylamino)methyl]-2- methyl phenyl}butyramide; N-{4-[(3-fluorophenylamino)methyl]-2- methylphenyl}butyramide; N-{4-[(4-chlorophenylamino)methyl]-2- methylphenyl}butyramide; N-{4-[(3,4-dichlorophenylamino)methyl]-2- methylphenyl}butyramide; N-{4-[(4-chloro-3-fluorophenylamino)methyl]-2-methyl phenyl}butyramide; 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- fluorophenyl}butyramide; 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. [0238] 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 R4 is selected from the group consisting of hydrogen, Cι-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en yn)yl and hydroxy-C3-8-cycloalk(en)yl; q is O or 1; R1 and R1' 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- C1-6-alk(en/yn)yl, acyl, hydroxy-Cι-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-C1-6- 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-Cι-6- alk(en/yn)yl, Ar, Ar-C1-6- alk(en/yn)yl, Ar-C3-8-cycloalk(en)yl, acyl, hydroxy-Cι-6- alk(en/yn)yl, hydroxy- C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and cyano; provided that when R2 is halogen or cyano then s is 0; when s is 1 and U is NR2' then R2' is selected from the group consisting of hydrogen, C1-6-alk(en yn)yl, C -8- cycloalk(en)yl, C3-8-cycloallc(en)yl-Cι-6- alk(en/yn)yl, Ar, Ar-C1-6-alk(en/yn)yl, Ar-C3-8- cycloalk(en)yl, acyl, hydroxy- ..6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, halo-C1-6- alk(en/yn)yl and halo-C3-8- cycloalk(en)yl; or R2 and R2' together form a 5-8 membered saturated or unsaturated ring which optionally contains one further heteroatom; R3 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-Cι-6-alk(en/yn)yl, Ar, Ar-C1-6-alk(en/yn)yl, Ar-C3-8- cycloalk(en)yl, hydroxy- Cι-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:
Figure imgf000123_0001
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 R5 is independently selected from the group consisting of a C1-6- alk(en yn)yl, C3-8- cycloalk(en)yl, Ar, C3-8-cycloalk(en)yl-C1-6-alk(en yn)yl, Ar- Cι-6-alk(en/yn)yl, acyl, C1-6- alk(an/en/yn)yloxy, halogen, halo-Cι-6-alk(en/yn)yl, -CO-NR6R6', cyano, nitro, -NR7R7', - S-R8, -SO2R8 and SO2OR8, or two substituents together form a 5-8 membered saturated or unsaturated ring which optionally contains one or two heteroatoms; R6 and R6' 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-C1-6-alk(en/yn)yl and Ar; R7 and R7' 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-C1-6-alk(en/yn)yl, Ar and acyl; and R8 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-Cι-6- alk(en/yn)yl, Ar and -NR9R9 ; wherein R9 and R9' 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-C1-6-alk(en/yn)yl; with the provisos that when R5 is SO2OR8 then R8 is not -NR9R9' and when R5 is SO2R8 , then R8 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]methyljρhenyl]-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. [0239] In further embodiments, the Kv7 channel activator is a compound according to formula 11 wherein: wherein U is O, S or NR2 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, C1-6-alk(en/yn)yl, C3- 8-cycloalk(en)yl, C3-s-cycloaUc(en)yl-Cι-6-alk(en/yn)yl, hydroxy-Cι-6-alk(en/yn)yl and hydroxy-C3-8-cycloalk(en)yl; q is O or 1; 11 ' R and R are independently selected from the group consisting of hydrogen, Cι_ 6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1.6-alk(en/yn)yl, acyl, hydroxy-Cι-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, halo-C1_.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-Cι-6-alk(en yn)yl, Ar, Ar-Cι-6- alk(en yn)yl, Ar-C3-8-cycloalk(en)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy- C3-8-cycloalk(en)yl, halo-Cι-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl and cyano; provided that when R2 is halogen or cyano then s is 0; when s is 1 and U is NR2 then R2' is selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C -8-cycloalk(en)yl, C .8-cycloalk(en)yl-C1-6- alk(en/yn)yl, Ar, Ar-C1-6- alk(en/yn)yl, Ar-C3.8-cycloalk(en)yl, acyl, hydroxy-C^ 6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, halo-C1-6-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; R3 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en yn)yl, Ar, Ar-C1-6-alk(en/yn)yl, Ar-C3-8- cycloalk(en)yl, hydroxy-C1-6-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:
Figure imgf000125_0001
[0240] 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 R5 is independently selected from the group consisting of a Cι-6- alk(en/yn)yl, C3.8- cycloalk(en)yl, Ar, Cs-s-cycloall^ei^yl-Ci-e-all^en/^yl, Ar- Cι-6-alk(en/yn)yl, acyl, C1-6- alk(an/en/yn)yloxy, halogen, halo-C1-6-alk(en/yn)yl, -CO-NR6R6', cyano, nitro, -NR7R7', - S-R8, -SO2R8 and SO2OR8, or two substituents together form a 5-8 membered saturated or unsaturated ring which optionally contains one or two heteroatoms; R6 and R6 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-C1-6-alk(en/yn)yl and Ar; R7 and R7' are independently selected from the group consisting of hydrogen, Cj.6-alk(en/yn)yl, C3-8-cycloalk(en)yl, Cs-s-cycloall^en l- -e-all^en/yn l, Ar and acyl; and R8 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, Ar and -NR9R9 ; wherein R9 and R9' 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-Cι-6-alk(en yn)yl; with the provisos that when R5 is SO2OR8 then R8 is not -NR9R9' and when R5 is SO2R8 , then Rs 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 [0241] 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. WO2009015667A1, published February 5, 2009, and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2004096767A1, 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. [0242] In an embodiment, the Kv7 channel activator is a compound according to formula 12: Formula 12
Figure imgf000127_0001
wherein, the dotted line represents an optional bond; R1 and R1′ 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-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano- C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R1 and R1′ 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, NR11, S, SO2, SO2NR11, CO—O or CO—NR11; wherein: R11 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-C1-6- alk(en/yn)yl; or R2 and R2′ 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; R2 is selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6- alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8- cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, —NO2, NR10R10′—C 1-6- alk(en/yn)yl, NR10R10′—C3-8-cycloalk(en)yl and NR10R10′—C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl; wherein: R10 and R10′ 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-C1-6-alk(en/yn)yl, hydroxy-Cl—6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1- 6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl; or R10 and R10′ 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 R2 is NO2, halogen or cyano, then s is 0; and when R2, R2 is a hydrogen atom or acyl and s is 1, then U is NR11, O or S; wherein the group —(U)s—R2 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; R3 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, heterocycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6- alk(en/yn)yl-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar—C1-6- alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar-heterocycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1- 6-alk(en/yn)yl, Ar—C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ar—C1-6-alk(en/yn)yl- heterocycloalk(en)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6- alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yloxy- heterocycloalk(en)yl, Ar-oxy-C1-6-alk(en/yn)yl, Ar—C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-carbonyl-C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, hydroxy- C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3- 8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, hydroxy- C1-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6- alk(en/yn)yl-C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-C1-6- alk(en/yn)yl-Ar, halo-C3-8-cycloalk(en)yl-Ar, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl-Ar, halo-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl-Ar, cyano-C1-6-alk(en/yn)yl, cyano-C3-8- cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, acyl-C1-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-C1-6- alk(en/yn)yl-heterocycloalk(en)yl, —NR12R12′, optionally substituted NR12R12′—C1-6- alk(en/yn)yl, optionally substituted NR12R12′—C3-8-cycloalk(en)yl, and optionally substituted NR12R12′—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; wherein: R12 and R12′ 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-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8- cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano- C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl; or R12 and R12′ 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 R3 is NR12R12′, then q is 0; and Y represents a group of formula from the group:
Figure imgf000129_0001
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 R5 is independently selected from the group consisting of a C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar-thio, Ar- oxy, acyl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yloxy, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, —CO—NR6R6′, cyano, cyano-C1-6-alk(en/yn)yl, cyano- C3-8-cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, —NR7R7′, —S—R8 and —SO2R8; or two adjacent R5 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: R6 and R6′ 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-C1-6-alk(en/yn)yl and Ar; R7 and R7′ 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-C1-6-alk(en/yn)yl, Ar and acyl; and R8 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar and —NR9R9′; wherein R9 and R9′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; provided that when R8 is —NR9R9′, then R5 is not —S—R8, or a pharmaceutically acceptable salt thereof. with the proviso that the compound of formula I is not: N-[1-(phenylmethyl)-1H-indol-5-yl]-Methanesulfonamide; N-[1-[(4-fluorophenyl)methyl]-1H-indol-5-yl]-Methanesulfonamide; N-[2,3-dihydro-1- (phenylmethyl)-1H-indol-5-yl]-Methanesulfonamide; N-[1-(phenylmethyl)-1H-indol-5-yl]- N′-4-quinolinyl-Urea; N-[1-(phenylmethyl)-1H-indol-5-yl]-N′-4-quinolinyl-Urea; or 1-(1- benzyl-5-indolinyl)-3-phenyl-Urea; or salts thereof. [0243] In further embodiments, least one of R1 or R1′ is a hydrogen atom. [0244] In further embodiments, R1 and R1′ are hydrogen atoms. [0245] In further embodiments, s is 0. [0246] In further embodiments, s is 1. [0247] In further embodiments, R2 is a hydrogen atom. [0248] In further embodiments, R2 is NO2 or a halogen atom. [0249] In further embodiments, U is NR11. [0250] In further embodiments, R11 is a hydrogen atom. [0251] In further embodiments, X is CO. [0252] In further embodiments, X is SO2. [0253] In further embodiments, q is 0. [0254] In further embodiments, q is 1. [0255] In further embodiments, Z is an oxygen atom. [0256] In further embodiments, R3 is selected from the group consisting of C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar-oxy-C1-6-alk(en/yn)yl, Ar— C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl and —NR12R12′; with the proviso that when R3 is NR12R12′ then q is 0. [0257] In further embodiments, R3 is NR12R12′, q is 0 and R12 and R12′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, Ar and Ar—C1-6- alk(en/yn)yl, or R12 and R12′ 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. [0258] In further embodiments, each R5 is independently selected from the group consisting of C1-6-alk(en/yn)yl, Ar, Ar-thio, Ar-oxy, halogen and halo-C1-6-alk(en/yn)yl or two adjacent R5 together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms. [0259] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[4-Chloro-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3- dimethylbutyramide; N-[4-Chloro-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol- 5-yl]-3,3-dimethylbutyramide; [1-(4-Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid propyl ester; N-[1-(4-Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-C-phenyl- methanesulfonamide; 4-Fluoro-N-[1-(4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]- benzamide; N-[1-(4-Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N- [1-(4-Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide; N-[1-(4- Fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 3-[1-(5- Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1,1-diisopropylurea; Morpholine- 4-carboxylic acid [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-amide; Pyrrolidine-1-carboxylic acid [1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]- amide; [1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-carbamic acid 2- benzyloxyethyl ester; 3-[1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-1- methyl-1-propylurea; [1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]- carbamic acid tert-butyl ester; N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol- 5-yl]-C-phenyl-methanesulfonamide; Butane-1-sulfonic acid [1-(5-chlorothiophen-2- ylmethyl)-2,3-dihydro-1H-indol-5-yl]-amide; N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-4-fluorobenzamide; N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide; N-[1-(5-Chlorothiophen-2-ylmethyl)- 2,3-dihydro-1H-indol-5-yl]-2-phenoxyacetamide; N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-butyramide; Cyclopentanecarboxylic acid [1-(5-chlorothiophen-2- ylmethyl)-2,3-dihydro-1H-indol-5-yl]-amide; N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-2-thiophen-2-ylacetamide; N-[1-(5-Chlorothiophen-2-ylmethyl)- 2,3-dihydro-1H-indol-5-yl]-isonicotinamide; N-[1-(5-Chlorothiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-4-dimethylaminobenzamide; N-[1-(5-Chlorothiophen-2-ylmethyl)- 2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[1-(5-Chlorothiophen-2- ylmethyl)-2,3-dihydro-1H-indol-5-yl]-6-trifluoromethylnicotinamide; 1-tert-Butyl-3-[1-(5- chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea; 1-[1-(5-Chlorothiophen-2- ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3-ethyl urea; 1-Benzyl-3-[1-(5-chlorothiophen-2- ylmethyl)-2,3-dihydro-1H-indol-5-yl]-urea; 1-[1-(5-Chlorothiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-3-phenethyl urea; 1-[1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro- 1H-indol-5-yl]-3-thiophen-2-ylurea; 1-[1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H- indol-5-yl]-3-thiophen-3-ylurea; [1-(5-Chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5- yl]-carbamic acid propyl ester; 2,2-Dimethyl-N-[6-nitro-1-(4-trifluoromethylbenzyl)-2,3- dihydro-1H-indol-5-yl]-propionamide; N-[1-(5-Chlorothiophen-2-ylmethyl)-6-nitro-2,3- dihydro-1H-indol-5-yl]-2,2-dimethylpropionamide; 2-(4-Fluorophenyl)-N-[6-nitro-1-(4- trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide; N-[1-(5-Chlorothiophen-2- ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[1-(5- Chlorothiophen-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amino-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3- dimethylbutyramide; N-[6-Amino-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]- 2,2-dimethylpropionamide; N-[6-Amino-1-(5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H- indol-5-yl]-2,2-dimethylpropionamide; N-[6-Amino-1-(4-trifluoromethylbenzyl)-2,3- dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-[6-Amino-1-(4- trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide, N-[6-Amino-1- (4-fluorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Amino-1-(3- fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[1- (5-Chlorothiophen-2-ylmethyl)-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Bromo-1-(4- trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[6-Bromo-1- (5-chlorothiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[1- (4-Chlorobenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[1- (4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-butyramide; N-[1-(4- Isopropylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[1-(3-Fluoro-4- trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; N-[1-(6- Chlorobenzo[1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide, N-[1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3- dimethylbutyramide; N-[1-(2-Chloro-5-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]- 3,3-dimethylbutyramide; N-{1-[5-(4-Chlorophenoxy)-1,3-dimethyl-1H-pyrazol-4- ylmethyl]-2,3-dihydro-1H-indol-5-yl}-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[1-(6-p- tolyloxy-pyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butyramide; N-{1-[6-(4- Chlorophenyl sulfanyl)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-3,3- dimethylbutyramide, N-{1-[6-(4-Cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-1H- indol-5-yl}-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[1-(6-trifluoromethylpyridin-3- ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butyramide; 3,3-Dimethyl-N-[1-(3-methyl- benzo[b]thiophen-2-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butyramide; N-[1-(6-Fluoro-4H- benzo[1,3]dioxin-8-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-3,3-dimethylbutyramide; 3,3- Dimethyl-N-[1-(6-phenoxypyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butyramide; 3,3- Dimethyl-N-[1-(3-methyl-5-phenyl-isoxazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]- butyramide, N-(1-Benzo[b]thiophen-2-ylmethyl-2,3-dihydro-1H-indol-5-yl)-3,3- dimethylbutyramide; N-{1-[1-(4-Fluorophenyl)-5-methyl-1H-pyrazol-4-ylmethyl]-2,3- dihydro-1H-indol-5-yl}-3,3-dimethylbutyramide; 3,3-Dimethyl-N-[1-(5-methyl thiophen-2- ylmethyl)-2,3-dihydro-1H-indol-5-yl]-butyramide; 3,3-Dimethyl-N-[1-(4-pyrrol-1-yl- benzyl)-2,3-dihydro-1H-indol-5-yl]-butyramide; N-[1-(4-Chlorobenzyl)-2,3-dihydro-1H- indol-5-yl]-2-(4-fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-[1-(4- trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide; 2-(4-Fluorophenyl)-N-[1-(4- isopropylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide; 2-(4-Fluorophenyl)-N-[1-(3- fluoro-4-trifluoromethylbenzyl)-2,3-dihydro-1H-indol-5-yl]-acetamide; N-[1-(6- Chlorobenzo[1,3]dioxol-5-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)- acetamide; N-[1-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-2,3-dihydro-1H-indol-5- yl]-2-(4-fluorophenyl)-acetamide; N-[1-(2-Chloro-5-trifluoromethylbenzyl)-2,3-dihydro- 1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; N-{1-[5-(4-Chlorophenoxy)-1,3-dimethyl- 1H-pyrazol-4-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-2-(4-fluorophenyl)-acetamide; N-{1-[6- (4-Cyanophenoxy)-pyridin-3-ylmethyl]-2,3-dihydro-1H-indol-5-yl}-2-(4-fluorophenyl)- acetamide; 2-(4-Fluorophenyl)-N-[1-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-acetamide; N-[1-(6-Fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-2-(4-fluorophenyl)-acetamide; 2-(4-Fluorophenyl)-N-[1-(6- phenoxypyridin-3-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-acetamide; N-(1- Benzo[b]thiophen-2-ylmethyl-2,3-dihydro-1H-indol-5-yl)-2-(4-fluorophenyl)-acetamide; 2- (4-Fluorophenyl)-N-{1-[1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-ylmethyl]-2,3-dihydro- 1H-indol-5-yl}-acetamide; 2-(4-Fluorophenyl)-N-[1-(5-methylthiophen-2-ylmethyl)-2,3- dihydro-1H-indol-5-yl]-acetamide; 2-(4-Fluorophenyl)-N-[1-(4-pyrrol-1-yl-benzyl)-2,3- dihydro-1H-indol-5-yl]-acetamide; and pharmaceutically acceptable salts thereof. Formula 13 [0260] 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. WO2009015667A1, 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. [0261] In an embodiment, the Kv7 channel activator is a compound according to formula 13. Formula 13
Figure imgf000135_0001
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, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy and C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yloxy; R2 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo- C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6- alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-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, C1-6-alk(en/yr)yl, C3-8-cycloalk(en)yl or C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; R3 is selected from the group consisting of C1-10-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8- cycloalk(en)yl-C1-6-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. [0262] 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-fluoro-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-cyclopentyl- propionamide; N-(2-Chloro-6-cyano-4-morpholin-4-yl-phenyl)-3-cyclohexyl- propionamide; 2-Cyclopentyl-N-(2,6-dimethyl-4-thiomorpholin-4-yl-phenyl)-acetamide; 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]-acetamide; 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- phenyl)-acetamide; 2-Cyclohexyl-N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-acetamide; 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)-propionamide; 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-phenyl)-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-trifluoromethyl-phenyl)-acetamide; N-(2,6-Dimethyl-4- morpholin-4-yl-phenyl)-2-naphthalen-2-yl-acetamide; 3-(3-Chloro-phenyl)-N-(2,6- dimethyl-4-morpholin-4-yl-phenyl)-propionamide; N-(2,6-Dimethyl-4-morpholin-4-yl- phenyl)-2-(3,4-dimethyl-phenyl)-acetamide; 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-cyclopentyl- 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-phenyl}-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)-acetamide; 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)-acetamide; 2-(4-Fluoro-phenyl)-N-(4-morpholin-4-yl-2-pyridin-3-yl-6-trifluoromethyl-phenyl)- acetamide; 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)-acetamide; 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-phenyl)-acetamide; 2- Bicyclo[2.2.1]hept-2-yl-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-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-trifluoromethyl- 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-phenyl)-butyramide; 2-(3,4-Difluoro-phenyl)-N-(2-methyl-4-morpholin-4-yl-6-trifluoromethyl-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-phenyl)-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 [0263] 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. WO2009015667A1, published February 5, 2008 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2006029623A1, 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. [0264] In an embodiment, the Kv7 channel activator is a compound according to formula 14: Formula 14
Figure imgf000139_0001
wherein, Z is O or S; q is 0 or 1; each of R1 and R2 is independently selected from the group consisting of halogen, cyano, amino, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl, Aryl, Heteroaryl, halo-C1-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6- alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, and C3- 8-heterocycloalk(en)yloxy; R3 is selected from the group consisting of C1-8-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8- cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl-C1-6- alk(en/yn)yl, C1-6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn)yl, Heteroaryl-C alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl, Heteroaryl-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, amino-C1-6-alk(en/yn)yl, amino-C3-8-cycloalk(en)yl, amino-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy-C1-6- alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl; and R4 is selected from the group consisting of halogen, cyano, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8- heterocycloalk(en)yl, Aryl, Heteroaryl, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C3-8-heterocycloalk(en)yl, halo-C1-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1- 6-alk(en/yn)yl-C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn)yl, NR5R6 and R7NH—C1-6- alk(en/yn)yl; wherein: R5 and R6 are independently selected from the group consisting of hydrogen, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Heteroaryl-C1-6-alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl and Heteroaryl-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, with the proviso that R5 and R6 are not hydrogen at the same time; and R7 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl, halo-C1-6-alk(en/yn)yl, halo-C3- 8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6-alk(en/yn)yl, Aryl-C3- 8-cycloalk(en)yl and Heteroaryl; or a pharmaceutically acceptable salt thereof. [0265] 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)- acetamide; 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- trifluoromethyl-benzyl)-amino]-phenyl}-3- methyl-butyramide; (S)-2-Amino-4-methyl- pentanoic acid {2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-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-1- yl]-phenyl}-acetamide; N-(4-Azepan-1-yl-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide; 2-Cyclopentyl-N-(2,6-dimethyl-4-pyrrol-1-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-biphenyl-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- biphenyl-2-yl)-acetamide; N-(4′-Isopropyl-3,5-dimethyl-biphenyl-2-yl)-3,3-dimethyl- butyramide; 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-phenyl)-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)-acetamide; 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)-acetamide; N-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-4,6-dimethyl-phenyl]-2-(4- fluoro-phenyl)-acetamide; N-[2,4-Dimethyl-6-(2,2,5-trimethyl-2,3-dihydro-benzofuran-7- yl)-phenyl]-2-(4-fluoro-phenyl)-acetamide; N-[2,6-Dimethyl-4-(4-trifluoromethyl- benzylamino)-phenyl]-acetamide; 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]-phenyl}-carbamic acid propyl ester; {4-[(6-Methoxy-pyridin-3- ylmethyl)-amino]-2,6-dimethyl-phenyl}-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-dimethyl-butyramide; N-{2-Bromo-4-[(5-chloro-thiophen-2-ylmethyl)- amino]-6-trifluoromethyl-phenyl}-3-cyclohexyl-propionamide; {4-[(3-Fluoro- phenylamino)-methyl]-2,6-dimethyl-phenyl}-carbamic acid ethyl ester; {2,6-Dimethyl-4- [(4-trifluoromethyl-phenylamino)-methyl]-phenyl}-carbamic acid ethyl ester; 2- Cyclopentyl-N-{4-[(3-fluoro-phenylamino)-methyl]-2,6-dimethyl-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- butyramide; {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-dimethyl phenyl)-acetamide; {2,6-Dimethyl-4-[(4- trifluoromethylphenylamino)-methyl]-phenyl}-carbamic acid 2-methoxyethyl ester; N-{4- [(5-Chloro-pyridin-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-cyclopentylacetamide; [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}-acetamide; 2- Cyclopentyl-N-{2,6-dichloro-4-[(5-trifluoromethylpyridin-2-ylamino)-methyl]-phenyl}- acetamide; and pharmaceutically acceptable salts thereof. [0266] In further embodiments, Z is O or S; q is 0; R1 and R2 are each independently selected from the group consisting of halogen, cyano, amino, C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl, halo-C1-6-alk(en/yn)yl, halo-C3- 8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8- cycloalk(en)yloxy, and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy; R3 is selected from the group consisting of C1-8-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, amino-C1-6-alk(en/yn)yl, amino-C3-8-cycloalk(en)yl, amino-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy-C1-6- alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl; and R4 is selected from the group consisting of halogen, cyano, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl, Aryl-C3-8- cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR5R6 and R7NH—C1-6- alk(en/yn)yl; wherein: R5 and R6 are each independently selected from the group consisting of hydrogen, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, and C3-8- cycloalk(en)yl-C1-6alk(en/yn)yl, with the proviso that R5 and R6 can not both be hydrogen; and R7 is selected from the group consisting of C1-6-alk(en/yn)yl; C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl, halo-C1-6-alk(en/yn)yl, halo-C3- 8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6-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. [0267] In further embodiments, R1 and R2 are each independently selected from the group consisting of halogen, amino, C1-6-alk(en/yn)yl, Aryl, and halo-C1-6-alk(en/yn)yl. [0268] In further embodiments, R3 is selected from the group consisting of C1-8- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6- alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, and amino-C1-6-alk(en/yn)yl. [0269] In further embodiments, R4 is selected from the group consisting of halogen, C1-6- alk(en/yn)yl, NR5R6 and R7NH—C1-6-alk(en/yn)yl, wherein R5, R6 and R7 are as previously defined. [0270] In further embodiments, R4 is NR5R6, wherein R5 and R6 are independently selected from the group consisting of hydrogen, Aryl-C1-6-alk(en/yn)yl, and C1-6- alk(en/yn)yl, with the proviso that R5 and R6 cannot both be hydrogen. [0271] In further embodiments, R4 is R7NH—C1-6-alk(en/yn)yl, wherein R7 is Aryl. [0272] In further embodiments, any Aryl is optionally substituted with one or more substituents independently selected from the group consisting of amino, halogen, cyano, C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, hydroxy, C1-6-alk(en/yn)yloxy, halo-C1-6- alk(en/yn)yloxy, di-(C1-6-alk(en/yn)yl)amino, C1-6-alk(en/yn)yl-CO—NH— and C1-6- 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 C1-6-alk(en/yn)yl groups. [0273] In further embodiments, the Kv7 channel activator is a compound according to formula 14, wherein: Z is O or S; q is 0; R1 and R2 are each independently selected from the group consisting of halogen, cyano, amino, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3- 8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy; R3 is selected from the group consisting of C1-8-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6- alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, amino-C1- 6-alk(en/yn)yl, amino-C3-8-cycloalk(en)yl, amino-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1- 6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl and halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; and R4 is selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1- 6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl, NR5R6 and R7NH—C1-6-alk(en/yn)yl; wherein: R5 and R6 are each independently selected from the group consisting of hydrogen, Aryl-C1-6-alk(en/yn)yl, Aryl-C3-8-cycloalk(en)yl, Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, with the proviso that R5 and R6 cannot both be hydrogen; and R7 is selected from the group consisting of C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl, halo-C1-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Aryl-C1-6- 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 [0274] 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. WO2009015667A1, published February 5, 2009 and corresponding to International Application No. PCT/DK2008/050191 filed July 31, 2008; International Publication No. WO2006092143A1, 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. [0275] In an embodiment, the Kv7 channel activator is a compound according to formula 15: Formula 15
Figure imgf000145_0001
wherein, q is 0 or 1; each of R1 and R2 is independently selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy and C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yloxy; and R3 is selected from the group consisting of C1-8- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, optionally substituted Aryl-C1-6-alk(en/yn)yl, optionally substituted Aryl-C3-8-cycloalk(en)yl, optionally substituted Aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl-C3-8- heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6- alk(en/yn)yl, C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn)yl, Heteroaryl-C1-6-alk(en/yn)yl, Heteroaryl-C3-8-cycloalk(en)yl, Heteroaryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR4R5— C1-6-alk(en/yn)yl, NR4R5—C3-8-cycloalk(en)yl NR4R5—C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, halo-C1-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; wherein each of R4 and R5 is independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; as the free base or a pharmaceutically acceptable salt thereof. [0276] 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-pyridin-3-yl)-carbamic acid 2-chloro-benzyl ester; 2-(4- Chloro-phenyl)-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-acetamide; 2-Phenyl- cyclopropanecarboxylic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-amide; N-(2,4- Dimethyl-6-morpholin-4-yl-pyridin-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- pyridin-3-yl)-carbamic acid isobutyl ester; 3-(3-Chloro-phenyl)-N-(2,4-dimethyl-6- morpholin-4-yl-pyridin-3-yl)-propionamide; N-(2,4-Dimethyl-6-morpholin-4-yl-pyridin-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-Chloro-phenyl)-N-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)- acetamide; 2-(3,4-Dichloro-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-thiophen-3-yl-acetamide; N- (2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-yl)-2-p-tolyl-acetamide; 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-pyridin-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-pyridin-3-yl)-2-(3,4-dimethyl-phenyl)-acetamide; 2-Cyclohex- 1-enyl-N-(2,4-dimethyl-6-morpholin-4-yl-pyridin-3-yl)-acetamide; N-(2,4-Dimethyl-6- morpholin-4-yl-pyridin-3-yl)-2-(4-methoxy-3-methyl-phenyl)-acetamide; N-(2,4-Dimethyl- 6-morpholin-4-yl-pyridin-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-phenyl)-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-morpholin-4-yl-pyridin-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-pyridin-3-yl)-acetamide; 2- Cyclohexyl-N-(2,4-dimethyl-6-morpholin-4-yl-pyridin-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)-acetamide; 3-Cyclopentyl-N-(2,4-dimethyl-6-morpholin-4- yl-pyridin-3-yl)-propionamide; Hexanoic acid (2,4-dimethyl-6-morpholin-4-yl-pyridin-3- yl)-amide; N-(4-Chloro-2-methoxy-6-morpholin-4-yl-pyridin-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)- propionamide; and pharmaceutically acceptable salts thereof. [0277] In further embodiments, q is 0 or 1; R1 and R2 each is independently selected from the group consisting of halogen, cyano, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3- 8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy and C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yloxy; and R3 is selected from the group consisting of C1-8- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, optionally substituted aryl-C1-6-alk(en/yn)yl, optionally substituted aryl-C3-8-cycloalk(en)yl, optionally substituted aryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yl-C3-8- heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6- alk(en/yn)yl-C3-8-heterocycloalk(en)yl-C1-6-alk(en/yn)yl, heteroaryl-C1-6-alk(en/yn)yl, heteroaryl-C3-8-cycloalk(en)yl, heteroaryl-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, NR4R5— C1-6-alk(en/yn)yl, NR4R5—C3-8-cycloalk(en)yl, NR4R5—C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, halo-C1-6- alk(en/yn)yl, halo-C3-8-cycloalk(en)yl and halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, wherein: R4 and R5 each is independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl. Formula 16 [0278] 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. WO2009015667A1, 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. [0279] In an embodiment, the Kv7 channel activator is a compound according to formula 16: Formula 16
Figure imgf000149_0001
wherein: q is 0 or 1; R1 and R2 are independently selected from the group consisting of hydrogen and optionally substituted aryl-C1-6-alk(en/yn)yl, provided that R1 and R2 are not both hydrogen; or R1 and R2 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further heteroatom; R2 and R4 are independently selected from hydrogen, halogen, cyano, amino, C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yloxy, C3-8- cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, halo-C1-6-alk(en/yn)yloxy, halo-C3-8-cycloalk(en)yloxy and halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, provided that R3 and R4 are not both hydrogen; and R5 is selected from the group consisting of C1- 10-alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, optionally substituted aryl-C1-6- alk(en/yn)yl and optionally substituted aryl; as the free base or a pharmaceutically acceptable salt thereof. [0280] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin-5-yl]-2- cyclopentylacetamide; N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin- 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-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. WO2007065449A1, 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. [0281] In an embodiment, the Kv7 channel activator is a compound according to formula 17: Formula 17
Figure imgf000150_0001
, wherein: q is 0 or 1; R1 and R2 are independently selected from the group consisting of hydrogen and optionally substituted aryl-C1-6-alk(en/yn)yl, provided that R1 and R2 are not both hydrogen, or R1 and R2 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further heteroatom;R3 and R4 are independently selected from hydrogen, halogen, cyano, amino, C1-6- alk(en/yn)yl, C3-8- cycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yloxy, C3-8- cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy, halo-C1-6-alk(en/yn)yloxy, halo-C3-8-cycloalk(en)yloxy and halo-C3-8-cycloalk(en)yl- C1-6-alk(en/yn)yloxy, provided that R3 and R4 are not both hydrogen;R5 is selected from the group consisting of C1-10- alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, optionally substituted aryl-C1-6- alk(en/yn)yl and optionally substituted aryl; as the free base or salts thereof. [0282] In further embodiments, q is 0. [0283] In further embodiments, q is 1. [0284] In further embodiments, R1 and R2 are independently selected from hydrogen and optionally substituted aryl-C1-6-alk(en/yn)yl, provided that R1 and R2 are not both hydrogen. [0285] In further embodiments, R1 and R2 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing a further hetero atom. [0286] In further embodiments, said further hetero atom is oxygen. [0287] In further embodiments, said ring is a 6 membered ring. [0288] In further embodiments, said ring is a morpholine ring. [0289] In further embodiments, R3 and R4 are independently selected from amino and C1-6-alk(en/yn)yl, preferably methyl. [0290] In further embodiments, R5 is selected from the group consisting of C1-10- alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, optionally substituted aryl-C1-6- alk(en/yn)yl and optionally substituted aryl. [0291] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin-5-yl]-2- cyclopentylacetamide, N-[4-Amino-6-methyl-2-(4-trifluoromethylbenzylamino)-pyrimidin- 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-moφholin-4-yl-pyrimidin-5-yl)-acetamide, N-(4,6- Dimethyl-2-moφholin-4-yl-pyrimidin-5-yl)-3,3-dimethylbutyramide, N-(4,6-Dimethyl-2- moφholin-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-moφholin-4- ylpyrimidin-5-yl)-2-(3-fluorophenyl)-acetamide and Hexanoic acid (4,6-dimethyl-2- moφholin-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. WO2004096767A1, 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. [0292] In an embodiment, the Kv7 channel activator is a compound according to formula 18: mula 18
Figure imgf000152_0001
wherein, the dotted line represents an optional bond; R1 and R1′ 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-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8- cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano- C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; or R1 and R1′ 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, NR11, S, SO2, SO2NR11, CO—O or CO—NR11; wherein R11 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl; or R2 and R11 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; R2 is selected from the group consisting of hydrogen, C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6- alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano, cyano-C1-6-alk(en/yn)yl, cyano-C3-8- cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, —NO2, NR10R10′—C1-6- alk(en/yn)yl, NR10R10′—C3-8-cycloalk(en)yl and NR10R10′—C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl; wherein R10 and R10′ 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-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1- 6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, or R10 and R10′ 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 R2 is NO2, halogen or cyano then s is 0; and with the proviso that when R2 is a hydrogen atom or acyl and s is 1 then U is NR11, O or S; wherein the group —(U)s—R2 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; R3 is selected from the group consisting of C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, heterocycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, C1-6- alk(en/yn)yl-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yl-heterocycloalk(en)yl, Ar, Ar—C1-6- alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar-heterocycloalk(en)yl, Ar—C3-8-cycloalk(en)yl-C1- 6-alk(en/yn)yl, Ar—C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, Ar—C1-6-alk(en/yn)yl- heterocycloalk(en)yl, C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-C1-6- alk(en/yn)yl, C1-6-alk(en/yn)yloxy-C3-8-cycloalk(en)yl, C1-6-alk(en/yn)yloxy- heterocycloalk(en)yl, Ar-oxy-C1-6-alk(en/yn)yl, Ar—C1-6-alk(en/yn)yloxy-C1-6-alk(en/yn)yl, C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yloxy-carbonyl-C1-6- alk(en/yn)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yloxy-carbonyl-C1-6-alk(en/yn)yl, hydroxy- C1-6-alk(en/yn)yl, hydroxy-C3-8-cycloalk(en)yl, hydroxy-heterocycloalk(en)yl, hydroxy-C3- 8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, hydroxy- C1-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-heterocycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6- alk(en/yn)yl-C3-8-cycloalk(en)yl, halo-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, halo-C1-6- alk(en/yn)yl-Ar, halo-C3-8-cycloalk(en)yl-Ar, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl-Ar, halo-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl-Ar, cyano-C1-6-alk(en/yn)yl, cyano-C3-8- cycloalk(en)yl, cyano-heterocycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, cyano-C1-6-alk(en/yn)yl-heterocycloalk(en)yl, acyl-C1-6-alk(en/yn)yl, acyl-C3-8-cycloalk(en)yl, acyl-heterocycloalk(en)yl, acyl-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, acyl-C1-6-alk(en/yn)yl-C3-8-cycloalk(en)yl, acyl-C1-6- alk(en/yn)yl-heterocycloalk(en)yl and —NR12R12′, optionally substituted NR12R12′—C1-6- alk(en/yn)yl, optionally substituted NR12R12′—C3-8-cycloalk(en)yl, optionally substituted NR12R12′—C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; wherein R12 and R12′ 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-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar—C3-8-cycloalk(en)yl, Ar— C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, hydroxy-C1-6-alk(en/yn)yl, hydroxy-C3-8- cycloalk(en)yl, hydroxy-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, halo-C1-6-alk(en/yn)yl, halo- C3-8-cycloalk(en)yl, halo-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, cyano-C1-6-alk(en/yn)yl, cyano-C3-8-cycloalk(en)yl and cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, or R12 and R12′ 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 R3 is NR12R12′ then q is 0; and Y is selected from the groups according to the following formulas:
Figure imgf000155_0001
, 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 R5 is independently selected from the group consisting of a C1-6-alk(en/yn)yl, C3-8- cycloalk(en)yl, C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar, Ar—C1-6-alk(en/yn)yl, Ar-thio, Ar- oxy, acyl, C1-6-alk(en/yn)yloxy, C3-8-cycloalk(en)yloxy, C3-8-cycloalk(en)yl-C1-6- alk(en/yn)yloxy, halogen, halo-C1-6-alk(en/yn)yl, halo-C3-8-cycloalk(en)yl, halo-C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, —CO—NR6R6′, cyano, cyano-C1-6-alk(en/yn)yl, cyano- C3-8-cycloalk(en)yl, cyano-C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl, —NR7R7′, —S—R8 and —SO2R8, or two adjacent R5 together with the aromatic group to which they are attached form a 4-8 membered ring which optionally contains one or two heteroatoms; R6 and R6′ 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-C1-6-alk(en/yn)yl and Ar; R7 and R7′ 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-C1-6-alk(en/yn)yl, Ar and acyl; and R8 is selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl, C3-8- cycloalk(en)yl-C1-6-alk(en/yn)yl, Ar and —NR9R9′; wherein R9 and R9′ are independently selected from the group consisting of hydrogen, C1-6-alk(en/yn)yl, C3-8-cycloalk(en)yl and C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl; provided that when R8 is —NR9R9′ then R5 is not —S—R8; 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. [0293] In an embodiment, the Kv7 channel activator is a compound according to formula 19: Formula 19
Figure imgf000156_0001
wherein, A1, A2 and A3 independently of each other represent CR4, N, O, S or N(CH3), A4 represents CR4 or N, and n denotes 0 or 1, with the proviso, that at least one of A1, A2, A3 and A4 does not represent CR4, and with the proviso, that if n denotes 0, then precisely one of A1, A2 and A3 represents O, S or N(CH3), or if n denotes 1, then A1, A2 and A3 independently of each other represent CR4 or N, R1 represents C1-10-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; aryl or heteroaryl, 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; R2 represents F; Cl; Br; I; CN; CF3; C(═O)H; NO2; OCF3; SCF3; C1-4-aliphatic residue, C(═O)—C1-4-aliphatic residue, C(═O)—O—C1-4-aliphatic residue, C(═O)—NH—C1-4- aliphatic residue, C(═O)—N(C1-4-aliphatic residue)2, O—C1-4-aliphatic residue, O— C(═O)—C1-4-aliphatic residue, S—C1-4-aliphatic residue, S(═O)2—C1-4-aliphatic residue, S(═O)2—O—C1-4-aliphatic residue, wherein the C1-4-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; R3 represents C2-10-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 S—R5, O—R6 or N(R7R8), wherein R5 and R6 in each case represent C1-10-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; with the proviso, that if R5 or R6 denote a 3 to 10 membered heterocycloaliphatic residue, than the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, R7 represents C1-10-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; with the proviso that if R7 denotes 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom; and R8 denotes C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; or R7 and R8 form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted; and each R4 independently represents H, F; Cl; Br; I; CN; CF3; CHF2; CH2F; OCF3; OCHF2; OCH2F; SCF3; O—C1-4-aliphatic residue, C1-4-aliphatic residue or S(═O)2—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, NH—C(═O)—C1- 4aliphatic residue, N(C1-4aliphatic residue)-C(═O)—C1-4 aliphatic residue, NH—S(═O)2— C1-4 aliphatic residue, N(C1-4 aliphatic residue)-S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, O—C1-4-aliphatic residue, O—C(═O)—C1-4-aliphatic residue, SH, SCF3, S—C1-4- aliphatic residue, S(═O)2OH, S(═O)2—C1-4-aliphatic residue, S(═O)2—O—C1-4-aliphatic residue, S(═O)2—NH(C1-4-aliphatic residue), S(═O)2—N(C1-4-aliphatic residue)2, CN, CF3, CHO, COOH, C1-4-aliphatic residue, C(═O)—C1-4-aliphatic residue, C(═O)—O— C1-4-aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, C(═O)NH2, a C(═O)—NH(C1-4-aliphatic residue) and C(═O)—N(C1-4-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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000158_0001
1-4-aliphatic residue), N(C1-4-aliphatic residue)2, NH—C(═O)—C1-4-aliphatic residue, N(C1-4 aliphatic residue)-C(═O)—C1- 4 aliphatic residue, NH—S(═O)2—C1-4 aliphatic residue, N(C1-4 aliphatic residue)- S(═O)2—C1-4 aliphatic residue, OH, OCF3, O—C1-4-aliphatic residue, O—C(═O)—C1-4- aliphatic residue, SH, SCF3, S—C1-4-aliphatic residue, S(═O)2OH, S(═O)2—C1-4- aliphatic residue, S(═O)2—O—C1-4-aliphatic residue, S(═O)2—NH(C1-4-aliphatic residue), S(═O)2—N(C1-4-aliphatic residue)2, CN, CF3, C(═O)H, C(═O)OH, C1-4-aliphatic residue, C(═O)—C1-4-aliphatic residue, C(═O)—O—C1-4-aliphatic residue, C3-6- cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(═O)NH2, C(═O)—NH(C1-4-aliphatic residue) and C(═O)—N(C1-4-aliphatic residue)2; 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. [0294] In further embodiments, A1, A2 and A3 independently of each other represent CR4, N, O, S or N(CH3), A4 represents CR4 or N, and n denotes 0 or 1, with the proviso, that at least one of A1, A2, A3 and A4 does not represent CR4, and with the proviso, that if n denotes 0, then precisely one of A1, A2 and A3 represents O, S or N(CH3), or if n denotes 1, then A1, A2 and A3 independently of each other represent CR4 or N, R1 denotes 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)—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—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked 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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, O3-8- cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue,
Figure imgf000160_0001
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 O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S—C1-4- aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the aryl or the heteroaryl residue may in each case be optionally linked 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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN and C(═O)OH, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; C1-4-aliphatic residue, S—C1-4-aliphatic residue, O—C1-4-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, OH, OCF3, CF3 and O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN and C(═O)OH, R3 denotes 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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 O—C1-4-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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 O—C1-4-aliphatic residue, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked 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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O— C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4- aliphatic residue and C(═O)OH, Or denotes S—R5, O—R6 or N(R7R8), wherein R5 and R6 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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 O—C1-4-aliphatic residue, or in each case represent 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)—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—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked 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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, on the condition that if R5 or R6 denote a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, R7 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)—O—C1-4-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—C1-4-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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)—O—C1-4-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 O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a O1-0- 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, and/or R8 denotes 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 O—C1-4-aliphatic residue, Or R7 and R8 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)— OH, 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 O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R7 and R8 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 and C(═O)OC2H5, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue,
Figure imgf000165_0001
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 O—C1- 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4- aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)—OH, and each R4 independently represents H, F, Cl, Br, I, CN, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, SCF3, O—C1-4-aliphatic residue, C1-4-aliphatic residue or S(═O)2—C1-4-aliphatic residue. In further embodiments, n denotes 1 and A1 represents N, A2 represents CR4, A3 represents CR4 and A4 represents CR4; or n denotes 1 and A1 represents CR4, A2 represents N, A3 represents CR4 and A4 represents CR4; or n denotes 1 and A1 represents CR4, A2 represents CR4, A3 represents N and A4 represents CR4; or n denotes 1 and A1 represents CR4, A2 represents CR4, A3 represents CR4 and A4 represents N; or n denotes 1 and A1 represents N, A2 represents N, A3 represents CR4 and A4 represents CR4; or n denotes 1 and A1 represents N, A2 represents CR4, A3 represents N and A4 represents CR4; or n denotes 1 and A1 represents N, A2 represents CR4, A3 represents CR4 and A4 represents N; or n denotes 1 and A1 represents CR4, A2 represents N, A3 represents N and A4 represents CR4; or n denotes 1 and A1 represents CR4, A2 represents N, A3 represents CR4 and A4 represents N; or n denotes 1 and A1 represents CR4, A2 represents CR4, A3 represents N and A4 represents N; or n denotes 0 and A1 represents CR4, A2 represents CR4, and A3 represents S; or n denotes 0 and A1 represents N, A2 represents CR4, and A3 represents S; or n denotes 0 and A1 represents S, A2 represents CR4 and A3 represents CR4; or n denotes 0 and A1 represents S, A2 represents CR4 and A3 represents N. [0295] In further embodiments, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; C1-4-aliphatic residue, S—C1-4-aliphatic residue or 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, ═O, OH and O—C1-4-aliphatic residue. [0296] In further embodiments, R2 represents C1-4-aliphatic residue. [0297] In further embodiments, each R4 independently represents H; F; Cl; Br; CN; CF3; OCF3; CH3, OCH3 or S(═O)2CH3. [0298] In further embodiments, R1 represents the partial structure:
Figure imgf000166_0001
wherein, m denotes 0, 1, or 2, R1a and R1b each independently of one another represent H, F, Cl, Br, I, O—C1-4-aliphatic residue or C1-4-aliphatic residue, R1c 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—C1-4-aliphatic residue, CF3 and 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, CF3 and O—C1-4-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, O—C1-4-aliphatic residue, CF3 and 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, CF3 and 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—C1-4-aliphatic residue, OCF3, CF3, CN, C1-4- aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, 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—C1-4-aliphatic residue, OCF3, CF3, CN, C1-4- aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, OH, ═O, O—C1-4-aliphatic residue, OCF3, CF3 C1-4-aliphatic residue and C(═O)OH. [0299] In further embodiments, m denotes 1 or 2, R1a and R1b represent H, R1c 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—C1-4-aliphatic residue, CF3 and C1-4-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, O—C1-4-aliphatic residue, CF3 and C1-4-aliphatic residue, or m denotes 0 and R1c 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— C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, 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— C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, OH, ═O, O—C1-4-aliphatic residue, OCF3, CF3, C1-4-aliphatic residue and C(═O)OH. [0300] In further embodiments, R3 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, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4- aliphatic residue, CF3, CN and 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, CF3 and O—C1-4- 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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, (═O)—O—C1-4-aliphatic residue, S—C1-4- aliphatic residue, CF3, CN and 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, OCF3, CF3 and O—C1- 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 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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3, CN and C1-4-aliphatic residue, or R3 denotes S—R5 or O— R6, wherein R5 and R6 in each case denote 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, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4- aliphatic residue, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, CF3 and 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, CF3 and O—C1-4-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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, OCF3, CF3 and O—C1-4-aliphatic residue, and wherein the C3-6-cycloaliphatic residue or the 3 to 7 membered heterocycloaliphatic residue may be 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, OH, ═O, O—C1-4-aliphatic residue, OCF3, CF3, CN and C1-4-aliphatic residue, on the condition that if R5 or R6 denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, or R3 denotes N(R7R8), wherein R7 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, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, CF3 and O—C1-4-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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, OCF3, CF3 and O—C1-4-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 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, ═O, O—C1-4- aliphatic residue, OCF3, SCF3, CF3, CN and C1-4-aliphatic residue, on the condition that if R7 denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, and R8 denotes C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3, CN and 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, OH, CF3 and O—C1-4-aliphatic residue, or R7 and R8 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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3, CN and 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, CF3 and O—C1-4- aliphatic residue, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R7 and R8 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—C1-4- aliphatic residue, OCF3, SCF3, CF3, ON, C1-4-aliphatic residue, C(═O)OH, C3- 6 cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue,
Figure imgf000170_0001
benzyl, phenyl, thienyl, and pyridyl, 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—C1-4-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—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SCF3, CF3, CN, C1-4-aliphatic residue and C(═O)OH, 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, ═O, O—C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue and C(═O)OH. [0301] In further embodiments, R3 denotes C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and C1-4- 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, ═O, O— C1-4-aliphatic residue, OCF3, SCF3, CF3 and C1-4-aliphatic residue, wherein the C1-4- aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or O—C1-4-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 C1-4- aliphatic group, or R3 denotes S—R5 or O—R6, wherein R5 and R6 in each case denote C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, CF3 and O—C1-4-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, ═O, O— C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, OCF3, CF3 and O—C1-4-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 C1-4-aliphatic group, on the condition that if R5 or R6 denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, or R3 denotes N(R7R8), wherein R7 denotes C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, CF3 and O—C1-4-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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, OCF3, CF3 and O—C1-4-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 C1-4-aliphatic group, on the condition that if R7 denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, and R8 denotes unsubstituted C1-4-aliphatic residue, or R7 and R8 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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3, CN and 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, OH, CF3 and O—C1-4-aliphatic residue, and wherein the 3 to 7 membered heterocycloaliphatic residue formed by R7 and R8 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—C1-4- aliphatic residue, OCF3, SCF3, CF3, CN, C1-4-aliphatic residue, C(═O)OH, benzyl, phenyl, and pyridyl, 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 and O—C1-4-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, OCH2CH2OCH3, SCF3, CF3 and C1-4-aliphatic residue. [0302] In further embodiments, A1, A2 and A3 independently of each other represent CR4, N, O, S or N(CH3), A4 represents CR4 or N, and n denotes 0 or 1, with the proviso, that at least one of A1, A2, A3 and A4 does not represent CR4, and with the proviso, that if n denotes 0, then precisely one of A1, A2 and A3 represents O, S or N(CH3), or if n denotes 1, then A1, A2 and A3 independently of each other represent CR4 or N, R1 represents the partial structure:
Figure imgf000173_0001
wherein: m denotes 0, 1, or 2, R1a and R1b each independently of one another represent H, F, Cl, O—C1-4-aliphatic residue or C1-4-aliphatic residue, R1c denotes C1-4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, C1-10—C1-4 aliphatic residue, CF3 and 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, CF3 and O—C1-4-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, C1- 10—C1-4-aliphatic residue, CF3 and 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, CF3 and 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, OH, O—C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, 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— C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, OH, ═O, O—C1-4-aliphatic residue, OCF3, CF3 C1-4-aliphatic residue and C(═O)OH, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; C1-4- aliphatic residue, S—C1-4-aliphatic residue or 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, ═O, OH and O—C1- 4-aliphatic residue, R3 denotes C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and C1-4-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, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and C1-4-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or O—C1-4-aliphatic residue, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally linked via a C1-4-aliphatic group, or R3 denotes S—R5 or O—R6, wherein R5 and R6 in each case denote C1-8- aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, CF3 and O—C1-4-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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, OCF3, CF3 and O—C1-4- 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 C1-4- aliphatic group, on the condition that if R5 or R6 denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, or R3 denotes N(R7R8), wherein R7 denotes C1-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3 and 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, OH, CF3 and O—C1-4-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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, C(═O)—O—C1-4- aliphatic residue, CF3 and 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, OH, OCF3, CF3 and O—C1-4- 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 C1-4-aliphatic group, on the condition that if R7 denotes 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, and R8 denotes unsubstituted C1-4-aliphatic residue, or R7 and R8 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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, CF3, CN and 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, OH, CF3 and O—C1-4-aliphatic residue, and wherein the 3 to 7 membered heterocycloaliphatic residue formed by R7 and R8 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—C1-4-aliphatic residue, OCF3, SCF3, CF3, CN, C1-4- aliphatic residue, C(═O)OH, benzyl, phenyl, and pyridyl, 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, and O—C1-4-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, SCF3, CF3 and C1-4-aliphatic residue; and each R4 independently represents H, F, Cl, Br, CN, CF3, OCF3, CH3, OCH3 or S(═O)2CH3. [0303] In further embodiments, the Kv7 channel activator is selected from the group consisting of:12-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-[1,5]naphthyridine- 3-carboxylic acid amide; 22-Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl- [1,5]naphthyridine-3-carboxylic acid amide; 3-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]- 4-methyl-[1,6]naphthyridine-3-carboxylic acid amide; 42-Ethylsulfanyl-N-[(4- fluorophenyl)-methyl]-4-methyl-[1,6]naphthyridine-3-carboxylic acid amide; 52- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-[1,7]naphthyridine-3-carboxylic acid amide; 6-Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-[1,7]naphthyridine-3- carboxylic acid amide; 72-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl- [1,8]naphthyridine-3-carboxylic acid amide; 82-Ethylsulfanyl-N-[(4-fluorophenyl)- methyl]-4-methyl-[1,8]naphthyridine-3-carboxylic acid amide; 92-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-[1,8]naphthyridine-3-carboxylic acid amide; 102-Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)- [1,8]naphthyridine-3-carboxylic acid amide; 112-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-4-methyl-7-(trifluoromethyl)-[1,6]naphthyridine-3-carboxylic acid amide; 122- Ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-[1,6]naphthyridine- 3-carboxylic acid amide; 132-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-7- (trifluoromethyl)-[1,5]naphthyridine-3-carboxylic acid amide; 142-Ethylsulfanyl-N-[(4- fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-[1,5]naphthyridine-3-carboxylic acid amide; 155-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-methyl-thieno[3,2-b]pyridine-6- carboxylic acid amide; 166-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl- thieno[2,3-b]pyridine-5-carboxylic acid amide; 175-Ethoxy-N-[(3-fluorophenyl)-methyl]- 7-methyl-2-(trifluoromethyl)-thieno[3,2-b]pyridine-6-carboxylic acid amide; 186-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. PCT/EP2013/003572 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. [0304] In an embodiment, the Kv7 channel activator is a compound according to formula 20: Formula 20
Figure imgf000177_0001
wherein: A1 represents CR10R11 or S; A2 represents CR12R13, C(═O), O, S, S(═O) or S(═O)2; A3, A4 and A5 independently of each other represent CR7, N, O, S or NR8, A6 represents CR7 or N, and n denotes 0 or 1, with the proviso, that if n denotes 0, then precisely one of A3, A4 and A5 represents O, S or NR8, or if n denotes 1, then A3, A4 and A5 independently of each other represent CR7 or N; and with the proviso, that if n denotes 1 and A3, A4 and A5 each represent CR7, then A6 does not represent N; R1 represents C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; C3-10- 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 C1-4- 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 C1-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R2, R3; R4, R5, R10, R11, R12 and R13 each independently of another represent H; F; Cl; Br; I; NO2; CF3; CN; OH; OCF3; SH; SCF3; C1-10-aliphatic residue, O—C1-10-aliphatic residue or S—C1-10-aliphatic residue, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; or C3-10-cycloaliphatic residue, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; or R2 and R3 or R4 and R5 or R10 and R11 or R12 and R13 or R2 and R11 or R2 and R4 or R2 and R13 or R4 and R13 or R4 and R11 or R12 and R13, together with the carbon atom(s) joining them, form a C3-10-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 R2, R3; R4; R5; R10, R11, R12 and R13 in each case have the meaning given above; R6 represents a C3-10-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 R7 independently of each other represents H, F; Cl; CN; CF3; CHF2; CH2F; OCF3; OCHF2; OCH2F; SCF3; O—C1-4- aliphatic residue, C1-4-aliphatic residue or S(═O)2—C1-4-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; and R8 represents H or a C1-4- 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, NH—C(═O)—C1-4aliphatic residue, N(C1-4-aliphatic residue)-C(═O)—C1-4-aliphatic residue, NH—S(═O)2—C1-4-aliphatic residue, N(C1-4-aliphatic residue)-S(═O)2—C1-4- aliphatic residue, ═O, OH, OCF3, O—C1-4-aliphatic residue, O—C(═O)—C1-4-aliphatic residue, SH, SCF3, S—C1-4-aliphatic residue, S(═O)2OH, S(═O)2—C1-4-aliphatic residue, S(═O)2—O—C1-4-aliphatic residue, S(═O)2—NH(C1-4-aliphatic residue), S(═O)2—N(C1-4-aliphatic residue)2, CN, CF3, CHO, COOH, C1-4-aliphatic residue, C(═O)—C1-4-aliphatic residue, C(═O)—O—C1-4-aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(═O)NH2, a C(═O)—NH(C1-4-aliphatic residue) and C(═O)—N(C1-4-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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000179_0001
NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, NH—C(═O)—C1-4-aliphatic residue, N(C1-4 aliphatic residue)-C(═O)—C1-4 aliphatic residue, NH—S(═O)2—C1- 4 aliphatic residue, N(C1-4 aliphatic residue)-S(═O)2—C1-4 aliphatic residue, OH, OCF3, O—C1-4-aliphatic residue, O—C(═O)—C1-4-aliphatic residue, SH, SCF3, S—C1-4- aliphatic residue, S(═O)2OH, S(═O)2—C1-4-aliphatic residue, S(═O)2—O—C1-4-aliphatic residue, S(═O)2—NH(C1-4-aliphatic residue), S(═O)2—N(C1-4-aliphatic residue)2, CN, CF3, C(═O)H, C(═O)OH, C1-4-aliphatic residue, C(═O)—C1-4-aliphatic residue, C(═O)— O—C1-4-aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(═O)NH2, C(═O)—NH(C1-4- aliphatic residue) and C(═O)—N(C1-4-aliphatic residue)2; 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. [0305] In further embodiments, A1 represents CR10R11 or S; A2 represents CR12R13, C(═O), O, S, S(═O) or S(═O)2; A3, A4 and A5 independently of each other represent CR7, N, O, S or NR8, A6 represents CR7 or N, and n denotes 0 or 1, with the proviso, that if n denotes 0, then precisely one of A3, A4 and A5 represents O, S or NR8, or if n denotes 1, then A3, A4 and A5 independently of each other represent CR7 or N; and with the proviso, that if n denotes 1 and A3, A4 and A5 each represent CR7, then A6 does not represent N; R1 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 O—C1-4-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, NH(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case be 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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, NH(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, C3-6 cycloaliphatic residue, 3 to 6 membered heterocycloaliphatic residue,
Figure imgf000181_0001
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 O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, 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, NH(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the aryl or the heteroaryl residue may in each case be 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, NO2, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN and C(═O)OH, R2, R3, R5, R10, R11, R12 and R13 each independently of the others represents H; F; Cl; Br; I; NO2; CF3; CN; OH; OCF3; SH; SCF3; C1-4-aliphatic residue, O—C1-4-aliphatic residue or S—C1-4- 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—C1-4-aliphatic residue, or a C3-10-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 O—C1-4-aliphatic residue, and wherein the C3-10-cycloaliphatic residue may 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, or R2 and R3 or R4 and R5 or R10 and R11 or R12 and R13 or R2 and R11 or R2 and R4 or R2 and R13 or R4 and R13 or R4 and R11 or R12 and R13, together with the carbon atom(s) joining them, form a C3-10-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 O—C1- 4-aliphatic residue, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the remaining substituents R2, R3, R4, R5, R10, R11, R12 and R13 in each case have the meaning given above; R6 represents a C3-10-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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, 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 O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the C3-10- cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, 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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue,
Figure imgf000184_0001
be y, 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 O—C1-4-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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the aryl or the heteroaryl residue may in each case be 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O— C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN and C(═O)OH, each R7 independently of each other represents H, F; Cl; CN; CF3; CHF2; CH2F; OCF3; OCHF2; OCH2F; SCF3; a O—C1-4-aliphatic residue, a C1-4-aliphatic residue or a S(═O)2—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, OCF3, CF3 and O—C1-4-aliphatic residue. and R8 represents H or C1-4-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, OCF3, CF3 and O—C1-4-aliphatic residue. [0306] In further embodiments, A1 represents S; and A2 represents S, S(═O)2 or CR12R13, wherein R12 and R13 both represent H or both represent F. [0307] In further embodiments, n denotes 1 and A3 represents CR7, A4 represents CR7, A5 represents CR7 and A6 represents CR7; or n denotes 1 and A3 represents N, A4 represents CR7, A5 represents CR7 and A6 represents CR7; or n denotes 1 and A3 represents CR7, A4 represents N, A5 represents CR7 and A6 represents CR7; or n denotes 1 and A3 represents CR7, A4 represents CR7, A5 represents N and A6 represents CR7; or n denotes 1 and A3 represents N, A4 represents N, A5 represents CR7 and A6 represents CR7; or n denotes 1 and A3 represents N, A4 represents CR7, A5 represents N and A6 represents CR7; or n denotes 1 and A3 represents N, A4 represents CR7, A5 represents CR7 and A6 represents N; or n denotes 1 and A3 represents CR7, A4 represents N, A5 represents CR7 and A6 represents N; or n denotes 1 and A3 represents CR7, A4 represents N, A5 represents N and A6 represents CR7; or n denotes 1 and A3 represents CR7, A4 represents CR7, A5 represents N and A6 represents N; or n denotes 0 and A3 represents S, A4 represents CR7 and A5 represents CR7; or n denotes 0 and A3 represents S, A4 represents CR7 and A5 represents N; or n denotes 0 and A3 represents O, A4 represents CR7 and A5 represents CR7, or n denotes 0 and A3 represents O, A4 represents CR7 and A5 represents N; or n denotes 0 and A3 represents CR7, A4 represents CR7 and A5 represents S; or n denotes 0 and A3 represents N, A4 represents CR7 and A5 represents S; or n denotes 0 and A3 represents CR7, A4 represents CR7 and A5 represents O; or n denotes 0 and A3 represents N, A4 represents CR7 and A5 represents O. [0308] In further embodiments, R1 represents the partial structure:
Figure imgf000185_0001
wherein: R14a and R14b each independently of the other represent H; F; Cl; Br; CF3; CN; OH; OCF3; NH2; C1-4-aliphatic residue, O—C1-4-aliphatic residue, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, 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—C1-4-aliphatic residue, OH and OCF3; or independently represent C3-10-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, C1-4- aliphatic residue, OH, ═O, O—C1-4-aliphatic residue, OCF3, NH2, NH(C1-4-aliphatic residue) and N(C1-4-aliphatic residue)2; m represents 0, 1, 2 or 3; Y represents O or NR15, wherein R15 represents H or C1-4-aliphatic residue, 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, C1-4-aliphatic residue, OH, O—C1-4-aliphatic residue, OCF3, NH2, NH(C1-4- aliphatic residue) and N(C1-4-aliphatic residue)2; or C3-10-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, C1-4-aliphatic residue, OH, O—C1-4-aliphatic residue, OCF3, NH2, NH(C1-4- aliphatic residue) and N(C1-4-aliphatic residue)2; o represents 0 or 1, B represents C1-8- aliphatic residue, 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, CN, OH, ═O, O—C1-4-aliphatic residue, OCF3, C(═O)OH, CF3, NH2, NH(C1-4-aliphatic residue) and N(C1-4-aliphatic residue)2; or C3-10-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—C1-4-aliphatic residue, OCF3, C1-4- aliphatic residue, C(═O)—OH, CF3, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2 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—C1-4-aliphatic residue, OCF3, C1-4-aliphatic residue, C(═O)OH, CF3, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, S—C1-4-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—C1-4-aliphatic residue, OCF3, C1-4- aliphatic residue, C(═O)—OH, CF3, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, S—C1-4-aliphatic residue and SCF3. [0309] In further embodiments, R14a and R14b each independently of the other represents H; F; Cl; CH3; CH2CH3; (CH2)2CH3; CH(CH3)2; (CH2)3CH3; CH(CH)3CH2CH3; C(CH3)3; OH; OCH3; OCH2CH3; O(CH2)2OCH3 or O(CH2)2OH; m represents 0, 1 or 2 and represents 0 and B represents CH3; CH2CH3; (CH2)2CH3; CH(CH3)2; (CH2)3CH3; CH(CH3)CH2CH3; C(CH3)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— C1-4-aliphatic residue, OCF3, C1-4-aliphatic residue, CF3, NH2, NH(C1-4-aliphatic residue) and N(C1-4-aliphatic residue)2. [0310] In further embodiments, R2; R3; R4; R5; R10, R11, R12 and R13 each independently of the others represents H; F; Cl; CF3; CN; OH; OCF3; SCF3; CH3; CH2CH3; (CH2)2CH3; CH(CH3)2; (CH2)3CH3; CH(CH)3CH2CH3; C(CH3)3; OCH3; OCH2CH3; O(CH2)2OCH3; O(CH2)2OH; SCH3; SCH2CH3; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or R2 and R3 or R4 and R5 or R10 and R11 or R12 and R13 or R2 and R11 or R2 and R4 or R2 and R13 or R4 and R13 or R4 and R11 or R12 and R13, together with the carbon atom(s) joining them, form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in each case unsubstituted; wherein the remaining substituents R2, R3; R4; R5; R10, R11, R12 and R13 in each case have the meaning given above. [0311] In further embodiments, each R7 represents H, F; Cl; CN; CF3; CHF2; CH2F; OCF3; OCHF2; OCH2F; SCF3; CH3; CH2CH3; CH2CH2CH3; CH(CH3)2; OH2CH2CH2CH3; CH(CH)3CH2CH3; CH2CH(CH3)2; O(CH3)3; OCH3; OCH2CH3; O(CH2)2OCH3; O(CH2)2OH; S(═O)2CH3 S(═O)2CH2CH3 S(═O)2CH(CH3)2 or S(═O)2CH2CH2CH3; and R8 represents H or CH3 or CH2CH3 or CH(CH3)2. [0312] In further embodiments, R6 represents a C3-10-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, NO2, CN, OH, ═O, O—C1-4-aliphatic residue, OCF3, C1-4-aliphatic residue, CF3, SH, S—C1-4-aliphatic residue and SCF3; 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, NO2, CN, OH, O—C1-4-aliphatic residue, OCF3, C1-4-aliphatic residue, CF3, NH2, NH(C1-4-aliphatic residue), N(C1-4- aliphatic residue)2, SH, S—C1-4-aliphatic residue and SCF3. [0313] In further embodiments, R6 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—C1-4- aliphatic residue, OCF3, C1-4-aliphatic residue, CF3 and SCF3. [0314] In further embodiments, A1 represents S; and A2 represents S, S(═O)2 or CR12R13, wherein R12 and R13 both represent H or both represent F; and R1 represents the partial structure:
Figure imgf000188_0001
wherein: R14a and R14b each independently of the other represents H; F; Cl; CH3; CH2CH3; (CH2)2CH3; CH(CH3)2; (OH2)3CH3; CH(CH)3CH2CH3; C(CH3)3; OH; OCH3; OCH2CH3; O(CH2)2OCH3; or O(CH2)2OH; 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-1-4-aliphatic residue, OCF3, C1-4- aliphatic residue, C(═O)—OH, CF3, NH2, NH(C1-4-aliphatic residue) and N(C1-4-aliphatic residue)2; R2, R3, R4; R5, R10, R11, R12 and R13 each independently of the others represent H; F; Cl; Br; I; NO2; CF3; CN; OH; OCF3; SH; SCF3; CH3; CH2CH3; CH2CH2CH3; CH(CH3)2; CH2CH2CH2CH3; CH(CH)3CH2CH3; CH2CH(CH3)2; C(CH3)3; OCH3; OCH2CH3; O(CH2)2OCH3; O(CH2)2OH; SCH3; SCH2CH3; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or R2 and R3 or R4 and R5 or R10 and R11 or R12 and R13 or R2 and R11 or R2 and R4 or R2 and R13 or R4 and R13 or R4 and R11 or R12 and R13, together with the carbon atom(s) joining them, form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in each case unsubstituted; wherein the remaining substituents R2, R3; R4; R5; R10, R11, R12 and R13 in each case have the meaning given above; R6 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, CH3, CH2CH3, CH(CH3)2 and CF3; each R7 represents H, F; CI; CN; CF3; CHF2; CH2F; OCF3; OCHF2; OCH2F; SCF3; CH3; CH2CH3; CH2CH2CH3; CH(CH3)2; CH2CH2CH2CH3; CH(CH)3CH2CH3; CH2CH(CH3)2; C(CH3)3; OCH3; OCH2CH3; O(CH2)2OCH3; O(CH2)2OH; S(═O)2CH3 S(═O)2CH2CH3, S(═O)2CH(CH3)2 or S(═O)2CH2CH2CH3; and R8 represents H or CH3 or CH2CH3 or CH(CH3)2. [0315] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 12-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-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-methyl-butyl)-pyridine-2- carboxylic acid amide; 43-[2-(Benzenesulfonyl)-ethylsulfanyl]-N-(thiophen-2-yl-methyl)- pyridine-2-carboxylic acid amide; 54-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N- (3-methyl-butyl)-pyridine-3-carboxylic acid amide; 64-[[3,3-Difluoro-3-(4-fluorophenyl)- propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-pyridine-3-carboxylic acid amide; 73-[[3,3- Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-butyl)-pyridine-4-carboxylic acid amide; 83-[2-(Benzenesulfonyl)-ethylsulfanyl]-N-(thiophen-2-yl-methyl)-pyridine-4- carboxylic acid amide; 93-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl- butyl)-pyrazine-2-carboxylic acid amide; 104-[[3,3-Difluoro-3-(4-fluorophenyl)- propyl]sulfanyl]-N-(3-methyl-butyl)-pyrimidine-5-carboxylic acid amide; 114-[[3,3- Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-pyrimidine-5- carboxylic acid amide; 123-[[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3- methyl-butyl)-pyridazine-4-carboxylic acid amide; 133-[[3,3-Difluoro-3-(4-fluorophenyl)- propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-pyridazine-4-carboxylic acid amide; 144- [[3,3-Difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-thiazole-5- carboxylic acid amide; 154-[[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 [0316] 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. [0317] In an embodiment, the Kv7 channel activator is a compound according to formula 21: Formula 21
Figure imgf000190_0001
wherein, A1 represents CR5 or N; A2 represents CR6, N, O, S or NR7; A3 represents CR8 or N, and n denotes 0 or 1, on the condition, that if n denotes 0, then A2 represents O, S or NR7, or if n denotes 1, then A2 represents CR6 or N, wherein R5 is selected from F, Cl, Br, CN, CH3, CF3, CHF2, CH2F, OCH3, C2H5, SCH3, OCF3, OCHF2 or OCH2F; R6 is selected from H, F, Cl, Br, CN, CH3, CF3, CHF2, CH2F, OCH3, C2H5, SCH3, OCF3, OCHF2 or OCH2F; R7 represents C1-4-aliphatic residue or C3-5-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; R8 is selected from H, F, Cl, Br, CN, CH3, CF3, CHF2, CH2F, OCH3, C2H5, SCH3, OCF3, OCHF2 or OCH2F; with the proviso, that, if n denotes 1, then at least one of A1, A2 and A3 denotes N, with the proviso, that if n denotes 1 and A3 denotes N, then A1 and/or A2 denotes N, and with the proviso, that if n denotes 1 and A2 denotes N and A1 denotes CR5 and A3 denotes CR8, then R5 denotes F, Cl, CH3, CF3, CHF2 or CH2F; R13 represents H or C1-4-aliphatic residue, R1 represents C1-10-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 C1-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R2 represents a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-6-cycloaliphatic residue or a 3 to 7 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, or denotes S—R9, O—R10 or N(R11R12), wherein R9 and R10 in each case represent C1-6-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 C1-4- aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; with the proviso, that if R9 or R10 denote a 3 to 7 membered heterocycloaliphatic residue, than the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, R11 represents C1-6-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 C1-4- aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; with the proviso that if R11 denotes a 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom; and R12 denotes C1- 6-aliphatic residue, unsubstituted or mono- or polysubstituted; or R11 and R12 form together with the nitrogen atom connecting them a 3 to 7 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted; R3 represents C1-10-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 C1-4-aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; on the condition that if R3 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 R4 denotes H or C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; or R3 and R4 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, NH—C(═O)—C1-4- aliphatic residue, N(C1-4 aliphatic residue)-C(═O)—C1-4 aliphatic residue, NH—S(═O)2— C1-4 aliphatic residue, N(C1-4 aliphatic residue)-S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, O—C1-4-aliphatic residue, O—C(═O)—C1-4-aliphatic residue, SH, SCF3, S—C1-4- aliphatic residue, S(═O)2OH, S(═O)2—C1-4-aliphatic residue, S(═O)2—O—C1-4-aliphatic residue, S(═O)2—NH(C1-4-aliphatic residue), S(═O)2—N(C1-4-aliphatic residue)2, CN, CF3, CHO, COOH, C1-4-aliphatic residue, C(═O)—C1-4-aliphatic residue, C(═O)—O— C1-4-aliphatic residue, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, C(═O)NH2, a C(═O)—NH(C1-4-aliphatic residue) and C(═O)—N(C1-4-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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000193_0001
NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, NH—C(═O)—C1-4-aliphatic residue, N(C1-4 aliphatic residue)-O(═O)—C1- 4 aliphatic residue, NH—S(═O)2—C1-4 aliphatic residue, N(C1-4 aliphatic residue)- S(═O)2—C1-4 aliphatic residue, OH, OCF3, O—C1-4-aliphatic residue, O—C(═O)—C1-4- aliphatic residue, SH, SCF3, S—C1-4-aliphatic residue, S(═O)2OH, S(═O)2—C1-4- aliphatic residue, S(═O)2—O—C1-4-aliphatic residue, S(═O)2—NH(C1-4-aliphatic residue), S(═O)2—N(C1-4-aliphatic residue)2, CN, CF3, C(═O)H, C(═O)OH, C1-4-aliphatic residue, C(═O)—C1-4-aliphatic residue, C(═O)—O—C1-4-aliphatic residue, C3-6- cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, benzyl, aryl, heteroaryl, C(═O)NH2, C(═O)—NH(C1-4-aliphatic residue) and C(═O)—N(C1-4-aliphatic residue)2; 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. [0318] In further embodiments, A1 represents CR5 or N; A2 represents CR6, N, O, S or NR7; A3 represents CR8 or N, and n denotes 0 or 1, on the condition, that if n denotes 0, then A2 represents O, S or NR7, or if n denotes 1, then A2 represents CR6 or N, wherein R5 is selected from F, Cl, Br, CN, CH3, CF3, CHF2, CH2F, OCH3, C2H5, SCH3, OCF3, OCHF2 or OCH2F; R6 is selected from H, F, Cl, Br, CN, CH3, CF3, CHF2, CH2F, OCH3, C2H5, SCH3, OCF3, OCHF2 or OCH2F; R7 represents C1-4-aliphatic residue or C3-5- 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, NO2, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 unsubstituted O—C1-4-aliphatic residue, R8 is selected from H, F, Cl, Br, CN, CH3, CF3, CHF2, CH2F, OCH3, C2H5, SCH3, OCF3, OCHF2 or OCH2F; with the proviso, that, if n denotes 1, then at least one of A1, A2 and A3 denotes N, with the proviso, that if n denotes 1 and A3 denotes N, then A1 and/or A2 denotes N, and with the proviso, that if n denotes 1 and A2 denotes N and A1 denotes CR5 and A3 denotes CR8, then R5 denotes F, Cl, CH3, CF3, CHF2 or CH2F; R13 represents H or C1-4-aliphatic residue, R1 denotes 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 unsubstituted O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, 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—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)—OH, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4 aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, C3-6- cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue,
Figure imgf000195_0001
zyl, 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 unsubstituted O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, a C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)—OCH3 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(C1-4- aliphatic residue), an N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the aryl or the heteroaryl residue may in each case be 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O— C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN and C(═O)OH, R2 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, NO2, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 unsubstituted O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4- aliphatic residue, CF3, CN, C1-4-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 unsubstituted O—C1-4-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 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O— C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4- aliphatic residue and C(═O)OH, or denotes S—R9, O—R10 or N(R11R12); wherein R9 and R10 in each case represent C1-6-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 unsubstituted O—C1-4-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, NO2, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, 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—C1-4-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(C1-4- aliphatic residue), an N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, on the condition that if R9 or R10 denote a 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, R11 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, NO2, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)— O—C1-4-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 unsubstituted O— C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)—O—C1-4-aliphatic residue, 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 unsubstituted O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, on the condition that if R11 denotes a 3 to 7 membered heterocycloaliphatic residue, the 3 to 7 membered heterocycloaliphatic residue is linked via a carbon atom, and R12 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, NO2, NH2, NH(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 unsubstituted O—C1-4aliphatic residue, or R11 and R12 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)—OH, 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—C1-4- 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R11 and R12 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)— OH, C(═O)—CH3, C(═O)—C2H5, C(═O)—OCH3 and C(═O)—OC2H5, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue,
Figure imgf000199_0001
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 unsubstituted O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, NH(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, R3 denotes 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)— O—C1-4-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 unsubstituted O—C1-4- 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)—O—C1-4-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—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, on the condition that if R3 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue,
Figure imgf000201_0001
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 unsubstituted O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, NH(C1-4- aliphatic residue), an N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the aryl or the heteroaryl residue may in each case be 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O— C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN and C(═O)OH, R4 denotes H or 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4- aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-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 unsubstituted O—C1-4-aliphatic residue, or R3 and R4 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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, 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, ═O, OH, OCF3, CF3 and unsubstituted O—C1-4-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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R3 and R4 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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue,
Figure imgf000202_0001
, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R3 and R4 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 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(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, ═O, OH, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, C3-6-cycloaliphatic residue, 3 to 7 membered heterocycloaliphatic residue, 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 unsubstituted O—C1-4-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(C1-4-aliphatic residue), N(C1-4-aliphatic residue)2, OH, O—C1-4-aliphatic residue, OCF3, OCH2CH2OH, OCH2OCH3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, NH(C1-4- aliphatic residue), N(C1-4-aliphatic residue)2, OH, ═O, O—C1-4-aliphatic residue, OCF3, SH, SCF3, S—C1-4-aliphatic residue, CF3, CN, C1-4-aliphatic residue and C(═O)OH. [0319] In further embodiments, the compound is according to formula 21 wherein n denotes 0 and is according to the formula:
Figure imgf000204_0001
wherein, A2 represents O and A3 represents CR8; or A2 represents S and A3 represents CR8; or A2 represents NR7 and A3 represents CR8; or A2 represents O and A3 represents N; or A2 represents S and A3 represents N; or A2 represents NR7 and A3 represents N. [0320] In further embodiments, the compound is according to formula 21 wherein n denotes 1 and is according to the formula:
Figure imgf000204_0002
wherein: A1 represents N and A2 represents CR6 and A3 represents CR8; or A1 represents CR5 and A2 represents N and A3 represents CR8; or A1 represents N and A2 represents N and A3 represents CR8; or A1 represents N and A2 represents CR6 and A3 represents N; or A1 represents CR5 and A2 represents N and A3 represents N; or A1 represents N and A2 represents N and A3 represents N. [0321] In further embodiments, R5 denotes F, Cl, CH3, OCH3 or CH2CH3; and/or R6 denotes H; and/or R7 denotes CH3, CH2CH3 or cyclopropyl; and/or R8 denotes H. [0322] In further embodiments, R1 represents the partial structure:
Figure imgf000205_0001
wherein: m denotes 0, 1, or 2, R1a and R1b each independently of one another represent H, F, Cl, Br, I, O—C1-4-aliphatic residue or C1-4-aliphatic residue, R1c 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—C1-4-aliphatic residue, CF3 and 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, CF3 and O—C1-4-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, O—C1-4-aliphatic residue, CF3 and 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, 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—C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, 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—C1-4-aliphatic residue, OCF3, CF3, CN, C1-4- aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, OH, ═O, O—C1-4-aliphatic residue, OCF3, CF3C1-4-aliphatic residue and C(═O)OH. [0323] In further embodiments, m denotes 1 or 2, R1a and R1b represent H, R1c 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—C1-4-aliphatic residue, CF3 and C1-4-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, O—C1-4-aliphatic residue, CF3 and C1-4-aliphatic residue, or m denotes 0 and R1c 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— C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, 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— C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, OH, ═O, O—C1-4-aliphatic residue, OCF3, CF3C1-4-aliphatic residue and C(═O)OH. [0324] In further embodiments, R2 is selected from the group consisting of CH3, C2H5, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, CH2-cyclopropyl, OCH3, OC2H5, OCH2CH2CH3, OCH(CH3)2, O-cyclopropyl, SCH3, SC2H5, SCH2CH2CH3, SCH(CH3)2, S-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N(CH3)2, N(CH3)C2H5, N(CH3)CH2CH2CH3, N(CH3)CH(CH3)2, N(CH3)- cyclopropyl, N(C2H5)2, N(C2H5)CH2CH2CH3, N(C2H5)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. [0325] In further embodiments, R3 represents the partial structure:
Figure imgf000207_0001
wherein: o denotes 0, 1, 2 or 3, R3a and R3b each independently of one another represent H, F, Cl, Br, I, O—C1-4-aliphatic residue or C1-4-aliphatic residue or together denote ═O, and R3c 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, O—C1-4-aliphatic residue, CF3 and 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, CF3 and O—C1-4- 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, O—C1-4- aliphatic residue, CF3 and 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, 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—C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, 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, ═O, O—C1-4-aliphatic residue, OCF3, CF3, C1-4-aliphatic residue and C(═O)— OH, and R4 denotes H or unsubstituted C1-4-aliphatic residue or C1-4-aliphatic residue, monosubstituted with OCH3, or R3 and R4 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, ═O, C(═O)OH, O—C1-4-aliphatic residue, OCF3, SCF3, S—C1-4-aliphatic residue, CF3, C1-4-aliphatic residue, cyclopropyl, cyclobutyl and cyclopentyl, wherein the C1-4-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, ═O, CF3 and O—C1-4-aliphatic residue, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R3 and R4 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—C1-4-aliphatic residue, OCF3, SCF3, S—C1-4- aliphatic residue, CF3, C1-4-aliphatic residue, C(═O)OH and C3-6-cycloaliphatic 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 unsubstituted O—C1-4-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, ═O, O—C1-4-aliphatic residue, OCF3, SCF3, S—C1-4-aliphatic residue, CF3, C1-4-aliphatic residue and C(═O)OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R3 and R4 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, ═O, OH, O—C1-4-aliphatic residue, OCF3, SCF3, CF3, CN, C1-4-aliphatic residue, C(═O)OH, C(═O)CH3, C(═O)C2H6, C(═O)OCH3 and C(═O)OC2H6. [0326] In further embodiments, R3 represents the partial structure:
Figure imgf000209_0001
Wherein, o denotes 0, 1, 2 or 3, R3a and R3b each independently of one another represent H, F, CH3 or OCH3, or together denote ═O, R3c 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, 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, O—C1-4- aliphatic residue, CF3 and 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, OH, O—C1-4-aliphatic residue, OCF3, CF3, CN, and C1-4-aliphatic residue, and R4 denotes H, CH3, CH2CH3, CH2CH2OCH3 or CH2CH2CH2OCH3, or R3 and R4 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, tetrahydroimidazo[1,2-a]pyrazinyl, octahydropyrrolo[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, ═O, C(═O)OH, OCH3, OCH2CH3, OCF3, SCF3, CF3, C(═O)CH3, C(═O)OCH3, CH2CF3, CH2OH, CH2OCH3, CH2CH2OCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 and cyclopropyl. [0327] In further embodiments, A1 represents CR5, N; A2 represents CR6, N, O, S or NR7; A3 represents CR8 or N, and n denotes 0 or 1, on the condition, that if n denotes 0, then A2 represents O, S or NR7, or if n denotes 1, then A2 represents CR6 or N, wherein R5 denotes F, Cl, CH3, OCH3 or CH2CH3; and/or R6 denotes H; and/or R7 denotes CH3, CH2CH3 or cyclopropyl; and/or R8 denotes H; with the proviso, that, if n denotes 1, then at least one of A1, A2 and A3 denotes N, with the proviso, that if n denotes 1 and A3 denotes N, then A1 and/or A2 denotes N, and with the proviso, that if n denotes 1 and A2 denotes N and A1 denotes CR5 and A3 denotes CR8, then R5 denotes F, Cl, CH3, CF3, CHF2 or CH2F; R13 represents H or CH3; R1 represents the partial structure:
Figure imgf000210_0001
wherein, m denotes 1 or 2, R1a and R1b represent H and R1c 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—C1-4-aliphatic residue, CF3 and C1-4-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, O—C1-4- aliphatic residue, CF3 and C1-4-aliphatic residue, or wherein m denotes 0 and R1c 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— C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)—CH3, C(═O)C2H5, C(═O)OCH3, C(═O)OC2H5, 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— C1-4-aliphatic residue, OCF3, CF3, CN, C1-4-aliphatic residue, C(═O)CH3, C(═O)C2H5, C(═O)OCH3 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, OH, ═O, an O—C1-4-aliphatic residue, OCF3, CF3C1-4-aliphatic residue and C(═O)OH; R2 is selected from the group consisting of CH3, C2H5, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, CH2-cyclopropyl, OCH3, OC2H5, OCH2CH2CH3, OCH(CH3)2, O-cyclopropyl, SCH3, SC2H5, SCH2CH2CH3, SCH(CH3)2, S-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N(CH3)2, N(CH3)C2H5, N(CH3)CH2CH2CH3, N(CH3)CH(CH3)2, N(CH3)- cyclopropyl, N(C2H5)2, N(C2H5)CH2CH2CH3, N(C2H5)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; R3 represents the partial structure:
Figure imgf000211_0001
wherein: denotes 0, 1, 2 or 3, R3a and R3b each independently of one another represent H, F, CH3 or OCH3, or together denote ═O, R3c 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, 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, O—C1-4- aliphatic residue, CF3 and 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, OH, O—C1-4-aliphatic residue, OCF3, CF3, CN, and C1-4-aliphatic residue, and R4 denotes H, CH3, CH2CH3, CH2CH2OCH3 or CH2CH2CH2OCH3, or R3 and R4 form together with the nitrogen atom connecting them a morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazepanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, azepanyl, tetrahydroimidazo[1,2-a]pyrazinyl, octahydropyrrolo[1,2-a]-pyrazinyl,
Figure imgf000211_0002
Figure imgf000211_0003
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, ═O, C(═O)OH, OCH3, OCH2CH3, OCF3, SCF3, CF3, C(═O)CH3, C(═O)OCH3, CH2CF3, CH2OH, CH2OCH3, CH2CH2OCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 and cyclopropyl. [0328] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[(4-Chlorophenyl)-methyl]-4-ethylsulfanyl-6-methyl-2-morpholin-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-carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-methyl-6-morpholin-4-yl-4-propyl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-ethoxy-2-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-[(3R)-3-fluoro-pyrrolidin-1-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-[1-[3-(trifluoromethyloxy)-phenyl]-ethyl]-thiazole- 5-carboxylic acid amide; 4-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-methyl-2- morpholin-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-carboxylic acid amide; N- (4,4-Dimethyl-pentyl)-4-ethylsulfanyl-2-methyl-6-morpholin-4-yl-pyridine-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- carboxylic 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-(1-methyl-propyl)-5-morpholin-4-yl-pyrazine-2-carboxylic acid amide; N-(2-Cyclopentyl-ethyl)-3-(1-methyl-propyl)-5-morpholin-4-yl-pyrazine-2- carboxylic acid amide; 4-Isopropyl-2-[methyl-(tetrahydro-pyran-4-yl-methyl)-amino]-N-[1- [3-(trifluoromethyloxy)-phenyl]-ethyl]-thiazole-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]-thiazole-5-carboxylic acid amide; N-[(4-Chlorophenyl)- methyl]-4-isopropyl-2-morpholin-4-yl-thiazole-5-carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-4-isopropyl-2-piperidin-1-yl-thiazole-5-carboxylic acid amide; N- (4,4-Dimethyl-pentyl)-4-isopropyl-2-piperidin-1-yl-thiazole-5-carboxylic acid amide; N- [(4-Chlorophenyl)-methyl]-4-isopropyl-2-([1,4]oxazepan-4-yl)-thiazole-5-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-isopropyl-2-([1,4]oxazepan-4-yl)-thiazole-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-carboxylic acid amide; 2-(Methyl- tetrahydro-pyran-4-yl-amino)-4-(trifluoromethyl)-N-[1-[3-(trifluoromethyloxy)-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-[1-(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-methyl)-amino]-4- (trifluoromethyl)-thiazole-5-carboxylic acid amide; 2-Morpholin-4-yl-4-(trifluoromethyl)-N- [[3-(trifluoromethyloxy)-phenyl]-ethyl]-thiazole-5-carboxylic acid amide; 2-Morpholin-4-yl- 4-(trifluoromethyl)-N-[1-[3-(trifluoromethyloxy)-phenyl]-ethyl]-thiazole-5-carboxylic acid amide; N-[1-(4-Chlorophenyl)-ethyl]-2-morpholin-4-yl-4-(trifluoromethyl)-thiazole-5- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-morpholin-4-yl-4-(trifluoromethyl)- thiazole-5-carboxylic acid amide; 2-Morpholin-4-yl-4-(trifluoromethyl)-N-[1-[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. [0329] In an embodiment, the Kv7 channel activator is a compound according to formula 22: Formula 22
Figure imgf000214_0001
, wherein, R1 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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; aryl or heteroaryl, 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; R2 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—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; R3 represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a C1-4-aliphatic residue, a O—C1-4-aliphatic residue, a S—C1-4-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; R6 represents a C2-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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 R6 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or denotes, O—R8, wherein R8 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3- 10-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 R8 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH— S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O— C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH— C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4- aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000216_0001
NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, an NH—C(═O)—C1-4 aliphatic residue, an NH—S(═O)2—C1-4 aliphatic residue, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, C(═O)H, C(═O)OH, a C1-4-aliphatic residue, a C(═O)—C1-4-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(C1- 4 aliphatic residue), and a C(═O)—N(C1-4 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. [0330] In further embodiments, R1 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, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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)C1-4 aliphatic residue), an N(C1-4 aliphatic residue, OH, an O—C1- 4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a S(═O)2—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 residue,
Figure imgf000218_0001
Figure imgf000218_0002
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—C1-4-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(C1-4 aliphatic residue), an N(C1- 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 C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, and wherein the aryl or the heteroaryl residue may in each case be optionally 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 sleeted from the group consisting of F, Cl, Br, I, NO2, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN and C(═O)—OH, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, or a 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4-aliphatic residue, R3 represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a C1-4-aliphatic residue, a O—C1-4-aliphatic residue, a S—C1-4-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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and a 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4-aliphatic residue, R6 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4- aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R6 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 R6 denotes O—R8, wherein R8 represents 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, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- 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—C1-4- aliphatic residue, or represent 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R8 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. [0331] In further embodiments, R1 represents the partial structure:
Figure imgf000221_0001
wherein: m denotes 0, 1, 2, 3 or 4, R12a and R12b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 ═O, and R12c 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a S(═O)2—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a S(═O)2—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 residue,
Figure imgf000222_0001
nzyl, 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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, 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH. [0332] In further embodiments, R1 represents the partial structure:
Figure imgf000223_0001
wherein: m denotes 0, 1, or 2 or 3, R12a and R12b 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 ═O, and R12c 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—C1-4 aliphatic residue, CN, a S(═O)2—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, an O—C1-4 aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-aliphatic 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 C1-4-aliphatic residue, CH2—OH, CH2—OCH3, S(═O)2—CH3, SCF3, NO2, N(C1-4 aliphatic residue)2,
Figure imgf000224_0001
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—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, 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, ═O, an O—C1-4 aliphatic residue, OCF3, CF3 a C1-4-aliphatic residue and C(═O)—OH. [0333] In further embodiments, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, or a 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4-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 C1-4-aliphatic residue and an unsubstituted O—C1-4-aliphatic residue. [0334] In further embodiments, R3 represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a C1-4-aliphatic residue, a O—C1-4-aliphatic residue, or a S—C1-4-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, ═O, OH, and an unsubstituted O—C1-4 aliphatic residue. [0335] In further embodiments, R6 denotes a C2-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S— C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a C(═O)—O—C1-4-aliphatic residue, a S—C1-4 aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, on the condition that if R6 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R6 denotes O—R8 wherein R8 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, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, CF3, a C(═O)—O—C1-4-aliphatic residue, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, on the condition that if R8 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0336] In further embodiments, R6 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, ═O, an O—C1-4-aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, OCF3, SH, SCF3, a S aliphatic residue, CF3, and a C1-4-aliphatic residue wherein the C1-4-aliphatic residue in each case is unsubstituted, 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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a C1-4- aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or an unsubstituted O—C1-4-aliphatic residue, and wherein the C3-10-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 R6 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R6 denotes O—R8 wherein R8 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, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a C(═O)—O—C1-4- aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4 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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1- 4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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 R7 or R8 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0337] In further embodiments, R1 represents the partial structure:
Figure imgf000227_0001
wherein: m is 0, 1 or 2, and R12a and R12b each independently of one another represent H, F, OH, CH3 or OCH3, or together denote ═O, R12c 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 C3-10-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, an unsubstituted O—C1-4 aliphatic residue, CF3, and an unsubstituted C1-4-aliphatic residue, or wherein m is 0 or 2, and R12a and R12b each independently of one another represent H, F, OH, CH3 or OCH3; and R12c 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, OCF2H, CH2— OH, CH2—OCH3, S(═O)2—CH3, SCF3, NO2, N(CH3)2,
Figure imgf000228_0001
CN, a C1-4-aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O—CH, C(═O)—O— 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 C1-4-aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O—CH3 and C(═O)— O—C2H5, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec.-butyl; tert.-butyl; CH2—OH; CH2—O—CH3; CH2—CH2—OH; CH2—CH2—OCH3; O-methyl; O-ethyl; O—(CH2)2—O—CH3; O—(CH2)2—OH; S-Methyl; S-Ethyl; cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, R3 represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec.-butyl; tert.- butyl; O-methyl; O-ethyl; O—(CH2)2—O—CH3; O—(CH2)2—OH; S-Methyl; or S-Ethyl, R6 denotes ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2—CH(CH3)(C2H5), C(CH3)2(C2H5), CH2—OCH3, C2H4—OCH3, C3H6—OCH3, cyclopropyl, cyclobutyl, or tetrahydropyranyl, ethenyl or propenyl (—CH2CH═CH2, —CH═CH—CH3, —C((═CH2)—CH3), in each case unsubstituted, or R6 denotes O—R8 wherein R8 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(C1-4 aliphatic residue) and an O—C1- 4-aliphatic residue, or in each case denote CH2-cyclopropyl or oxetanyl, wherein the C1- 4-aliphatic residue in each case is unsubstituted. [0338] 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-morpholin-4-yl- pyridine-3-carboxylic acid amide; 9 N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4- yl-2-[(E)-prop-1-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-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-[(4- Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-[(E)-prop-1-enyl]-pyridine-3- carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl- 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; 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-carboxylic acid amide; 2-Methoxy-4-methyl-6-morpholin-4-yl-N-[(2-phenyl-phenyl)- methyl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethoxy-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2- ethoxy-4-methyl-6-morpholin-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- carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2- propoxy-pyridine-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-pyridine-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-methyl-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-carboxylic acid amide; 2-Ethoxy-N-[(4-fluorophenyl)-methyl]-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-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl- 6-[(3R)-3-methyl-morpholin-4-yl]-2-(1-methyl-propyl)-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-2-(1-methyl-propyl)- pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-[(4-fluorophenyl)-methyl]-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-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; 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-(1-methyl- propyl)-6-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-(1-methyl-propyl)-6-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; 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-carboxylic 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-methyl-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-morpholin-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-carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-ethoxy-4-methyl-6-[(3R)-3-methyl-morpholin-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-morpholin-4-yl-pyridine-3- carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(1,1-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-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; 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-morpholin-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-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-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-(oxetan-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)-phenyl]-methyl]-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl-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-pyridine-3-carboxylic acid amide; 2- Cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morpholin-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]-methyl]-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-2-(1-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-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-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-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 23 [0339] 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. PCT/EP2011/005265 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. [0340] In an embodiment, the Kv7 channel activator is a compound according to formula 23: Formula 23
Figure imgf000233_0001
wherein, R1 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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; aryl or heteroaryl, 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; R2 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—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; R3 represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a C1-4-aliphatic residue, a O—C1-4-aliphatic residue, a S—C1-4-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; R4 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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; aryl or heteroaryl, 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 R4 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; R5 denotes H or a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; or R4 and R5 form together with the nitrogen atom connecting them a 3 to 10 membered heterocycloaliphatic residue, unsubstituted or mono- or polysubstituted; R6 represents a C2-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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 R6 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or denotes S—R7, O—R8 or N(R9R10), wherein R7 and R8 in each case represent a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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 R7 or R8 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, R9 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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 R9 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom; R10 denotes a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; or R9 and R10 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O— C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O— C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000236_0001
an NH(C1-4 aliphatic residue), an N(C1- 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—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, C(═O)H, C(═O)OH, a C1-4-aliphatic residue, a C(═O)—C1-4-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(C1- 4 aliphatic residue), and a C(═O)—N(C1-4 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. [0341] In further embodiments, R1 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, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, an O— C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a S(═O)2—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 residue,
Figure imgf000238_0001
Figure imgf000238_0002
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—C1-4-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(C1-4 aliphatic residue), an N(C1- 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 C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, and wherein the aryl or the heteroaryl residue may in each case be optionally 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, NO2, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN and C(═O)—OH, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, or a 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4-aliphatic residue, R3 represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a C1-4-aliphatic residue, a O—C1-4-aliphatic residue, a S—C1-4- 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and a 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4-aliphatic residue, R4 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, an NH(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4- aliphatic residue, CF3, CN, a C1-4-aliphatic residue, a C(═O)—O—C1-4-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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 C(═O)—O—C1-4-aliphatic residue a C3-6 cycloaliphatic residue, and a 3 to 6 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 an unsubstituted O—C1-4- 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(═O)—OH, 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R4 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000241_0001
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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 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 C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN and C(═O)—OH, R5 denotes H or 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, an NH(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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—C1-4-aliphatic residue, or R4 and R5 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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, ═O, OH, OCF3, CF3 and an unsubstituted O—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R4 and R5 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000243_0001
benzyl, phenyl, thienyl, pyridyl, furyl, thiazolyl and oxazolyl, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R4 and R5 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, ═O, 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 residue, 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 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 C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, R6 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R6 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 R6 denotes S—R7, O—R8 or N(R9R10), wherein R7 and R8 in each case represent 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, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4-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—C1-4-aliphatic residue, or in each case represent 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R7 or R9 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, R9 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, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4-aliphatic residue, a C(═O)—O—C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 C(═O)—O—C1-4-aliphatic residue a C3-6 cycloaliphatic residue, and a 3 to 6 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 an unsubstituted O—C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R9 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, R10 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, an NH(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-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—C1-4-aliphatic residue, or R9 and R10 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R9 and R10 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000247_0001
enzyl, 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 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 C1-4- 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(═O)—OH. [0342] In further embodiments, R1 represents the partial structure:
Figure imgf000248_0001
wherein: m denotes 0, 1, 2, 3 or 4, R12a and R12b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 ═O, and R12c 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a S(═O)2—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a S(═O)2—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 residue,
Figure imgf000249_0001
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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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, 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O) —OH. [0343] In further embodiments, R1 represents the partial structure:
Figure imgf000250_0001
wherein: m denotes 0, 1, or 2 or 3, R12a and R12b 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 ═O, and R12c 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—C1-4 aliphatic residue, CN, a S(═O)2—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, an O—C1-4 aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-aliphatic 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 C1-4-aliphatic residue, CH2—OH, CH2—OCH3, S(═O)2—CH3, SCF3, NO2, N(C1-4 aliphatic residue)2,
Figure imgf000250_0002
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—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, 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, ═O, an O—C1-4 aliphatic residue, OCF3, CF3 a C1-4-aliphatic residue and C(═O)—OH. [0344] In further embodiments, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, or a 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, ═O, 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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4-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 C1-4-aliphatic residue and an unsubstituted aliphatic residue. [0345] In further embodiments, R3 represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; a C1-4-aliphatic residue, a O—C1-4-aliphatic residue, or a S—C1-4-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, ═O, OH, and an unsubstituted O—C1-4-aliphatic residue. [0346] In further embodiments, R4 represents the partial structure:
Figure imgf000251_0001
wherein: n denotes 0, 1, 2, or 3, R13a and R13b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 ═O, and R13c 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000252_0001
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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, R5 denotes H or 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, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a 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, CF3 and an unsubstituted O—C1-4- aliphatic residue, or R4 and R5 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, ═O, C(═O)—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 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, ═O, CF3 and an unsubstituted O—C1-4- 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(═O)—OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R4 and R5 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 C1-4-aliphatic residue, C(═O)—OH, a C3- 6 cycloaliphatic residue a 3 to 6 membered heterocycloaliphatic residue,
Figure imgf000254_0001
benzyl, phenyl, thienyl, and pyridyl, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R4 and R5 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, ═O, 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, 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—C1-4-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 C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH. [0347] In further embodiments, R4 represents the partial structure:
Figure imgf000255_0001
wherein: n denotes 0, 1, 2 or 3, R13a and R13b each independently of one another represent H, F, Cl, Br, I, an O—C1-4 aliphatic residue or a C1-4 aliphatic residue or together denote ═O, and R13c 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, ═O, an O—C1-4 aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, an O—C1-4 aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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—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, 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, ═O, an O—C1-4 aliphatic residue, OCF3, CF3 a C1-4-aliphatic residue and C(═O)—OH, R5 denotes H or an unsubstituted C1-4-aliphatic residue or a C1-4-aliphatic residue monosubstituted with O-methyl, or R4 and R5 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, ═O, C(═O)—OH, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, CF3, and a C1-4-aliphatic residue, cyclopropyl, cyclobutyl and cyclopentyl, wherein the C1-4-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, ═O, CF3 and an unsubstituted O—C1-4-aliphatic residue, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R4 and R5 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(═O)— OH, and a C3-6 cycloaliphatic 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 an unsubstituted O—C1-4- 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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, CF3, a C1-4-aliphatic residue and C(═O)—OH, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R4 and R5 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, ═O, OH, an O—C1-4 aliphatic residue, OCF3, SCF3, 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. [0348] In further embodiments, R6 denotes a C2-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S— C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a C(═O)—O—C1-4-aliphatic residue, a S—C1-4 aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, and a C1-4-aliphatic residue. on the condition that if R6 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R6 denotes S—R7 or O—R8 wherein R7 and R8 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, ═O, an O—C1-4- aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, CF3, a C(═O)—O—C1-4-aliphatic residue, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1- 4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, on the condition that if R7 or R8 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R6 denotes N(R9R10), wherein R9 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, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S— C1-4-aliphatic residue, CF3, a C(═O)—O—C1-4-aliphatic residue, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-aliphatic residue, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case be bridged, preferably is 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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)— O—C1-4-aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, on the condition that if R9 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, and R10 denotes a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, NO2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a 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, CF3 and an unsubstituted O—C1-4-aliphatic residue, or R9 and R10 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, ═O, an O—C1- 4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a 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, CF3 and an unsubstituted O—C1-4-aliphatic residue, and wherein the 3 to 10 membered heterocycloaliphatic residue formed by R9 and R10 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 C1-4-aliphatic residue, C(═O)—OH, residue, benzyl, phenyl, thienyl, and pyridyl, wherein the
Figure imgf000260_0001
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, 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 C1-4-aliphatic residue, and C(═O)—OH. [0349] In further embodiments, R6 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, ═O, an O—C1-4-aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, and a C1-4-aliphatic residue wherein the C1-4-aliphatic residue in each case is unsubstituted, 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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a C1-4- aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with OH or an unsubstituted O—C1-4-aliphatic residue. and wherein the C3-10-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 R6 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R6 denotes S—R7 or O—R8 wherein R7 and R8 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, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1- 4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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 R7 or R8 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, or R6 denotes N(R9R10), wherein R9 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, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1- 4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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 R9 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom, and R10 denotes an unsubstituted C1-4-aliphatic residue, or R9 and R10 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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a 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, CF3 and an unsubstituted O—C1-4-aliphatic residue, and wherein the 3 to 6 membered heterocycloaliphatic residue formed by R9 and R10 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 C1-4-aliphatic residue, C(═O)—OH, residue, benzyl, phenyl, and pyridyl, 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, and an unsubstituted O— C1-4-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 C1-4-aliphatic residue. [0350] In further embodiments, R1 represents the partial structure:
Figure imgf000262_0001
wherein: m is 0, 1 or 2, and R12a and R12b each independently of one another represent H, F, OH, CH3 or OCH3, or together denote ═O, R12c 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 C3-10-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, an unsubstituted O—C1-4 aliphatic residue, CF3, and an unsubstituted C1-4-aliphatic residue, or wherein m is 0 or 2, and R12a and R12b each independently of one another represent H, F, OH, CH3 or OCH3; and R12c 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, OCF2H, CH2— OH, CH2—OCH3, S(═O)2—CH3, SCF3, NO2, N(CH3)2, CF3, CN, a C1-4-aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O—CH3, C(═O)—O— 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 C1-4-aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O—CH3 and C(═O)— O—C2H5, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec.-butyl; tert.-butyl; CH2—OH; CH2—O—CH3; CH2—CH2—OH; CH2—CH2—OCH3; O-methyl; O-ethyl; O—(CH2)2—O—CH3; O—(CH2)2—OH; S-Methyl; S-Ethyl; cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, R3 represents H; F; Cl; Br; I; CN; CF3; SCF3; NO2; OCF3; methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec.-butyl; tert.- butyl; O-methyl; O-ethyl; O—(CH2)2—O—CH3 O (CH ) OH SM thyl; or S-Ethyl, R4 represents the partial structure (T2)
Figure imgf000263_0001
wherein n denotes 0, 1, 2 or 3, R13a and R13b each independently of one another represent H, F, CH3 or OCH3, or together denote ═O, R13c 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, ═O, 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 C1-4-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, R5 denotes H, methyl or ethyl, C2H4OCH3 or C3H6OCH3, or R4 and R5 form together with the nitrogen atom connecting them a morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazepanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, azepanyl,
Figure imgf000264_0001
ydroimidazo[1,2-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl,
Figure imgf000264_0002
y dolinyl, or dihydroisoindolyl, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, OH, ═O, C(═O)—OH, O- methyl, O-ethyl, OCF3, SCF3, CF3, C(═O)—CH3, C(═O)—OCH3, CH2CF3, CH2OH, CH2—OCH3, CH2CH2—OCH3, methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, and cyclobutyl, R6 denotes ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2—CH(CH3)(C2H5), C(CH3)2(C2H5), CH2— OCH3, C2H4—OCH3, C3H6—OCH3, cyclopropyl, cyclobutyl, or tetrahydropyranyl, ethenyl or propenyl (—CH2CH═CH2, —CH═CH—CH3, —C((═CH2)—CH3), in each case unsubstituted, or R6 denotes S—R7 or O—R8 wherein R7 and R8 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(C1- 4 aliphatic residue) and an O—C1-4-aliphatic residue, or in each case denote CH2- cyclopropyl or oxetanyl, wherein the C1-4-aliphatic residue in each case is unsubstituted, or R6 denotes N(R9R10), wherein R9 denotes methyl, C(═O)—CH3, ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl, R10 denotes methyl or ethyl, or R9 and R10 form together with the nitrogen atom connecting them a morpholinyl, piperidinyl, pyrrolidinyl, or azetidinyl, in each case unsubstituted. [0351] 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-fluorophenyl)-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-1-yl)-4-methyl-pyridine-3-carboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(3-hydroxy-azetidin-1-yl)-4-methyl-pyridine- 3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(4-fluorophenyl)- methylamino]-4-methyl-pyridine-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4- methyl-6-morpholin-4-yl-2-[(E)-prop-1-enyl]-pyridine-3-carboxylic acid amide; N-[(3- Fluorophenyl)methyl]-4-methyl-6-morpholin-4-yl-2-propyl-pyridine-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; 1-[6-Ethylsulfanyl-5-[(3-fluorophenyl)-methyl- carbamoyl]-4-methyl-pyridin-2-yl]-piperidine-4-carboxylic acid methyl ester; 1-[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-piperidin-1-yl)- 4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(4-oxo-piperidin-1-yl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(4- fluoro-2-methoxy-phenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(4-fluoro-2-hydroxy-phenyl)-methyl]-4-methyl-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-pyrrolidin-1-yl- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- pyrrolidin-1-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-4-methyl-6-(1,2,3,4-tetrahydro-isoquinolin-2-yl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[6-(trifluoromethyl)- 1,2,3,4-tetrahydro-isoquinolin-2-yl]-pyridine-3-carboxylic acid amide; N-[(4- Fluorophenyl)methyl]-4-methyl-6-morpholin-4-yl-2-[(E)-prop-1-enyl]-pyridine-3- carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(3- methoxy-pyrrolidin-1-yl)-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N- [(3-fluorophenyl)-methyl]-4-methyl-6-(4-methyl-piperazin-1-yl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-piperidin-1-yl-pyridine-3- carboxylic 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-methylamino-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-6-(2-methoxy-ethyl-methyl-amino)-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(2-methoxy-ethylamino)-4- methyl-pyridine-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-carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2- ethylsulfanyl-4-methyl-6-morpholin-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- pyridin-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-methyl-morpholin-4-yl)- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(4- methoxy-piperidin-1-yl)-4-methyl-pyridine-3-carboxylic 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-(trifluoromethyl)-phenyl]-methyl]- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(4- fluorophenyl)-methyl-methyl-amino]-4-methyl-pyridine-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-pyridine-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-(trifluoromethyl)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-yl-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-pyran-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-1-yl)-pyridine-3-carboxylic 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-1-yl)-2-ethylsulfanyl-N- [(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide; 6-(4,4-Dimethyl- piperidin-1-yl)-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-[[4-(trifluoromethylsulfanyl)- phenyl]-methyl]pyridine-3-carboxylic 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-yl-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-carboxylic acid amide; N-(2-tert-Butoxy-ethyl)-2- ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-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]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-carboxylic acid amide; 2- Methoxy-4-methyl-6-morpholin-4-yl-N-[(2-phenyl-phenyl)-methyl]-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethoxy-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid amide; N-[(3,5-Difluoro-phenyl)-methyl]-2-ethoxy-4-methyl-6-morpholin- 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]methyl]-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- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- ([1,4]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-([1,4]oxazepan-4-yl)-pyridine- 3-carboxylic acid amide; 2-Ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-6- ([1,4]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-carboxylic 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-morpholin-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-propyl)-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-propoxy-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-azetidin-1-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-propyl)-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-methyl)-amino]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[methyl-(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-[methyl-(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-carboxylic acid amide; 6-(Acetyl-methyl- amino)-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-ethylsulfanyl-4-methyl-6-morpholin-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-pyridine-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-propyl- 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-(trifluoromethyloxy)-phenyl]- methyl]pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[[3-(methoxymethyl)- phenyl]methyl]-4-methyl-6-morpholin-4-yl-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; N-(1,3-Benzodioxol-5-yl-methyl)-2-ethylsulfanyl-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[[2-fluoro-4- (trifluoromethyl)-phenyl]methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 6-(Azepan-1-yl)-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3- carboxylic acid amide; 2-Ethylsulfanyl-N-[(4-methoxyphenyl)-methyl]-4-methyl-6- morpholin-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)-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-(3-Cyclopropyl-propyl)-2- ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2- Ethylsulfanyl-N-[[3-fluoro-4-(trifluoromethyl)-phenyl]methyl]-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- (3-oxo-piperazin-1-yl)-pyridine-3-carboxylic acid amide; 6-(4-Acetyl-piperazin-1-yl)-2- ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide; N- [(4-Cyano-phenyl)-methyl]-2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic 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-carboxylic acid amide; 2-Ethylsulfanyl-N-[[4-fluoro-3-(methoxymethyl)- phenyl]methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(4-methyl-3-oxo-piperazin-1-yl)- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- (6-oxa-2-azaspiro[3.3]heptan-2-yl)-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl- pentyl)-4-methyl-2-methylsulfanyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 4- Methyl-2-methylsulfanyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-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-pyridine-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-hexahydro-1H-pyrrolo[1,2-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-carboxylic acid amide; N-(3-Cyano-propyl)-2- ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2- Ethylsulfanyl-4-methyl-6-morpholin-4-yl-N-(p-tolyl-methyl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-4-methyl-N-(3-methylsulfonyl-propyl)-6-morpholin-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-methyl-pyridine-3- carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-2-methylsulfanyl-6- morpholin-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-pyridin-2-yl-amino)- pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6- (methyl-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-carboxylic 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- fluorophenyl)-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- (methoxymethyl)-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- carboxylic acid amide; 2-Ethoxy-N-[(4-fluorophenyl)-methyl]-4-methyl-6-[(3R)-3-methyl- morpholin-4-yl]-pyridine-3-carboxylic acid amide; 2-Dimethylamino-N-(4,4-dimethyl- pentyl)-4-methyl-6-[(3R)-3-methyl-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- carboxylic acid amide; 2-(Ethyl-methyl-amino)-4-methyl-6-morpholin-4-yl-N-[[4- (trifluoromethyl)-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-morpholin-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]-pyridine-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-4-methyl-6-[(3R)-3- methyl-morpholin-4-yl]-2-(1-methyl-propyl)-pyridine-3-carboxylic acid amide; N-(4,4- Dimethyl-pentyl)-4-methyl-6-[(3R)-3-methyl-morpholin-4-yl]-2-(1-methyl-propyl)-pyridine- 3-carboxylic acid amide; 2-Cyclopropyl-N-[(4-fluorophenyl)-methyl]-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-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-(methyl-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- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3,4-Difluoro-phenyl)-methyl]-2- (ethyl-methyl-amino)-4-methyl-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-morpholin-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]- pyridine-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-methyl-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-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-(3-propyl-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-(1-methyl-propyl)-6-morpholin-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-(1-methyl-propyl)-6-morpholin-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-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(2R)-2- (methoxymethyl)-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-morpholin-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-[1,6]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-carboxylic 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]pyridine-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-1-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-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[2-(trifluoromethyl)- 5,6,7,8-tetrahydro-imidazo[1,2-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-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[4-(2,2,2-trifluoro- ethyl)-piperazin-1-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- (methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide; N-[(4- Chlorophenyl)-methyl]-2-ethylsulfanyl-6-[(2S)-2-(methoxymethyl)-morpholin-4-yl]-4- methyl-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-ethylsulfanyl-6- [(3R)-3-(methoxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide; N- [(4-Chlorophenyl)-methyl]-2-ethylsulfanyl-6-[(3S)-3-(methoxymethyl)-morpholin-4-yl]-4- methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-(methyl-tetrahydro-pyran-4-yl-amino)-pyridine-3-carboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(4-methoxy-cyclohexyl)-methyl-amino]-4- methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-6-[2-(trifluoromethyl)-morpholin-4-yl]-pyridine-3-carboxylic acid amide; 2- Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(methyl-tetrahydro-pyran-3-yl- amino)-pyridine-3-carboxylic acid amide; 6-(3,5-Dimethyl-morpholin-4-yl)-2- ethylsulfanyl-N-[(3-fluorophenyl)-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-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6- [(3R)-3-(hydroxymethyl)-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-carboxylic 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-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-morpholin-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-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-2-ethoxy- 4-methyl-6-[(3R)-3-methyl-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- carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-ethylsulfanyl-4-methyl-6-[(2R)-2- methyl-morpholin-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- morpholin-4-yl-pyridine-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-2-(1,1- 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-methyl-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-methyl-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-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluoro-4- methoxy-phenyl)-methyl]-4-methyl-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-(1,3-Dihydro-isobenzofuran-5-yl-methyl)-2- ethylsulfanyl-4-methyl-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-(hydroxymethyl)-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)-methyl]-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-[methyl-(tetrahydro-furan-2-yl-methyl)-amino]-pyridine- 3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[(3R)-3- methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-[(3S)-3-methyl-morpholin-4-yl]-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[methyl-[[4- (trifluoromethyl)-phenyl]-methyl]-amino]-pyridine-3-carboxylic acid amide; 6-(1,1-Dioxo- [1,4]thiazinan-4-yl)-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3- carboxylic acid amide; 6-(Azetidin-1-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-1H-isoindol-2-yl)-2-ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-(1,2,3,4-tetrahydro-quinolin-1-yl)-pyridine-3-carboxylic acid amide; 6-(2,3-Dihydro-1H-indol-1-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-pentyl)-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-6-[(3-methoxy-cyclohexyl)-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-pyridine-3-carboxylic acid amide; 2-Isopropyl-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-(3-oxo-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-morpholin-4-yl-pyridine-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-(oxetan-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)-phenyl]-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]octan- 3-yl)-pyridine-3-carboxylic acid amide; N-[(4-Chlorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-2-propyl-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-pyridine-3- carboxylic acid amide; 2-Cyclopropyl-N-[(4-fluorophenyl)-methyl]-4-methyl-6-morpholin- 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]methyl]-pyridine-3- carboxylic acid amide;N-[(4-Chlorophenyl)-methyl]-2-cyclopropyl-4-methyl-6-morpholin- 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-pyridine-3- carboxylic acid amide; 2-(Acetyl-methyl-amino)-N-[(3-fluorophenyl)-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-6-[(4-fluorophenyl)-methyl-(2-methoxy-ethyl)-amino]-4-methyl-pyridine-3- carboxylic 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-morpholin-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-carboxylic 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-(1-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- (1-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-morpholin-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-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-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 [0352] 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. [0353] In an embodiment, the Kv7 channel activator is a compound according to formula 24: Formula 24
Figure imgf000281_0001
wherein, X1 represents a C2-6-aliphatic residue, 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 in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or represents OX6, wherein X6 represents a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted; or a C3-6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted; X2 and X3 independently of one another represent H; F; Cl; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-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 X2 and X3 denotes H or is linked via a carbon atom, X4 and X5 independently of one another represent H; CH2F; CHF2; CF3; a C1-4-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 X4 and/or X5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X2 and X3 and/or X4 and X5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and the respective remaining substituents of X2 and X3 each independently of one another represent H; F; Cl; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-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 X2 and X3 denotes H or is linked via a carbon atom, and the respective remaining substituents of X4 and X5 each independently of one another represent H; CH2F; CHF2; CF3; a C1-4-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 X4 and/or X5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X2 and X4 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, and X3 represents H; F; Cl; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-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; and X5 represents H; CH2F; CHF2; CF3; a C1-4-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 X5 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a N(C1-4-aliphatic residue)-C(═O)—C1- 4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, a N(C1-4-aliphatic residue)- S(═O)2—C1-4 aliphatic residue, ═O, OH, OCH2F, OCHF2, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, a S(═O)2— N(C1-4-aliphatic residue)2, CN, CH2F, CHF2, CF3, CHO, COOH, a C1-4-aliphatic residue, CH2OH, CH2—OCH3, C2H4—OH, C2H4—OCH3 CH2—CF3, a C(═O)—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a N(C1-4-aliphatic residue)- C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, a N(C1-4-aliphatic residue)-S(═O)2—C1-4 aliphatic residue, ═O, OH, OCH2F, OCHF2, OCF3, a O—C1-4- aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, a S(═O)2— N(C1-4-aliphatic residue)2, CN, CH2F, CHF2, CF3, CHO, COOH, a C1-4-aliphatic residue, CH2OH, CH2—OCH3, C2H4—OH, C2H4—OCH3 CH2—CF3, a C(═O)—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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. [0354] In further embodiments, X1 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-aliphatic residue, and wherein the C3-6-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—C1-4-aliphatic residue, or represents OX6, wherein X6 represents a C1-6-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-aliphatic residue, X2 and X3 independently of one another represent H; F; Cl; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1- 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-aliphatic residue, with the proviso that at least one of X2 and X3 denotes H or is linked via a carbon atom, X4 and X5 independently of one another represent H; CH2F; CHF2; CF3; or a C1-4-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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4- 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4- aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a C1-4-aliphatic residue, on the condition that if X4 and/or X5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, 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—C1-4- aliphatic residue, or X2 and X3 and/or X4 and X5 in pairs, in each case independently of one another, together with the carbon atom 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, NO2, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-aliphatic residue, and the respective remaining substituents of X2 and X3 each independently of one another represent H; F; Cl; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-aliphatic residue, with the proviso that at least one of X2 and X3 denotes H or is linked via a carbon atom, and the respective remaining substituents of X4 and X5 each independently of one another represent H; CH2F; CHF2; CF3; a C1-4- 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4- 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4- aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a C1-4-aliphatic residue, on the condition that if X4 and/or X5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, 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—C1-4- aliphatic residue, or X2 and X4 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, NO2, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-aliphatic residue, and the remaining substituent X3 represents H; F; Cl; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4- aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4- aliphatic residue, and the remaining substituent X5 represents H; CH2F; CHF2; CF3; OCH2F; OCHF2; OCF3; SCF3; a C1-4-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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a C1-4-aliphatic residue, on the condition that if X5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, 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—C1-4-aliphatic residue. [0355] In further embodiments, X1 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-aliphatic residue, or represents OX6, wherein X6 represents a C1-6-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a 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, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O—C1-4-aliphatic residue. [0356] In further embodiments, X1 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue is in each case unsubstituted, or represents OX6, wherein X6 represents a C1-6-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a S(═O)—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue is in each case unsubstituted. [0357] In further embodiments, X1 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—C1-4-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—C1-4-aliphatic residue, or represents OX6, wherein X6 represents 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, and an unsubstituted O—C1-4-aliphatic residue. [0358] In further embodiments, X1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2—CH(CH3)(C2H5), C(CH3)2(C2H5), ethenyl or propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)— CH3), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OX6, wherein X6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, CH2OH, CH2OCH3, CH2CH2OH, CH2CH2OCH3, and CH(OH)CH2OH. [0359] In further embodiments, X2 and X3 independently of one another represent H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a C1-4-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—C1-4-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, OH, an O—C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a 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—C1-4-aliphatic residue, with the proviso that at least one of X2 and X3 denotes H or is linked via a carbon atom, X4 and X5 independently of one another represent H; CH2F; CHF2; CF3; a C1-4-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, and an unsubstituted O—C1-4- 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, OH, an O—C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a 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—C1-4-aliphatic residue, on the condition that if X4 and/or X5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X2 and X3 and/or X4 and X5 in pairs, in each case independently of one another, together with the carbon atom 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—C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a 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—C1-4-aliphatic residue, and the respective remaining substituents of X2 and X3 each independently of one another represent H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a C1-4-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—C1-4-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, OH, an O—C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a 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—C1-4-aliphatic residue, with the proviso that at least one of X2 and X3 denotes H or is linked via a carbon atom, and the respective remaining substituents of X4 and X5 each independently of one another represent H; CH2F; CHF2; CF3; a C1-4- 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, and an unsubstituted O—C1-4-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, OH, an O—C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4-aliphatic residue, on the condition that if X4 and/or X5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, 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—C1-4-aliphatic residue, or X2 and X4 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—C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a 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—C1-4-aliphatic residue, and the remaining substituent X3 represents H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a C1-4-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—C1-4-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—C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a 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—C1-4-aliphatic residue, and the remaining substituent X5 represents H; CH2F; CHF2; CF3; a C1-4-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, and an unsubstituted O—C1-4-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—C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4-aliphatic residue, on the condition that if X5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, 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—C1-4-aliphatic residue. [0360] In further embodiments, X2 and X3 independently of one another represent H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; a C1-4-aliphatic residue, or an O—C1-4 aliphatic residue, wherein the C1-4-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 X2 and X3 denotes H or is linked via a carbon atom, X4 and X5 independently of one another represent H; CH2F; CHF2; CF3; a C1-4-aliphatic residue, wherein the C1-4-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 X4 and/or X5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X2 and X3 and/or X4 and X5 in pairs, in each case independently of one another, together with the carbon atom 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—C1-4-aliphatic residue, CH2F, CHF2, CF3, and a C1-4- aliphatic residue, wherein the C1-4-aliphatic residue is in each case unsubstituted, and the respective remaining substituents of X2 and X3 each independently of one another represent H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; a C1-4-aliphatic residue, or an O—C1- 4 aliphatic residue, wherein the C1-4-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 X2 and X3 denotes H or is linked via a carbon atom, and the respective remaining substituents of X4 and X5 each independently of one another represent H; CH2F; CHF2; CF3; a C1-4- aliphatic residue, wherein the C1-4-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 X4 and/or X5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or X2 and X4 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—C1-4-aliphatic residue, CH2F, CHF2, CF3, and a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue is in each case unsubstituted, and the remaining substituent X3 represents H; F; Cl; Br; I; CH2F; CHF2; CF3; OH; a C1-4-aliphatic residue, or an O—C1-4 aliphatic residue, wherein the C1-4- 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 X5 represents H; CH2F; CHF2; CF3; a C1-4-aliphatic residue, wherein the C1-4-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 X5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom. [0361] In further embodiments, X2 and X3 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 X2 and X3 denotes H or is linked via a carbon atom, X4 and X5 independently of one another represent H; CH2F; CHF2; CF3; an unsubstituted C1-4-aliphatic residue, or X2 and X3 or X4 and X5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-10-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—C1-4-aliphatic residue, and an unsubstituted C1-4-aliphatic residue, and the respective remaining substituents of X2 and X3 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 X2 and X3 denotes H or is linked via a carbon atom, and the respective remaining substituents of X4 and X5 each independently of one another represent H; CH2F; CHF2; CF3; an unsubstituted C1-4- aliphatic residue, or X2 and X4 together with the carbon atoms connecting them, form a C3-10-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 C1-4-aliphatic residue, and the remaining substituent X3 represents H; F; Cl; Br; I; OH; an unsubstituted C1-4-aliphatic residue, or an unsubstituted O—C1-4 aliphatic residue, and the remaining substituent X5 represents H; CH2F; CHF2; CF3; an unsubstituted C1-4-aliphatic residue. [0362] In further embodiments, X2 and X3 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)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of X2 and X3 denotes H or is linked via a carbon atom, X4 and X5 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)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3; or X2 and X3 or X4 and X5 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 X2 and X3 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)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of X2 and X3 denotes H or is linked via a carbon atom, and the respective remaining substituents of X4 and X5 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)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3; or X2 and X4 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 X3 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2— CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, and the respective remaining substituent X5 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.- butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2—CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3. [0363] In further embodiments, X1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OX6, wherein X6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, or tert.-butyl, X2 and X3 in dependently of one another represent H; methyl; ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, or tert.-butyl, X4 and X5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, CH2F, CHF2, or CF3; or X2 and X3 or X4 and X5 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 X2 and X3 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 X4 and X5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, CH2F, CHF2, or CF3; or X2 and X4 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 X3 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, or tert.- butyl, and X5 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, CH2F, CHF2, or CF3. [0364] 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-morpholin-4- yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N-[[(1S,2R)-2-hydroxy-cyclohexyl]- methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide; 2-Cyclopropyl-N- [[(1R,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-[[(1S,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 [0365] 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. [0366] In an embodiment, the Kv7 channel activator is a compound according to formula 25. Formula 25
Figure imgf000298_0001
wherein, R1 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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; aryl or heteroaryl, 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; R2 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, wherein the C1-4 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 C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(═O)H; C(═O)—OH; C(═O)—NH2; SCF3; S(═O)2—OH; NO2; OCF3; 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4- aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, wherein the C1- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4-aliphatic residue, a N(C1-4 aliphatic residue)-C(═O)—C1- 4 aliphatic residue, or a N(C1-4 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; R7 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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 R7 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O— C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O— C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000300_0001
NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, an NH—C(═O)—C1-4 aliphatic residue, an NH—S(═O)2—C1-4 aliphatic residue, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, C(═O)H, C(═O)OH, a C1-4-aliphatic residue, a C(═O)—C1-4-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(C1- 4 aliphatic residue), and a C(═O)—N(C1-4 aliphatic residue)2; 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. [0367] In further embodiments, R1 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, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(═O)—OH, 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000302_0001
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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 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 C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN and C(═O)—OH, R2 represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a O—C1-4-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, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; 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(C1-4 aliphatic residue)2, a O—C1-4-aliphatic residue, a O—C(═O)— C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, and a NH—S(═O)2—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, ═O, OH, and a O—C1-4- 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, ═O, OH, a C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, R7 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, an NH(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4- aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0368] In further embodiments, R2 represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a 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, ═O, 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, ═O, OH, a C1-4-aliphatic residue and a 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, ═O, 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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4-aliphatic residue. [0369] In further embodiments, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; a C1-4-aliphatic residue, a C(═O)—C1-4 aliphatic residue, a C(═O)— O—C1-4 aliphatic residue, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—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, ═O, OH, and a O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group. [0370] In further embodiments, R3, R4, R5 and R6 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 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, and O—CH3. [0371] In further embodiments, at least one of R3, R4, R5 and R6 is ≠H. [0372] In further embodiments, R1 represents the partial structure:
Figure imgf000305_0001
wherein: m denotes 0, 1, 2, 3 or 4, R8a and R8b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 ═O, R8c 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000306_0001
yl, 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH. [0373] In further embodiments, R1 represents the partial structure:
Figure imgf000307_0001
wherein: m denotes 0, 1, or 2, R8a and R8b each independently of one another represent H, F, Cl, Br, I, an O—C1-4 aliphatic residue or a C1-4 aliphatic residue, R8c 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 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, CF3 and an unsubstituted O—C1-4-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, an O—C1- 4 aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1- 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 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, 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, ═O, an O—C1-4 aliphatic residue, OCF3, CF3 a C1-4-aliphatic residue and C(═O)—OH. [0374] In further embodiments, R7 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, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, OH, ═O, an O—C1- 4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, CF3, CN, a C1-4-aliphatic residue, a C3-6 cycloaliphatic residue, and a 3 to 6 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 an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, 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, OH, ═O, an O—C1-4 aliphatic residue, a C(═O)— O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4-aliphatic residue. on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0375] In further embodiments, R7 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, ═O, an O—C1-4-aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted C1-4-aliphatic residue, and wherein the C3- 10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue is bridged via a unsubstituted C1-8 aliphatic group. [0376] In further embodiments, R1 represents the partial structure:
Figure imgf000309_0001
wherein: m is 0, 1 or 2 and R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; R8c 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 C1-4-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, an unsubstituted O—C1-4 aliphatic residue, CF3, and an unsubstituted C1-4- aliphatic residue, or wherein m is 0, R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; and R8c 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, C(═O)—O—C2H5 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 C1-4- aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O—CH3 and C(═O)—O—C2H5, R2 is selected from the group consisting of H; F; Cl; CF3; CH3; C2H5, iso-propyl; cyclopropyl; and O—CH3; R3, R4, R5 and R6 are each independently of one another selected from the group consisting of H; F; Cl; Br; CF3; CN; OCF3 and NO2; R7 denotes a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ═O, an O—C1-4- aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4- aliphatic residue, CF3, and a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue in each case is unsubstituted. [0377] 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-(trifluoromethyl)- 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-(trifluoromethyl)-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-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- (trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2- isopropoxy-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; 2-ethoxy-N- [(3-fluorophenyl)-methyl]-4-methoxy-7-(trifluoremethyl)-quinoline-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- (trifluoromethyl)-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)- quinoline-3-carboxylic acid amide; 2-ethoxy-N-[(3-fluoro-4-methyl-phenyl)-methyl]-4- methyl-7-(trifluoromethyl)-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-carboxylic 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)-quinoline-3-carboxylic acid amide; 2-ethoxy-4-methyl-N-(p-tolyl-methyl)- 7-(trifluoromethyl)-quinoline-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- carboxylic acid amide; 7-bromo-N-[(3-fluorophenyl)-methyl]-2-methoxy-4-methyl- quinoline-3-carboxylic acid amide; 7-bromo-N-[(4-fluorophenyl)-methyl]-2-methoxy-4- methyl-quinoline-3-carboxylic acid amide; 7-cyano-2-ethoxy-N-[(4-fluorophenyl)-methyl]- 4-methyl-quinoline-3-carboxylic acid amide; 7-cyano-2-ethoxy-N-[(3-fluorophenyl)- methyl]-4-methyl-quinoline-3-carboxylic acid amide; 7-cyano-N-[(3-fluorophenyl)- methyl]-2-methoxy-4-methyl-quinoline-3-carboxylic acid amide; 7-cyano-N-[(4- fluorophenyl)-methyl]-2-methoxy-4-methyl-quinoline-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-carboxylic acid amide; N-[(5-fluoro-2-methoxy-phenyl)- methyl]-2-methoxy-4-methyl-7-(trifluoromethyl)-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-carboxylic acid amide; N-[(5-fluoro-2-hydroxy-phenyl)- methyl]-2-methoxy-4-methyl-7-(trifluoromethyl)-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-carboxylic acid amide; 7,8-difluoro-N-[(3-fluorophenyl)- methyl]-2-methoxy-4-methyl-quinoline-3-carboxylic 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 [0378] 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. [0379] In an embodiment, the Kv7 channel activator is a compound according to formula 26: Formula 26
Figure imgf000313_0001
wherein, R1 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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; aryl or heteroaryl, 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; R2 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—C1-4-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; R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(═O)H; C(═O)—OH; C(═O)—NH2; SCF3; S(═O)2—OH; NO2; OCF3; 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4- aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, wherein the C1- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4-aliphatic residue, a N(C1-4 aliphatic residue)-C(═O)—C1- 4 aliphatic residue, or a N(C1-4 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; R7 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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 R7 represents an unsubstituted aliphatic residue, then R7 does not represent methyl or ethyl, and on the condition that if R7 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1- 4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4- aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000315_0001
NH(C1-4 aliphatic residue), an N(C1- 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—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, C(═O)H, C(═O)OH, a C1-4-aliphatic residue, a C(═O)—C1-4-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(C1- 4 aliphatic residue), and a C(═O)—N(C1-4 aliphatic residue)2; 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. [0380] In further embodiments, R1 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, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(═O)—OH, 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000317_0001
nzyl, 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 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 C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN and C(═O)—OH, R2 represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a O—C1-4-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, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; 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(C1-4 aliphatic residue)2, a O—C1-4-aliphatic residue, a O—C(═O)— C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, and a NH—S(═O)2—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, ═O, OH, and a O—C1-4- 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, ═O, OH, a C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, R7 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, an NH(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4- aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R7 represents an unsubstituted aliphatic residue, then R7 does not represent methyl or ethyl, and on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0381] In further embodiments, R2 represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and a 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4- aliphatic residue. [0382] In further embodiments, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; a C1-4-aliphatic residue, a C(═O)—C1-4 aliphatic residue, a C(═O)— O—C1-4 aliphatic residue, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—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, ═O, OH, and a O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group. [0383] In further embodiments, R3, R4, R5 and R6 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 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, and O—CH3. [0384] In further embodiments, at least one of R3, R4, R5 and R6 is ≠H. [0385] In further embodiments, R1 represents the partial structure:
Figure imgf000320_0001
wherein: m denotes 0, 1, 2, 3 or 4, R8a and R8b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 ═O, R8c 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000321_0001
enzyl, 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH. [0386] In further embodiments, R1 represents the partial structure:
Figure imgf000322_0001
wherein: m denotes 0, 1, or 2, R8a and R8b each independently of one another represent H, F, Cl, Br, I, an O—C1-4 aliphatic residue or a C1-4 aliphatic residue, R8c 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 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, CF3 and an unsubstituted O—C1-4-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, an O—C1- 4 aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1- 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 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, 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, ═O, an O—C1-4 aliphatic residue, OCF3, CF3 a C1-4-aliphatic residue and C(═O)—OH. [0387] In further embodiments, R7 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, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, OH, ═O, an O—C1- 4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, CF3, CN, a C1-4-aliphatic residue, a C3-6 cycloaliphatic residue, and a 3 to 6 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 an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, 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, OH, ═O, an O—C1-4 aliphatic residue, a C(═O)— O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, on the condition that if R7 represents an unsubstituted aliphatic residue, then R7 does not represent methyl or ethyl, and on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0388] In further embodiments, R7 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, ═O, an O—C1-4-aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-aliphatic residue, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue is bridged via a unsubstituted C1-8 aliphatic group, on the condition that if R7 represents an unsubstituted aliphatic residue, then R7 does not represent methyl or ethyl. [0389] In further embodiments, R1 represents the partial structure:
Figure imgf000325_0001
wherein: m is 0, 1 or 2 and R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; R8c 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 C1-4-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, an unsubstituted O—C1-4 aliphatic residue, CF3, and an unsubstituted C1-4- aliphatic residue, or wherein m is 0, R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; and R8c 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, C(═O)—O—C2H5 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 C1-4- aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O—CH3 and C(═O)—O—C2H5, R2 is selected from the group consisting of H; F; Cl; CF3; CH3; C2H5, iso-propyl; cyclopropyl; and O—CH3; R3, R4, R5 and R6 are each independently of one another selected from the group consisting of H; F; Cl; Br; CF3; CN; OCF3 and NO2; R7 denotes a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ═O, an O—C1-4- aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4- aliphatic residue, CF3, and a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue in each case is unsubstituted, and on the condition that if R7 represents an unsubstituted aliphatic residue, then R7 does not represent methyl or ethyl. [0390] In further embodiments, the Kv7 channel activator may be selected from the group consisting of: [0391] 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-(trifluoromethyl)-quinoline- 3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2-isopropoxy-4-methyl-7- (trifluoromethyl)-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-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 27 [0392] 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. PCT/EP2011/004279 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. [0393] In an embodiment, the Kv7 channel activator is a compound according to formula 27:
Figure imgf000327_0001
wherein: R1 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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; aryl or heteroaryl, 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; R2 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, wherein the C1-4 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 C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(═O)H; C(═O)—OH; C(═O)—NH2; SCF3; S(═O)2—OH; NO2; OCF3; 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4- aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, wherein the C1- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4-aliphatic residue, a N(C1-4 aliphatic residue)-C(═O)—C1- 4 aliphatic residue, or a N(C1-4 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; on the condition that at least one of R3, R4, R5 and R6 is ≠H, R7 represents a C2-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3- 10-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 R7 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, NO2, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)— NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH— S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O— C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH— C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4- aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000329_0001
1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, an NH—C(═O)—C1-4 aliphatic residue, OH, OCF3, a O— C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4- aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4- aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, C(═O)H, C(═O)OH, a C1-4-aliphatic residue, a C(═O)—C1-4-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(C1-4 aliphatic residue), and a C(═O)—N(C1-4 aliphatic residue)2; 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. [0394] In further embodiments, R1 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, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(═O)—OH, 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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—O2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue,
Figure imgf000331_0001
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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 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 C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN and C(═O)—OH, R2 represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a O—C1-4-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, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; 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(C1-4 aliphatic residue)2, a O—C1-4-aliphatic residue, a O—C(═O)— C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, and a NH—S(═O)2—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, ═O, OH, and a O—C1-4- 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, ═O, OH, a C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, on the condition that at least one of R3, R4, R5 and R6 is ≠H, R7 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4- 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—C1-4- 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0395] In further embodiments, R2 represents H; F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a 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, ═O, 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, ═O, OH, a C1-4-aliphatic residue and a 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, ═O, 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, ═O, OH, an unsubstituted C1-4-aliphatic residue and an unsubstituted O—C1-4-aliphatic residue. [0396] In further embodiments, R2 is ≠H. [0397] In further embodiments, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; a C1-4-aliphatic residue, a C(═O)—C1-4 aliphatic residue, a C(═O)— O—C1-4 aliphatic residue, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—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, ═O, OH, and a O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, on the condition that at least one of R3, R4, R5 and R6 is ≠H. [0398] In further embodiments, R3, R4, R5 and R6 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 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, and O—CH3, on the condition that at least one of R3, R4, R5 and R6 is ≠H. [0399] In further embodiments, R1 represents the partial structure:
Figure imgf000334_0001
[0400] Wherein, m denotes 0, 1, 2, 3 or 4, R8a and R8b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, 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 ═O, R8c 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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)—O2H5, C(═O)—O—CH3 and C(═O)—O—O2H5, a C3-6 cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue,
Figure imgf000335_0001
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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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)—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, NO2, NH2, an NH(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH. [0401] In further embodiments, R1 represents the partial structure:
Figure imgf000336_0001
wherein: m denotes 0, 1, or 2, R8a and R8b each independently of one another represent H, F, Cl, Br, I, an O—C1-4 aliphatic residue or a C1-4 aliphatic residue, R8c 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 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, CF3 and an unsubstituted O—C1-4-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, an O—C1- 4 aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1- 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—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 C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, CF3 a C1-4-aliphatic residue and C(═O)—OH. [0402] In further embodiments, R7 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, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, OH, ═O, an O—C1- 4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, CF3, CN, a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, OH, ═O, an O—C1-4 aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4- aliphatic residue. on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0403] In further embodiments, R7 denotes a C2-8-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, Cl, Br, I, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S— C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-aliphatic residue, and wherein the C3-10-cycloaliphatic residue or the 3 to 10 membered heterocycloaliphatic residue may in each case optionally bridged via a unsubstituted C1-8 aliphatic group, on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0404] In further embodiments, R1 represents the partial structure:
Figure imgf000338_0001
wherein: m is 0, 1 or 2 and R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; R8c 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 C1-4-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, an unsubstituted O—C1-4 aliphatic residue, CF3, and an unsubstituted C1-4- aliphatic residue, or wherein m is 0, R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; and R8c 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, C(═O)—O—C2H5 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 C1-4- aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O—CH3 and C(═O)—O—C2H5, R2 is selected from the group consisting of H; F; Cl; CF3; CH3; C2H5, iso-propyl; cyclopropyl; and O—CH3; R3, R4, R5 and R6 are each independently of one another selected from the group consisting of H; F; Cl; Br; CH3; CF3; CN; OCF3 and NO2; on the condition that at least one of R3, R4, R5 and R6 is ≠H, R7 denotes ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl or propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), 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(CH3)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—C1-4-aliphatic residue, CF3, and a C1-4-aliphatic residue, wherein the C1-4-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 R7 denotes piperidinyl tetrahydrofuranyl, or tetrahydropyranyl, each of these residues is linked via a carbon atom. [0405] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 4-methyl-2-propyl-N-(thiophene-2-yl-methyl)-7-(trifluoromethyl)-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-(trifluoromethyl)-quinoline-3- carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2-isopropyl-4-methyl-7- (trifluoromethyl)-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)-quinoline-3-carboxylic acid amide; N-[(4-fluorophenyl)-methyl]-2-isopropyl-7-(trifluoromethyl)-quinoline-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-carboxylic acid amide; N-[(3-fluorophenyl)-methyl]-2-(hydroxymethyl)-4-methyl-7-(trifluoromethyl)- 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-(trifluoromethyl)-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-1-enyl]-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide; N-[(3- fluorophenyl)-methyl]-4-methyl-2-(2-methyl-prop-1-enyl)-7-(trifluoromethyl)-quinoline-3- carboxylic acid amide; 7-bromo-2-ethyl-N-[(3-fluorophenyl)-methyl]-4-methyl-quinoline- 3-carboxylic acid amide; 7-bromo-2-ethyl-N-[(4-fluorophenyl)-methyl]-4-methyl- quinoline-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)- quinoline-3-carboxylic acid amide; 2-ethyl-N-[(4-fluoro-3-methyl-phenyl)-methyl]-4- methyl-7-(trifluoromethyl)-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- carboxylic 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-quinoline-3-carboxylic acid amide; 7-cyano-N-[(3-fluorophenyl)-methyl]-2- isopropyl-4-methyl-quinoline-3-carboxylic acid amide; and 7-cyano-N-[(4-fluorophenyl)- methyl]-2-isopropyl-4-methyl-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 28 [0406] 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. WO2012028300A1, 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. [0407] In an embodiment, the Kv7 channel activator is a compound according to formula 28:
Figure imgf000342_0001
wherein, R1 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-cycloaliphatic residue, unsubstituted or mono- or polysubstituted and optionally bridged via a C1-8 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 C1-8 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; R2 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4-aliphatic residue, a O— C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-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; R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(═O)H; C(═O)—OH; C(═O)—NH2; SCF3; S(═O)2—OH; NO2; OCF3; 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH— S(═O)2—C1-4-aliphatic residue, a N(C1-4 aliphatic residue)-C(═O)—C1-4 aliphatic residue, or a N(C1-4 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; R7 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3- 10-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 R7 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, ═O, OCF3, a O—C1-4-aliphatic residue, a O— C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH— C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4- aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)— NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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 of F, Cl, Br, I, NO2, NH2,
Figure imgf000344_0001
NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, an NH—C(═O)—C1-4 aliphatic residue, an NH—S(═O)2—C1-4 aliphatic residue, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH— C1-4-aliphatic residue, CN, CF3, C(═O)H, C(═O)OH, a C1-4-aliphatic residue, a C(═O)— C1-4-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(C1-4 aliphatic residue), and a C(═O)—N(C1-4 aliphatic residue)2; 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. [0408] In further embodiments, R1 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, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4-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—C1-4-aliphatic residue, or denotes a C3-10- 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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, ═O, OH, OCF3, CF3 and an unsubstituted O—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, and wherein the C3-10-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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1- 4 aliphatic residue)2, 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 residue,
Figure imgf000345_0001
Figure imgf000346_0001
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, ═O, OH, OCF3, CF3 and an unsubstituted O—C1-4-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(C1-4 aliphatic residue), an N(C1-4 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 C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN and C(═O)—OH, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a O—C1-4-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, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; 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(C1- 4 aliphatic residue)2, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, and a NH—S(═O)2— 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, ═O, OH, and a O—C1-4-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 C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, R7 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, OH, ═O, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, CN, a C1-4- 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, ═O, OCF3, CF3 and an unsubstituted O—C1-4- 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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, ═O, OH, OCF3, CF3 and an unsubstituted O—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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, ═O, OH, an O—C1- 4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(═O)—OH, on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0409] In further embodiments, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a 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, ═O, OH, and an unsubstituted O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and a 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, ═O, OH, and an unsubstituted O—C1-4-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 C1-4-aliphatic residue and an unsubstituted O—C1-4-aliphatic residue. [0410] In further embodiments, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; a C1-4-aliphatic residue, a C(═O)—C1-4 aliphatic residue, a C(═O)— O—C1-4 aliphatic residue, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—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, ═O, OH, and a O—C1-4-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, ═O, OH, a C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group. [0411] In further embodiments, R3, R4, R5 and R6 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 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, and O—CH3. [0412] In further embodiments, at least one of R3, R4, R5 and R6 is ≠H. [0413] In further embodiments, R1 represents the partial structure:
Figure imgf000349_0001
wherein: m denotes 0, 1, 2, 3 or 4, R8a and R8b 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 ═O, R8c 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, ═O, OH, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, or denotes a C3-10- 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000350_0001
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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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, 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH. [0414] In further embodiments, R1 represents the partial structure
Figure imgf000351_0001
wherein, m denotes 0, 1, or 2, R8a and R8b each independently of one another represent H, F, Cl, Br, I, an O—C1-4 aliphatic residue or a C1-4 aliphatic residue, R8c 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 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, CF3 and an unsubstituted O—C1-4-aliphatic residue, or denotes a C3-10-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 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, CF3 and an unsubstituted O—C1-4-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—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, 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, ═O, an O—C1-4 aliphatic residue, OCF3, CF3 a C1-4-aliphatic residue and C(═O)—OH. [0415] In further embodiments, R7 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, ═O, OH, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, and a 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, ═O, OH, OCF3, CF3 and an unsubstituted O—C1-4-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, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, CN, a C1-4-aliphatic residue, a C3-6 cycloaliphatic residue, and a 3 to 6 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, ═O, OH, OCF3, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, 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, OH, ═O, an O—C1-4 aliphatic residue, a C(═O)— O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4-aliphatic residue. on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0416] In further embodiments, R7 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, an O—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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 R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0417] In further embodiments, R1 represents the partial structure:
Figure imgf000353_0001
wherein: m is 0, 1 or 2 and R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; R8c 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 C1-4-aliphatic residue, or denotes a C3-10-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 C1-4-aliphatic residue, or wherein m is 0, R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; R8c 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, C(═O)—O—C2H5 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 C1-4-aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O— CH3 and C(═O)—O—C2H5, R2 is selected from the group consisting of F; Cl; CF3; CH3; C2H5, iso-propyl; cyclopropyl; and O—CH3; R3, R4, R5 and R6 are each independently of one another selected from the group consisting of H; F; Cl; CF3; CN; OCF3 and NO2; R7 denotes a C1-6-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—C1-4- aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4- aliphatic residue, CF3, and a 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 OH, and an unsubstituted O—C1-4- aliphatic residue. [0418] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-(3-fluorobenzyl)-2,4-dimethyl-1-oxo-7-(trifluoromethyl)-1,2- dihydroisoquinoline-3-carboxamide; N-(3-fluorobenzyl)-4-methyl-1-oxo-2-propyl-7- (trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide; 2-ethyl-N-(3-fluorobenzyl)-4- methyl-1-oxo-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide; N-(3- fluorobenzyl)-2-isopropyl-4-methyl-1-oxo-7-(trifluoromethyl)-1,2 dihydroisoquinoline-3- carboxamide; andN-(3-fluorobenzyl)-2-(2-methoxyethyl)-4-methyl-1-oxo-7- (trifluoromethyl)-1,2-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 [0419] 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. WO2012025239A1filed 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. [0420] In an embodiment, the Kv7 channel activator is a compound according to formula 29:
Figure imgf000355_0001
wherein: X denotes O or S, R1 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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; aryl or heteroaryl, 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; R2 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—C1-4-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; R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; C(═O)H; C(═O)—OH; C(═O)—NH2; SCF3; S(═O)2—OH; NO2; OCF3; 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(C1-4 aliphatic residue)2, wherein the C1-4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a O—C1-4- aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, wherein the C1- 4 aliphatic residue may be in each case be unsubstituted or mono- or polysubstituted; a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH—S(═O)2—C1-4-aliphatic residue, a N(C1-4 aliphatic residue)-C(═O)—C1- 4 aliphatic residue, or a N(C1-4 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; R7 represents a C1-10-aliphatic residue, unsubstituted or mono- or polysubstituted; a C3-10-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 R7 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(C1-4 aliphatic residue), a NH—C(═O)—C1- 4 aliphatic residue, a NH—S(═O)2—C1-4 aliphatic residue, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)— NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, a NH— S(═O)2—C1-4 aliphatic residue, ═O, OH, OCF3, a O—C1-4-aliphatic residue, a O— C(═O)—C1-4-aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4-aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH— C1-4-aliphatic residue, CN, CF3, CHO, COOH, a C1-4-aliphatic residue, a C(═O)—C1-4- aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, a C3-6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(═O)—NH2, a C(═O)—NH(C1-4 aliphatic residue), and a C(═O)—N(C1-4 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 of F, Cl, Br, I, NO2, NH2, (C1 aliphatic residue),
Figure imgf000357_0001
-4 an N(C1-4 aliphatic residue)2, an NH—C(═O)—C1-4 aliphatic residue, an NH—S(═O)2— C1-4 aliphatic residue, OH, OCF3, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4- aliphatic residue, SH, SCF3, a S—C1-4-aliphatic residue, S(═O)2OH, a S(═O)2—C1-4- aliphatic residue, a S(═O)2—O—C1-4-aliphatic residue, a S(═O)2—NH—C1-4-aliphatic residue, CN, CF3, C(═O)H, C(═O)OH, a C1-4-aliphatic residue, a C(═O)—C1-4-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(C1-4 aliphatic residue), and a C(═O)—N(C1-4 aliphatic residue)2; with the exception of the following compound: 1-ethyl-N-(4-methoxybenzyl)-4-methyl-2-oxo-1,2- 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. [0421] In further embodiments, R1 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, an NH(C1-4 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000359_0001
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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 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 C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—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(C1- 4 aliphatic residue), OH, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1- 4 aliphatic residue, CF3, CN and C(═O)—OH, X represents O or S; R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a O—C1-4-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, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; 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(C1-4 aliphatic residue)2, a O—C1-4-aliphatic residue, a O—C(═O)— C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—C1-4-aliphatic residue, a NH(C1-4 aliphatic residue), a N(C1-4 aliphatic residue)2, a NH—C(═O)—C1-4 aliphatic residue, and a NH—S(═O)2—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 a O—C1-4- 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 C1- 4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group, R7 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, an NH(C1-4 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, a C(═O)—O—C1-4-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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4- aliphatic residue and C(═O)—OH, 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(C1-4 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 and C(═O)—OH, on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0422] In further embodiments, R2 represents F; Cl; Br; I; CN; CF3; NO2; OCF3; SCF3; a C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a 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 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, ═O, OH, a C1-4-aliphatic residue and a 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 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 C1-4- aliphatic residue and an unsubstituted O—C1-4-aliphatic residue. [0423] In further embodiments, R3, R4, R5 and R6 each independently of one another represent H; F; Cl; Br; I; CN; CF3; OCF3; SCF3; C(═O)H; C(═O)—OH; C(═O)—NH2; S(═O)2—OH; NO2; a C1-4-aliphatic residue, a C(═O)—C1-4 aliphatic residue, a C(═O)— O—C1-4 aliphatic residue, a O—C1-4-aliphatic residue, a O—C(═O)—C1-4-aliphatic residue, a S—C1-4-aliphatic residue, a S(═O)2—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 a O— C1-4-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, ═O, OH, a C1-4-aliphatic residue and a O—C1-4-aliphatic residue, and in each case optionally bridged via an unsubstituted C1-4 aliphatic group. [0424] In further embodiments, R3, R4, R5 and R6 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 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, and O—CH3. [0425] In further embodiments, at least one of R3, R4, R5 and R6 is ≠H. [0426] In further embodiments, R1 represents the partial structure:
Figure imgf000362_0001
wherein, m denotes 0, 1, 2, 3 or 4, R8a and R8b each independently of one another represent H, F, Cl, Br, I, NO2, NH2, a NH(C1-4 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, R8c 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(C1-4 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 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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, 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 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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-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(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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 residue,
Figure imgf000363_0001
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—C1-4-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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, 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, 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(C1- 4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, a C1-4-aliphatic residue and C(═O)—OH. [0427] In further embodiments, R1 represents the partial structure:
Figure imgf000364_0001
wherein: m denotes 0, 1, or 2, R8a and R8b each independently of one another represent H, F, Cl, Br, I, an O—C1-4 aliphatic residue or a C1-4 aliphatic residue, R8c 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 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, CF3 and an unsubstituted O—C1-4-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, an O—C1- 4 aliphatic residue, CF3, and a 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, CF3 and an unsubstituted O—C1- 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 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, 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, ═O, an O—C1-4 aliphatic residue, OCF3, CF3 a C1-4-aliphatic residue and C(═O)—OH. [0428] In further embodiments, R7 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, OH, an O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S— C1-4-aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, COOH, CF3, CN, and a 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, OCF3, CF3 and an unsubstituted O—C1-4-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, OH, ═O, an O—C1- 4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4- aliphatic residue, CF3, CN, a C1-4-aliphatic residue, a C3-6 cycloaliphatic residue, and a 3 to 6 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 an unsubstituted O—C1-4-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, ═O, an O—C1-4 aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4-aliphatic residue, 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, OH, an O—C1-4 aliphatic residue, a C(═O)—O—C1- 4-aliphatic residue, OCF3, SH, SCF3, a S—C1-4 aliphatic residue, CF3, CN, and a C1-4- aliphatic residue. on the condition that if R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0429] In further embodiments, R7 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, an O—C1-4-aliphatic residue, COOH, a C(═O)—O—C1-4- aliphatic residue, OCF3, SH, SCF3, a S—C1-4-aliphatic residue, CF3, and a 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, CF3 and an unsubstituted 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, ═O, an O—C1-4 aliphatic residue, OCF3, SCF3, a S—C1-4 aliphatic residue, a C(═O)—O—C1-4-aliphatic residue, CF3, and a 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, OCF3, CF3 and an unsubstituted C1-4-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 R7 denotes a 3 to 10 membered heterocycloaliphatic residue, the 3 to 10 membered heterocycloaliphatic residue is linked via a carbon atom. [0430] In further embodiments, R1 represents the partial structure:
Figure imgf000367_0001
wherein: m is 0, 1 or 2 and R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; R8c 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 C1-4-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, an unsubstituted O—C1-4 aliphatic residue, CF3, and an unsubstituted C1-4- aliphatic residue, or wherein m is 0, R8a and R8b each independently of one another represent H, F, a O—C1-4 aliphatic residue or a C1-4 aliphatic residue; and R8c 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, C(═O)—O—C2H5 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 C1-4- aliphatic residue, C(═O)—CH3, C(═O)—C2H5, C(═O)—O—CH3 and C(═O)—O—C2H5, X represents O or S; R2 is selected from the group consisting of F; Cl; Br; CF3; CH3; C2H5, iso-propyl; cyclopropyl; and O—CH3; R3, R4, R5 and R6 are each independently of one another selected from the group consisting of H; F; Cl; Br; CF3; CN; OCF3 and NO2; R7 denotes a C1-6-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—C1-4- aliphatic residue, COOH, a C(═O)—O—C1-4-aliphatic residue, OCF3, SH, SCF3, a S— C1-4-aliphatic residue, CF3, and a 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 OH, and an unsubstituted O—C1-4- aliphatic residue, or denotes an unsubstituted C3-6-cycloaliphatic residue or an unsubstituted 3 to 6 membered heterocycloaliphatic residue, on the condition that if R7 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom. [0431] In further embodiments, the Kv7 channel activator is selected from the group consisting of: N-[(3-Fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-7-(trifluoromethyl)-1H- quinoline-3-carboxylic acid amide; 1-Butyl-N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1,4- dimethyl-2-thioxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-1-(2-methoxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H- quinoline-3-carboxylic acid amide; 1-Ethyl-N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(4-Fluorophenyl)-methyl]-1,4- dimethyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(4- Fluorophenyl)-methyl]-1-(2-methoxy-ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H- quinoline-3-carboxylic acid amide; 1-Ethyl-N-[(4-fluorophenyl)-methyl]-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1,4- dimethyl-2-oxo-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1-(2- methoxy-ethyl)-4-methyl-2-oxo-1H-quinoline-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-4-methyl-2-oxo-1-propyl-7-(trifluoromethyl)-1H-quinoline-3- carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4-methyl-1-(3-methyl-butyl)-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4- methyl-1-(4-methyl-pentyl)-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1-(3-methoxy-propyl)-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1-[2- (2-methoxy-ethoxy)-ethyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; 7-Bromo-N-[(3-fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-1H-quinoline-3- carboxylic acid amide; 7-Bromo-N-[(4-fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-1H- quinoline-3-carboxylic acid amide; 7-Bromo-N-[(3-fluorophenyl)-methyl]-1-(2-methoxy- ethyl)-4-methyl-2-oxo-1H-quinoline-3-carboxylic acid amide; 7-Bromo-N-[(4- fluorophenyl)-methyl]-1-(2-methoxy-ethyl)-4-methyl-2-oxo-1H-quinoline-3-carboxylic acid amide; 7-Cyano-N-[(3-fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-1H-quinoline-3- carboxylic acid amide; 7-Cyano-N-[(4-fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-1H- quinoline-3-carboxylic acid amide; 7-Cyano-N-[(3-fluorophenyl)-methyl]-1-(2-methoxy- ethyl)-4-methyl-2-oxo-1H-quinoline-3-carboxylic acid amide; 7-Cyano-N-[(4- fluorophenyl)-methyl]-1-(2-methoxy-ethyl)-4-methyl-2-oxo-1H-quinoline-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-1-(2-methoxy-ethyl)-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-(4,4-Dimethyl-pentyl)-1,4- dimethyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; 2-[3-[(3- Fluorophenyl)-methyl-carbamoyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinolin-1-yl]- acetic acid methyl ester; 3-[3-[(3-Fluorophenyl)-methyl-carbamoyl]-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinolin-1-yl]-propionic acid methyl ester; 2-[3-[(3-Fluorophenyl)- methyl-carbamoyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinolin-1-yl]-acetic acid; 3-[3- [(3-Fluorophenyl)-methyl-carbamoyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinolin-1- yl]-propionic acid; N-[(3-Fluorophenyl)-methyl]-1-[1-(methoxymethyl)-propyl]-4-methyl-2- oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)- methyl]-1-[2-methoxy-1-(methoxymethyl)-ethyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H- quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1-(2-methoxy-butyl)-4- methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-7-(trifluoromethyloxy)-1H-quinoline-3- carboxylic acid amide; 7-Fluoro-N-[(3-fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-1H- quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1-(2-methoxy-1-methyl- ethyl)-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(4- Fluorophenyl)-methyl]-1,4-dimethyl-2-thioxo-7-(trifluoromethyl)-1H-quinoline-3- carboxylic acid amide; 7-Chloro-N-[(3-fluorophenyl)-methyl]-1,4-dimethyl-2-oxo-1H- quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1-(2-hydroxy-ethyl)-4- methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; 1-(2-Ethoxy- ethyl)-N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3- carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1-isopropyl-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4- methyl-2-oxo-1-pentyl-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3- Fluorophenyl)-methyl]-1-methyl-2-oxo-4-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-1-(2-methoxy-propyl)-4-methyl-2-oxo-7- (trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; N-[(3-Fluorophenyl)-methyl]-4- methyl-2-oxo-1-tetrahydro-pyran-4-yl-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide; and N-[(3-Fluorophenyl)-methyl]-4-methoxy-1-methyl-2-oxo-7-(trifluoromethyl)- 1H-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 [0432] 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. WO2010075973A1, 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. [0433] In an embodiment, the Kv7 channel activator is a compound according to formula 30:
Figure imgf000370_0001
, wherein, R0 stands for 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; 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; R1 stands for 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; 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; R2 stands for H; F; Cl; Br; or C1- 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; or R1 and R2 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; R3, R4, R5 and R6 each mutually independently denote H; F; Cl; Br; I; NO2; CF3; CN; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; OR0; —O—(C1-8 alkyl)-O—; O— C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O—C(═O)—N(R0)2; O— S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O—S(═O)2NHR0; O— S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)—O—R0; NH— C(═O)—NH2; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)—R0; NR0— C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)—)—N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH— S(═O)2NHR0; NH—S(═O)2N(R0)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0— S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; or S(═O)2N(R)2; R7, R8, R9, R10 each mutually independently stand for H; F; Cl; Br; or C1- 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; R11 stands for H; F; Cl; Br; CN; or R0; R12 stands for H; F; Cl; Br; CN; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; R13 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; 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 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; R14 stands for H; F; Cl; Br; CN; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; or R11 and R13 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 R11 and R12; or R13 and R14, 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; R15 stands for R0; 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; ═O; ═NH; ═C(NH2)2; NO2; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; OR0; O—(C1- 8 alkyl)-O; O—C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O—C(═O)— N(R0)2; O—S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O— S(═O)2NHR0; O—S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)— O—R0; NH—C(═O)—NH2; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)— R0; NR0—C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)— N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH— S(═O)2NHR0; NH—S(═O)2N(R)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0—S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; or S(═O)2N(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; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; OR0; O—(C1-8 alkyl)-O; O—C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O— C(═O)—N(R0)2; O—S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O— S(═O)2NHR0; O—S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)— O—R0; NH—C(═O)—NH2; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)— R0; NR0—C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)— N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH— S(═O)2NHR0; NH—S(═O)2N(R0)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0— S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; or S(═O)2N(R)2; in the form of a free compound or salt of a physiologically compatible acid or base. [0434] In further embodiments, R1 stands for C1-10 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, 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; R2 stands for H; or C1- 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted. [0435] In further embodiments, R3, R4, R5 and R6 each mutually independently denote H; F; Cl; Br; I; NO2; CF3; CN; R0; C(═O)(R0 or H); C(═O)O(R0 or H); C(═O)N(R0 or H)2; OH; OR0; —O—(C1-8 alkyl)-O—; O—(C1-8 alkyl)-O—C1-8 alkyl; OCF3; N(R0 or H)2; N(R0 or H)—C(═O)—R0; N(R0 or H)—C(═O)—N(R0 or H)2; SH; SCF3; SR0; S(═O)2R0; S(═O)2O(R0 or H); S(═O)2—N(R0 or H)2. [0436] In further embodiments, R7, R8, R9, R10 mutually independently stand for H; or C1- 10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted. [0437] In further embodiments, R11 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; R13 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 C2-4 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 R11 and R13 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. [0438] In further embodiments, R12 and R14 each mutually independently stand for H; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted. [0439] In further embodiments, R15 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 [0440] 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. WO2010075973A1, 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. [0441] In an embodiment, the Kv7 channel activator is a compound according to formula 31:
Figure imgf000375_0001
wherein, R1 stands for C1-10 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; phenyl or thienyl, each unsubstituted or mono- or polysubstituted; C1-8 alkyl-bridged C3-7 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted; C1-8 alkyl-bridged phenyl, unsubstituted or mono- or polysubstituted, wherein the alkyl chain can be branched or unbranched, saturated or unsaturated, unsubstituted; or C1-8 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; R3, R4, R5 and R6 each mutually independently denote H; F; Cl; Br; I; NO2; CF3; CN; R0; C(═O)(R0 or H); C(═O)O(R0 or H); C(═O)N(R0 or H)2; OH; OR0; O— (C1-8 alkyl)-O; O—(C1-8 alkyl)-O—C1-8 alkyl; N(R0 or H)2; N(R0 or H)—C(═O)—R0; N(R0 or H)—C(═O)—N(R0 or H)2; SH; SR0; S(═O)2R0; S(═O)2O(R0 or H); or S(═O)2—N(R0 or H)2; R7, R8, R9, R10 each mutually independently stand for H; or C1-4 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; R11 and R13 each independently stand for H; or C1-10 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; or R11 and R13 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; R15 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; 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. [0442] In further embodiments, R15 stands for C3-10 alkyl, saturated or unsaturated; branched or unbranched, unsubstituted or mono- or polysubstituted; or is selected from the following substructures:
Figure imgf000377_0001
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; R18 and R19 mutually independently denote H; F; Cl; Br; I; NO2; CF3; CN; R0; C(═O)(R0 or H); C(═O)O(R0 or H); C(═O)N(R0 or H)2; OH; OR0; O—(C1-8 alkyl)-O; O—(C1-8 alkyl)-O—C1-8 alkyl; N(R0 or H)2; N(R0 or H)— C(═O)—R0; N(R0 or H)—C(═O)—N(R0 or H)2; SH; SR0; S(═O)2R0; S(═O)2O(R0 or H); or S(═O)2—N(R0 or H)2H; or R18 and R19 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; R20 and R21 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 R20 and R21 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; R22 and R23 mutually independently denote H; or C1-10 alkyl, saturated or unsaturated; branched or unbranched, unsubstituted. [0443] In further embodiments, the Kv7 channel activator is selected from the group consisting of: 4-Oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3- (trifluoromethyl)benzyl)butyric acid amide; 4-(1-Methyl-3,4-dihydro-1H-isoquinolin-2-yl)- 4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide; 4-Oxo-4-(1-thien-2-yl-3,4- dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric acid amide; 4-Oxo-4-[1- (4-pyridyl)-3,4-dihydro-1H-isoquinolin-2-yl]-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(7-Fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxo-N-(3- (trifluoromethyl)benzyl)butyric acid amide; 4-(5-Fluoro-1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide; 4-Oxo-4- (1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[2-(trifluoromethyl)phenyl]methyl]butyric acid amide; 4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(4-Methyl-1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(4,4- Dimethyl-1-phenyl-1,3-dihydroisoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(7-Methoxy-1-phenyl-3,4-dihydro- 1H-isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(5- Methoxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(3-Methyl-1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]butyric acid amide; N-(2- Chlorophenyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid amide; N- (2,1,3-Benzothiadiazol-4-yl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid amide; N-(1-Methyl-6-indazolyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide; N-(2-Furylmethyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide; N-Benzyl-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide; 4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2- pyridylmethyl)butyric acid amide; N-[(4-Methoxyphenyl)methyl]-4-oxo-4-(1-phenyl-3,4- dihydro-1H-isoquinolin-2-yl)butyric acid amide; 4-Oxo-N-phenethyl-4-(1-phenyl-3,4- dihydro-1H-isoquinolin-2-yl)butyric acid amide; 4-Oxo-4-(1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-N-(4-pyridylmethyl)butyric acid amide; 4-Oxo-4-(1-phenyl-3,4-dihydro- 1H-isoquinolin-2-yl)-N-(3-phenylpropyl)butyric acid amide; N-[2-(1H-Indol-3-yl)ethyl]-4- oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid amide; 4-(5,7-Dimethyl-1- phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(4-methoxyphenyl)-4-oxobutyric acid amide; N-(2-Chlorophenyl)-4-(5,7-dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide; -(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(1- methyl-6-indazolyl)-4-oxobutyric acid amide; 4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-N-(2-furylmethyl)-4-oxobutyric acid amide; N-Benzyl-4-(5,7-dimethyl-1- phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide;4 -(5,7-Dimethyl-1- phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl)butyric acid amide; 4- (5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-[(4-methoxyphenyl)methyl]-4- oxobutyric acid amide; 4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo- N-phenethylbutyric acid amide; 4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)-4-oxo-N-(3-phenylpropyl)butyric acid amide; N-(4-Methoxyphenyl)-4-(5-methyl-1- phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide; N-(2-Chlorophenyl)-4- (5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide; N-(1- Methyl-6-indazolyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide; N-(2-Furylmethyl)-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide; N-Benzyl-4-(5-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)- 4-oxobutyric acid amide; 4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N- (2-pyridylmethyl)butyric acid amide; N-[(4-Methoxyphenyl)methyl]-4-(5-methyl-1-phenyl- 3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide; 4-(5-Methyl-1-phenyl-3,4- dihydro-1H-isoquinolin-2-yl)-4-oxo-N-phenethylbutyric acid amide; 4-(5-Methyl-1-phenyl- 3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(3-phenylpropyl)butyric acid amide; N-(4- Methoxyphenyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide; N-(2-Chlorophenyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide; N-(1-Methyl-6-indazolyl)-4-(7-methyl-1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-4-oxobutyric acid amide; N-(2-Furylmethyl)-4-(7-methyl-1-phenyl-3,4- dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide; N-Benzyl-4-(7-methyl-1-phenyl- 3,4-dihydro-1H-isoquinolin-2-yl)-4-oxobutyric acid amide; 4-(7-Methyl-1-phenyl-3,4- dihydro-1H-isoquinolin-2-yl)-4-oxo-N-(2-pyridylmethyl)butyric acid amide; N-[(4- Methoxyphenyl)methyl]-4-(7-methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxobutyric acid amide; 4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N- phenethylbutyric acid amide; 4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-4- oxo-N-(4-pyridylmethyl)butyric acid amide; 4-Oxo-4-(1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-N-(2-thienylmethyl)butyric acid amide; N-[(2-Chlorophenyl)methyl]-4- oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid amide; N-[(2,4- Dichlorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid amide; N-[(3,4-Dichlorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide; 4-Oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(p- tolylmethyl)butyric acid amide; N-(1,3-Benzodioxol-5-ylmethyl)-4-oxo-4-(1-phenyl-3,4- dihydro-1H-isoquinolin-2-yl)butyric acid amide; N-[(3-Fluorophenyl)methyl]-4-oxo-4-(1- phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid amide; N-[(2-Fluorophenyl)methyl]-4- oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid amide; N-[(4- Fluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)butyric acid amide; N-[(2,5-Difluorophenyl)methyl]-4-oxo-4-(1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)butyric acid amide; N-(1-Naphthylmethyl)-4-oxo-4-(1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)butyric acid amide; 4-(7-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin-2- yl)-4-oxo-N-propylbutyric acid amide; 4-(5-Methyl-1-phenyl-3,4-dihydro-1H-isoquinolin- 2-yl)-4-oxo-N-propylbutyric acid amide; 4-(5,7-Dimethyl-1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-4-oxo-N-propylbutyric acid amide; 4-Oxo-4-(1-phenyl-3,4-dihydro-1H- isoquinolin-2-yl)-N-propylbutyric acid amide; 4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H- isoquinolin-2-yl)-N-[[3-(trifluoromethyl)-phenyl]methyl]butyric acid amide;4-Oxo-4-(1-(2- tolyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[4-(trifluoromethyl)-phenyl]methyl]butyric acid amide; 4-Oxo-4-(1-(2-tolyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[2-(trifluoromethyl)- phenyl]methyl]butyric acid amide; 4-Oxo-4-(1-(2-tolyl)-6-methyl-3,4-dihydro-1H- isoquinolin-2-yl)-N-[[3-(trifluoromethyl)-phenyl]methyl]butyric acid amide; 4-(1-(2-Methyl- prop-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl)-4-oxo-N-[[3- (trifluoromethyl)phenyl]methyl]butyric acid amide; 4-(1-Cyclohexyl-3,4-dihydro-1H- isoquinolin-2-yl)-4-oxo-N-[[3-(trifluoromethyl)-phenyl]methyl]butyric acid amide; and 4- Oxo-4-(1-(2-fluorophenyl)-3,4-dihydro-1H-isoquinolin-2-yl)-N-[[3- (trifluoromethyl)phenyl]methyl]butyric acid amide. Formula 32 [0444] 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. WO2010037863A1, 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. [0445] In an embodiment, the Kv7 channel activator is a compound according to formula 32:
Figure imgf000381_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-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; R3 represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one or more times with substituents selected from C1-6-alkyl, C1-6-alkoxy, halo and trifluoromethyl; R4 represents C1-6-alkyl; and R5 and R6, together with the nitrogen to which they are attached, form a heterocyclic ring selected from morpholinyl and 1,4-oxazepanyl. [0446] In further embodiments, R1 and R2 together with the nitrogen to which they are attached is pyrrolidinyl which is optionally substituted one or more times with halo. [0447] In further embodiments, R3 represents furanyl which is optionally substituted with C1-6-alkyl. [0448] In further embodiments, R4 represents C1-6-alkyl. [0449] In further embodiments, R5 and R6, together with the nitrogen to which they are attached, represents morpholinyl. [0450] 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-pyridin-3-yl]-amide. [0451] In further embodiments, the compound is 3-Methyl-furan-2-carboxylic acid [2- ((R)-3-fluoro-pyrrolidin-1-yl)-4-methyl-6-morpholin-4-yl-pyridin-3-yl]-amide; Formula 33 [0452] 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. WO2011026891A1, 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. [0453] In an embodiment, the Kv7 channel activator is a compound according to formula 33:
Figure imgf000382_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 represents C1-6-alkyl; R3 represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one or more times with substituents selected from C1-6- alkyl, C1 -6-alkoxy, halo and trifluoromethyl; R4 represents C1-6-alkyl; and R5 and R6, together with the nitrogen to which they are attached, form a heterocyclic ring selected from morpholinyl and 1,4-oxazepanyl. [0454] In further embodiments, R1 represents metyl or iso-propyl. [0455] In further embodiments, R3 represents furanyl which is optionally substituted with C1-6-alkyl. [0456] In further embodiments, R4 represents C1-6-alkyl. [0457] In further embodiments, R5 and R6, together with the nitrogen to which they are attached, represents 1,4-oxazepanyl. [0458] In further embodiments, the compound is 3-Methyl-furan-2-carboxylic acid(2- isopropyl-4-methyl-6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide; or 3-Methyl-furan-2- carboxylic acid(2,4-dimethyl-6-[1,4]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 [0459] 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. WO2010122064A1, 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. [0460] In an embodiment, the Kv7 channel activator is a compound according to formula 34:
Figure imgf000384_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-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, C1- 6-alkyl, trifluoromethyl, C1-6-alkoxy, hydroxy-C1-6-alkyl and C1-6-alkoxy-C1-C6-alkyl; L represents a linker selected from —CR′R″—, —CH2—CR′R″—, —CR′R″-CH2—, and — O—, wherein R′ and R″, independently of each other, represent hydrogen, C1-6-alkyl or halo; n is 0 or 1; R3 represents C1-6-alkyl, phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or C3-6-cycloalkyl, which phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl is optionally substituted one or more times with substituents selected from C1-6-alkyl, C3-6-cycloalkyl, phenyl, C1-6- alkoxy, halo and trifluoromethyl; R4 represents hydrogen, halo or C1-6-alkyl; and R5 represents hydrogen or halo. [0461] In further embodiments, R1 and R2 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. [0462] In further embodiments, R1 and R2 together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halo. [0463] In further embodiments, L represents —CH2—. [0464] In further embodiments, R3 represents C1-6-alkyl. [0465] In further embodiments, R3 represents phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or C3-6-cycloalkyl, which phenyl, pyridyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl is optionally substituted one or more times with substituents selected from C1-6-alkyl and halo. [0466] In further embodiments, R4 represents C1-6-alkyl. [0467] In further embodiments, R5 represents hydrogen. [0468] 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-[1,6]naphthyridin-6-yl)-4- methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-acetamide N-[6-(7,8-Dihydro-5H-[1,6]naphthyridin- 6-yl)-4-methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-3,3-dimethyl-butyramide; N-[6-(7,8-Dihydro- 5H-[1,6]naphthyridin-6-yl)-4-methyl-2-pyrrolidin-1-yl-pyridin-3-yl]-3-fluoro-benzamide; N- [6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-[(3R)-3-fluoropyrrolidin-1-yl]-4-methyl-3- pyridyl]-3-methyl-furan-2-carboxamide; 2-(3,5-difluorophenyl)-N-[6-(7,8-dihydro-5H-1,6- naphthyridin-6-yl)-2-[(3R)-3-fluoropyrrolidin-1-yl]-4-methyl-3-pyridyl]acetamide; N-[2- (4,4-difluoro-1-piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]-3- methyl-furan-2-carboxamide; 2-(3,5-difluorophenyl)-N-[2-(4,4-difluoro-1-piperidyl)-6- (7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]acetamide; N-[2-(4,4-difluoro- 1-piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]-1-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-carboxamide; N-[2-(4,4- difluoro-1-piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]-4- methyl-thiazole-5-carboxamide; N-[2-(4,4-difluoro-1-piperidyl)-6-(7,8-dihydro-5H-1,6- naphthyridin-6-yl)-4-methyl-3-pyridyl]-3-methyl-isoxazole-4-carboxamide; N-[2-(4,4- difluoro-1-piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]-4- methyl-oxazole-5-carboxamide; 2-cyclopropyl-N-[2-(4,4-difluoro-1-pipridyl)-6-(7,8- dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]acetamide; N-[2-(4,4-difluoro-1- piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]-5-ethyl-oxazole-4- carboxamide; N-[2-(4,4-difluoro-1-piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4- methyl-3-pyridyl]-3-methyl-pyridine-2-carboxamide; N-[2-(4,4-difluoro-1-piperidyl)-6-(7,8- dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]-2,5-dimethyl-oxazole-4- carboxamide; N-[2-(4,4-difluoro-1-piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4- methyl-3-pyridyl]-5-phenyl-oxazole-4-carboxamide; 5-cyclopropyl-N-[2-(4,4-difluoro-1- piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]oxazole-4-carb oxamide; N-[2-(4,4-difluoro-1-piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4- methyl-3-pyridyl]-5-methyl-isothiazole-4-carboxamide; ethyl N-[2-(4,4-difluoro-1- piperidyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-4-methyl-3-pyridyl]carbamate; N-[6- (3-chloro-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-[(3R)-3-fluoropyrrolidin-1-yl]-4,6- dimethyl-1H-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 [0469] 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. WO2010105960A1, 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. [0470] In an embodiment, the Kv7 channel activator is a compound according to formula 35:
Figure imgf000386_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, independently of each other, represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl or C1-6-alkoxy-C1-6-alkyl; or R1 and R2, together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-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 halogen, hydroxy, amino, C1-6-alkyl, trifluoromethyl, C1-6-alkoxy, hydroxy- C1-6-alkyl and C1-6-alkoxy-C1-6-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; R3 represents C1-6-alkyl, phenyl or furanyl, which phenyl and furanyl is optionally substituted one or more times with substituents selected from C1-6-alkyl, C1-6-alkoxy, halogen and trifluoromethyl; and R4 represents hydrogen, halogen or C1-6-alkyl. [0471] In further embodiments, R1 and R2 together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen. [0472] In further embodiments, L represents —CH2—, and n is 1. [0473] In further embodiments, R3 represents phenyl, which phenyl is optionally substituted one or more times with halogen. [0474] In further embodiments, R3 represents C1-6-alkyl. [0475] In further embodiments, R4 represents halogen. [0476] In further embodiments, R4 represents hydrogen. [0477] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-{6-[(6-Chloro-pyridin-3-ylmethyl)-amino]-2-pyrrolidin-1-yl-pyridin-3-yl}-2- (3,5-difluoro-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-{6-[(pyridin-3-ylmethyl)- amino]-2-pyrrolidin-1-yl-pyridin-3-yl}-acetamide; N-{6-[(6-Chloro-pyridin-3-ylmethyl)- amino]-2-pyrrolidin-1yl-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 36 [0478] 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. [0479] In an embodiment, the Kv7 channel activator is a compound according to formula 36:
Figure imgf000388_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, independently of each other, represent hydrogen, Ci-6-alkyl, hydroxy- C-ι-6-alkyl or Ci-6-alkoxy-Ci-6-alkyl; or R1 and R2, together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1 H-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 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 -CR1R"-, -CH2- CR1R"- and -CR'R"-CH2-, wherein R' and R", independently of each other, represent hydrogen, d-6-alkyl or halogen; R3 represents Ci-6-alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from C1-6-alkyl, Ci-6- alkoxy, halogen and trifluoromethyl; and R4 represents H or Ci-6-alkyl. [0480] In further embodiments, R1 and R2, independently of each other, represent Ci-6- alkyl. [0481] In further embodiments, R1 and R2 together with the nitrogen to which they are attached, is morpholinyl. [0482] In further embodiments, L represents -CH2-. [0483] In further embodiments, R3 represents phenyl, which phenyl is optionally substituted one or more times with halogen. [0484] In further embodiments, R4 represents methyl. [0485] 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-[(tetrahydro-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 [0486] 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. WO2010094644A1, 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. [0487] In an embodiment, the Kv7 channel activator is a compound according to formula 37:
Figure imgf000389_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, independently of each other, represent Ci-6-alkyl; or R1 and R2, together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1 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, C1-6-alkyl, trifluoromethyl, Ci-6-alkoxy, hydroxy-d-6-alkyl and Ci-6-alkoxy- Ci-6-alkyl; L represents a linker selected from -CR1R"- and -O-CR'R"-, wherein R' and R", independently of each other, represent hydrogen, d-6-alkyl or halogen; n is 0 or 1 ; R3 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 trifluoromethyl; and R4 represents Ci-6-alkyl. [0488] In further embodiments, R1 and R2 together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen. [0489] In further embodiments, R' and R", independently of each other, represents hydrogen or methyl. [0490] In further embodiments, R3 represents phenyl, which phenyl is optionally substituted one or more times with halogen. [0491] In further embodiments, R3 represents d-e-alkyl. [0492] In further embodiments, R4 represents methyl. [0493] 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-1-yl-pyridin-3-yl)- butyramide; 2-(3,5-Difluoro-phenyl)-N-(5-methyl-6-morpholin-4-yl-2-pyrrolidin-1-yl- pyridin-3-yl)-acetamide; N-[2-((R)-3-Fluoro-pyrrolidin-1-yl)-5-methyl-6-morpholin-4-yl- pyridin-3-yl]-3,3-dimethylbutyramide; (S)-N-[2-((R)-3-Fluoro-pyrrolidin-1-yl)-5-methyl-6- morpholin-4-yl-pyridin-3-yl]-2-phenylpropionamide;[2-((R)-3-Fluoro-pyrrolidin-1-yl)-5- methyl-6-morpholin-4-yl-pyridin-3-yl]-carbamic acid ethyl ester; (S)-N-[2-((R)-3-Fluoro- pyrrolidin-1-yl)-5-methyl-6-morpholin-4-yl-pyridin-3-yl]-2-methyl-butyramide;or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an /V-oxide thereof. Formula 38 [0494] 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. WO2010094645A1, 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. [0495] In an embodiment, the Kv7 channel activator is a compound according to Formula 38:
Figure imgf000391_0001
, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, independently of each other, represent d-e-alkyl; or R1 and R2, together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1 H-pyrrol-1-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 -CR1R"- and -O- CR'R"-, wherein R' and R", independently of each other, represent hydrogen, Ci-6-alkyl or halogen; n is 0 or 1 ; R3 represents C1-6-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 R4 represents d-6-alkyl. [0496] In further embodiments, R1 and R2 together with the nitrogen to which they are attached is pyrrolidinyl, which pyrrolidinyl is optionally substituted one or more times with halogen. [0497] In further embodiments, R1 and R2 together with the nitrogen to which they are attached is 1 ,4-oxazepanyl. [0498] In further embodiments, L is -CH2- and n is 1. [0499] In further embodiments, n is 0. [0500] In further embodiments, R3 represents phenyl, which phenyl is optionally substituted one or more times with halogen. [0501] 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-1-yl)-5-methyl-6- [1 ,4]oxazepan-4-yl-pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-/V-(5-methyl-2,6-bis-[1 ,4]oxazepan-4-yl-pyridin-3-yl)- acetamide; 3-Fluoro-/V-(5-methyl-6-[1 ,4]oxazepan-4-yl- 2-pyrrolidin-1-yl-pyridin-3-yl)- benzamide; 3-methyl-N-[5-methyl-6-(1 ,4-oxazepan-4-yl)- 2-pyrrolidin-1-yl-3-pyridyl]furan-2-carboxamide; 2-(3-fluorophenyl)-N-[2-[(3R)-3- fluoropyrrolidin-1-yl]-5-methyl-6-(1 ,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 [0502] 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. WO2008142140A2, 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. [0503] In an embodiment, the Kv7 channel activator is a compound according to Formula 39:
Figure imgf000392_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 represents hydrogen, alkyl or halo; and R2 represents hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenyl-alkyl, amino, alkyl-carbonyl-amino, cyano or nitro; or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl (spiro) group; or R1 represents hydrogen; and R2 together with one of R3, R4 and R5, attached in ortho-position on the aromatic ring, form a —(CH2)n— bridge, wherein n is 1, 2 or 3; R3, R4 and R5, 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 R3, R4 and R5, together form a methylenedioxy group; and the remaining of R3, R4 and R5 is as defined above; or two of R3, R4 and R5, together with the phenyl ring to which they are attached, form a naphthyl group; and the remaining of R3, R4 and R5 is as defined above; or one of R3, R4 and R5, attached in ortho-position on the aromatic ring, and together with R2 form a —(CH2)n— bridge, wherein n is 1, 2 or 3; and the remaining of R3, R4 and R5, are as defined above; R6 and R7, 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-1H-pyrrol-1-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, amino-alkyl, 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. [0504] In further embodiments, R1 represents hydrogen or alkyl; and R2 represents hydrogen or alkyl. [0505] In further embodiments, R3, R4 and R5, independently of each other, represent hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, alkyl-sulfanyl, alkyl-sulfonyl, phenyl or phenoxy. [0506] In further embodiments, R6 and R7, independently of each other, represent hydrogen, halo, haloalkyl, hydroxy, alkoxy, or amino. [0507] In further embodiments, R′ and R″, independently of each other, represent alkyl, hydroxy-alkyl, cycloalkyl, or phenyl-alkyl. [0508] 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. [0509] In further embodiments, the Kv7 Channel activator is selected from the group consisting 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-quinazolin-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-quinazolin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-(2-dimethylamino-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)- propionamide; N-(2-Diethylamino-4-oxo-4H-quinazolin-3-yl)-2-(4-methanesulfonyl- 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-1-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[1,3]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. [0510] 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-1-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-Difluoro-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)-acetamide; 2-(3,5-Difluoro- phenyl)-N-{7-fluoro-2-[(2-methoxy-ethyl)-methyl-amino]-4-oxo-4H-quinazolin-3-yl}- acetamide; 2-(4-Chloro-phenyl)-N-(2-dimethylamino-4-oxo-4H-quinazolin-3-yl)- acetamide; N-(2-Diethylamino-6-fluoro-4-oxo-4H-quinazolin-3-yl)-2-(3,5-difluoro- phenyl)-acetamide; 2-(4-Chloro-phenyl)-N-(2-diethylamino-6-fluoro-4-oxo-4H- quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-(4-methyl-piperazin-1-yl)-4oxo- 4H-quinazolin-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-1-yl-7-trifluoromethyl-4H-quinazolin-3-yl)- acetamide; 2-(3,5-Difluoro-phenyl)-N-(4-oxo-2-pyrrolidin-1-yl-7-trifluoromethyl-4H- quinazolin-3-yl)-acetamide; 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)-acetamide; N-(5-Chloro-4-oxo-2-pyrrolidin-1-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-phenyl)-acetamide; N-(2-Diethylamino-7-fluoro-4-oxo-4H-quinazolin- 3-yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(2-Diethylamino-5-fluoro-4-oxo-4H- quinazolin-3-yl)-2-(3,5-difluoro-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-1-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-1-yl-4H- quinazolin-3-yl)-acetamide; N-(6-Chloro-7-fluoro-4-oxo-2-pyrrolidin-1-yl-4H-quinazolin-3- yl)-2-(3,5-difluoro-phenyl)-acetamide; N-(5,7-Difluoro-4-oxo-2-pyrrolidin-1-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)-acetamide; 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-quinazolin-3-yl)-acetamide; N- (2-Dimethylamino-4-oxo-4H-quinazolin-3-yl)-2-(3-fluoro-4-trifluoromethyl-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-fluoro- 4-trifluoromethyl-phenyl)-acetamide; N-(6-Fluoro-4-oxo-2-pyrrolidin-1-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-1-yl-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N- (6-fluoro-4-oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)-acetamide; 2-(4-Chloro-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)-acetamide; 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-quinazolin- 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-fluoro-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-1yl-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]-acetamide; 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-1- yl-4H-quinazolin-3-yl)-propionamide; 2-(4-Chloro-phenyl)-N-(4-oxo-2-pyrrolidin-1-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-1- yl-4H-quinazolin-3-yl)-acetamide; 2-Naphthalen-2-yl-N-(4-oxo-2-pyrrolidin-1-yl-4H- quinazolin-3-yl)-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-oxo-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-1-yl-4H-quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-(ethyl- methyl-amino)-5,7-difluoro-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)-acetamide; N-[2-(Ethyl-methyl-amino)-7-fluoro-4-oxo-4H-quinazolin-3-yl]-2-(4- methylsulfanyl-phenyl)-acetamide; 2-(4-Isobutyl-phenyl)-N-(4-oxo-2-pyrrolidin-1-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-1-yl-4H- quinazolin-3-yl)-2-(4-phenoxy-phenyl)-acetamide; 2-Biphenyl-4-yl-N-(7-fluoro-4-oxo-2- pyrrolidin-1-yl-4H-quinazolin-3-yl)-acetamide; 2-(4-Chloro-phenyl)-N-(4-oxo-2-pyrrolidin- 1-yl-4H-quinazolin-3-yl)-acetamide; 2-(3,4-Difluoro-phenyl)-N-(4-oxo-2-pyrrolidin-1-yl- 4H-quinazolin-3-yl)-acetamide; N-[2-(Ethyl-methyl-amino)-7-fluoro-4-oxo-4H-quinazolin- 3-yl]-2-(4-isopropyl-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-(isopropyl-methyl- amino)-4-oxo-4-quinazolin-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-1-yl-4H-quinazolin-3-yl)-acetamide; 2-(3,4-Difluoro-phenyl)-N-(8- fluoro-4-oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)-acetamide; 2-(3,4-Difluoro-phenyl)-N- [2-(isobutyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)- N-[2-(isobutyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-acetamide; 2-(3,4-Difluoro- phenyl)-N-[7-fluoro-2-(isopropyl-methyl-amino)-4-oxo-4H-quinazolin-3-yl]-acetamide; N- (7-Chloro-6-fluoro-4-oxo-2-pyrrolidin-1-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-1-yl-4H- quinazolin-3-yl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-(4-oxo-2-piperidin-1-yl-4H- quinazolin-3-yl)-acetamide; N-(8-Chloro-4-oxo-2-pyrrolidin-1-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-1-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. [0511] In further embodiments, 2-(3,5-difluorophenyl)-N-(2-dimethylamino-4-oxo-7- trifluoromethyl-4H-quinazolin-3-yl )-propionamide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof. Formula 40 [0512] 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. WO2010060955A1, 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. [0513] In an embodiment, the Kv7 channel activator is a compound according to Formula 40:
Figure imgf000399_0001
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; R1 represents C1-6-alkyl, benzo[1,3]dioxolyl, phenyl or pyridyl, which phenyl and pyridyl are optionally substituted one or more times with substituents selected from the group consisting of C1-6-alkyl, halogen, trifluoromethyl, hydroxy, C1-6-alkoxy and trifluoromethoxy; R2 and R3, independently of each other, represent hydrogen or C1-6-alkyl; and R4 and R5, independently of each other, represent hydrogen, C1-6-alkyl, halogen, trifluoromethyl, hydroxy, C1-6-alkoxy or trifluoromethoxy. [0514] In further embodiments, Y represents —(CH2)n—, wherein n is 0 or 1; R1 represents C1-6-alkyl, benzo[1,3]dioxolyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from the group consisting of C1-6-alkyl, halogen, trifluoromethyl, hydroxy, C1-6-alkoxy and trifluoromethoxy; R2 and R3, independently of each other, represent hydrogen or C1-6-alkyl; and R4 and R5, independently of each other, represent hydrogen, C1-6-alkyl, halogen, trifluoromethyl, hydroxy, C1-6-alkoxy or trifluoromethoxy. [0515] In further embodiments, n is 1. [0516] In further embodiments, R1 represents phenyl optionally substituted one or more times with substituents selected from the group consisting of C1-6-alkyl, halogen, trifluoromethyl and C1-6-alkoxy. [0517] In further embodiments, R2 and R3 represent hydrogen. [0518] In further embodiments, R2 and R3 represent C1-6-alkyl. [0519] In further embodiments, R4 and R5, independently of each other, represent hydrogen or halogen. [0520] 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-morpholin-4-yl- pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-{6-[1-(4-fluoro-phenyl)-1-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[1,3]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-phenyl)-acetamide; 2-(2,4- Dichloro-phenyl)-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-(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-chloro-3- pyridyl)-N-[6-[(4-fluorophenyl)-methylamino]-2-morpholino-3-pyridyl]acetamide; 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 [0521] 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. WO2010051819A1, 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. [0522] In an embodiment, the Kv7 channel activator is a compound according to Formula 41:
Figure imgf000401_0001
A stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein L represents a linker selected from —(CR′R″)2—, —CR′R″—S—, —CR′R″—O— or wherein R′ and R″, independently of each other, represent hydrogen, C1-6-alkyl or halogen; R1 and R2, independently of each other, represent C1-6-alkyl, hydroxy-C1-6-alkyl-, C1-6-alkoxy-C1-6- alkyl-, phenyl, phenyl-C1-6-alkyl-, which phenyl is optionally substituted with one or two times with a substituent selected from the group consisting of C1-6-alkoxy, halogen and cyano; or R1 and R2, together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-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 halogen, hydroxy, amino, C1-6-alkyl, trifluoromethyl, C1-6-alkoxy, hydroxy-C1-6-alkyl- and C1-6-alkoxy-C1-6-alkyl-; R3, R4 and R5, independently of each other, represent hydrogen, C1-6-alkyl, halogen, trihalomethyl, hydroxy, C1-6-alkoxy, trifluoromethoxy, amino, cyano or nitro; and R6 and R7, independently of each other, represent hydrogen, C1-6-alkyl, halogen, trihalomethyl, hydroxy, C1-6-alkoxy, trifluoromethoxy, amino, nitro, cyano or phenyl. [0523] In further embodiments, R1 and R2, independently of each other, represent C1-6- alkyl, alkoxy-C1-6-alkyl- or phenyl-C1-6-alkyl-. [0524] In further embodiments, R1 and R2, together with the nitrogen to which they are attached, form a pyrrolidinyl ring. [0525] In further embodiments, R3, R4 and R5, independently of each other, represent hydrogen, C1-6-alkyl or halogen. [0526] In further embodiments, R6 and R7, independently of each other, represent hydrogen or halogen. [0527] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-(7-Fluoro-4-oxo-2-pyrrolidin-1-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-1-yl-4H- quinazolin-3-yl)-propionamide; N-(4-Oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)-3-phenyl- propionamide; N-(2-Dimethylamino-7-fluoro-4-oxo-4H-quinazolin-3-yl)-3-(3-fluoro- phenyl)-propionamide; N-(4-Oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)-2-phenylsulfanyl- acetamide; N-(4-Oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)-2-phenoxy-acetamide; N-(5- Fluoro-4-oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)-3-(3-fluoro-phenyl)-propionamide; 2- (4-Fluoro-phenylsulfanyl)-N-(4-oxo-2-pyrrolidin-1-yl-4H-quinazolin-3-yl)-acetamide; N- (5,7-Difluoro-4-oxo-2-pynolidin-1-yl-4H-quinazolin-3-yl)-3-(3-fluoro-phenyl)- propionamide; 2-(4-tert-Butyl-phenylsulfanyl)-N-(4-oxo-2-pyrrolidin-1-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-1-yl-4H-quinazolin-3- yl)-3-(3,5-difluoro-phenyl)-propionamide; (S)-N-(5,7-Difluoro-4-oxo-2-pyrrolidin-1-yl-4H- quinazolin-3-yl)-3-phenyl-butyramide; 3-(4-Chloro-phenyl)-N-(4-oxo-2-pyrrolidin-1-yl-4H- quinazolin-3-yl)-butyramide; 3-(3-Fluoro-phenyl)-N-(4-oxo-2-pyrrolidin-1-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- quinazolin-3-yl]-amide; cis-2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid(5,7- difluoro-4-oxo-2-pyrrolidin-1-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-1-yl-4H-quinazolin-3-yl)-amide; or a stereoisomer or a mixture of its stereoisomers, a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof. [0528] In further embodiments, the compound is of formula:
Figure imgf000403_0001
wherein: X represents —CR′R″—, —S—, or —O—, wherein R′ and R″, independently of each other, represent hydrogen, C1-6-alkyl or halogen, and R′, R2, R3, R4, R5, R6 and R7 are as defined above. [0529] In further embodiments, the compound is of formula:
Figure imgf000403_0002
wherein: R1, R2, R3, R4, R5, R6 and R7 are as defined above. Formula 42 [0530] In another embodiment, the Kv7 channel activator may be selected from one of the following compounds. Such compounds are described in International Publication No. WO2011026890A1, 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. [0531] In an embodiment, the Kv7 channel activator is a compound according to Formula 42:
Figure imgf000404_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a heterocyclic ring selected from pyrrolidinyl, 2,5-dihydro-1H-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; R3 represents a heterocyclic ring selected from furanyl and pyrrolyl which furanyl and pyrrolyl is optionally substituted one or more times with substituents selected from C1-6-alkyl, C1-6-alkoxy, halo and trifluoromethyl; R4 represents C1-6-alkyl; and R5 and R6, together with the nitrogen to which they are attached, form a heterocyclic ring selected from morpholinyl and 1,4-oxazepanyl. [0532] In further embodiments, R1 and R2 together with the nitrogen to which they are attached is pyrrolidinyl which is optionally substituted one or more times with halo. [0533] In further embodiments, R3 represents furanyl which is optionally substituted with C1-6-alkyl. [0534] In further embodiments, R4 represents C1-6-alkyl. [0535] In further embodiments, R5 and R6, together with the nitrogen to which they are attached, represents morpholinyl. [0536] 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-1-yl)-4-methyl- 6-[1,4]oxazepan-4-yl-pyridin-3-yl]-amide; 3-Methyl-furan-2-carboxylic acid [2-((R)-3- fluoro-pyrrolidin-1-yl)-4-methyl-6-morpholin-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 43 [0537] 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. WO2010026104A1, 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. [0538] In an embodiment, the Kv7 channel activator is a compound according to Formula 43:
Figure imgf000405_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, independently of each other, represent Ci-6-alkyl, hydroxy-d-e-alkyl or Ci-6- alkoxy-Ci-6-alkyl; or R1 and R2, 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; R3 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 - CR1R"-, -CH2-CR1R"- and -CR1R1^CH2-, wherein R1 and R", independently of each other, represent hydrogen, Ci-6-alkyl or halo. [0539] In further embodiments, R1 and R2, independently of each other, represent Ci-6- alkyl. [0540] In further embodiments, R1 and R2, 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. [0541] In further embodiments, R1 and R2, 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 trifluoromethyl. [0542] In further embodiments, R1 and R2, 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 trifluoromethyl. [0543] In further embodiments, R3 represents te/t-butyl. [0544] In further embodiments, R3 represents phenyl, which is optionally substituted one or more times with substituents selected from Ci-6-alkyl, Ci-6-alkoxy, halo and trifluoromethyl. [0545] In further embodiments, L represents -CH2-. [0546] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(3,5-Difluorophenyl)-N-{2-pyrrolidin-1-yl-6-[(tetrahydro-pyran-4- ylmethyl)-amino]- pyridin-3-yll-acetamide; 3,3-Dimethyl-N-{2-pyrrolidin-1-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]- pyridin-3-yll-acetamide; 2- (3,5-Difluoro-phenyl)-N-{2-dimethylamino-6-[(tetrahydro-pyran-4-ylmethyl)-amino]- pyridin-3-yll-acetamide; N-{2-Dimethylamino-6-[(tetrahydro-pyran-4-ylmethyl)-amino]- pyridin-3-yll-3,3-dimethyl-butyramide; 2-(3,5-Difluoro-phenyl)-N-{2-((S)-3-fluoro- pyrrolidin-1-yl)-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-pyridin-3-yll-acetamide; N-{2- ((S)-3-Fluoro-pyrrolidin-1-yl)-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-pyridin-3-yll-3,3- dimethyl-butyramide; 2-(3,5-Difluoro-phenyl)-N-{2-(3,3-dimethyl-pyrrolidin-1-yl)-6- [(tetrahydro-pyran-4-ylmethyl)-amino]-pyridin-3-yll-acetamide; N-{2-(3,3-Dimethyl- pyrrolidin-1-yl)-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-pyridin-3-yll-3,3-dimethyl- butyramide; N-{2-((R)-3-Fluoro-pyrrolidin-1-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-1-yl)-6-[(tetrahydro-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-1-yl)-pyridin-3-yl]-acetamide; 3,3-Dimethyl-N-[6-[(tetrahydro-pyran-4- ylmethyl)-amino]-2-((S)-2-trifluoromethylpyrrolidin-1-yl)-pyridin-3-yl]-butyramide; or a pharmaceutically-acceptable addition salt thereof. Formula 44 [0547] 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. WO2010105960A1, 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. [0548] In an embodiment, the Kv7 channel activator is a compound according to Formula 44:
Figure imgf000408_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R2 represents hydrogen; R3 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. [0549] In further embodiments, R1 represents alkyl. [0550] In further embodiments, R1 represents phenyl optionally substituted one or more times with substituents selected from alkyl and halo. [0551] In further embodiments, R3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl. [0552] In further embodiments, R3 represents alkyl. [0553] 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. [0554] 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- difluoro-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 [0555] 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. WO2009074593A1, 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. [0556] In an embodiment, the Kv7 channel activator is a compound according to Formula 45:
Figure imgf000410_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 represents alkyl, phenyl, benzo[1,3]dioxolyl or benzo[1,4]dioxinyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, trifluoromethyl, alkoxy, cyano and difluoromethoxy; R2 represents hydrogen; R3 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. [0557] In further embodiments, R1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R2 represents hydrogen; R3 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. [0558] In further embodiments, R1 represents alkyl. [0559] In further embodiments, R1 represents phenyl, benzo[1,3]dioxolyl or benzo[1,4]dioxinyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, trifluoromethyl, alkoxy, cyano and difluoromethoxy. [0560] In further embodiments, R3 represents alkyl. [0561] In further embodiments, R3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl. [0562] 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. [0563] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-[6-(4-Fluoro-benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-2-(3-fluoro-4- trifluoromethyl-phenyl)-acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(4-fluoro-benzylamino)- 2-pyrrolidin-1-yl-pyridin-3-yl]-acetamide; 2-(3,4-Difluoro-phenyl)-N-[6-(4-fluoro- benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-acetamide; (S)-N-[6-(4-Fluoro-benzylamino)- 2-pyrrolidin-1-yl-pyridin-3-yl]-2-phenyl-propionamide; N-[6-(4-Fluoro-benzylamino)-2- pyrrolidin-1-yl-pyridin-3-yl]-3-(3-fluoro-phenyl)-propionamide; (R)-N-[6-(4-Fluoro- benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-3-phenyl-butyramide; (R)-2-Phenyl- cyclopropanecarboxylic acid [6-(4-fluoro-benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]- amide; N-[6-(4-Fluoro-benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-2-(3-fluoro-phenyl)- acetamide; N-[6-(4-Fluoro-benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-3,3-dimethyl- butyramide; 2-(3,5-Difluoro-phenyl)-N-(6-isobutylamino-2-pyrrolidin-1-yl-pyridin-3-yl)- acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(5-fluoro-2-methyl-benzylamino)-2-pyrrolidin-1- yl-pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-[6-(2,6-dimethyl-benzylamino)-2- pyrrolidin-1-yl-pyridin-3-yl]-acetamide; 2-(3,5-Difluoro-phenyl)-N-[2-pyrrolidin-1-yl-6-(4- trifluoromethyl-benzylamino)-pyridin-3-yl]-acetamide; N-{6-[(Benzo[1,3]dioxol-5- ylmethyl)-amino]-2-pyrrolidin-1-yl-pyridin-3-yl}-3,3-dimethyl-butyramide; N-[6-(3,4- Difluoro-benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-acetamide; N-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-2-pyrrolidin-1-yl-pyridin-3-yl}-2-(3,5-difluoro- phenyl)-acetamide; N-[6-(4-Cyano-benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-2-(3,5- difluoro-phenyl)-acetamide; N-[6-(3,4-Difluoro-benzylamino)-2-pyrrolidin-1-yl-pyridin-3- yl]-3,3-dimethyl-butyramide; 2-(3,5-Difluoro-phenyl)-N-[6-(4-methoxy-benzylamino)-2- pyrrolidin-1-yl-pyridin-3-yl]-acetamide; N-[6-(4-Difluoromethoxy-benzylamino)-2- pyrrolidin-1-yl-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-acetamide; N-[6-(4-Difluoromethoxy- benzylamino)-2-pyrrolidin-1-yl-pyridin-3-yl]-3,3-dimethyl-butyramide; 2-(3,5-Difluoro- phenyl)-N-{6-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-2-pyrrolidin-1-yl-pyridin- 3-yl}-acetamide; N-{6-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-2-pyrrolidin-1- 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 [0564] 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. WO2009074591A1, 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. [0565] In an embodiment, the Kv7 channel activator is a compound according to Formula 46:
Figure imgf000412_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R2 represents hydrogen; R3 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. [0566] In further embodiments, R1 represents alkyl. [0567] In further embodiments, R1 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl. [0568] In further embodiments, R3 represents alkyl. [0569] In further embodiments, R3 represents phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl. [0570] 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. [0571] 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-trimethyl- 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 [0572] 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. WO2009074594A1, 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. [0573] In an embodiment, the Kv7 channel activator is a compound according to Formula 47:
Figure imgf000414_0001
a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 represents alkyl or phenyl, which phenyl is optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl; R2 represents hydrogen; R3 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. [0574] In further embodiments, R1 represents alkyl. [0575] In further embodiments, R1 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo and trifluoromethyl. [0576] In further embodiments, R3 represents phenyl, optionally substituted one or more times with substituents selected from alkyl, halo, alkoxy and trifluoromethyl. [0577] In further embodiments, R3 represents alkyl. [0578] 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. [0579] 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-butyramide; 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]-acetamide; or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof. Formula 48 [0580] 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. WO2007104717A1, 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. [0581] In an embodiment, the Kv7 channel activator is a compound according to Formula 48:
Figure imgf000416_0001
including any of its stereoisomers, or any mixture of its stereoisomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 and R2, independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, baloalkoxy, amino, alkyl-carbonyl-amino, alkyl-sulfonyl, cyano or nitro; R3 represents alkyl, cycloalkyl or alkoxy; and R4 and R5, independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl-carbonyl-amino, nitro or cyano. [0582] In further embodiments, R1 and R2, independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl- carbonyl-amino, alkyl-sulfonyl, cyano or nitro. [0583] In further embodiments, R3 represents alkyl, cycloalkyl or alkoxy. [0584] In further embodiments, R4 and R5, independently of each other, represent hydrogen, alkyd, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl- carbonyl-amino, nitro or cyano. [0585] 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 [0586] 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. WO2007057447A1, 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. [0587] In an embodiment, the Kv7 channel activator is a compound according to Formula 49:
Figure imgf000417_0001
, including any of its stereoenantiomers or any mixture of its stereoenantiomers, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof, wherein R1 represents hydrogen or alkyl; and R2 represents alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenylalkyl, amino, alkyl-carbonyl-amino, cyano or nitro; or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl group; or R1 represents hydrogen; and R2 together with R3 attached in ortho- position on the aromatic ring form a —(CH2)n— bridge, wherein n is 1, 2 or 3; R3 and R4, 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 R3 and R4 together form a methylenedioxy group; or R3 attached in ortho-position on the aromatic ring and together with R2 form a — (CH2)n— bridge, wherein n is 1, 2 or 3; and R4 is as defined above; R5 represents alkyl, cycloalkyl, alkoxy, alkylthio or phenyl; and R6 and R7, 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 R1 is hydrogen, R2 is methyl, R3 and R4 represent hydrogen, R5 is isopropyl, and R6 and R7 represent hydrogen, then the compound it is not a quinazoline derivative racemate but the R- or S-enantiomer of the quinazoline derivative. [0588] In further embodiments, R1 represents hydrogen or alkyl. [0589] In further embodiments, R2 represents alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, phenyl, phenylalkyl, amino, alkyl-carbonyl-amino, cyano or nitro. [0590] In further embodiments, R1 represents hydrogen or methyl; and R2 represents methyl, ethyl, isopropyl, cyclohexyl, fluoro or benzyl. [0591] In further embodiments, R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl group. [0592] In further embodiments, R1 represents hydrogen; and R2 together with R3 attached in ortho-position on the aromatic ring form a —(CH2)n— bridge, wherein n is 1, 2 or 3. [0593] In further embodiments, R3 and R4, 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 R3 and R4 together form a methylenedioxy group. [0594] In further embodiments, R3 attached in ortho-position on the aromatic ring and together with R2 form a —(CH2)n— bridge, wherein n is 1, 2 or 3; and R4 is as defined in claim 7. [0595] In further embodiments, R5 represents alkyl, cycloalkyl, alkoxy, alkylthio or phenyl. [0596] In further embodiments, R6 and R7, independently of each other, represent hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, alkyl- carbonyl-amino(acetamido), nitro, cyano or phenyl. [0597] 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-butyramide; 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-trifluoromethyl-4H-quinazolin-3-yl)- propionamide; N-(2-Ethyl-7-fluoro-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionamide; (S)-N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-propionamide; N-(2-Isopropyl-4- oxo-4H-quinazolin-3-yl)-2,3-diphenyl-propionamide; Bicyclo[4.2.0]octa-1,3,5-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- propionamide; N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-phenyl-isobutyramide; 2-(4- Chloro-phenyl)-N-(2-isopropyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-propionamide; N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-(4-trifluoromethyl-phenyl)-propionamide; 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)- propionamide; 2-(4-Chloro-phenyl)-N-(2-isopropyl-4-oxo-4H-quinazolin-3-yl)- propionamide; N-(2-Isopropyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-2-(4- trifluoromethyl-phenyl)-propionamide; N-(2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-2-(4- methoxy-phenyl)-propionamide; 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)-propionamide; 2-(3-Fluoro-4-methyl-phenyl)-N-(2-isopropyl-4-oxo-7- trifluoromethyl-4H-quinazolin-3-yl)-propionamide; 2-(3-Fluoro-4-methyl-phenyl)-N-(2- isopropyl-4-oxo-4H-quinazolin-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)-propionamide; N-(6-Chloro-2-isopropyl-4-oxo-4H-quinazolin-3- yl)-2-(3-fluoro-phenyl)-propionamide; 2-(4-Fluoro-phenyl)-N-(2-isopropyl-4-oxo-4H- quinazolin-3-yl)-propionamide; 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-1(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-propionamide; 2-(4-Chloro-phenyl)-N-(2-isopropylsulfanyl-4- oxo-4H-quinazolin-3-yl)-propionamide; 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)-propionamide; 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-phenyl-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 [0598] 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. WO2004080377A2, 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. [0599] In an embodiment, the Kv7 channel activator is a compound according to Formula 50:
Figure imgf000420_0001
any of its enantiomers or any mixture of its enantiomers, or a prodrug, or a pharmaceutically-acceptable addition salt thereof, wherein R1 represents —CN; R2 represents halo, haloalkyl, hydroxyl or alkoxy; X represents, NR″ or NR″CH2 (read in the stated direction); wherein R″ represents hydrogen; R4 represents aryl-alkyl, which is substituted one or more times with substituents selected from the group consisting of halo, or methylenedioxy; or R4 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 R4 represents aryl-alkyl and when X represents NR″CH2, then R4 represents a group of formula -Z′-L″-Z″. [0600] In further embodiments, R4 represents benzyl which is substituted one or two times with halo or one time with methylenedioxy. [0601] In further embodiments, R4 represents 4-fluoro-benzyl, 3,4-dichloro-benzyl or benzo[1,3]dioxol-5-ylmethyl. [0602] 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[1,3]dioxol-5-ylmethyl)-amino]-2- hydroxy-benzonitrile; or a pharmaceutically-acceptable addition salt thereof. [0603] In further embodiments, R4 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 OCH2. [0604] In further embodiments, R4 represents 3-phenoxy-phenyl, 3-benzyloxy-phenyl, or biphenyl-4-yl. [0605] 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 [0606] 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. WO2004080377A2, 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. [0607] In an embodiment, the Kv7 channel activator is a compound according to Formula 51:
Figure imgf000422_0001
wherein, R represents hydrogen, halogen or hydroxy. R1, R2, R3 and R4 independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl- phenyl or p-trihalogenmethyl-phenyl, or R1 and R2, R2 and R3, or R3 and R4 are joined together to form a benzo fused ring, R5 represents hydrogen or alkyl, and R6 represents halogen or trihalogenmethyl, or a pharmaceutically-acceptable addition salt thereof. [0608] In further embodiments, R represents hydrogen, halogen or hydroxy, R1, R2, R3 and R4 independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, and when R1 and R4 are hydrogen, then R2 or R3 is phenyl, p-methyl-phenyl or p-trihalogenmethyl- phenyl; or R1 and R2, R2 and R3, or R3 and R4 are joined together to form a benzo fused ring, R5 represents hydrogen or alkyl, and R6 represents halogen or trihalogenmethyl. [0609] In further embodiments, R1, R3 and R4 represent hydrogen, and R2 represents halogen, trihalogenmethyl or phenyl. [0610] In further embodiments, R1 and R2, R2 and R3, or R3 and R4 are joined together to form a benzo fused ring. [0611] In further embodiments, R5 is hydrogen or methyl. [0612] In further embodiments, R6 is chlorine. [0613] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: (+)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol- 2-one; (−)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6(4-methylphenyl)-2H-indol-2-one; (±)-3- (5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-one; (±)-3-(5-chloro-2-hydroxyphenyl)- 4,6-dichloro-1,3-dihydro-2H-indol-one; (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-6- phenyl-2H-indol-one; (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-6-iodo-2H-indol-one; (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-6-trifluoromethyl)-2H-indol-2-one; (±)-3-(5- chloro-2-hydroxyphenyl)-1,3-dihydro-6-[4-(trifluoromethyl)-phenyl]-2H-indol-2-one; (±)-3- (5-chloro-2-hydroxyphenyl)-1,3-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)- 1,3-dihydro-2H-benx[g]indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3- hydroxy-6-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)-1,3- dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-methoxyphenyl)- 1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one; (−)-3-(5-chloro-2- methoxyphenyl)-1,3-dihydro-hydroxy-6-(trifluoromethyl)-2H-indol--2-one; (±)-3-(5-chloro- 2-methoxyphenyl)-1,3-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)-1,3-dihydro-3-hydroxy-6-iodo-2H-indol-2-one; (±)-3-(5-chloro- 2-methoxyphenyl)-4,6-dichloro-1,3-dihydro-3-hydroxy-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)-1,3-dihydro-3-hydroxy-4,6-bis-(trifluoromethyl)-2H-indol-2-one; (±)-3-(5- chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4-(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)-1,3-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)-1,3-dihydro-3-hydroxy-7-(trifluoromethyl)- 2H-indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-3-hydroxy- 2H-indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-5-bromo-2H- indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-iodo-2H-indol-2- one; (±)-1,3-dihydro-3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)-phenyl]-6- (trifluoromethyl)-2H-indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3- hydroxy-2H-benz[g]indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3- hydroxy-2H-benz[f]indol-2-one; (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-fluoro-6- (trifluoromethyl)-2H-indol-2-one; (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3- fluoro-6-(trifluoromethyl)-2H-indol-2-one; (3R)-(−)-(5-chloro-2-methoxyphenyl)-1,3- dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol2-one; (±)-3-(5-chloro-2-methoxyphenyl)- 1,3-dihydro-3-fluoro-7-(trifluoromethyl)2H-indol-2-one; (±)-3-(5-chloro-2- methoxyphenyl)-1,3-dihydro-3-fluoro-6-phenyl-2H-indol-2-one; (±)-3-(5-chloro-2- methoxyphenyl)-1,3-dihydro-3-fluoro-6-iodo-2H-indol-2-one; (±)-3-(5-chloro-2- methoxyphenyl)-1,3-dihydro-3-fluoro-5-methyl-2H-indol-2-one; (±)-3-(5-chloro-2- methoxyphenyl)-1,3-dihydro-3-fluoro-5-bromo-2H-indol-2-one; (±)-3-(5-chloro-2- methoxyphenyl)-1,3-dihydro-3-fluoro-4,6-bis-(trifluoromethyl)-2H-indol-2-one; or (±)-3- (5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-7-(trifluoromethyl)-2H-indol-2-one; or a pharmaceutically-acceptable addition salt thereof. [0614] In further embodiments, R represents hydrogen, halogen or hydroxy, R1, R2, R3 and R4 independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, or R1 and R2, R2 and R3, or R3 and R4 are joined together to form a bezo fused ring, R5 represents hydrogen or alkyl, and R6 represents halogen or trihalogenmethyl, or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent. Formula 52 [0615] 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. CN114380731A, 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. [0616] In an embodiment, the Kv7 channel activator is a compound according to Formula 52:
Figure imgf000425_0001
wherein, R1 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. [0617] In further embodiments, R2 is selected from H, C1-C3Alkyl radical, C1-C3Alkenyl or C1-C3Alkynyl. [0618] In further embodiments, R 3 and R4 are each independently selected from H or C1-C6An alkyl group. [0619] In further embodiments, R5 is selected from substituted or unsubstituted C1- C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl radical, C1-C6Alkoxy or furyl, the substituents of the alkyl or the alkoxy being selected from C1-C6Alkoxy, di (C)1-C4Alkyl) amino or C1-C6Alkoxycarbonyl, the substituents of cycloalkyl being selected from halogen. [0620] In further embodiments, the formula is one of formulas II – IV:
Figure imgf000426_0001
wherein, n is more than or equal to 0;R11and R12 each independently selected from H, halogen or halomethyl; R2 is selected from H, C1-C3Alkyl radical, C2-C3Alkenyl or C2- C3An alkynyl group; R3and R4 are independently selected from H or C1-C6 alkyl group; y is selected from O or S; R5 is selected from substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6Cycloalkyl radical, C1-C6Alkoxy or furyl, the substituents of the alkyl being selected from C1-C6Alkoxy, di (C)1-C4Alkyl) amino or C1- C6Alkoxycarbonyl, the substituents of cycloalkyl being selected from halogen. [0621] In further embodiments, n is 0 to 3, R 11 is selected from H, F or trifluoromethyl, and R12 is selected from H, F, Cl or methyl. [0622] In further embodiments, R3 is one of H or methyl, and R4 is other of H or methyl. [0623] In further embodiments, R5 is selected from methyl, ethyl, isopropyl, isobutyl, neopentyl, cyclobutyl, ethoxy, isopropoxy, tert-butoxy or tetrahydrofuranyl. Formula 53 [0624] 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. WO2021260090A1, 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. [0625] In an embodiment, the Kv7 channel activator is a compound according to Formula 53:
Figure imgf000427_0001
, wherein, X1 represents nitrogen or CRX1; wherein RX1 represents hydrogen, halogen, (C1-4)alkyl, or (C1-4)alkoxy; X2 represents nitrogen or CRX2; wherein RX2 represents hydrogen, halogen, (C1-4)alkyl, or (C1-4)alkoxy; X3 represents nitrogen or CRX3; wherein RX3 represents hydrogen, halogen, (C1-4)alkyl, (C1- 4)alkoxy, or hydroxy; R1 represents hydrogen or methyl; RX4 represents hydrogen, halogen, or (C1-4)alkyl; • R2A represents hydrogen; (C1-4)alkyl; (C2-4)alkenyl; (C2-4)alkynyl; (C3-6)cycloalkyl; (C1- 4)fluoroalkyl; (C1- 4)hydroxyalkyl; (C1-4)alkoxy-(C1-2)alkyl; (C1-2)alkoxy-(C1-2)alkoxy-(C1- 2)alkyl; (C1-2)alkyl- S-(C1-2)alkyl; (C1-2)alkyl-(SO2)-(C1-2)alkyl; cyano; (C1-2)cyanoalkyl; H2N- C(O)-(C1-2)alkyl; (RN1)2N-(C1-2)alkyl or (RN1)2N-C(O)-, wherein RN1 independently represents hydrogen or (C1-2)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 (C1-4)alkyl; and R2B represents hydrogen or methyl; or • R2A and R2B 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, -CHRL-O-*, -O-CH2-*, -CH2-NH- *, -CH2- N(CH3)-*, -O-, or –(SO2)-; wherein RL represents hydrogen, (C1-4)alkyl, CH3-O- CH2-, or (CH3)2NCH2-; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; R3 represents hydrogen or fluoro; • R4 represents hydrogen or (C1-4)alkyl; R5 represents hydrogen, fluoro, or hydroxy; and R6 represents fluoro or (C1)fluoroalkyl; or • R4 and R5 together represent a bridge selected from -CH2- and - CH2CH2-; and R6 represents hydrogen, fluoro, (C1)fluoroalkyl, or (C1-4)alkyl; or a salt thereof. [0626] In further embodiments, X1 represents CRX1; wherein RX1 represents hydrogen or halogen; X2 represents nitrogen or CH; X3 represents nitrogen or CH; R1 represents hydrogen; RX4 represents hydrogen, halogen, or (C1-4)alkyl; R2A represents hydrogen; (C1-4)alkyl; (C1-4)fluoroalkyl; (C1-4)hydroxyalkyl; or (C1-4)alkoxy-(C1- 2)alkyl; R2B 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; R3 represents hydrogen or fluoro; • R4 represents hydrogen or (C1-4)alkyl; R5 represents hydrogen, fluoro, or hydroxy; and R6 represents fluoro or (C1)fluoroalkyl; or • R4 and R5 together represent a bridge selected from -CH2- and -CH2CH2-; and R6 represents hydrogen, fluoro, (C1)fluoroalkyl, or (C1-4)alkyl; or a salt thereof (meaning a salt of the compound of Formula 53). [0627] In further embodiments, R2A represents hydrogen, (C1-4)alkyl, (C1-4)fluoroalkyl, (C1-4)hydroxyalkyl, or methoxymethyl; and R2B represents hydrogen; or a salt thereof. [0628] In further embodiments, L represents a direct bond; or a salt thereof. [0629] In further embodiments, R3 represents fluoro; or a salt thereof. [0630] In further embodiments, RX4 represents hydrogen; or a salt thereof. [0631] In further embodiments, each of X1, X2, and X3 represents CH; or a salt thereof. [0632] In further embodiments, the fragment
Figure imgf000428_0001
represents:
Figure imgf000428_0002
; wherein RX4 represents hydrogen or halogen; R3 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 X3 represents nitrogen or CH; RX4 represents hydrogen or (C1-4)alkyl; R3 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. [0633] In further embodiments, R4 represents hydrogen; R5 represents hydrogen or fluoro; and R6 represents fluoro, difluoromethyl or trifluoromethyl; or a salt thereof. [0634] In further embodiments, R4 and R5 together represent a -CH2- bridge; and R6 represents hydrogen, fluoro, difluoromethyl, or trifluoromethyl; or a salt thereof. [0635] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 1-(3,3-Difluoro-cyclobutyl)-3-(3-trifluoromethyl-benzyl)-urea; 1- Bicyclo[1.1.1]pent-1-yl-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl- cyclobutyl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Fluoro-bicyclo[1.1.1]pent-1- yl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl-bicyclo[1.1.1]pent-1- yl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-Bicyclo[1.1.1]pent-1-yl-3-[1-(3- trifluoromethoxy-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl-cyclobutyl)-3-[1-(3- trifluoromethoxy-phenyl)-ethyl]-urea; 1-(3-Fluoro-bicyclo[1.1.1]pent-1-yl)-3-[1-(3- trifluoromethoxy-phenyl)-ethyl]-urea; 1-[2,2-Difluoro-1-(3-trifluoromethyl-phenyl)-ethyl]-3- (3-hydroxy-3-trifluoromethyl-cyclobutyl)-urea; 1-(3,3-Difluoro-1-methyl-cyclobutyl)-3- [2,2-difluoro-1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-Bicyclo[1.1.1]pent-1-yl-3-[1-(3- difluoromethoxy-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl-bicyclo[1.1.1]pent-1-yl)-3-[2- hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl-bicyclo[1.1.1]pent- 1-yl)-3-[2,2-difluoro-1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3-Difluoromethyl- bicyclo[1.1.1]pent-1-yl)-3-[2-methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-urea; 1-(3- Difluoromethyl-bicyclo[1.1.1]pent-1-yl)-3-(2-fluoro-3-trifluoromethyl-benzyl)-urea; 1-(3- Difluoromethyl-bicyclo[1.1.1]pent-1-yl)-3-(3-fluoro-5-trifluoromethyl-benzyl)-urea; 1-(3- Fluoro-bicyclo[1.1.1]pent-1-yl)-3-[3-(2,2,2-trifluoro-ethoxy)-benzyl]-urea; 1-(3- Difluoromethyl-cyclobutyl)-3-[3-(2,2,2-trifluoro-ethoxy)-benzyl]-urea; 1-[3-(2,2,2- Trifluoro-ethoxy)-benzyl]-3-(3-trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-urea; 1-(3- Difluoromethoxy-benzyl)-3-(3-fluoro-bicyclo[1.1.1]pent-1-yl)-urea; 1-(3-Difluoromethoxy- benzyl)-3-(3-difluoromethyl-cyclobutyl)-urea; 1-(3-Difluoromethoxy-benzyl)-3-(3- trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-urea; 1-(3-Trifluoromethoxy-benzyl)-3-(3- trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-urea; 1-(3-Fluoro-bicyclo[1.1.1]pent-1-yl)-3-(3- trifluoromethoxy-benzyl)-urea; 1-(3-Difluoromethyl-cyclobutyl)-3-(3-trifluoromethoxy- benzyl)-urea; 1-Bicyclo[1.1.1]pent-1-yl-3-(3-trifluoromethoxy-benzyl)-urea; 1-(3- Difluoromethyl-benzyl)-3-(3-difluoromethyl-cyclobutyl)-urea; 1-(3-Difluoromethyl-benzyl)- 3-(3-trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-urea; 1-(3-Difluoromethyl-cyclobutyl)-3-(2- trifluoromethoxy-pyridin-4-ylmethyl)-urea; 1-(2-Trifluoromethoxy-pyridin-4-ylmethyl)-3- (3-trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-urea; 1-(3-Difluoromethyl-cyclobutyl)-3-{2- methoxy-1-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-ethyl}-urea; 1-{2-Methoxy-1-[2-(2,2,2- trifluoro-ethoxy)-pyridin-4-yl]-ethyl}-3-(3-trifluoromethyl-cyclobutyl)-urea; 1-[1-(2- Difluoromethoxy-pyridin-4-yl)-ethyl]-3-(3-difluoromethyl-cyclobutyl)-urea; 1-{1-[2-Methyl- 6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-3-(3-trifluoromethyl-bicyclo[1.1.1]pent-1- yl)-urea; 1-Bicyclo[1.1.1]pent-1-yl-3-(3-trifluoromethyl-benzyl)-urea; 1-(3-Fluoro- bicyclo[1.1.1]pent-1-yl)-3-(3-trifluoromethyl-benzyl)-urea; 1-(3-Trifluoromethyl-benzyl)-3- (3-trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-urea; 1-(3-Difluoromethyl-cyclobutyl)-3-(3- trifluoromethyl-benzyl)-urea; 1-(3-Methyl-bicyclo[1.1.1]pent-1-yl)-3-(3-trifluoromethyl- benzyl)-urea; 1-(3-Fluoromethyl-bicyclo[1.1.1]pent-1-yl)-3-(3-trifluoromethyl-benzyl)- urea; 1-(3-Trifluoromethyl-benzyl)-3-(3-trifluoromethyl-cyclobutyl)-urea; 1-(3-Hydroxy-3- trifluoromethyl-cyclobutyl)-3-(3-trifluoromethyl-benzyl)-urea; 1-Bicyclo[1.1.1]pent-1-yl-3- [2-(2,2,2-trifluoro-ethoxy)-pyridin-4-ylmethyl]-urea; 1-(3-Fluoro-bicyclo[1.1.1]pent-1-yl)-3- [2-(2,2,2-trifluoro-ethoxy)-pyridin-4-ylmethyl]-urea; 1-[2-(2,2,2-Trifluoro-ethoxy)-pyridin- 4-ylmethyl]-3-(3-trifluoromethyl-bicyclo[1.1.1]pent-1-yl)-urea; 1-(3-Difluoromethyl- cyclobutyl)-3-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-ylmethyl]-urea; 1-(3-Difluoromethyl- bicyclo[1.1.1]pent-1-yl)-3-(3-trifluoromethyl-benzyl)-urea; 1-Bicyclo[2.1.1]hex-1-yl-3-(3- trifluoromethyl-benzyl)-urea; 1-(3,3-Difluoro-1-methyl-cyclobutyl)-3-(3-trifluoromethyl- benzyl)-urea; 1-(3-(trifluoromethyl)benzyl)-3-((1s,3s)-3-(trifluoromethyl)cyclobutyl)urea; 1-(3-(trifluoromethyl)benzyl)-3-((1r,3r)-3-(trifluoromethyl)cyclobutyl)urea; 1-((1s,3s)-3- (difluoromethyl)cyclobutyl)-3-(3-(trifluoromethyl)benzyl)urea; 1-((1r,3r)-3- (difluoromethyl)cyclobutyl)-3-(3-(trifluoromethyl)benzyl)urea; 1-{(S)-1-[2-Methyl-6-(2,2,2- trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-3-(3-trifluoromethyl-bicyclo[1.1.1]pent-1-yl)- urea; 1-((1r,3r)-3-(difluoromethyl)cyclobutyl)-3-((2-(2,2,2-trifluoroethoxy)pyridin-4- yl)methyl)urea; 1-((1s,3s)-3-(difluoromethyl)cyclobutyl)-3-((2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)urea; 1-((1s,3R)-3-(difluoromethyl)cyclobutyl)-3-((S)- 1-(3-(trifluoromethoxy)phenyl)ethyl)urea; and 1-((1r,3S)-3-(difluoromethyl)cyclobutyl)-3- ((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)urea; or a salt thereof. Formula 54 [0636] 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. [0637] In an embodiment, the Kv7 channel activator is a compound according to Formula 54:
Figure imgf000431_0001
wherein, X1 represents nitrogen or CRx1; wherein RX1 represents hydrogen, halogen, (C1-4)alkyl, or (C1- 4)alkoxy;X2 represents nitrogen or CRX2; wherein RX2 represents hydrogen, halogen, (C1-4)alkyl, or (C1- 4)alkoxy; X3 represents nitrogen or CRX3; wherein RX3 represents hydrogen, halogen, (C1-4)alkyl, (C1- 4)alkoxy, or hydroxy;• R1 represents hydrogen, or methyl; or• R1 and RX1 together represent a -CH2CH2- bridge; Y represents -C(RY1)(RY2)-, or *-CH2-C(RY3)(RY4)-, wherein the asterisk indicates the bond which is linked to the cyclobutyl ring;RY1 represents hydrogen, or fluoro;RY2 represents hydrogen or fluoro;RY3 represents hydrogen, fluoro or iodo;RY4 represents hydrogen or fluoro; R2A represents hydrogen; (C1-4)alkyl; (C2-4)alkenyl; (C2-4)alkynyl; (C3-6)cycloalkyl; (C1- 4)fluoroalkyl; (C1-4)hydroxyalkyl; (C1-4)alkoxy-(C1-2)alkyl; (C1-2)alkoxy-(C1-2)alkoxy- (C1- 2)alkyl; (C1-2)alkyl-S-(C1-2)alkyl; (C1-2)alkyl-(SO2)-(C1-2)alkyl; cyano; (C1-2)cyanoalkyl; H2N- C(O)-(C1-2)alkyl; (RN1)2N-(C1-2)alkyl or (RN1)2N-C(O)-, wherein RN1 independently represents hydrogen or (C1-2)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(C1-4)alkyl; and R2B represents hydrogen, or methyl; or R2A and R2B 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 R2A and RX3 together represent a -CH2-O-* bridge, wherein the asterisk indicates the bond which is linked to the aromatic carbon atom, andR2B represents hydrogen;R3 represents -SFs; (C1-2)alkyi-S(O)2-; or a fragment R31 represents hydrogen, or fluoro; and L represents a direct bond,
Figure imgf000432_0001
cycloprop-1 ,1-diyl, -CHRL-O-*, -O-CH2-*, -CH2-NH-*, - CH2-N(CH3)-*, -O-, or -(SO2)-; wherein RL represents hydrogen, (C1- )alkyl, CH3-0-CH2-, or (CH3)2NCH2-; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; orR3 and RX1 together represent a -O-CF2-O- bridge; orR3 and RX2 together represent a -O-CF2- O- bridge; and R4 represents hydrogen, halogen, or (C1-4)alkyl; or a salt thereof. [0638] In further embodiments, R1 represents hydrogen; or a salt thereof (meaning a salt of compound of Formula 54). [0639] In further embodiments, RY1, RY2, RY3 and RY4 all represent hydrogen; or a salt thereof. [0640] In further embodiments, R2A represents hydrogen, (C1-4)alkyl, (C3-6)cycloalkyl, (C1-4)fluoroalkyl, (C1-4)hydroxyalkyl, (C1-4)alkoxy-(C1-2)alkyl, (C1-2)alkyl-S-(C1-2)alkyl, (C1- 2)alkyl-(SO2)-(C1-2)alkyl, cyano, (C1- 2)cyanoalkyl, H2N-C(O)-(C1-2)alkyl, (RN1)2N-(C1- 2)alkyl, or (RN1)2N-C(O)-, wherein RN1 independently represents hydrogen or (C1-2)alkyl; and R2B represents hydrogen; or R2A and R2B 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. [0641] In further embodiments, R2A represents hydrogen, methyl, or hydroxymethyl; and R2B represents hydrogen; or a salt thereof. [0642] In further embodiments, R3 represents a fragment
Figure imgf000432_0002
whereinR31 represents hydrogen, or fluoro; and L represents a direct bond, -CHRL-O-*, - O-CH2-*, -CH2-NH-*, -CH2-N(CH3)-*, or -O-; wherein RL 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. [0643] In further embodiments, R4 represents hydrogen; or a salt thereof. [0644] In further embodiments, the fragment ents:
Figure imgf000433_0001
Figure imgf000433_0002
or wherein X3 represents nitrogen and X1 represents CRX1; X1 represents nitrogen and X3 represents CRX3; or X1 represents CRX1 and X3 represents CRX3; or a salt thereof. [0645] In further embodiments, the fragment
Figure imgf000433_0003
represents
Figure imgf000433_0004
wherein RX1 represents hydrogen, fluoro, chloro, methyl, or methoxy; RX2 represents hydrogen; RX3 represents hydrogen, fluoro, or chloro; R4 represents hydrogen, fluoro, chloro, or methyl; R31 represents hydrogen, or fluoro; and L represents a direct bond, - CHRL-O-*, -CH2-NH-*, -CH2-N(CH3)-*, -O-, or ; wherein RL represents hydrogen, or methyl; wherein the asterisks indicate the bond which is linked to the aromatic carbon atom; or
Figure imgf000433_0005
wherein X3 represents nitrogen and X1 represents CRX1; X1 represents nitrogen and X3 represents CRX3; or X1 represents CRX1 and X3 represents CRX3; wherein RX1 represents hydrogen, or methoxy; RX3 represents hydrogen; R4 represents hydrogen, or methyl; and L represents -CHRL-O-*, -CH2-NH-*, or -CH2-N(CH3)-*; wherein RL 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. [0646] In further embodiments, X1 represents CRX1; wherein RX1 represents hydrogen; X2 represents nitrogen or CRX2; wherein RX2 represents hydrogen; X3 represents nitrogen or CRX3; wherein RX3 represents hydrogen; R1 represents hydrogen; Y represents -CH2-, or -CH2-CH2-; R2A represents hydrogen, or hydroxymethyl;R2B represents hydrogen; R3 represents trifluoromethyl or 2,2,2- trifluoroethoxy; and R4 represents hydrogen; or a salt thereof. [0647] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 1-Spiro[3.3]hept-2-yl-3-(3-trifluoromethyl-benzyl)-urea;1-Spiro[2.3]hex-5- yl-3-(3-trifluoromethyl-benzyl)-urea;1 -(1 , 1 -Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-((3r,5r)-1,1-Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-((3s,5s)-1 , 1 -Difluoro-spiro[2.3]hex-5-yl)-3-(3- trifluoromethyl-benzyl)-urea; 1-(6,6-Difluoro-spiro[3.3]hept-2-yl)-3-(3-trifluoromethyl- benzyl)-urea;1-[1-(3-Difluoromethoxy-phenyl)-cyclopropyl]-3-spiro[3.3]hept-2-yl-urea;1- (2-Fluoro-3-trifluoromethoxy-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;1-[1-(2-Difluoromethoxy-pyridin- 4-yl)-2-methoxy-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-(5- trifluoromethoxy-2,3-dihydro-benzofuran-3-yl)-urea;1-(2-Fluoro-3-trifluoromethyl- benzyl)-3-spiro[3.3]hept-2-yl-urea;1-(3-Difluoromethoxy-benzyl)-3-spiro[3.3]hept-2-yl- urea;1-Spiro[3.3]hept-2-yl-3-[3-(2,2,2-trifluoro-ethoxy)-benzyl]-urea;1-(3-Difluoromethyl- benzyl)-3-spiro[3.3]hept-2-yl-urea;1-(2-Fluoro-5-trifluoromethyl-benzyl)-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;1-[1-(2-Bromo-5-trifluoromethyl- phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-[1-(2-Methoxy-5-trifluoromethyl-phenyl)- ethyl]-3-spiro[3.3]hept-2-yl-urea;1-[1-(2-Methoxy-3-trifluoromethyl-phenyl)-ethyl]-3- spiro[3.3]hept-2-yl-urea;1-(2-Methoxy-3-trifluoromethyl-benzyl)-3-spiro[3.3]hept-2-yl- urea;1-Spiro[3.3]hept-2-yl-3-[1-(3-trifluoromethyl-phenyl)-ethyl]-urea;1-[Cyclopropyl-(3- trifluoromethyl-phenyl)-methyl]-3-spiro[3.3]hept-2-yl-urea;1-[Cyclopropyl-(3- difluoromethoxy-phenyl)-methyl]-3-spiro[3.3]hept-2-yl-urea;1-{1-[4-Methyl-3-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[4-Chloro-3-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[4-Methoxy-3-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[2-Methyl-3-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[2-Chloro-3-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[2-Methoxy-3-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[3-Methyl-5-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[3-Chloro-5-(2,2,2- trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-(1-(3-(pentafluoro-l6- sulfaneyl)phenyl)ethyl)-3-(spiro[3.3]heptan-2-yl)urea;1-(3-(pentafluoro-l6- sulfaneyl)benzyl)-3-(spiro[3.3]heptan-2-yl)urea;1-[1-(3-Methanesulfonyl-phenyl)-ethyl]-3- spiro[3.3]hept-2-yl-urea; 1-Spiro[3.3]hept-2-yl-3-[3-(1-trifluoromethyl-cyclopropyl)- benzyl]-urea;1-(2-Hydroxy-5-trifluoromethyl-benzyl)-3-spiro[3.3]hept-2-yl-urea;1-{1-[2- Chloro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[2- Methoxy-5-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1- Spiro[3.3]hept-2-yl-3-(3-trifluoromethoxy-benzyl)-urea;1-Spiro[3.3]hept-2-yl-3-(3- trifluoromethanesulfonyl-benzyl)-urea;1-Spiro[3.3]hept-2-yl-3-(3-trifluoromethoxymethyl- benzyl)-urea;1-Spiro[3.3]hept-2-yl-3-[3-(3-trifluoromethyl-phenyl)-oxetan-3-yl]-urea;1-[2- Hydroxy-2-methyl-1-(3-trifluoromethyl-phenyl)-propyl]-3-spiro[3.3]hept-2-yl-urea;1-(2,2- Difluoro-benzo[1,3]dioxol-4-ylmethyl)-3-spiro[3.3]hept-2-yl-urea;1-[1-(2,2-Difluoro- benzo[1,3]dioxol-4-yl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-{2-Dimethylamino-1-[6-(2,2,2- trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-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;1-[1-(2- Difluoromethoxy-pyridin-4-yl)-cyclobutyl]-3-spiro[3.3]hept-2-yl-urea;1-[1-(2- Difluoromethoxy-pyridin-4-yl)-1 -methyl-ethyl]-3-spiro[3.3]hept-2-yl-urea; 5-(2,2,2- Trifluoro-ethoxy)-3,4-dihydro-1H-[2,6]naphthyridine-2-carboxylic acid spiro[3.3]hept-2- ylamide; 1-Methoxymethyl-5-(2,2,2-trifluoro-ethoxy)-3,4-dihydro-1 H-isoquinoline-2- carboxylic acid spiro[3.3]hept-2- ylamide;1-[Cyano-(3-trifluoromethyl-phenyl)-methyl]-3- spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-[(1 H-[1 ,2,4]triazol-3-yl)-(3- trifluoromethyl-phenyl)-methyl]-urea;1-[2,2-Difluoro-1-(3-trifluoromethyl-phenyl)-ethyl]-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;1-Spiro[3.3]hept-2-yl-3-[6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4- ylmethyl]-urea;1-[2-Methyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-ylmethyl]-3- spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-{1-[6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4- yl]-ethyl}-urea;2-(3-Spiro[3.3]hept-2-yl-ureido)-2-(3-trifluoromethyl-phenyl)-acetamide; N-Methyl-2-(3-spiro[3.3]hept-2-yl-ureido)-2-(3-trifluoromethyl-phenyl)-acetamide; 1-[2- Methanesulfonyl-1-(3-trifluoromethoxy-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea; 1-[1- (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-ethyl]-3-spiro[3.3]hept-2-yl-urea; 1-[2-Cyano-1-(3- trifluoromethoxy-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea; 1-[2-Cyano-1-(3- trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-{1-[2-Methyl-6-(2,2,2-trifluoro- ethoxy)-pyrimidin-4-yl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-[2-Methanesulfonyl-1-(3- trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-[2-(2,2,2- trifluoro-ethoxy)-pyrimidin-4-ylmethyl]-urea;1-[2-(2-Methoxy-ethoxy)-1-(3-trifluoromethyl- phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-[2-lsopropoxy-1-(3-trifluoromethyl-phenyl)- ethyl]-3-spiro[3.3]hept-2-yl-urea;1-[3-Ethoxy-1-(3-trifluoromethyl-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;1-[2-Hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-3- spiro[3.3]hept-2-yl-urea;1-{3-Ethoxy-1 -[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-propyl)-3- spiro[3.3]hept-2-yl-urea;1-{2-Methoxy-1-[6-(2,2,2-trifluoro-ethoxy)-pyrimidin-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;1-Spiro[3.3]hept-2-yl-3-[1 -(3-trifluoromethyl-phenyl)-but-3-enyl]-urea;1-[3- Methanesulfonyl-1-(3-trifluoromethyl-phenyl)-propyl]-3-spiro[3.3]hept-2-yl-urea;1-{2- Hydroxy-1-[2-methyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-3-spiro[3.3]hept-2-yl- urea;1-{2-Hydroxy-1-[6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-3-spiro[3.3]hept-2- yl-urea;1-[3,3-Difluoro-1-(3-trifluoromethyl-phenyl)-propyl]-3-spiro[3.3]hept-2-yl-urea;1- {3-Hydroxy-1-[6-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl]-propyl}-3-spiro[3.3]hept-2-yl- urea;1-[1-(3-Methanesulfonyl-phenyl)-2-methoxy-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-{2- Hydroxy-1-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{3- Hydroxy-1-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-propyl)-3-spiro[3.3]hept-2-yl-urea;1- [Cyano-(3-trifluoromethyl-phenyl)-methyl]-3-spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2- yl-3-{1-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-urea;1-{2-Methoxy-1-[3-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{2-Methoxy-1-[2-(2,2,2-trifluoro- ethoxy)-pyridin-4-yl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-{1-[2-(2,2,2- trifluoro-ethoxy)-pyridin-4-yl]-ethyl}-urea;1-{2-Dimethylamino-1-[2-(2,2,2-trifluoro- ethoxy)-pyridin-4-yl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-{1-[3-Fluoro-5-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-(2- trifluoromethoxy-pyridin-4-ylmethyl)-urea;1-Spiro[3.3]hept-2-yl-3-[1-(2-trifluoromethoxy- pyridin-4-yl)-ethyl]-urea; 1-{1-[2-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3- spiro[3.3]hept-2-yl-urea;1-{1-[2-Huoro-5-(2,2,2-trifluoro- ethoxy)-phenyl]-ethyl}-3- spiro[3.3]hept-2-yl-urea;1-[1-(2-Difluoromethoxy-pyridin-4-yl)-ethyl]-3-spiro[3.3]hept-2-yl- urea;1-(Spiro[3.3]heptan-2-yl)-3-(1-(2-((1,1,1-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;1-Spiro[3.3]hept-2-yl-3-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4- ylmethyl]-urea;1-Spiro[3.3]hept-2-yl-3-[6-(2,2,2-trifluoro-1-methoxymethyl-ethoxy)- pyridin-2-ylmethyl]-urea;1-[6-(1-Dimethylaminomethyl-2,2,2-trifluoro-ethoxy)-pyridin-2- ylmethyl]-3-spiro[3.3]hept-2-yl-urea;1-[2-(1-Dimethylaminomethyl-2,2,2-trifluoro-ethoxy)- pyridin-4-ylmethyl]-3-spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-[2-(2,2,2-trifluoro-1- methoxymethyl-ethoxy)-pyridin-4-ylmethyl]-urea;1-[5-Methyl-6-(2,2,2-trifluoro-ethoxy)- pyridin-2-ylmethyl]-3-spiro[3.3]hept-2-yl-urea;1-[4-Methyl-3-(2,2,2-trifluoro-ethoxy)- benzyl]-3-spiro[3.3]hept-2-yl-urea;1-[3-Huoro-5-(2,2,2-trifluoro-1-methyl-ethoxy)-benzyl]- 3-spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-{1-[3-(2,2,2-trifluoro-1-methyl-ethoxy)- phenyl]-cyclopropyl}-urea;1-Spiro[3.3]hept-2-yl-3-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2- ylmethyl]-urea;1-{1-[4-Huoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2- yl-urea;1-[4-Huoro-3-(2,2,2-trifluoro-ethoxy)-benzyl]-3-spiro[3.3]hept-2-yl-urea;1-{2- [Methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-4-ylmethyl}-3-spiro[3.3]hept-2-yl-urea;1- Spiro[3.3]hept-2-yl-3-[2-(2,2,2-trifluoro-ethylamino)-pyridin-4-ylmethyl]-urea;1- Spiro[3.3]hept-2-yl-3-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-2-ylmethyl]-urea;1- Spiro[3.3]hept-2-yl-3-[2-(2,2,2-trifluoro-1-methyl-ethoxy)-pyrimidin-4-ylmethyl]-urea;1- Spiro[3.3]hept-2-yl-3-[1-(3-trifluoromethoxy-phenyl)-ethyl]-urea;1-Spiro[2.3]hex-5-yl-3-[6- (2,2,2-trifluoro-1-methyl-ethoxy)-pyrimidin-4-ylmethyl]-urea;1-[1-(2,2-Difluoro-benzo[1 ,3]dioxol-4-yl)-ethyl]-3-spiro[2.3]hex-5-yl-urea; 1-{2-Hydroxy-1-[6-(2,2,2-trifluoro-ethoxy)- pyrimidin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;1-{2-Hydroxy-1 -[2-methyl-6-(2,2,2- trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;1-[1-(3-Difluoromethoxy- phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;1-(2-Methoxy-5-trifluoromethyl-benzyl)-3- spiro[2.3]hex-5-yl-urea;1-Spiro[2.3]hex-5-yl-3-[4-(2,2,2-trifluoro-ethoxy)-pyrimidin-2- ylmethyl]-urea;1-(1-(3-(pentafluoro-l6-sulfaneyl)phenyl)ethyl)-3-(spiro[2.3]hexan-5- yl)urea;1-(2-Methoxy-3-trifluoromethyl-benzyl)-3-spiro[2.3]hex-5-yl-urea; 1-{1-[2-Huoro- 5-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;1-(3-(pentafluoro-l6- sulfaneyl)benzyl)-3-(spiro[2.3]hexan-5-yl)urea;1-{1-[2-Huoro-3-(2,2,2-trifluoro-ethoxy)- phenyl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;1-{1-[3-Huoro-5-(2,2,2-trifluoro-ethoxy)-phenyl]- ethyl}-3-spiro[2.3]hex-5-yl-urea;1-[1-(2-Methoxy-3-trifluoromethyl-phenyl)-ethyl]-3- spiro[2.3]hex-5-yl-urea;1-(2-Huoro-3-trifluoromethoxy-benzyl)-3-spiro[2.3]hex-5-yl- urea;1-Spiro[2.3]hex-5-yl-3-{1-[3-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-cyclopropyl}- urea;1-[1-(3-Difluoromethoxy-phenyl)-cyclopropyl]-3-spiro[2.3]hex-5-yl-urea;1-[1-(2- Methoxy-5-trifluoromethyl-phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;1-[3-Hydroxy-1-(3- trifluoromethoxy-phenyl)-propyl]-3-spiro[2.3]hex-5-yl-urea;1-[1-(2-Difluoromethoxy- pyridin-4-yl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;1-Spiro[2.3]hex-5-yl-3-[1-(3-trifluoromethyl- phenyl)-ethyl]-urea;1-Spiro[2.3]hex-5-yl-3-[1-(3-trifluoromethoxy-phenyl)-ethyl]-urea;1- (3-Huoro-5-trifluoromethyl-benzyl)-3-spiro[2.3]hex-5-yl-urea;1-[2-Hydroxy-1-(3- trifluoromethyl-phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;1-Spiro[2.3]hex-5-yl-3-{1-[6- (2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl]-ethyl}-urea;1-{1-[2-Methyl-6-(2,2,2-trifluoro- ethoxy)-pyrimidin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;1-[2,2-Difluoro-1 -(3- trifluoromethyl-phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;1-[2-Methoxy-1-(3- trifluoromethyl-phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;1-(4-Huoro-3-trifluoromethyl- benzyl)-3-spiro[2.3]hex-5-yl-urea;1-(2-Huoro-3-trifluoromethyl-benzyl)-3-spiro[2.3]hex-5- yl-urea;1-(2-Chloro-3-trifluoromethyl-benzyl)-3-spiro[2.3]hex-5-yl-urea;1-(2-Huoro-5- trifluoromethyl-benzyl)-3-spiro[2.3]hex-5-yl-urea;1-{1-[5-Methoxy-6-(2,2,2-trifluoro- ethoxy)-pyrimidin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;1-Spiro[2.3]hex-5-yl-3-(2- trifluoromethoxy-pyridin-4-ylmethyl)-urea;1-{2-Methoxy-1-[2-(2,2,2-trifluoro-ethoxy)- pyridin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;1-(3-Difluoromethoxy-benzyl)-3- spiro[2.3]hex-5-yl-urea;1 -Spiro [2.3] h ex-5-y I -3-(3-trifIuoromethoxy-benzyI )-urea; 1- Spiro[2.3]hex-5-yl-3-[3-(2,2,2-trifluoro-ethoxy)-benzyl]-urea; 1-(3-Difluoromethyl-benzyl)- 3-spiro[2.3]hex-5-yl-urea; 1-Spiro[2.3]hex-5-yl-3-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4- ylmethyl]-urea; 1-(6,6-Difluoro-spiro[3.3]hept-2-yl)-3-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4- ylmethyl]-urea;1-(6,6-Difluoro-spiro[3.3]hept-2-yl)-3-[1-(3-trifluoromethyl-phenyl)-ethyl]- urea;1-Spiro[3.3]hept-2-yl-3-[(1 H-[1 ,2,3]triazol-4-yl)-(3-trifluoromethyl-phenyl)-methyl]- urea;1-[(1-Methyl-1 H-tetrazol-5-yl)-(3-trifluoromethyl-phenyl)-methyl]-3-spiro[3.3]hept-2- yl-urea;1-[(2-Methyl-2H-tetrazol-5-yl)-(3-trifluoromethyl-phenyl)-methyl]-3-spiro[3.3]hept- 2-yl-urea;1-[(3-Methyl-3H-[1,2,3]triazol-4-yl)-(3-trifluoromethyl-phenyl)-methyl]-3- spiro[3.3]hept-2-yl-urea;1-[1-(2-Difluoromethoxy-pyridin-4-yl)-ethyl]-3-(6-iodo- spiro[3.3]hept-2-yl)-urea;1-[(R)-1-(2-Difluoromethoxy-pyridin-4-yl)-ethyl]-3- spiro[3.3]hept-2-yl-urea;1-[(S)-1-(2-Difluoromethoxy-pyridin-4-yl)-ethyl]-3-spiro[3.3]hept- 2-yl-urea;1-Spiro[3.3]hept-2-yl-3-{1-[3-((R)-2,2,2-trifluoro-1-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;1-Spiro[3.3]hept-2-yl-3-[2-((R)-2,2,2-trifluoro-1- methoxymethyl-ethoxy)-pyridin-4-ylmethyl]-urea;1-Spiro[3.3]hept-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;1-[(R)-1-(3-Difluoromethoxy-phenyl)-ethyl]-3- spiro[3.3]hept-2-yl-urea;1-Spiro[3.3]hept-2-yl-3-[(S)-1-(3-trifluoromethyl-phenyl)-ethyl]- urea;1-Spiro[3.3]hept-2-yl-3-{(S)-1-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-urea;1-{(S)- 1-[4-Fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-3-spiro[3.3]hept-2-yl-urea;1- Spiro[3.3]hept-2-yl-3-[(R)-2,2,2-trifluoro-1-(3-trifluoromethyl-phenyl)-ethyl]-urea;1- Spiro[3.3]hept-2-yl-3-[(R)-(1H-[1,2,4]triazol-3-yl)-(3-trifluoromethyl-phenyl)-methyl]- urea;1-Spiro[3.3]hept-2-yl-3-[2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-pyrimidin-4- ylmethyl]-urea;1-Spiro[3.3]hept-2-yl-3-[2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyrimidin- 4-ylmethyl]-urea;1-Spiro[3.3]hept-2-yl-3-{(S)-1-[6-(2,2,2-trifluoro-ethoxy)-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;1-[(R)-2-Hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;1- [(S)-2-Hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-[(R)-2- Hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-3-spiro[2.3]hex-5-yl-urea;1-[(R)-1-(2- Difluoromethoxy-pyridin-4-yl)-2-methoxy-ethyl]-3-spiro[3.3]hept-2-yl-urea;1-{(R)-2- Methoxy-1-[2-(2,2,2-trifluoro-ethoxy)-pyridin-4-yl]-ethyl}-3-spiro[2.3]hex-5-yl-urea;1-[(S)- 1-(2-Difluoromethoxy-pyridin-4-yl)-ethyl]-3-spiro[2.3]hex-5-yl-urea; or 1-[(S)-1-(2-Bromo- 5-trifluoromethyl-phenyl)-ethyl]-3-spiro[3.3]hept-2-yl-urea; or a salt thereof. Formula 55 [0648] 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. [0649] In an embodiment, the Kv7 channel activator is a compound according to Formula 55:
Figure imgf000440_0001
or a tautomer, salt, solvate, stereoisomer or isotope thereof, wherein: Y is selected from: C1-C10 alkylamino, C1-C10 alkyl, C1-C10 alkoxy, C3-C8 cycloalkyl, Cl- C10 alkylcarbonyl, Cl -CIO alkylaminocarbonyl, Cl -CIO alkylthio, aryl, heterocycle, Cl -CIO carbonyl, C1-C10 amide and C1-C10 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, N¾, 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, SO2NH, CONH, CSNH, C=NH, CNHNH, and C=S; when Q is C=0 or C=S, R6 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, SO2NH, CONH, CSNH, C=NH, or CNHNH, R6 is selected from: linear or branched C1-C30 alkyl, C3-C8 cycloalkyl, linear or branched C1-C30 alkylcarbonyl, linear or branched C1-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. [0650] In further embodiments, b is 1. [0651] In further embodiments, Q is C=0 or SO2. [0652] In further embodiments, Y is Cl -CIO alkylamino, Cl -CIO alkyl or Cl -CIO alkoxy. [0653] 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. [0654] 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. [0655] In further embodiments, when Q is C=0 or C=S, R6 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 S02, 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. [0656] In further embodiments, the Kv7 Channel activator is selected from the group consisting of those listed in the following table
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Figure imgf000470_0001
Figure imgf000471_0001
Figure imgf000472_0001
Figure imgf000473_0001
Figure imgf000474_0001
Figure imgf000475_0001
Figure imgf000476_0001
Figure imgf000477_0001
Figure imgf000478_0001
Figure imgf000479_0001
Figure imgf000480_0001
Figure imgf000481_0001
Figure imgf000482_0001
Figure imgf000483_0001
Figure imgf000484_0001
Figure imgf000485_0001
Figure imgf000486_0001
Figure imgf000487_0001
Figure imgf000488_0001
Figure imgf000489_0002
Formula 56 [0657] 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. WO2020016297A1, published January 23, 2020, and corresponding to International Application No. PCT/EP2019/069240 filed July 17, 2019; Patent Cooperation Treaty application No. PCT/EP2019/069240 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. [0658] In an embodiment, the Kv7 channel activator is a compound according to Formula 56:
Figure imgf000489_0001
wherein, R1 is selected from a branched or unbranched C1 to C5 alkyl group and – NR1a R1b group, where R1a and R1b are selected independently of one another from hydrogen atom and branched or unbranched C1 to C5 alkyl group or with one another and with the nitrogen atom the NR1a R1b 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 C1 to C3 alkyl group and optionally in addition to the nitrogen atom of the NR1a R1b - Group has at least one further heteroatom in the cycle; R 2 is selected from the group consisting of branched or unbranched C1 to C10 alkyl group, C3 to C10 cycloalkyl group, C3 to C10 heterocycloalkyl group, at least one hetero atom being selected from nitrogen and oxygen atom, C6 to C12 aryl group; and C5 to C11 heteroaryl group, the C1 to C10 alkyl group, C3 to C10 cycloalkyl group, C3 to C10 heterocycloalkyl group, C6 to C12 aryl group, or C5 to C11 heteroaryl group in each case at least one further Substituents R 2a , wherein R 2a is selected from the group consisting of hydrogen atom, halogen atom, branched or unbranched C1 to C3 alkyl group, branched or unbranched (per) halogenated C1 to C3 alkyl group and branched or unbranched C1 to C3 Alkoxy group, and wherein the C3 to C10 cycloalkyl group, C3 to C10 heterocycloalkyl group, C6 to C12 aryl group or C5 to C11 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 C1 to C10 alkoxy group; branched or unbranched C1-C10 alkyl group and - (CH2 ) P -C6 to C12 aryl group, which has at least one substituent selected from hydrogen atom, halogen atom and C1 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 C1 -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. [0659] In further embodiments, n is zero and / or m is 1 and / or X is a nitrogen atom. [0660] In further embodiments, R1 is selected from the group consisting of branched or unbranched C1- to C3-alkyl group and - NR1a R1b group, wherein R1a and R1b are independently selected from hydrogen atom and branched or unbranched C1- to C3-alkyl group or with one another and form a C4 to C6 heterocycloalkyl group with the nitrogen atom of the NR1a R1b group, the C4 to C6 heterocycloalkyl group each having at least one substituent selected from the hydrogen atom and C1 to C3 alkyl group and optionally in addition to the nitrogen atom of the NR1a R1b 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 C1 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. [0661] In further embodiments, the Kv7 channel activator is selected from the group consisting of:
Figure imgf000491_0001
Formulas 57 – 139 [0662] 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. WO2018204765A1, 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. [0663] In an embodiment, the Kv7 channel activator is a compound according to any one of formulas 57 – 139:
Figure imgf000492_0001
Figure imgf000493_0001
Figure imgf000494_0001
Figure imgf000495_0001
Figure imgf000496_0001
Figure imgf000497_0001
Figure imgf000498_0001
Figure imgf000499_0001
wherein (for any of compounds 57 – 139), each and any of R1, R2, and R3 independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 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(C1-6 saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C1- 6 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; and wherein each X = independently C, CH, CH2, S, SO, SO2, NH, NC1-6saturated, unsaturated alkyl, or cycloalkyl, or O, and wherein each n, where present, is independently = 0-6. Formula 140 [0664] 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. [0665] In an embodiment, the Kv7 channel activator is a compound according to Formula 140:
Figure imgf000500_0001
wherein, R1 is H or optionally-substituted alkyl;R2 is optionally-substituted alkyl;R3 and R4 are each independently H or optionally-substituted alkyl;R5 is H, optionally- substituted alkyl, acyl, or alkoxycarbonyl;R6 and R7 are each independently H, deuterium, optionally- substituted alkyl, or R6 and R7 together form a carbocycle;R8 is optionally-substituted thiazolyl, optionally-substituted thiophenyl, or substituted phenyl, provided that if R8 is 4-halophenyl, then R2 is substituted alkyl or branched alkyl or at least one of R6 or R7 is not H; andR30, R31 and R32 are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy. [0666] In further embodiments, R1 is H. [0667] In further embodiments, R2 is C1-C6 alkyl. [0668] In further embodiments, R2 is carbocyclic-substituted alkyl or heterocyclic- substituted alkyl. [0669] In further embodiments, R3 and R4 are each H. [0670] In further embodiments, R5 is H. [0671] In further embodiments, R6 and R7 are both H; R6 and R7 are both deuterium; R6 and R7 together form a cycloalkyl; or at least one of R6 or R7 is a substituted alkyl. [0672] In further embodiments, R8 is selected from:
Figure imgf000500_0002
Figure imgf000500_0003
w erein R9-R25 are each independently H, halogen, optionally-substituted sulfanyl, or optionally-substituted alkyl. [0673] In further embodiments, R8 is: eein at least one of R9 or R10 is halogen. [0674] In further embodiments, R8 is: wherein at least one of R19 or R20 is halogen. [0675] In further embodiments, R8 is: wherein at least one of R14-R18 is substituted sulfanyl or haloalkyl; or wherein R16 is F. [0676] In further embodiments, at least one of R14-R18 is —SF5 or CF3. [0677] In further embodiments, R8 is: wherein at least one of R11-R13 or R23-R25 is substituted sulfanyl. [0678] In further embodiments, R8 is: wherein at least one of R14-R18 is halo-substituted sulfanyl, haloalkyl or halogen. [0679] In further embodiments, at least one of R14-R18 is —SF5 or —CF3. [0680] In further embodiments, R15, R16, or R17 is —SF5 or —CF3. [0681] In further embodiments, R32 is —F, and R30and R31 are each H. [0682] In further embodiments, the Kv7 Channel activator is selected from the group consisting of:
Figure imgf000502_0001
[0683] In further embodiments, the compound is according to formula 141 wherein: R1 is H or optionally-substituted alkyl; R2 is substituted alkyl having one or more hydrogen atoms substituted with a substituent selected from halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl; R3 and R4 are each independently H or optionally- substituted alkyl; R5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R6 and R7 are each independently H, deuterium, optionally-substituted alkyl, or R6 and R7 together form a carbocycle; R8 is optionally-substituted thiazolyl, optionally- substituted thiophenyl, or substituted phenyl; andR30, R31 and R32 are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy. [0684] In further embodiments, the compound is according to formula 141 wherein: R1 is H or optionally-substituted alkyl; R2 is optionally-substituted alkyl; R3 and R4 are each independently H or optionally-substituted alkyl; R5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R6 and R7 are each independently H, deuterium, optionally- substituted alkyl, or R6 and R7 together form a carbocycle, provided at least one R6 or R7 is not H; R8 is optionally-substituted thiazolyl, optionally-substituted thiophenyl, or substituted phenyl, provided that if R8 is 4-halophenyl, then R2 is substituted alkyl or branched alkyl or at least one of R6 or R7 is not H; andR30, R31 and R32 are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy. [0685] In further embodiments, the compound is according to formula 141 wherein: R1 is H or optionally-substituted alkyl;R2 is optionally-substituted alkyl;R3 and R4 are each independently H or optionally-substituted alkyl;R5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl;R6 and R7 are each independently H, deuterium, optionally-substituted alkyl, or R6 and R7 together form a carbocycle;R8 is
Figure imgf000503_0001
in at least one of R14-R18 is substituted sulfanyl or haloalkyl; andR3 and R31 are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy; andR32 is deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy. [0686] In further embodiments, R32 is halogen. [0687] In further embodiments, R32 is —F. [0688] In further embodiments, at least one of R14-R18 is halo-substituted sulfanyl. [0689] In further embodiments, at least one of R14-R18 is haloalkyl. [0690] In further embodiments, at least one of R14-R18 is —SF5. [0691] In further embodiments, at least one of R14-R18 is —CF3. [0692] In further embodiments, R16 is —SF5. [0693] In further embodiments, R16 is —CF3. [0694] In further embodiments, R2 is alkyl. [0695] In further embodiments, R2 is C1-C6 alkyl. [0696] In further embodiments, R2 is ethyl. [0697] In further embodiments, R3, R4, R5, R6, and R7 are each H. [0698] In further embodiments, R32 is —F and R16 is —CF3. [0699] In further embodiments, R2 is alkyl. [0700] In further embodiments, R3and R31 are each H. [0701] In further embodiments, R15, R16, or R17 is —SF5 or —CF3. [0702] In further embodiments, R1, R1, R3, R4, R5, R6, and R7 are each H; R2 is alkyl; and R32 is —F. Formula 141 [0703] 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. [0704] In an embodiment, the Kv7 channel activator is a compound according to Formula 141:
Figure imgf000504_0001
wherein, R1 is H or optionally-substituted alkyl; R2 is optionally-substituted alkyl; R3 and R4 are each independently H or optionally-substituted alkyl; R5 is H, optionally- substituted alkyl, acyl, or alkoxycarbonyl; R6 and R7 are each independently H, deuterium, optionally-substituted alkyl, or R6 and R7 together form a carbocycle; andR8 is optionally-substituted thiazolyl. [0705] In further embodiments, the compound is according to formula 142 wherein: R1 is H or optionally-substituted alkyl; R2 is optionally-substituted alkyl; R3 and R4 are each independently H or optionally-substituted alkyl; R5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R6 and R7 are each independently H, deuterium, optionally- substituted alkyl, or R6 and R7 together form a carbocycle; and R8 is substituted thiophenyl, wherein at least one substituent on the thiophenyl is halo-substituted sulfanyl. Formula 142 [0706] 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. [0707] In an embodiment, the Kv7 channel activator is a compound according to Formula 142:
Figure imgf000505_0001
wherein, X is selected from a group consisting of oxygen and sulfur; n is 1, 2 or 3;R1 is H or halogen;R2 and R3 are each independently selected from a group consisting of H, D and C1-C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3-C6 saturated ring;R4 and R5 are each independently selected from a group consisting of H; halogen; C1-C6 alkyl; C3-C6 cycloalkyl; cyano; alkoxyl; C1-C6 alkyl substituted by hydroxy, amino, C1-C4 alkoxy, C1-C4 alkylcarbonyl, or halogen; C1-C4 alkoxy substituted by halogen; C1-C6 alkylcarbonyl; C1-C6 alkoxycarbonyl; C1-C6 alkylaminocarbonyl; C2- C6 alkenyl; and C2-C6 alkynyl; provided that R4 and R5 are not simultaneously hydrogen; R6 is selected from a group consisting of C1-C6 alkoxy; C1-C6 alkylamino; C1-C6 alkyl; C3- C6 cycloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C6-C10 aryl; C1-C6 alkyl substituted by halogen, cyano, hydroxy, C1-C6 alkoxyl, di(C1-C4 alkyl) amino, C1-C6 alkylcarbonyl, C1- C6 alkylcarbonylamino, or C1-C6 alkoxycarbonyl; C3-C6 cycloalkyl substituted by halogen; C2-C6 alkenyl substituted by halogen; C2-C6 alkynyl substituted by halogen; tetrahydrofuranyl; and wherein, R7 and R8 are each independently selected from a group consisting of C1-C4 alkyl. [0708] In further embodiments, R1 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. [0709] In further embodiments, one of R4 and R5 is methyl, and the other is H or methyl. Formula 143 [0710] 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. [0711] In an embodiment, the Kv7 channel activator is a compound according to Formula 143:
Figure imgf000506_0001
wherein, X: is selected from a group consisting of oxygen and sulfur;R1 is H or halogen;R2 and R3 are each independently selected from a group consisting of H, D and C1-C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3- C6 saturated ring;R4 and R5 are each independently selected from a group consisting of H; halogen; C1-C6 alkyl; C3-C6 cycloalkyl; cyano; C1-C4 alkoxyl; C1-C6 alkyl substituted by hydroxy, amino, C1-C4 alkoxy, C1-C4 alkylcarbonyl, or halogen; C1-C4 alkoxy substituted by halogen; C1-C6 alkylcarbonyl; C1-C6 alkoxycarbonyl; C1-C6 alkylaminocarbonyl; C2- C6 alkenyl; and C2-C6 alkynyl; provided that R4 and R5 are not simultaneously hydrogen;R6 is selected from a group consisting of C1-C6 alkoxy; C1-C6 alkylamino; C1- C6 alkyl; C3-C6 cycloalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C6-C10 aryl; C1-C6 alkyl substituted by halogen, cyano, hydroxy, C1-C6 alkoxyl, di(C1-C4 alkyl) amino, C1- C6 alkylcarbonyl, C1-C6 alkylcarbonylamino, or C1-C6 alkoxycarbonyl; C3-C6 cycloalkyl substituted by halogen; C2-C6 alkenyl substituted by halogen; C2-C6 alkynyl substituted by halogen; tetrahydrofuranyl; and wherein, R7 and R8 are each independently selected from a group consisting of C1-C4 alkyl. [0712] In further embodiments, R1 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 [0713] 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. [0714] In an embodiment, the Kv7 channel activator is a compound according to a formula from the group consisting of 144, 145, and 146:
Figure imgf000508_0001
, wherein, R2 and R3 are each independently selected from a group consisting of H, D and C1-C3 alkyl; or R2 and R3 together with the carbon atom to which they attached form C3- C6 saturated ring;R4 and R5 are each independently selected from a group consisting of H; C1-C6 alkyl; C1-C4 alkoxyl; C1-C6 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 C1-C6 alkyl and C3-C6 cycloalkyl;R10 is selected from a group consisting of C1-C6 alkyl; C1-C6 alkyl substituted by halogen, cyano, hydroxy, C1-C6 alkoxyl, di(C1-C4 alkyl)amino, C1-C6 alkylcarbonyl, C1-C6 alkylamido, or C1- C6 alkoxycarbonyl; C3-C6 cycloalkyl; and C3-C6 cycloalkyl substituted by halogen; tetrahydrofuranyl; and wherein, R7 and R8 are each independently selected from a group consisting of C1-C4 alkyl. [0715] 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;R9 is selected from a group consisting of C1-C6 alkyl and C3-C6 cycloalkyl;R10 is selected from a group consisting of C1-C6 alkyl; C1-C6 alkyl substituted by halogen, cyano, hydroxy, C1-C6 alkoxyl, di(C1-C4 alkyl)amino, C1-C6 alkylcarbonyl, C1- C6 alkylamido, or C1-C6 alkoxycarbonyl; C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted by halogen; tetrahydrofuranyl; and wherein, R7 and R8 are each independently selected from a group consisting of C1-C4 alkyl. [0716] In further embodiments, R9 is selected from a group consisting of methyl, ethyl and propyl;R10 is selected from a group consisting of C1-C3 alkyl; C1-C3 alkyl substituted by halogen, cyano, hydroxy, C1-C3 alkoxyl, di(C1-C3 alkyl)amino, C1-C3 alkylcarbonyl, C1- C3 alkylamido, or C1-C3 alkoxycarbonyl; C3-C6 cycloakyl; C3-C6 cycloakyl substituted by halogen; tetrahydrofuranyl; and wherein, R7 and R8 are each independently selected from a group consisting of C1-C3 alkyl. [0717] In further embodiments, the Kv7 Channel activator is selected from the group consisting of:
Figure imgf000510_0001
Formula 147 [0718] 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. [0719] In an embodiment, the Kv7 channel activator is a compound according to Formula 147:
Figure imgf000511_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: X1, X2, X3, X4, X5, X6, X7, and X8 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 X1, X2, and X3 is F. [0720] In further embodiments, the Kv7 channel activator is:
Figure imgf000511_0002
wherein, A is N or C—X3; X1, X2, X3, X4, X5, X6, X7, and X8 are each independently selected from hydrogen, 19F and 18F; and n is 2 or 3, provided that one of X1, X2, X3, X4, X5, X6, X7, and X8 is 18F. [0721] In further embodiments, two of X1, X2, X3, X4, X5, X6, X7 and X8 are F. [0722] In further embodiments, three of X1, X2, X3, X4, X5, X6, X7 and X8 are F. [0723] In further embodiments, the Kv7 channel activator is:
Figure imgf000512_0001
wherein, X1, X2, X3, and X6 are each independently selected from hydrogen, 18F, and 19F, provided that one of X1, X2, X3, and X6 is 18F. [0724] In further embodiments, X6 is fluorine and one of X1, X2, and X3 is fluorine. [0725] In further embodiments, one of X1, X2, X3, and X6 is 18F. [0726] In further embodiments, at least one of X1, X2, and X3 is 19F. [0727] In further embodiments, X6 is 19F or 18F. [0728] In further embodiments, the compound is selected from the group consisting of:
Figure imgf000512_0002
Formula 148 [0729] 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. WO2012038850A1, 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. [0730] In an embodiment, the Kv7 channel activator is a compound according to Formula 148:
Figure imgf000513_0001
wherein, R1 is alkyl, cycloalkyl, wherein alkyl or cycloalkyl may be substituted with one or more halogen, alkoxy, aryl, or aryloxy; R2 is cycloalkyl or NR4R5; R3 is H, halogen, alkyl, or alkoxy, wherein any alkyl may be substituted with one or more halogen atoms; R4 and R5 are independently selected from H, C1-6alkyl, C3-6cycloalkyl, or —C1-6alkyl-C3- 6cycloalkyl, wherein each alkyl or each cycloalkyl may be substituted with one or more halogen, provided that both R4 and R5 are not H simultaneously; or R4 and R5, 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. [0731] In further embodiments, R1 is C5-6 alkyl; R2 is NR4R5, wherein one of R4 or R5 is H and the other is C3-6alkyl, C3-6cycloalkyl, or —C1-3alkyl-C3-6cycloalkyl; R3 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. [0732] In further embodiments, R1 is —CH2C(CH3)3; R3 is chloro, methyl, trifluoromethyl or 1,1-difluoroethoxy; R4 is H and R5 is isopropyl, isobutyl, 1-cyclopropylethyl, cyclobutyl or cyclopentyl; —X—Y— is ═CH—CH═ or —CH2—CH2—; or a pharmaceutically acceptable salt thereof. [0733] In further embodiments, R1 is C5-6 alkyl; R2 is C3-6cycloalkyl; R3 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. [0734] In further embodiments, R1 is —CH2C(CH3)3; R2 is cyclopropyl; R3 is chloro, methyl, trifluoromethyl or 1,1-difluoroethoxy; —X—Y— is ═CH—CH═ or —CH2—CH2— ; or a pharmaceutically acceptable salt thereof. Formula 149 [0735] 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. WO2009071947A2, published June 11, 2009, and corresponding to International Application No. PCT/GB2008/051158 filed December 5, 2008; International Publication No. WO2010010380A1, 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. [0736] In an embodiment, the Kv7 channel activator is a compound according to Formula 149:
Figure imgf000514_0001
wherein, Ar1 and Ar2 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;R1 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, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R1 may be the same or different; b is an integer of from 0 to 5;R2 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 R2 may be the same or different; V is selected from the group consisting of (CR3aR3b)pSO2N(R3b)X;W is NR4a; 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 (CR5aR5b)n1, wherein each n1 is 0; and p is an integer of from 0 to 2,and wherein V is substituting said Ar1 at an ortho position with respect to said Z or said W. [0737] In further embodiments, a is an integer of from 0 to 3. [0738] In further embodiments, R1 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 R1 may be the same or different. [0739] In further embodiments, b is an integer of from 0 to 4. [0740] In further embodiments, R2 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. [0741] In further embodiments, R4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups. [0742] In further embodiments, V is selected from the group consisting of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of from 0 to 2, R3a and R3b 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 (CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d 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. [0743] In further embodiments, V is a group of formula of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of 0 or 1, R3a and R3b 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—[(CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c, R6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms. [0744] In further embodiments, V is a group of formula of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of 0 or 1, each of R3a and R3b 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—-[CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d is a hydrogen atom. [0745] In further embodiments, Ar1 and Ar2 are each phenyl; a is an integer of from 0 to 3;R1 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 R1 may be the same or different; b is an integer of from 0 to 4;R2 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 R2 may be the same or different; W is NR4a, wherein R4a 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 (CR5aR5b)n1, wherein each n1 is 0; and V is selected from the group consisting of (CR3aR3b)pSO2N(R3b)X and, wherein p is an integer of from 0 to 2,R3a and R3b 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-[(CR6aR6b)c1—O— (CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d 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. [0746] In further embodiments, Ar1 and Ar2 are each phenyl; a is 0 or 1;R1 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 R1 may be the same or different; b is an integer of from 0 to 3;R2 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, alkylsulphonyl 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 R2 may be the same or different; W is NR4a, wherein R4a 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 (CR5aR5b)n1, wherein each n1 is 0; and V is a group of formula of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of 0 or 1, R3a and R3b 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—[(CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, Rbc and R6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms. [0747] In further embodiments, Ar1 and Ar2 are each phenyl; a is 0 or 1;R1 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 R1 may be the same or different; b is 0 to 3;R2 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 NR4a, wherein R4a 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 (CR5aR5b)n1 wherein each n1 is 0; and V is a group of formula of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of 0 or 1, each of R3a and R3b 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—[(CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d is a hydrogen atom. [0748] In further embodiments, Ar1 and Ar2 are each phenyl; a is an integer of from 0 to 3;R1 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 R1 may be the same or different; b is an integer of from 0 to 4;R2 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 R2 may be the same or different; W is NR4a, wherein R4a 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 (CR3aR3b)pSO2N(R3b)X wherein p is an integer of from 0 to 2, R3a and R3b 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—[(CR6aR6c)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d 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. [0749] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 1-[2-(2,6-Dichlorophenylamino)phenyl]-N-[2-(2-hydroxyethoxy)ethyl]- methanesulfonamide,N-[2-(2-hydroxyethoxy)ethyl]-C-[2-(2,4,6- trichlorophenylamino)phenyl]-methanesulfonamide,1-[2-(2,6-dichloro-4- trifluoromethylphenylamino)phenyl]-N-{2-(2-hydroxyethoxy)ethyl]methanesulfonamide,1- [2-(2,6-dichloro-3-methylphenylamino)phenyl]-N-{2-(2-hydroxyethoxy)- ethyl]methanesulfonamide,N-(2-hydroxyethyl)-1-[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- methylphenylamino)-N-(2-hydroxyethyl)-benzenesulfonamide,2-(2,6-dichloro-4- trifluoromethylphenylamino)-N-[2-(2-hydroxyethoxy)ethyl]-benzenesulfonamide,2-(2,6- dichloro-3-methylphenylamino)-N-[2-(2-hydroxyethoxy)ethyl]-benzenesulfonamide,2- (3,5-dichlorophenylamino)-N-[2-(2-hydroxyethoxy)ethyl]-benzenesulfonamide, andN-[2- (2-hydroxyethoxy)ethyl]-2-(2,4,6-trichlorophenylamino)-benzenesulfonamide, or a pharmacologically acceptable salt or pro-drug thereof. [0750] In further embodiments, the compound is according to Formula 149 wherein: Ar1 and Ar2 are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5; R1 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, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R1 may be the same or different; b is an integer of from 0 to 5;R2 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, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and where b is greater than 1, each substituent R2 may be the same or different; V is selected from the group consisting of (CR3aR3b)pCON(R3b)X and (CR3aR3b)pN(R3b)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 NR4a, O, S, S═O, SO2 and C(R4aR4b)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 (CR5aR5b)n1, C═O, SO2, C(═O)NR5a; C(═O)NR5aSO2 and C═O(R5aR5b)n2;R3a, R3b, R4a, R4b, R5a and R5b 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;n1 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. [0751] In further embodiments, Ar1 and Ar2 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. [0752] In further embodiments, Ar1 and Ar2 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. [0753] In further embodiments, Ar1 and Ar2 are each phenyl. [0754] In further embodiments, R2 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. [0755] In further embodiments, W is a group of formula NR4a, wherein R4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups. [0756] In further embodiments, Y and Z are each a group of formula (CR5aR5b)n1 wherein each n1 is 0. [0757] In further embodiments, V is selected from the group consisting of (CR3aR3b)pCON(R3b)X and (CR3aR3b)pN(R3bCO(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, R3a and R3b 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— [(CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d 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. [0758] In further embodiments, V is selected from the group consisting of (CR3aR3b)pCON(R3b)X and (CR3aR3b)pN(R3b)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, R3a and R3b 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—[(CR6aR6b)c1— O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d 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. [0759] In further embodiments, V is selected from the group consisting of (CR3aR3b)pCON(R3b)X and (CR3aR3b)pN(R3b)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 R3a and R3b 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. [0760] In further embodiments, the compound is according to Formula 149 wherein: Ar1 and Ar2 are each phenyl; a is 0 or 1;R1 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, 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 R1 may be the same or different; b is 0 to 3; R2 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 NR4a, wherein R4a 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 (CR5aR5b)n1 wherein each n1 is 0; and V is selected from the group consisting of (CR3aR3b)pCON(R3b)X and (CR3aR3b)pN(R3b)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 R3a and R3b 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. [0761] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: N-(2-hydroxyethyl)-2-[3-(2,4,6-trichlorophenylamino)phenyl]acetamide;{2- [5-(3,5-dichlorophenylamino)-2-fluorophenyl]-acetylamino}acetic acid; 2-[4-(2,6-dichloro- 4-trifluoromethyl-phenylamino)-phenyl]-N-(2-hydroxyethyl)-acetamide; {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)-acetamide; 5-(2,6-dichloro-4-trifluoromethyl-phenylamino)-2-fluoro-N-(2- hydroxy-ethyl)-benzamide; 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. [0762] In further embodiments, the compound is according to formula 150 wherein: Ar1 and Ar2 are the same or different and each is an aryl group or a heteroaryl group; a is an integer of from 0 to 5; R1 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, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R1 may be the same or different; b is an integer of from 0 to 5; R2 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, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and where b is greater than 1, each substituent R2 may be the same or different; V is selected from the group consisting of (CR3aR3b)pCON(R3b)X and (CR3aR3b)pN(R3b)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 NR4a, O, S, S═O, SO2 and C(R4aR4b)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 (CR5aR5b)n1, C═O, SO2, C(═O)NR5a; C(═O)NR5aSO2 and C═O(R5aR5b)n2;R3a, R3b, R4a, R4b, R5a and R5b 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; n1 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. [0763] In further embodiments, the compound is according to Formula 149 wherein: Ar1 and Ar2 are each phenyl; a is 1; R1 is halogen; b is an integer of from 0 to 3; R2 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 R2 may be the same or different; V is (CR3aR3b)pCON(R3b)X, wherein said group is in the 3-(meta) or 4-(para) position with respect to the substituent Z;W is NR4a, wherein R4a 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—[(CR6aR6b)c1—O—(CR6cR6d)c2]c3—wherein c1 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 R6a, R6b, R6c and R6d 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 (CR5aR5b)n1 wherein each n1 is 0;R3a and R3b 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. [0764] In further embodiments, V is (CR3aR3b)pCON(R3b)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 R3a and R3b 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. [0765] 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-phenyl]-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-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. [0766] In further embodiments, the compound is according to Formula 149 wherein: Ar1 and Ar2 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; R1 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, alkoxycarbonylamino groups, alkylsulphonyl groups, alkylsulphonylamino groups and cyano groups and, where a is greater than 1, each substituent R1 may be the same or different; b is an integer of from 0 to 5; R2 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 R2 may be the same or different; V is selected from the group consisting of (CR3aR3b)pSO2N(R3b)X;W is NR4a;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 (CR5aR5b)n1, wherein each n1 is 0; and p is an integer of from 0 to 2,and wherein V is substituting said Ar1 at an ortho position with respect to said Z or said W. In further embodiments, [0767] In further embodiments, a is an integer of from 0 to 3. [0768] In further embodiments, R1 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 R1 may be the same or different. [0769] In further embodiments, b is an integer of from 0 to 4. [0770] In further embodiments, R2 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. [0771] In further embodiments, R4a is selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 3 carbon atoms and phenyl groups. [0772] In further embodiments, V is selected from the group consisting of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of from 0 to 2, R3a and R3b 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 (CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d 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. [0773] In further embodiments, V is a group of formula of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of 0 or 1, R3a and R3b 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—[(CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c, R6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms. [0774] In further embodiments, V is a group of formula of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of 0 or 1, each of R3a and R3b 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—-[CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d is a hydrogen atom. [0775] In further embodiments, the compound is according to Formula 149 wherein: Ar1 and Ar2 are each phenyl; a is an integer of from 0 to 3;R1 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 R1 may be the same or different; b is an integer of from 0 to 4;R2 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 R2 may be the same or different; W is NR4a, wherein R4a 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 (CR5aR5b)n1, wherein each n1 is 0; and V is selected from the group consisting of (CR3aR3b)pSO2N(R3b)X and, wherein p is an integer of from 0 to 2,R3a and R3b 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-[(CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d 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. [0776] In further embodiments, the compound is according to Formula 149 wherein: Ar1 and Ar2 are each phenyl; a is 0 or 1;R1 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 R1 may be the same or different; b is an integer of from 0 to 3;R2 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, alkylsulphonyl 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 R2 may be the same or different; W is NR4a, wherein R4a 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 (CR5aR5b)n1, wherein each n1 is 0; and V is a group of formula of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of 0 or 1, R3a and R3b 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— [(CR6aR6b)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, Rbc and R6d may be the same or different and each is a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms. [0777] In further embodiments, the compound is according to Formula 149 wherein: Ar1 and Ar2 are each phenyl; a is 0 or 1; R1 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 R1 may be the same or different; b is 0 to 3; R2 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 NR4a, wherein R4a 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 (CR5aR5b)n1 wherein each n1 is 0; and V is a group of formula of (CR3aR3b)pSO2N(R3b)X, wherein p is an integer of 0 or 1, each of R3a and R3b 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—[(CR6aR6b)c1— O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d is a hydrogen atom. [0778] In further embodiments, the compound is according to Formula 149 wherein: Ar1 and Ar2 are each phenyl; a is an integer of from 0 to 3; R1 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 R1 may be the same or different; b is an integer of from 0 to 4; R2 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 R2 may be the same or different; W is NR4a, wherein R4a 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 (CR3aR3b)pSO2N(R3b)X wherein p is an integer of from 0 to 2, R3a and R3b 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—[(CR6aR6c)c1—O—(CR6cR6d)c2]c3— wherein c1 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 R6a, R6b, R6c and R6d 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 [0779] 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. WO2012004698A1, 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. [0780] In an embodiment, the Kv7 channel activator is a compound according to Formula 150:
Figure imgf000535_0001
wherein, n is an integer of 1 or 2; t is 0 or 1; each R1 is independently selected from C1- 3 alkoxy, C1-3 alkyl, C1-3 alkyl-O—C1-3 alkyl; R2 and R3 are independently C1-3 alkyl, C1- 3 alkoxy, or C3-6cyloalkyl provided that at least one is C1-3 alkoxy; R4 is C1-6 alkyl, C1- 3 alkyl-C3-6cyloalkyl, C3-6 heterocycloalkyl; or a pharmaceutically acceptable salt thereof. [0781] In further embodiments, R1, R2, and R3 are each C1-3 alkoxy; wherein R4 is C4- 6 alkyl, and wherein n and t are each 1, or a pharmaceutically acceptable salt thereof. [0782] In further embodiments, R1, R2, and R3 are each methoxy; R4 is —CH2-t-butyl, and n and t are each 1, or a pharmaceutically acceptable salt thereof. [0783] In further embodiments, the compound is N-(4,6-dimethoxy-2-(4- methoxypiperidin-1-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide, or a pharmaceutically acceptable salt thereof. Formula 151 [0784] 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. WO2013060097A1, 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. [0785] In an embodiment, the Kv7 channel activator is a compound according to Formula 151:
Figure imgf000536_0001
, wherein, R1 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-C8 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 trifluoromethyl; Y is not present or Y is O;R4 is a radical selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C6-C10 aryl;R5 is a radical selected from the group consisting of H, halogen atom, amino and or R5, together with adjacent
Figure imgf000537_0002
a fused-ring structure of
Figure imgf000537_0001
R6 is H or C1-C6 alkyl. [0786] In further embodiments, the Kv7 Channel activator is selected from the group consisting of:
Figure imgf000538_0001
Figure imgf000539_0001
Figure imgf000540_0001
Formula 152 [0787] 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. [0788] In an embodiment, the Kv7 channel activator is a compound according to Formula 152:
Figure imgf000541_0001
, 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 heteroaryl;R1 is an optional substituent wherein each occurrence of R1 is independently Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, -OC(O)Ra, -OC(O)NRaRb, -NRaRb, - SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, - N(Ra)CONRaRb, -N(Ra)SO2NRaRb, -(CRzaRzb)m-CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, -(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m-OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, -(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m-S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m- C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, -(CRzaRzb)m-NRaRb,-(CRzaRzb)m-N(Ra)COORb, - (CRzaRzb)m-N(Ra)CONRaRb, -(CRzaRzb)m-N(Ra)SO2NRaRb, or -(CRzaRzb)m-Ga; p is 0, 1, 2, 3, or 4;R3 is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, -(CR3aR3b)m-G3a, or G3a; G3a, at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R4 is alkenyl, alkynyl, haloalkyl, G4a, -(CR4aR4b)n-G4a, or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R1a), 0(R1a) and N(R1a)2;each occurrence of R1a is independently hydrogen, Ga, -(CRzaRzb)m-Ga, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G4a, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G3a and G4a, at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, -OC(O)Ra, -OC(O)NRaRb, -NRaRb, - SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, - N(Ra)CONRaRb, -N(Ra)SO2NRaRb, -(CRzaRzb)m-Ga, -(CRzaRzb)m-CN, -(CRzaRzb)m-NO2, - (CRzaRzb)m-ORa, -(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m-OC(O)NRaRb, -(CRzaRzb)m-SRa, - (CRzaRzb)m-S(O)Ra, -(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m-S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, -(CRzaRzb)m-NRaRb, -(CRzaRzb)m- N(Ra)COORb, -(CRzaRzb)m-N(Ra)CONRaRb, and -(CRzaRzb)m-N(Ra)SO2NRaRb;Ga, 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, -ORa, -OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, - S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -N(Ra)COORb, - N(Ra)CONRaRb,-N(Ra)SO2NRaRb, -(CRzaRzb)m-CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa,- (CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m-OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra,- (CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m-S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m- C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, -(CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb,- (CRzaRzb)m-N(Ra)CONRaRb, and -(CRzaRzb)m-N(Ra)SO2NRaRb;Rza, Rzb, R3a, R3b, R4a, and R4b, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; Ra and Rb, 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 Z1 is benzo, p is 0 or 4, R1 is halogen, R3 is G3a, and G3a is aryl, substituted with 1 or 2 substituents selected from the group consisting of alkyl and unsubstituted aryl, then R4 is other than unsubstituted aryl, unsubstituted alkyl, or haloalkyl. [0789] In further embodiments, Z1 is benzo, heteroaryl, or cycloalkyl. [0790] In further embodiments, R3 is alkyl, halogen, haloalkyl, G3a, or -(CR3aR3b)m-G3a. [0791] In further embodiments, R4 is unsubstituted alkyl, haloalkyl, -C(R4aR4b)n-G4a, or alkyl substituted with a -S(Rla) group. [0792] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; and R4 is unsubstituted alkyl, haloalkyl, -C(R4aR4b)n-G4a, or alkyl substituted with a -S(Rla) group. In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; and R4 is -C(R4aR4b)n-G4a. [0793] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; R4 is -C(R4aR4b)n- G4a; and R3 is alkyl, halogen, haloalkyl, G3a, or -(CR3aR3b)m-G3a. [0794] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; R4 is -C(R4aR4b)n- G4a;R3 is alkyl, halogen, haloalkyl, G3a, or -(CR3aR3b)m-G3a; andG3a is aryl or cycloalkyl. [0795] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; andR4 is unsubstituted alkyl or haloalkyl. [0796] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; R4 is unsubstituted alkyl or haloalkyl; and R3 is alkyl, halogen, haloalkyl, G3a, or -(CR3aR3b)m-G3a. [0797] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; R4 is unsubstituted alkyl or haloalkyl; R3 is alkyl, halogen, haloalkyl, G3a, or -(CR3aR3b)m-G3a; and G3a is aryl or cycloalkyl. [0798] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; and R4 is alkyl substituted with a -S(Rla) group. [0799] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; R4 is alkyl substituted with a -S(Rla) group; and R3 is alkyl, halogen, haloalkyl, G3a, or -(CR3aR3b)m- G3a. [0800] In further embodiments, Z1 is benzo, cycloalkyl, or heteroaryl; R4 is alkyl substituted with a -S(Rla) group; R3 is alkyl, halogen, haloalkyl, G3a, or -(CR3aR3b)m-G3a; and G3a is aryl or cycloalkyl. [0801] 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)acetamide; 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)acetamide; 2-(4- chlorophenyl)-N-( 1 -oxo-4-phenylphthalazin-2( 1 H)-yl)acetamide; 2-(3,5- difluorophenyl)-N-(4-isopropyl-l-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]pyridazin-5(4H)-yl)acetamide; 2-(3,5-difluorophenyl)-N-[l-oxo-4- (trifluoromethyl)phthalazin-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-fluorophenyl)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)acetamide; 2-(4-chlorophenyl)-N-(4-cyclopropyl-l-oxophthalazin-2(lH)- yl)acetamide; 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]pyridazin-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)acetamide; 2- [l-(4-chlorophenyl)cyclopropyl]-N-[l-oxo-4-(trifluoromethyl)phthalazin-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)phthalazin-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-phenylacetamide; 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- thienyl)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]acetamide; 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-chloro-3-fluorophenyl)-N-[l-oxo-4-(trifluoromethyl)phthalazin-2(lH)-yl] acetamide; 2-(3-fluoroadamantan- 1-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[2.2.1]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[2.2.1]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[2.2.1]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-difluorophenyl)acetamide; (±)-2-(e o-bicyclo[2.2.1]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)acetamide; 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- 1-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-l- 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[2.2.1]heptan-2-yl)-N-[4-(4-bromophenyl)-l- oxophthalazin-2(lH)- 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- [(l 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-phenylacetamide; 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-(pyridin-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[2.2.1]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[2.2.1]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-oxophthalazin-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-oxophthalazin- 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[2.2.1]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[2.2.1]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- [(l 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-oxophthalazin-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-oxophthalazin- 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-oxophthalazin-2(lH)- yl] acetamide; 2-[(l S,2S,4S)- bicyclo[2.2.1]hept-5-en-2-yl]-N-[4-(2,4-dimethylphenyl)-l- oxophthalazin-2(lH)- yl]acetamide; (±)-2-(e o-bicyclo[2.2.1]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-tetrahydrophthalazin-2(lH)- yl)acetamide; 2-(3,5-difluorophenyl)-N-(l-oxo-4-phenyl-5,6,7,8-tetrahydrophthalazin- 2(lH)- yl)acetamide; 2-(4-chlorophenyl)-N-(l-oxo-4-phenyl-5,6,7,8-tetrahydrophthalazin- 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 [0802] 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. [0803] In an embodiment, the Kv7 channel activator is a compound according to Formula 153:
Figure imgf000550_0001
or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein, R1 is an optional substituent wherein each occurrence of R1 is independently Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, - OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, - C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, -N(Ra)CONRaRb, -N(Ra)SO2NRaRb, -(CRzaRzb)m- CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, -(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m- OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, -(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m- S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, - (CRzaRzb)m-NRaRb,-(CRzaRzb)m-N(Ra)COORb, -(CRzaRzb)m-N(Ra)CONRaRb, -(CRzaRzb)m- N(Ra)SO2NRaRb, or -(CRzaRzb)m-Ga; p is 0, 1, 2, 3, or 4;R3 is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, -(CR3aR3b)m-G3a, or G3a; G3a, at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R4 is alkenyl, alkynyl, haloalkyl, G4a, -(CR4aR4b)n-G4a, or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R1a), 0(R1a) and N(R1a)2;each occurrence of R1a is independently hydrogen, Ga, -(CRzaRzb)m-Ga, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G4a, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G3a and G4a, at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, -OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, - S(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, -N(Ra)CONRaRb, - N(Ra)SO2NRaRb, -(CRzaRzb)m-Ga, -(CRzaRzb)m-CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, - (CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m-OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, - (CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m-S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m- C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, -(CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb, - (CRzaRzb)m-N(Ra)CONRaRb, and -(CRzaRzb)m-N(Ra)SO2NRaRb;Ga, 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, -ORa, - OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, - C(O)ORa, -C(O)NRaRb, -N(Ra)COORb, -N(Ra)CONRaRb,-N(Ra)SO2NRaRb, -(CRzaRzb)m- CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa,-(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m- OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra,-(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m- S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, - (CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb,-(CRzaRzb)m-N(Ra)CONRaRb, and - (CRzaRzb)m-N(Ra)SO2NRaRb;Rza, Rzb, R3a, R3b, R4a, and R4b, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; Ra and Rb, 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 [0804] 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. [0805] In an embodiment, the Kv7 channel activator is a compound according to Formula 154:
Figure imgf000552_0001
or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, whereinR1 is an optional substituent wherein each occurrence of R1 is independently Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, - OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, - C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, -N(Ra)CONRaRb, -N(Ra)SO2NRaRb, -(CRzaRzb)m- CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, -(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m- OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, -(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m- S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, - (CRzaRzb)m-NRaRb,-(CRzaRzb)m-N(Ra)COORb, -(CRzaRzb)m-N(Ra)CONRaRb, -(CRzaRzb)m- N(Ra)SO2NRaRb, or -(CRzaRzb)m-Ga; p is 0, 1, 2, 3, or 4;R3 is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, -(CR3aR3b)m-G3a, or G3a; G3a, at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R4 is alkenyl, alkynyl, haloalkyl, G4a, -(CR4aR4b)n-G4a, or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R1a), 0(R1a) and N(R1a)2;each occurrence of R1a is independently hydrogen, Ga, -(CRzaRzb)m-Ga, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G4a, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G3a and G4a, at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, -OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, - S(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, -N(Ra)CONRaRb, - N(Ra)SO2NRaRb, -(CRzaRzb)m-Ga, -(CRzaRzb)m-CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, - (CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m-OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, - (CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m-S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m- C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, -(CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb, - (CRzaRzb)m-N(Ra)CONRaRb, and -(CRzaRzb)m-N(Ra)SO2NRaRb;Ga, 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, -ORa, - OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, - C(O)ORa, -C(O)NRaRb, -N(Ra)COORb, -N(Ra)CONRaRb,-N(Ra)SO2NRaRb, -(CRzaRzb)m- CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa,-(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m- OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra,-(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m- S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, - (CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb,-(CRzaRzb)m-N(Ra)CONRaRb, and - (CRzaRzb)m-N(Ra)SO2NRaRb;Rza, Rzb, R3a, R3b, R4a, and R4b, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; Ra and Rb, 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 [0806] 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. [0807] In an embodiment, the Kv7 channel activator is a compound according to Formula 155:
Figure imgf000554_0001
or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein R1 is an optional substituent wherein each occurrence of R1 is independently Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, - OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, - C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, -N(Ra)CONRaRb, -N(Ra)SO2NRaRb, -(CRzaRzb)m- CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, -(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m- OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, -(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m- S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, - (CRzaRzb)m-NRaRb,-(CRzaRzb)m-N(Ra)COORb, -(CRzaRzb)m-N(Ra)CONRaRb, -(CRzaRzb)m- N(Ra)SO2NRaRb, or -(CRzaRzb)m-Ga; p is 0, 1, 2, 3, or 4;R3 is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, -(CR3aR3b)m-G3a, or G3a; G3a, at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R4 is alkenyl, alkynyl, haloalkyl, G4a, -(CR4aR4b)n-G4a, or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R1a), 0(R1a) and N(R1a)2;each occurrence of R1a is independently hydrogen, Ga, -(CRzaRzb)m-Ga, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G4a, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G3a and G4a, at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, -OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, - S(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, -N(Ra)CONRaRb, - N(Ra)SO2NRaRb, -(CRzaRzb)m-Ga, -(CRzaRzb)m-CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, - (CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m-OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, - (CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m-S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m- C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, -(CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb, - (CRzaRzb)m-N(Ra)CONRaRb, and -(CRzaRzb)m-N(Ra)SO2NRaRb;Ga, 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, -ORa, - OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, - C(O)ORa, -C(O)NRaRb, -N(Ra)COORb, -N(Ra)CONRaRb,-N(Ra)SO2NRaRb, -(CRzaRzb)m- CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa,-(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m- OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra,-(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m- S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, - (CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb,-(CRzaRzb)m-N(Ra)CONRaRb, and - (CRzaRzb)m-N(Ra)SO2NRaRb;Rza, Rzb, R3a, R3b, R4a, and R4b, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; Ra and Rb, 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 [0808] 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. [0809] In an embodiment, the Kv7 channel activator is a compound according to Formula 156:
Figure imgf000556_0001
or a pharmaceutically acceptable salt, solvate, prodrug, or salt of a prodrug or solvate thereof, wherein R1 is an optional substituent wherein each occurrence of R1 is independently Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, - OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, - C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, -N(Ra)CONRaRb, -N(Ra)SO2NRaRb, -(CRzaRzb)m- CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, -(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m- OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, -(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m- S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, - (CRzaRzb)m-NRaRb,-(CRzaRzb)m-N(Ra)COORb, -(CRzaRzb)m-N(Ra)CONRaRb, -(CRzaRzb)m- N(Ra)SO2NRaRb, or -(CRzaRzb)m-Ga; p is 0, 1, 2, 3, or 4;R3 is hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, -(CR3aR3b)m-G3a, or G3a; G3a, at each occurrence, is independently aryl, cycloalkyl, or cycloalkenyl; each of which is optionally substituted;R4 is alkenyl, alkynyl, haloalkyl, G4a, -(CR4aR4b)n-G4a, or alkyl which is optionally substituted with one or two groups independently selected from the group consisting of S(R1a), 0(R1a) and N(R1a)2;each occurrence of R1a is independently hydrogen, Ga, -(CRzaRzb)m-Ga, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl;G4a, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; each of which is optionally substituted; G3a and G4a, at each occurrence, are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Ga, alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, -CN, -NO2, -ORa, -OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, - S(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb,-N(Ra)COORb, -N(Ra)CONRaRb, - N(Ra)SO2NRaRb, -(CRzaRzb)m-Ga, -(CRzaRzb)m-CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa, - (CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m-OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra, - (CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m-S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m- C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, -(CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb, - (CRzaRzb)m-N(Ra)CONRaRb, and -(CRzaRzb)m-N(Ra)SO2NRaRb;Ga, 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, -ORa, - OC(O)Ra, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)2NRaRb, -C(O)Ra, - C(O)ORa, -C(O)NRaRb, -N(Ra)COORb, -N(Ra)CONRaRb,-N(Ra)SO2NRaRb, -(CRzaRzb)m- CN, -(CRzaRzb)m-NO2, -(CRzaRzb)m-ORa,-(CRzaRzb)m-OC(O)Ra, -(CRzaRzb)m- OC(O)NRaRb, -(CRzaRzb)m-SRa, -(CRzaRzb)m-S(O)Ra,-(CRzaRzb)m-S(O)2Ra, -(CRzaRzb)m- S(O)2NRaRb, -(CRzaRzb)m-C(O)Ra, -(CRzaRzb)m-C(O)ORa, -(CRzaRzb)m-C(O)NRaRb, - (CRzaRzb)m-NRaRb, -(CRzaRzb)m-N(Ra)COORb,-(CRzaRzb)m-N(Ra)CONRaRb, and - (CRzaRzb)m-N(Ra)SO2NRaRb;Rza, Rzb, R3a, R3b, R4a, and R4b, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; Ra and Rb, 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, -CH2-, or -CH2CH2-. Formula 157 [0810] 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. WO2007087424A2, 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. [0811] In an embodiment, the Kv7 channel activator is a compound according to Formula 157:
Figure imgf000558_0001
[0812] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-5,7-Diiodo-8-hydroxyquinoline and zinc-8-Hydroxyquinoline. [0813] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-pyrrolidine dithiocarbamate, zinc-diethyldithiocarbamate, zinc- disulfiram and zinc-dimethyldithiocarbamate. [0814] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: zinc-vitamin E and zinc-vitamin A. Formula 158 [0815] 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. WO2007087424A2, 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. [0816] In an embodiment, the Kv7 channel activator is a compound according to Formula 158:
Figure imgf000558_0002
wherein, A is a bond, CH2, CHRb, CH2S, CHRbS, CH2O, CH2NRc, or NH; Rb is alkyl; Rc is H or S(O)m-aryl; R1 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted cycloalkyl, or an optionally substituted heteroaryl; R2 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,
Figure imgf000559_0002
R3 is 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 [0817] 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. WO2007087424A2, 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. [0818] In an embodiment, the Kv7 channel activator is a compound according to Formula 159:
Figure imgf000559_0001
wherein, R4 is H, an optionally substituted alkyl, an optionally substituted alkenyl, alkynyl, allyl, or an optionally substituted aryl; R5 is H, hal, or hydroxyl; R6 is H, hal, hydroxyl, NH2, a mono- or di-substituted amine, or an optionally substituted alkoxy; R7 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. [0819] 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-1,4-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- ethylsulfanyl)-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-1H-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)-1H-pyrrol-2-yl]-ethanone; 1,5-Diphenyl-1H- pyrazole-3-carboxylic acid tert-butylamide; 3-(4-Bromo-phenyl)-5-(3-phenyl-allylidene)- dihydro-pyrimidine-2,4-dione; 2-Amino-7-hydroxy-6-[(2-iodo-phenylimino)-methyl]-4- phenyl-4H-chromene-3-carbonitrile; 3-(1H-Benzoimidazol-2-yl)-6-nitro-chromen-2- ylideneamine; 6-Methoxy-3-(4-nitro-phenyl)-chroman-2-one; 2-(Benzo[1,2,5]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[1,2-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-Cyclohexyl-phenyl)-thiazol-2-ylamine. Formula 160 [0820] 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. WO2004060880A1, 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. [0821] In an embodiment, the Kv7 channel activator is a compound according to Formula 160:
Figure imgf000561_0001
wherein, R1 is C1-6alkyl, C3-7cycloalkyl, —(CH2)1-4C3-7cycloalkyl, —(CH2)2-4N(C1-6alkyl)2, —(CH2)2-4OC1-6alkyl,
Figure imgf000561_0002
hydrogen, C1-6alkyl, or — (CH2)2-4OC1-6alkyl; or where R1 and R2 taken together are —CH2CH2XCH2CH2—, where X is a chemical bond, CH2, CHOH, NH, NCH3, NCOCH3, O, or S; R3 is hydrogen or hydroxy, provided that where R3 is hydroxy, m is not 0; R4 is hydrogen, C1-6alkyl, hydroxymethyl, or trifluoromethyl; R5 is halogen, C1-6alkyl, C1-2perfluoroalkyl, C1-6alkoxy, C1-2perfluoroalkoxy, —N(R4)2, N-morpholinyl, or pyridyl; R6 is hydrogen, halogen, or C1- 6alkoxy; m is 0 or 1. [0822] In further embodiments, R3 is hydrogen and m is 1. [0823] In further embodiments, R4 is methyl. [0824] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-[2-(4-morpholinyl)ethyl]-N-[1-[3-(3-pyridinyl)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; N-[1-[3-(dimethylamino)phenyl]ethyl]-2-[2-(1- pyrrolidinyl)ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(1-pyrrolidinyl)ethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-[(2- furanylmethyl)methylamino]ethyl]-N-[(1S)-1-[3-(4-morpholinyl)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[(2-furanylmethyl)methylamino]ethyl]-N-[1- [3-(3-pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(1- pyrrolidinyl)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-[(2-furanylmethyl)methylamino]ethyl]-N-[1-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2- (diethylamino)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(diethylamino)ethyl]-N-[1-[3-(dimethylamino)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[ethyl(4-pyridinylmethyl)amino]ethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-(4- thiomorpholinyl)ethyl]-4-(trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5- thiazolecarboxamide; 2-[2-[[2-(dimethylamino)ethyl]methylamino]ethyl]-N-[1-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[[2- (dimethylamino)ethyl]methylamino]ethyl]-4-(trifluoromethyl)-N-[1-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-(4-methyl-1-piperazinyl)ethyl]- N-[1-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2- (1-piperidinyl)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; N-[1-[3-(dimethylamino)phenyl]ethyl]-2-[2-(1-piperidinyl)ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(1-piperidinyl)ethyl]-4-(trifluoromethyl)-N- [1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; N-[(1S)-1-[3-(4- morpholinyl)phenyl]ethyl]-2-[2-(1-piperidinyl)ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(4-hydroxy-1-piperidinyl)ethyl]-N-[1-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(4- hydroxy-1-piperidinyl)ethyl]-4-(trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5- thiazolecarboxamide; 2-[2-[(cyclopropylmethyl)propylamino]ethyl]-N-[1-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2- [(cyclopropylmethyl)propylamino]ethyl]-N-[1-[3-(dimethylamino)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[(cyclopropylmethyl)propylamino]ethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2- (diethylamino)ethyl]-N-[(1S)-1-[3-(3-pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(1-piperidinyl)ethyl]-N-[(1S)-1-[3-(3-pyridinyl)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[(1-ethylpropyl)amino]ethyl]-N-[1-[3- (trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[(1- ethylpropyl)amino]ethyl]-4-(trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5- thiazolecarboxamide; 2-[2-[(2-furanylmethyl)amino]ethyl]-N-[(1S)-1-[3-(3- pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2- (cyclopentylamino)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(cyclopentylamino)ethyl]-N-[(1S)-1-[3-(3- pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[2-[bis(2- methoxyethyl)amino]ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-[bis(2-methoxyethyl)amino]ethyl]-4-(trifluoromethyl)-N-[1-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-[bis(2- methoxyethyl)amino]ethyl]-N-[(1S)-1-[3-(3-pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-(4-morpholinyl)ethyl]-N-[(1S)-1-[3-(4- morpholinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; N-[1-[3- (dimethylamino)phenyl]ethyl]-2-[2-(4-thiomorpholinyl)ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-[[2-(dimethylamino)ethyl]methylamino]ethyl]-N-[1-[3- (dimethylamino)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; and 2-[2-(4- methyl-1-piperazinyl)ethyl]-N-[(1S)-1-[3-(4-morpholinyl)phenyl]ethyl]-4-(trifluoromethyl)- 5-thiazolecarboxamide. [0825] In further embodiments, R3 is hydroxy and m is 1. [0826] In further embodiments, R4 is methyl. [0827] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-[1-hydroxy-2-(1-piperidinyl)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]- 4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[1-hydroxy-2-(1-pyrrolidinyl)ethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[2-[(2- furanylmethyl)methylamino]-1-hydroxyethyl]-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)-1-hydroxyethyl]-N-[(1S)-1-[3-(4-morpholinyl)phenyl]ethyl]-4- (trifluoromethyl)-5-thiazolecarboxamide; 2-[2-(diethylamino)-1-hydroxyethyl]-N-[(1S)-1- [3-(3-pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[1-hydroxy-2- (4-morpholinyl)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[1-hydroxy-2-(4-morpholinyl)ethyl]-4-(trifluoromethyl)-N-[1-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[1-hydroxy-2-(4-methyl-1- piperazinyl)ethyl]-4-(trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5- thiazolecarboxamide; 2-[1-hydroxy-2-(4-methyl-1-piperazinyl)ethyl]-N-[(1S)-1-[3-(4- morpholinyl)phenyl]ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[1-hydroxy-2-(4- methyl-1-piperazinyl)ethyl]-N-[(1S)-1-[3-(3-pyridinyl)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[1-hydroxy-2-(1-piperidinyl)ethyl]-4-(trifluoromethyl)-N-[1-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; 2-[1-hydroxy-2-(1- pyrrolidinyl)ethyl]-N-[1-[3-(trifluoromethoxy)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; N-[1-[3-(dimethylamino)phenyl]ethyl]-2-[1-hydroxy-2-(1- pyrrolidinyl)ethyl]-4-(trifluoromethyl)-5-thiazolecarboxamide; 2-[1-hydroxy-2-(1- pyrrolidinyl)ethyl]-N-[(1S)-1-[3-(4-morpholinyl)phenyl]ethyl]-4-(trifluoromethyl)-5- thiazolecarboxamide; 2-[2-[(cyclopropylmethyl)propylamino]-1-hydroxyethyl]-4- (trifluoromethyl)-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide; and 2-[2- (4-acetyl-1-piperazinyl)-1-hydroxyethyl]-4-(trifluoromethyl)-N-[1-[3- (trifluoromethyl)phenyl]ethyl]-5-thiazolecarboxamide. [0828] In further embodiments, the compound has a stereochemical configuration according to the formula:
Figure imgf000564_0001
[0829] In further embodiments, the compound is according to the formula:
Figure imgf000564_0002
[0830] Wherein, R1is C1-6alkyl, C3-7cycloalkyl, —(CH2)1-4C3-7cycloalkyl, —(CH2)2-4N(C1- 6alkyl)2, —(CH2)2-4OC1-6alkyl,
Figure imgf000564_0003
s hydrogen C1-6alkyl, or —(CH2)2-4OC1-6alkyl; or where R1 and R2 taken together are —CH2CH2XCH2CH2—, where X is a chemical bond, CH2, CHOH, NH, NCH3, NCOCH3, O, or S; R3 is hydrogen or hydroxy, provided that where R3 is hydroxy, m is not 0; R4 is hydrogen, C1-6alkyl, hydroxymethyl, or trifluoromethyl; R5 is halogen, C1-6alkyl, C1-2perfluoroalkyl, C1-6alkoxy, C1-2perfluoroalkoxy, —N(R4)2, N-morpholinyl, or pyridyl; and m is 0 or 1; or a pharmaceutically acceptable salt thereof. Formula 161 [0831] 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. WO2004047738A2, 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. [0832] In an embodiment, the Kv7 channel activator is a compound according to Formula 161:
Figure imgf000565_0001
wherein, R is C1-4 alkyl, CF3 or hydroxymethyl; R1 and R2 are each independently hydrogen, C1-4 alkyl, halogen or morpholin-4-yl; R4 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 C1- 4alkyl, dimethylamino, hydroxymethyl, chloro and fluoro; R5 is hydrogen or fluoro; or R4 and R5 taken together are —CH═CH—CH═CH— or —CH2CH2O—; and R3, R6 and R7 are each independently selected from hydrogen or fluoro. Formula 162 [0833] 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. WO2004047738A2, 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. [0834] In an embodiment, the Kv7 channel activator is a compound according to Formula 162:
Figure imgf000566_0001
, wherein, R is methyl or hydroxymethyl; R1 and R2 are each independently hydrogen, C1- 4 alkyl, halogen or morpholin-4-yl; R4 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 C1-4alkyl, dimethylamino, hydroxymethyl, chloro and fluoro; R5 is hydrogen or fluoro; or R4 and R5 taken together are —CH═CH—CH═CH— or —CH2CH2O—; and R3, R6 and R7 are each independently selected from hydrogen or fluoro. [0835] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3-dihydro- benzofuran-5-yl)-ethyl]-amide; 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3- dihydro-benzofuran-5-yl)-ethyl]-amide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-amide; 2-(2-fluoro-phenyl)- cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide; 2-(3-fluoro- phenyl)-cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide; 2-(4- fluoro-phenyl)-cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2-yl-ethyl)-amide; 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid(2-hydroxy-1-naphthalen-2-yl-ethyl)- amide; 2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(4-fluoro-3-morpholin-4-yl- phenyl)-2-hydroxy-ethyl]-amide; 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid[1-(4- fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-amide; 2-(4-fluoro-phenyl)- cyclopropanecarboxylic acid[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]- amide; 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid[1-(4-fluoro-3-morpholin-4-yl- phenyl)-2-hydroxy-ethyl]-amide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid(1- naphthalen-2-yl-ethyl)-amide; 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid(1- naphthalen-2-yl-ethyl)-amide; 2-(4-fluoro-phenyl)-cyclopropanecarboxylic acid{1-[3-(3- dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyll}-amide; 2-(2,5-difluoro-phenyl)- cyclopropanecarboxylic acid{1-[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[1-(3-pyridin-3-yl-phenyl)-ethyl]- amide; (S)-2-phenyl-cyclopropanecarboxylic acid[1-(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{1-[3-(2-fluoro-pyridin-3-yl)- phenyl]-ethyl}-amide; and (S)-2-(2-fluoro-phenyl)-cyclopropanecarboxylic acid{1-[3-(2- fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; or a pharmaceutically acceptable salt thereof. Formula 163 [0836] 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. WO2004047743A2, 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. [0837] In an embodiment, the Kv7 channel activator is a compound according to Formula 163:
Figure imgf000567_0001
wherein, R1 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—; R2 is hydrogen or hydroxymethyl; n is an integer of 0, 1 or 2; R4 is selected from the group consisting of di(C1-4 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 R4 and R5 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 R3, R6, and R7 are each independently hydrogen or fluoro. Formula 164 [0838] 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. WO2004047743A2, 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. [0839] In an embodiment, the Kv7 channel activator is a compound according to Formula 164:
Figure imgf000569_0001
wherein, R1 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—; R2 is hydrogen; n is an integer of 0, 1 or 2; R4 is selected from the group consisting of di(C1-4 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 hydrogen or fluoro; or R4 and R5 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 R3, R6, and R7 are each independently hydrogen or fluoro. [0840] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: (R)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl- propionamide; (R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]- acrylamide; (R)-3-(3-fluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]- acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-[2-hydroxy-1-(3-morpholin-4-yl-phenyl)-ethyl]- acrylamide; (R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(2-fluoro- phenyl)-acrylamide (R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-3-(3- fluoro-phenyl)-acrylamide (R)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]- 3-(4-fluoro-phenyl)-acrylamide (R)-3-(2,4-difluoro-phenyl)-N-[1-(4-fluoro-3-morpholin-4- yl-phenyl)-2-hydroxy-ethyl]-acrylamide (R)-3-(3-fluoro-phenyl)-N-(2-hydroxy-1- naphthalen-2-yl-ethyl)-acrylamide; (R)-3-(4-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2- yl-ethyl)-acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)- acrylamide; (R)-3-(3,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)- acrylamide; (R)-4-fluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide; (R)-2,3- difluoro-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)-benzamide; (R)-2,4-difluoro-N-(2- hydroxy-1-naphthalen-2-yl-ethyl)-benzamide; (R)-3,4-difluoro-N-(2-hydroxy-1- naphthalen-2-yl-ethyl)-benzamide; (R)-2-(2,4-difluoro-phenyl)-N-(2-hydroxy-1- naphthalen-2-yl-ethyl)-acetamide; (R)-3-(2-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2- yl-ethyl)-propionamide; (R)-3-(3-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)- propionamide; (R)-3-(4-fluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)- propionamide; (R)-3-(2,4-difluoro-phenyl)-N-(2-hydroxy-1-naphthalen-2-yl-ethyl)- propionamide; (R)-3-(2-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)- ethyl]-acrylamide; (R)-3-(3-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)- ethyl]-acrylamide; (R)-3-(4-fluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)- ethyl]-acrylamide; (R)-3-(2,4-difluoro-phenyl)-N-[2-hydroxy-1-(7-methoxy-naphthalen-2- yl)-ethyl]-acrylamide; (1R, 2S)-N-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-3-(2-fluoro- phenyl)-acrylamide; (1R, 2S)-3-(2,4-difluoro-phenyl)-N-(2,3-dihydroxy-1-naphthalen-2- yl-propyl)-acrylamide; (1R, 2S)-3-(3,4-difluoro-phenyl)-N-(2,3-dihydroxy-1-naphthalen-2- yl-propyl)-acrylamide; and (1R, 2S)-3-(3,5-difluoro-phenyl)-N-(2,3-dihydroxy-1- naphthalen-2-yl-propyl)-acrylamide; or a pharmaceutically acceptable salt thereof. Formula 165 [0841] 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. WO2004047744A2, 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. [0842] In an embodiment, the Kv7 channel activator is a compound according to Formula 165:
Figure imgf000571_0001
, wherein, R1 is selected from the group consisting of straight or branched chain Cx_6 alkyl optionally substituted with amino, C alkylamino or di(C1.4 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-; R2 is CM alkyl, CF3 or hydroxymethyl; R3, R4, R5 and R6 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 [0843] 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. WO2004047744A2, 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. [0844] In an embodiment, the Kv7 channel activator is a compound according to Formula 166:
Figure imgf000572_0001
wherein, R1 is selected from the group consisting of straight or branched chain C1-6 alkyl optionally substituted with amino, C1-4 alkylamino or di(C1-4 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—; R2 is methyl or hydroxymethyl; R3, R4, R5 and R6 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—. [0845] 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-[1-(3-thiazol-2-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro- phenyl)-N-[1-(3-pyrazol-1-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-fluoro-phenyl)-N-[1-(3- imidazol-1-yl-phenyl)-ethyl]-acrylamide; (S)-4-phenyl-N-[1-(3-pyridin-3-yl-phenyl)-ethyl]- butyramide; (S)-N-[1-(3-pyridin-3-yl-phenyl)-ethyl]-benzamide; (S)-1H-imidazole-4- carboxylic acid [1-(3-pyridin-3-yl-phenyl)-ethyl]-amide; (S)-N-[1-(3-imidazol-1-yl-phenyl)- ethyl]-3-phenyl-acrylamide; (S)-N-[1-(3-oxazol-5-yl-phenyl)-ethyl]-3-phenyl-acrylamide; (S)-3-phenyl-N-[1-(3-thiazol-2-yl-phenyl)-ethyl]-acrylamide; (S)-3-phenyl-N-[1-(3- pyrazol-1-yl-phenyl)-ethyl]-acrylamide; and (S)-benzofuran-2-carboxylic acid {1-[3-(6- fluoro-pyridin-3-yl)-phenyl]-ethyl}-amide; or a pharmaceutically acceptable salt thereof. Formula 167 [0846] 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. WO2002096858A1, 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. [0847] In an embodiment, the Kv7 channel activator is a compound according to Formula 167:
Figure imgf000573_0001
, wherein, R is C1-4 alkyl or trifluoromethyl; R1 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, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, trifluoromethoxy and nitro; R2 and R3 are each independently selected from the group consisting of hydrogen, C1-4 alkyl and halogen; R4 is selected from the group consisting of di(C1-4 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 C1-4alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R5 is hydrogen, chloro or fluoro; or R4 and R5 taken together are —CH═CH— CH═CH— or —X(CH2)mY— in which X and Y are each independently selected from the group consisting of CH2, (CH2)nN(R9)— and O, wherein m is 1 or 2; n is 0 or 1; R6, R7, and R8 are each independently selected from hydrogen, chloro and fluoro; and R9 is selected from the group consisting of hydrogen, C1-4 alkyl, hydroxyethyl, C1- 4 alkoxyethyl, cyclopropylmethyl, —CO2(C1-4alkyl), and —CH2CH2NR10R11 in which R10 and R11 are each independently hydrogen or C1-4 alkyl. Formula 168 [0848] 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. WO2002096858A1, 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. [0849] In an embodiment, the Kv7 channel activator is a compound according to Formula 168:
Figure imgf000574_0001
, wherein, R1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, benzodioxanyl, 1,3-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; R4 is selected from the group consisting of optionally substituted di(C1-4 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 C1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R5 is hydrogen or fluoro; or R4 and R5 taken together are —CH═CH—CH═CH— or —X(CH2)mY—, in which X and Y are each independently selected from the group consisting of CH2, (CH2)nN(R9)— and O, wherein m is 1 or 2; n is 0 or 1; R6, R7, and R8 are each independently selected from hydrogen, chloro and fluoro; and R9 is selected from the group consisting of hydrogen, C1-4 alkyl, hydroxyethyl, C1-4 alkoxyethyl, cyclopropylmethyl, —CO2(C1-4alkyl), and —CH2CH2NR10R11 in which R10 and R11 are each independently hydrogen or C1-4 alkyl. [0850] In further embodiments, R1 is substituted phenyl or 1,3-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 R4 and R5 taken together are —X(CH2)mY— in which X and Y are each O, and m is 1. [0851] In further embodiments, R1 is selected from the group consisting of substituted phenyl, 1,3-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, C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy and trifluoromethyl; and R4 and R5 taken together are —X(CH2)mY— in which X is CH2, Y is O, and m is 1. [0852] In further embodiments, R1 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; R4 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 R5 is hydrogen or fluoro. [0853] In further embodiments, R1 is phenyl, fluorophenyl or difluorophenyl. [0854] In further embodiments, R1 is substituted phenyl or 1,3-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 R4 and R5 taken together are —X(CH2)mY— in which X and Y are O, and m is 2. [0855] In further embodiments, R1 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; R4 and R5 taken together are —X(CH2)mY— in which X is (CH2)nN(R9)—; Y is CH2, and m and n are 1; and R9 is CO2(C1-4alkyl). [0856] In further embodiments, R1 is substituted phenyl in which said substituted phenyl is substituted with one or two substituents each independently selected from halogen; R4 and R5 taken together are —X(CH2)mY— in which X is (CH2)nN(R9)— and Y is O wherein m is 2 and n is 0; and R9 is hydrogen, cyclopropylmethyl or C1-4alkyl. [0857] In further embodiments, R1 is 3-quinolinyl or pyridinyl; R4 is trifluoromethoxy; and R5 is hydrogen. [0858] In further embodiments, R1 is substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen or C1-4alkyl; R4 and R5 taken together are —X(CH2)mY—, in which X is CH2 and Y is (CH2)nN(R9)— wherein m is 1 and n is 0; and R9 is CO2(C1-4alkyl). [0859] In further embodiments, R1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R4 and R5 taken together are —X(CH2)mY—, in which X is (CH2)nN(R9)— and Y is CH2 wherein m is 2 and n is 0; and R9 is hydrogen, C1-4alkyl, acetyl, hydroxyethyl or methoxyethyl. [0860] In further embodiments, R1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R4 and R5 taken together are —X(CH2)nY—, in which X is CH2 and Y is (CH2)nN(R9)— wherein m is 2 and n is 0; and R9 is hydrogen, C1-4alkyl, acetyl, hydroxyethyl or methoxyethyl. [0861] In further embodiments, R1 is pyridinyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R4 is optionally substituted pyridinyl with one or two substituents each independently selected from C1-4 alkyl and halogen; and R5 is hydrogen or fluoro. [0862] In further embodiments, R1 is 1,3-benzodioxol-5-yl; R4 is di(C1-4alkyl)amino; and R5 is hydrogen or fluoro. [0863] In further embodiments, R1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R4 is pyrimidinyl; and R5 is hydrogen or fluoro. [0864] In further embodiments, R1 is phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R4 is pyrazinyl; and R5 is hydrogen or fluoro. [0865] In further embodiments, R1 is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from C1-4alkyl and halogen; R4 is piperazinyl or 4-methylpiperazinyl; and R5 is hydrogen or fluoro. [0866] In further embodiments, the Kv7 Channel activator is selected from the group consisting of: 2-Methyl-3-phenyl-but-2-enoic acid (1-naphthalen-2-ylethyl)-amide; N-(1- Benzo[1,3]dioxol-5-yl-ethyl)-3-(3-methoxy-phenyl)-acrylamide; N-[1-(2,3- Dihydrobenzofuran-5-yl)ethyl]-3-(3-methoxyphenyl)-acrylamide; (S)-3-Phenyl-N-[1-(3- morpholin-4-yl-phenyl)ethyl]acrylamide; 3-(3-Fluorophenyl)-N-[1-(2,3- dihydrobenzo[1,4]dioxin-6-yl)-ethyl]acrylamide; (±)-7-{1-[3-(4- Fluorophenyl)acryloylamino]ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester; 3-(2-Fluorophenyl)-N-[1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethyl]- acrylamide; (S)-N-(1-Naphthalen-2-yl-ethyl)-3-phenyl-acrylamide; (S)-3-(4-Fluoro- phenyl)-N-(1-naphthalen-2-yl-ethyl)-acrylamide; (±)-N-(1-Benzo[1,3]dioxol-5-yl-ethyl)-3- (2,4-difluoro-phenyl)-acrylamide; (±)-N-[1-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-3-(2- fluoro-phenyl)-acrylamide; (±)-3-(2,4-Difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5- yl)-ethyl]-acrylamide; (S)-3-(2,4-Difluoro-phenyl)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]- acrylamide; (S)-N-[1-(3-(2,6-Dimethyl-morpholin)-4-yl-phenyl)-ethyl]-3-phenyl- acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (S)-N-[1-(3-Morpholin-4-yl-phenyl)-ethyl]-3-thiophen-3-yl-acrylamide; (S)-3-(4-Fluoro- phenyl)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (S)-N-{1-[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-{1-[3-(cis-2,6-dimethyl-morpholin-4-yl)-phenyl]-ethyl}-acrylamide; (S)- 3-(2,5-Difluoro-phenyl)-N-{1-[3-(cis-2,6-dimethyl-morpholin-4-yl)-phenyl]-ethyl}- acrylamide; (S)-3-(2-Fluoro-phenyl)-N-{1-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}- acrylamide; (S)-3-(3-Fluoro-phenyl)-N-{1-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}- acrylamide; (S)-3-(4-Fluoro-phenyl)-N-{1-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}- acrylamide; (S)-3-(2,4-Difluoro-phenyl)-N-{1-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}- acrylamide; (S)-N-{1-[3-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)phenyl]ethyl}-3-phenyl- acrylamide; (S)-N-{1-[3-(2-Hydroxymethyl-morpholin-4-yl)-phenyl]-ethyl}-3-phenyl- acrylamide; (±)-N-[1-(3-Morpholin-4-yl-phenyl)-propyl]-3-phenyl-acrylamide; (±)-3-(2,4- Difluoro-phenyl)-N-[1-(3-morpholin-4-yl-phenyl)-propyl]-acrylamide; (±)-3-(2-Fluoro- phenyl)-N-[1-(3-morpholin-4-yl-phenyl)-propyl]-acrylamide; (±)-3-(3-Fluoro-phenyl)-N-[1- (3-morpholin-4-yl-phenyl)-propyl]-acrylamide; (±)-N-[1-(4-Fluoro-3-morpholin-4-yl- phenyl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide; (±)-N-[1-(4-Fluoro-3-morpholin-4-yl- phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide; (±)-3-(2,4-Difluoro-phenyl)-N-[1-(4-fluoro- 3-morpholin-4-yl-phenyl)-ethyl]-acrylamide; (±)-N-[1-(4-Fluoro-3-morpholin-4-yl-phenyl)- ethyl]-3-(4-fluoro-phenyl)-acrylamide; (±)-3-(3,4-Difluoro-phenyl)-N-[1-(4-fluoro-3- morpholin-4-yl-phenyl)-ethyl]-acrylamide; (±)-3-(2,5-Difluoro-phenyl)-N-[1-(4-fluoro-3- morpholin-4-yl-phenyl)-ethyl]-acrylamide; (±)-N-[1-(4-Fluoro-3-morpholin-4-yl-phenyl)- ethyl]-3-(3-fluoro-phenyl)-acrylamide; (±)-N-[1-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethyl]- 3-(2-fluoro-phenyl)-acrylamide; (±)-3-(3-Fluoro-phenyl)-N-[1-(1,2,3,4-tetrahydro-quinolin- 7-yl)-ethyl]-acrylamide; (±)-3-(4-Fluoro-phenyl)-N-[1-(1,2,3,4-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-{1-[1-(2-Hydroxy-ethyl)-1,2,3,4-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-{1-[1-(2- hydroxy-ethyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-ethyl}-acrylamide; (S)-3-Phenyl-N-[1-(3- pyridyl-phenyl)-ethyl]acrylamide; (S)-(2,4-Difluoro-phenyl)-N-[1-(3-pyridin-3-yl-phenyl)- ethyl]-acrylamide; (S)-3-Phenyl-N-[1-(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- [1-(3-pyrimidin-5-yl-phenyl)-ethyl]-acrylamide; (S)-3-Phenyl-N-[1-(3-pyridin-2-yl-phenyl)- ethyl]-acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[1-(3-pyridin-2-yl-phenyl)-ethyl]-acrylamide; (S)-3-(2-Fluoro-phenyl)-N-{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]ethyl}-acrylamide; (S)-3-(4- Fluoro-phenyl)-N-{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-acrylamide; (S)-N-{1-[3-(6- Fluoro-pyridin-3-yl)-phenyl]-ethyl}-3-pyridin-3-yl-acrylamide; (S)-N-{1-[3-(6-Fluoro- pyridin-3-yl)-phenyl]-ethyl}-3-pyridin-4-yl-acrylamide; (S)-N-{1-[3-(6-Chloro-pyridin-3-yl)- phenyl]-ethyl}-3-(3-fluoro-phenyl)-acrylamide; (S)-N-{1-[3-(6-Chloro-pyridin-3-yl)- phenyl]-ethyl}-3-pyridin-3-yl-acrylamide; (S)-N-{1-[3-(6-Chloro-pyridin-3-yl)-phenyl]- ethyl}-3-pyridin-2-yl-acrylamide; (S)-N-{1-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3- pyridin-4-yl-acrylamide; (S)-N-{1-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-(2-fluoro- phenyl)-acrylamide; (S)-N-{1-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-(2,4-difluoro- phenyl)-acrylamide; (S)-N-{1-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-(4-fluoro- phenyl)-acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[1-(3-pyridin-3-yl- phenyl)ethyl]acrylamide; (S)-N-{1-[3-(6-Fluoro-pyridin-3-yl)-phenyl]-ethyl}-3-phenyl- acrylamide; (S)-N-{1-[3-(6-Chloro-pyridin-3-yl)-phenyl]-ethyl}-3-phenyl-acrylamide; (S)- 3-(2-Fluoro-phenyl)-N-[1-(3-pyridin-4-yl-phenyl)ethyl]acrylamide; (S)-3-(2-Fluoro- phenyl)-N-[1-(3-pyrazin-2-yl-phenyl)ethyl]acrylamide; (S)-3-(2-Fluoro-phenyl)-N-[1-(3- pyrimidin-5-yl-phenyl)ethyl]acrylamide; (S)-3-(2-Fluoro-phenyl)-N-{1-[3-(4-methyl- pyridin-3-yl)phenyl]ethyl}acrylamide; (S)-3-(4-Fluorophenyl)-N-{1-[3-(4-methylpiperazin- 1-yl)phenyl]ethyl}acrylamide; and (S)-3-(2,3-Difluoro-phenyl)-N-{1-[3-(4-methyl- piperazin-1-yl)-phenyl]-ethyl}-acrylamide; or a pharmaceutically acceptable salt thereof. Formula 169 [0867] 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. WO2002096858A1, 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. [0868] In an embodiment, the Kv7 channel activator is a compound according to Formula 169:
Figure imgf000580_0001
wherein, R1 is selected from the group consisting of pyridinyl, 3-quinolinyl, 2-thienyl, benzodioxanyl, 1,3-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; R4 is selected from the group consisting of optionally substituted di(C1-4 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 C1-4 alkyl, aminomethyl, hydroxymethyl, chloro or fluoro; R5 is hydrogen or fluoro; or R4 and R5 taken together are —CH═CH—CH═CH— or —X(CH2)mY—, in which X and Y are each independently selected from the group consisting of CH2, (CH2)nN(R9)— and O, wherein m is 1 or 2; n is 0 or 1; R6, R7, and R8 are each independently selected from hydrogen, chloro and fluoro; and R9 is selected from the group consisting of hydrogen, C4 alkyl, hydroxyethyl, C1-4 alkoxyethyl, cyclopropylmethyl, —CO2(C1-4alkyl), and —CH2CH2NR10R11 in which R10 and R11 are each independently hydrogen or C1-4 alkyl. [0869] In further embodiments, R1 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 R4 and R5 taken together are —CH═CH—CH═CH—. [0870] In further embodiments, R1 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; R4 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 R5 is hydrogen or fluoro. [0871] In further embodiments, R1 is phenyl, fluorophenyl or difluorophenyl. [0872] In further embodiments, R1 is pyridinyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from halogen; R4 is optionally substituted pyridinyl with one or two substituents each independently selected from C1-4 alkyl and halogen; and R5 is hydrogen or fluoro. [0873] In further embodiments, R1 is thienyl, phenyl or substituted phenyl in which said substituted phenyl is substituted with one or two substituents selected from C1-4alkyl and halogen; R4 is piperazinyl or 4-methylpiperazinyl; and R5 is hydrogen or fluoro. Formula 170 [0874] 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. WO2001010381A2, 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. [0875] In an embodiment, the Kv7 channel activator is a compound according to Formula 170:
Figure imgf000581_0001
wherein, Ar1 and Ar2 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—R1, wherein R1 is a member selected from the group consisting of H, (C1-C8)alkyl, substituted (C1-C8)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl, substituted aryl(C1- C4)alkyl, CN, —C(O)R2, —OR3, —C(O)NR3R4, and —S(O)2NR3R4; wherein R2 is a member selected from the group consisting of (C1-C8)alkyl, substituted (C1-C8)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl and substituted aryl(C1-C4)alkyl; and R3 and R4 are each members independently selected from the group consisting of hydrogen, (C1-C8)alkyl, substituted (C1-C8)alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl and substituted aryl(C1-C4)alkyl, or R3 and R4 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. [0876] In further embodiments, Ar1 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. [0877] In further embodiments, Ar1 is substituted phenyl, substituted or unsubstituted 2- indolyl and substituted or unsubstituted 2-thienyl. [0878] In further embodiments, X is O. [0879] In further embodiments, the Ar1 substituents are selected from the group consisting of halogen, alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, nitro, cyano, —NHC(O)R7, —NHR7, phenyl and substituted phenyl, wherein R7 is a member selected from hydrogen, (C1-C8)alkyl, substituted (C1-C8)alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heterocyclyl, substituted hcterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl(C1-C4)alkyl and substituted aryl(C1-C4)alkyl, or R7 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. [0880] In further embodiments, Ar2 is selected from the group consisting of heteroaryl and substituted heteroaryl. [0881] In further embodiments, Ar1 is substituted aryl; Ar2 is heteroaryl or substituted heteroaryl; and X is O. [0882] In further embodiments, Ar2 is pyridyl or substituted pyridyl. [0883] In further embodiments, Ar2 is selected from the group consisting of 6-methyl-3- pyridyl and 2-chloro-5-pyridyl. [0884] In further embodiments, Ar1 is substituted phenyl. [0885] In further embodiments, the compound is according to the formula:
Figure imgf000583_0001
[0886] wherein, Y is a member selected from the group consisting of halogen, C1- C4 alkyl, C1-C4 substituted alkyl, —OCH3 and —OCF3, and R5 and R6 are members independently selected from the group consisting of H, halogen, alkyl, halo(C1-C4)alkyl, nitro, cyano and phenyl, with the proviso that both R5 and R6 are not H. [0887] In further embodiments, R5 and R6 are members independently selected from the group consisting of H, F, and Cl, with the optional proviso that both R5 and R6 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 TDP-43 Modulators section.) [0888] 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. WO2020092577A1, published May 7, 2020, and corresponding to International Application No. PCT/US2019/058878 filed October 30, 2019; International Publication No. WO2021119018A1, 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. [0889] 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 cyclopropyljacetamide; N- (6-cyano-l- cyclobutyl-4-fluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; N- (l- cyclobutyl-6-fluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; 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-dimethylbutanamide; N- (l- cyclobutyl-5-fluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide; 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. [0890] 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-butyramide in a crystalline form with XRPD reflections at 10.36, 12.67, 28.64 and 29.98 (°2θ) using CuKα1 radiation.; N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 8.68, 18.09, 22.60 and 30.62 (°2θ) using CuKα1 radiation.; N-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3,3-dimethyl-butyramide in a crystalline form with XRPD reflections at 8.63, 22.26, 23.40 and 30.49 (°2θ) using CuKα1 radiation. [0891] 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. [0892] 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. [0893] 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. [0894] In further embodiments, the Kv7 channel activator is selected from the group consisting of: linopirdine, (1,3-Dihydro-1-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-1-yl)phenyl)butanamide (ML252)) and UCL2077. [0895] In further embodiments, the Kv7 channel activator is an analog of flupirtine. [0896] 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[2.2.1]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-(l -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]sulfanyl-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; l-(l -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-ylpyridin-3-yl)methyl]-3-phenylbutanamide; 4-bromo-N-(thiophen-2- ylmethylideneamino)-lH-pyrazole-5-carboxamide; S-[2-[(6-fiuoro-3-prop-2-ynyl-l ,3- benzothiazol-2-ylidene)amino]-2-oxoethyl] ethanethioate; 1 -cyclohexyl-3-[l -(3,4- dimethylphenyl)ethyl]thiourea; N-[4-methyl-l -oxo-l-(l -phenylethylamino)pentan-2- yljcyclohexanecarboxamide; 5-chloro-2-[(3-methylphenyl)methylsulfonyl]-N-(5-propyl-I , 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. [0897] 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”; 31st International symposium on ALS/MND; Live Poster Session C, December 11, 2020. TDP-43 MODULATORS [0899] Amyotrophic lateral sclerosis (ALS) is a neurological disorder in which the upper and lower motor neurons progressively degenerate (Asakawa K, Handa H, Kawakami K. Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons. Nat Commun.2020 Feb 21;11(1):1004. doi: 10.1038/s41467-020-14815-x. PMID: 32081878; PMCID: PMC7035286.). The degradation of motor neurons leads to muscular atrophy and eventually paralysis. In many individuals afflicted with ALS, Trans-activation response element (TAR) DNA- binding protein 43 (TDP-43), a heterogeneous nuclear ribonucleoprotein, is incorrectly localized to the cytoplasm. In the cytoplasm is forms aggregates associated with degenerating motor neurons. TDP-43 aggregates are present in nearly all cases of sporadic ALS. Moreover, a proportion of familial ALS is associated with mutations in the TARDBP gene encoding TDP-43. Modulation of TDP-43 in combination with the metal channel activator may therefore provide a promising approach to treat neurodegenerative disease, such as ALS. [0900] Examples of TDP-43 modulators are disclosed in Formulas 200 – 220, and in the corresponding references applications. Such TDP-43 modulators are advantageously useful in combination therapies with Kv7 modulators as described herein. Formula 200 [0901] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 200. Such compounds are described in International Publication No. WO2021035101A1, published February 25, 2021, and corresponding to International Application No. PCT/US2020/047287 filed August 21, 2020; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 200, these references incorporated by reference herein control. [0902] In an embodiment, the TDP-43 modulator is a compound according to Formula 200:
Figure imgf000589_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein: X1 is selected from the group consisting of nitrogen and CH; R1a is selected from the group consisting of hydrogen, halogen, C1-20 linear alkyl, C3-20 branched alkyl, C1-20 linear heteroalkyl, C3-20 branched heteroalkyl, each of which except hydrogen and halogen are optionally substituted; R1b is selected from the group consisting of hydrogen, halogen, C1-20 linear alkyl, C3-20 branched alkyl, C1-20 linear heteroalkyl, C3-20 branched heteroalkyl, each of which except hydrogen and halogen are optionally substituted; R1c is selected from the group consisting of hydrogen, halogen, C1-20 linear alkyl, C3-20 branched alkyl, C1-20 linear heteroalkyl, C3-20 branched heteroalkyl, each of which except hydrogen and halogen are optionally substituted; and R1d is selected from the group consisting of hydrogen, halogen, C1-20 linear alkyl, C3-20 branched alkyl, C1-20 linear heteroalkyl, C3-20 branched heteroalkyl, each of which except hydrogen and halogen are optionally substituted; R2 is a substituted or unsubstituted C1-C20 linear, branched, or cyclic organic group including at least one nitrogen; and R4 is a hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted C0-C10 amino group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C2-C10 alkynyl group, and a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C10 heterocycloalkyl group, a substituted or unsubstituted C3-C10 cycloalkenyl group, a substituted or unsubstituted C2-C10 heterocycloalkenyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C6-C20 aryloxy group, a substituted or unsubstituted C6-C20 arylthio group, a substituted or unsubstituted C2-C20 heteroaryl group, a substituted or unsubstituted C2-C20 heteroaryloxy group, or a substituted or unsubstituted C2-C20 heteroarylthio group. [0903] In further embodiments, X1 is selected from the group consisting of nitrogen and CH; Rla is selected from the group consisting of hydrogen, halogen, CF3, OCF3, C1- 4 linear alkyl, C3-4 branched alkyl, (C2-8 dialkylamino)(C2-4 alkyl), (C3-6 alkyleneamino)(C2-4 alkyl), C1-4 linear alkoxy, and C3-4 branched alkoxy; Rlb is selected from the group consisting of hydrogen, halogen, CF3, OCF3, C1-4 linear alkyl, C3-4 branched alkyl, (C2-8 dialkylamino)(C2-4 alkyl), (C3-6 alkyleneamino)(C2-4 alkyl), C1- 4 linear alkoxy, and C3-4 branched alkoxy; Rlc is selected from the group consisting of hydrogen, halogen, CF3, OCF3, C1-4 linear alkyl, C3-4 branched alkyl, (C2-8 dialkylamino)(C2-4 alkyl), (C3-6 alkyleneamino)(C2-4 alkyl), C1-4 linear alkoxy, and C3- 4 branched alkoxy; Rld is selected from the group consisting of hydrogen, halogen, CF3, OCF3, C1-4 linear alkyl, C3-4 branched alkyl, (C2-8 dialkylamino)(C2-4 alkyl), (C3-6 alkyleneamino)(C2-4 alkyl), C1-4 linear alkoxy, and C3-4 branched alkoxy; wherein any two selected from the group consisting of Rla, Rlb, Rlc, and Rld are optionally connected to form a ring; R2 is selected from the group consisting of-(CH2)n-NR5R6, -(CH2)nC(0)- NR5R6,
Figure imgf000590_0001
n1 is 1 or 2; R4 is hydrogen; CF3; a five-membered monocyclic heteroaryl ring comprising at least one heteroatom selected from the group consisting from O, N, and S that is optionally substituted with up to 2 groups selected from C1-4 linear alkyl, C3-4 branched alkyl, C1-4 linear alkoxy, C3-4 branched alkoxy, CF3, CF3O, halogen, e-membered monocyclic
Figure imgf000591_0001
heteroaryl ring comprising at least one heteroatom selected from the group consisting from O, N, and S; a phenyl ring that is optionally substituted with up to 2 groups selected from C1-4 linear alkyl, C3-4 branched alkyl, C1-4 linear alkoxy, C3- 4 branched alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, CF3, CF3O, halogen,
wherein, R3a is at each occurrence independently selected from the group consisting of C1-4 linear alkyl and C3-4 branched alkyl; R3b is at each occurrence independently selected from the group consisting of C1-4 linear alkyl and C3-4 branched alkyl; R5 is selected from the group consisting of hydrogen, C1-4 linear alkyl, C3-4 branched alkyl, - CH2-(C1-6 cycloalkyl), C(0)C 1-6 linear alkyl, C(0)C3 -6 branched alkyl,
Figure imgf000593_0002
Figure imgf000593_0004
R6 is selected from the group consisting of C1-4 linear alkyl, C3-4 branched alkyl,
Figure imgf000593_0001
Figure imgf000593_0003
and an optionally substituted benzyl group wherein the optionally substituted benzyl group is substituted with 0 to 2 groups selected from the group consisting of halogen, - CN, -NO2, -OH, -NH2, Ci-6 alkyl, C3-7 branched alkyl, Ci-6 linear haloalkyl, C3-7 branched haloalkyl, Ci-6 linear alkoxy, C3-7 branched alkoxy, C1-6 linear haloalkoxy, C3- 7 branched haloalkoxy, C3-7 cycloalkyl, aryl, heterocycle, and heteroaryl, provided that when R2 is 6
Figure imgf000593_0005
, R is not hydrogen, C1-4 linear alkyl, C3-4 branched alkyl, or benzyl; n2 is 1 or 2; n3 is 0 or 1; n4 is 0 or 1; n5 is 0, 1, or 2; n6 is 0 or 1; R7 is selected from the group consisting of hydrogen and C(0)0R8; R8 is selected from the group consisting of C1-4 linear alkyl and C3-4 branched alkyl; X2 is selected from the group consisting of a single bond, oxygen, CH2, CHOH, and NR9; R9 is C1-4 linear alkyl that is optionally substituted with an NH2; R10 is selected from the group consisting of OH, OR11, NR12R13, NHSO2R22, and R11 is selected from the group consisting of C1-4 linear alkyl and C3-4 branched alkyl; R12 is selected from the group consisting of hydrogen, C1-4 linear alkyl, C3-4 branched alkyl, C1-4 linear fluoroalkyl, C(O)R14; R13 is selected from the group consisting of hydrogen, C1-4 linear alkyl, C3-4 branched alkyl, and heteroaryl; R12 and R13 are optionally taken together with the atoms to which they are connected to form a ring with 3 to 6 atoms; R14 is selected from the group consisting of C1-4 linear alkyl C3-4 branched alkyl, and R15 is selected from the group consisting of C1-4 linear alkyl and C3-4 branched alkyl; R16 is selected from the group consisting of hydrogen, C1-4 linear alkyl, C3-4 branched alkyl, CH2-(CI-6 cycloalkyl), and C(0)R18; R17 is selected from the group consisting of hydrogen, benzyl and C(0)R18; R18 is selected from the group consisting of C1-4 linear alkyl and C3-4 branched alkyl; R19 is selected from the group consisting of hydrogen and C(0)R20; R20 is selected from the group consisting of C1-4 linear alkyl and C3-4 branched alkyl; R21 is a benzene ring that is optionally substituted with 0 to 2 groups selected from the group consisting of halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C3-7 branched alkyl, C1-6 linear haloalkyl, C3- 7 branched haloalkyl, C1-6 linear alkoxy, C3-7 branched alkoxy, C1-6 linear haloalkoxy, C3-7 branched haloalkoxy, C3-7 cycloalkyl, aryl, heterocycle, and heteroaryl; R22 is selected from the group consisting of C1-4 linear alkyl, C3-4 branched alkyl, n
Figure imgf000594_0001
is 2, 3, or 4; m is 2, 3, or 4; q is 2, 3, or 4; y is 2, 3, or 4; u is 2, 3, or 4; v is 2, 3, or 4; w is 2, 3, or 4; z is 1, 2 or 3; r is 2, 3, or 4; and x is 2, 3, or 4. [0904] In further embodiments, the compound is:
Figure imgf000595_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, R5, and R6 are defined as above. [0905] In further embodiments, the compound is:
Figure imgf000595_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, R5, and R6 are defined as above. [0906] In further embodiments, the compound is:
Figure imgf000595_0003
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, R6, and R7 are defined as above. [0907] In further embodiments, the compound is:
Figure imgf000596_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein m, R1a , R1b, R1c, R1d, R4, R6, and R7 are defined as above. [0908] In further embodiments, the compound is:
Figure imgf000596_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein q, R1a , R1b, R1c, R1d, R4, R6, and R7 are defined as above. [0909] In further embodiments, the compound is:
Figure imgf000596_0003
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein q, R1a , R1b, R1c, R1d, R4, R6, and R7 are defined as above. [0910] In further embodiments, the compound is:
Figure imgf000597_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein y, R1a , R1b, R1c, R1d, R4, R6, and R7 are defined as above. [0911] In further embodiments, the compound is:
Figure imgf000597_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein y, R1a , R1b, R1c, R1d, R4, R6, and R7 are defined as above. [0912] In further embodiments, the compound is:
Figure imgf000597_0003
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein z, R1a , R1b, R1c, R1d, R4, and R6 are defined as above. [0913] In further embodiments, the compound is:
Figure imgf000598_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein z, R1a , R1b, R1c, R1d, R4, and R6 are defined as above. [0914] In further embodiments, the compound is:
Figure imgf000598_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein r, R1a , R1b, R1c, R1d, R4, and R7 are defined as above. [0915] In further embodiments, the compound is:
Figure imgf000598_0003
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein r, R1a , R1b, R1c, R1d, R4, and R7 are defined as above. [0916] In further embodiments, the compound is:
Figure imgf000599_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and R6 are defined as above. [0917] In further embodiments, the compound is:
Figure imgf000599_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and R6 are defined as above. [0918] In further embodiments, the compound is:
Figure imgf000599_0003
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, R5, and R6 are defined as above. [0919] In further embodiments, the compound is:
Figure imgf000600_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, R5, and R6 are defined as above. [0920] In further embodiments, the compound is:
Figure imgf000600_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, R5, and R6 are defined as above. [0921] In further embodiments, the compound is:
Figure imgf000600_0003
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and R6 are defined as above. [0922] In further embodiments, the compound is:
Figure imgf000601_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and u are defined as above. [0923] In further embodiments, the compound is:
Figure imgf000601_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and u are defined as above. [0924] In further embodiments, the compound is:
Figure imgf000601_0003
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and x are defined as above. [0925] In further embodiments, the compound is:
Figure imgf000602_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and x are defined as above. [0926] In further embodiments, the compound is:
Figure imgf000602_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, v, X2, and n1 are defined as above. [0927] In further embodiments, the compound is:
Figure imgf000602_0003
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, v, X2, and n1 are defined as above. [0928] In further embodiments, the compound is:
Figure imgf000603_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and w are defined as above. [0929] In further embodiments, the compound is:
Figure imgf000603_0002
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof, wherein R1a , R1b, R1c, R1d, R4, and w are defined as above. [0930] In further embodiments, the TDP-43 modulator is selected from the group consisting of: N1-(3-((2-(4-Methoxyphenyl)quinolin-4-yl)amino)propyl)-N1,N3,N3- trimethylpropane-1,3-diamine; 2-(4-Methoxyphenyl)-N-(3-{methyl[3- (methylamino)propyl]-amino}propyl)quinolin-4-amine; N1-(3-Aminopropyl)-N3-(2-(4- methoxyphenyl)quinolin-4-yl)-N1-methylpropane-l,3-diamine; N1-(2-(4- Methoxyphenyl)quinolin-4-yl)-N3-(3-(piperidin-1-yl)propyl)propane-1,3-diamine; N1-(2-(4- methoxyphenyl)quinolin-4-yl)-N3-methyl-N3-(3-(piperidin-l-yl)propyl)propane-1,3- diamine; tert-ButylN-{3-[(3-{[2-(4-methoxyphenyl)quinolin- 4yl]amino}propyl)amino]propyl}carbamate; N1-(3-aminopropyl)-N3-(5-fluoro-2-(4- methoxyphenyl)quinolin-4-yl)-N1-methylpropane-1,3-diamine:N-{3-[(3- Aminopropyl)amino]propyl}-2-(4-methoxyphenyl)quinolin-4-amine; N1-(3-Aminopropyl)- N3-(6-methoxy-2-(4-methoxyphenyl)quinolin-4-yl)-N1-methylpropane-1,3-diamine; N1-(3- Aminopropyl)-N3-(2-(2-methyl-4-methoxyphenyl)quinolin-4-yl)-N1-methylpropane-1,3- diamine; N1-(3-Aminopropyl)-N3-(6,7-dimethoxy-2-(4-methoxyphenyl)quinolin-4-yl)-N1- methylpropane-1,3-diamine; N1-(3-((2-(4-Methoxyphenyl)quinolin-4-yl)amino)propyl)- N1,N4-dimethylbutane-1,4-diamine; N1-(2-fluoroethyl)-N3-(3-((2-(4- methoxyphenyl)quinolin-4-yl)amino)propyl)-N1,N3-dimethylpropane-1,3-diamine; 3-((3- ((2-(4-Methoxyphenyl)quinolin-4-yl)amino)propyl)amino)-propan-l-ol; N-(3-(3- methoxypropylamino)propyl)-2-(4-methoxyphenyl)quinolin-4-amine; N-(3-(2-(4- Methoxyphenyl)quinolin-4-ylamino)propyl)-N-(3-aminopropyl)acetamide; N1- (Cyclopropylmethyl)-N1-(3-((2-(4-methoxyphenyl)quinolin-4-yl)amino)propyl)-N3,N3- dimethylpropane-1,3-diamine:tert-Butyl3-(((3-(dimethylamino)propyl)(3-((2-(4- methoxyphenyl)quinolin-4-yl)amino)propyl)amino)methyl)azetidine-1-carboxylate; tert- Butyl4-(((3-(dimethylamino)propyl)(3-((2-(4-methoxyphenyl)quinolin-4- yl)amino)propyl)amino)methyl)piperidine-l-carboxylate:N1-(Azetidin-3-ylmethyl)-N1-(3- ((2-(4-methoxyphenyl)quinolin-4-yl)amino)propyl)-N3,N3-dimethylpropane-1,3-diamine; N1-(3-((2-(4-Methoxyphenyl)quinolin-4-yl)amino)propyl)-N3,N3-dimethyl-N1-(piperidin-4- ylmethyl)propane-1,3-diamine; N1-(2-(4-Methoxyphenyl)quinolin-4-yl)-N3-((l-methyl-lH- imidazol-5-yl)methyl)propane-1,3-diamine; N-(3-(Hexahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)propyl)-2-(4-methoxyphenyl)quinolin-4-amine; N1-((6-Aminopyridin-3-yl)methyl)-N3-(2- (4-methoxyphenyl)-quinolin-4-yl)-N1-methylpropane-1,3-diamine; l-(Dimethylamino)-3- ((3-((2-(4-methoxyphenyl)quinolin-4-yl)-amino)propyl)(methyl)amino)propan-2-ol; 1-(3- ((3-((2-(4-Methoxyphenyl)quinolin-4-yl)amino)propyl)-methylamino)propyl)piperidin-4-ol; tert-butyl5-(3-((2-(4-methoxyphenyl)quinolin-4-yl)amino)propyl)hexahydro-pyrrolo[3,4- c]pyrrole-2(lH)-carboxylate; N1-((6-(dimethylamino)pyridin-3-yl)methyl)-N3-(2-(4- methoxyphenyl)quinolin-4-yl)-N^methylpropane-1,3-diamine; N1-(3-aminopropyl)-N1- methyl-N3-(2-(4-(piperazin-l-yl)phenyl)quinolin-4-yl)propane-1,3-diamine; N1-(2-(4- methoxyphenyl)quinolin-4-yl)-N3-methyl-N3-((l-methylpiperidin-4-yl)methyl)propane-l,3- diamine:N1-(2-(4-methoxyphenyl)quinolin-4-yl)-N3-methyl-N3-(2-(piperidin-2- yl)ethyl)propane-1,3-diamine; tert-Butyl(2-(3-((2-(4-methoxyphenyl)quinolin-4- yl)amino)propyl)octahydrocyclopenta[c]pyrrol-4-yl)carbamate:N1-(2-(4- Methoxyphenyl)quinolin-4-yl)-N3-(octahydrocyclopenta[c]pyrrol-4-yl)propane-1,3- diamine; N-(3-(4-Aminohexahydrocyclopenta[c]pyrrol-2(lH)-yl)propyl)-2-(4- methoxyphenyl)quinolin-4-amine; tert-Butyl2-(3-((2-(4-methoxyphenyl)quinolin-4- yl)amino)propyl)hexahydro-lH-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate; N-(3- (Hexahydro-lH-pyrrolo[3,4-c]pyridin-2(3H)-yl)propyl)-2-(4-methoxyphenyl)quinolin-4- amine; tert-Butyl4-((3-((2-(4-methoxyphenyl)quinolin-4- yl)amino)propyl)amino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate; N1-((l- (Cyclopropylmethyl)piperidin-4-yl)methyl)-N3-(2-(4-methoxypheny^quinolin-d-y^- N^methylpropane-1,3-diamine; N-(2-(l-(3-Aminopropyl)piperidin-2-yl)ethyl)-2-(4- methoxyphenyl)quinolin-4-amine:N1-(l-(4-Fluorobenzyl)piperidin-4-yl)-N3-(2-(4- methoxyphenyl)quinolin-4-yl)propane-1,3-diamine:tert-Butyl6-(3-((2-(4- methoxyphenyl)quinolin-4-yl)amino)propyl)-2,6-diazaspiro[3.4]octane-2-carboxylate; N- (3-(2,6-Diazaspiro[3.4]octan-6-yl)propyl)-2-(4-methoxyphenyl)quinolin-4-amine:2-(4- Methoxyphenyl)-N-(3-(4-methyl-l,4-diazepan-l-yl)propyl)quinolin-4-amine:tert-Butyl2-(2- ((3-((2-(4-methoxyphenyl)quinolin-4-yl)amino)propyl)amino)ethyl)piperidine-l- carboxylate; N1-(2-(4-methoxyphenyl)quinolin-4-yl)-N3-(2-(piperidin-2-yl)ethyl)propane- l,3-diamine; N-(3-(4-(3-Aminopropyl)piperazin-1-yl)propyl)-2-(4-methoxyphenyl)quinolin- 4-amine; tert-Butyl4-{[(3-{[2-(4-methoxyphenyl)quinolin-4- yl]amino}propyl)(methyl)amino]methyl}piperidine-1-carboxylate; N-(3-(N-Methyl-N- ((piperidin-4-yl)methyl)amino)propyl)-2-(4-methoxyphenyl)quinolin-4-amine; N-(3-((2-(4- Methoxyphenyl)quinolin-4-yl)amino)propyl)-4-(2H-tetrazol-5-yl)benzenesulfonamide; N1- (4-(2H-Tetrazol-5-yl)phenyl)-N3-(2-(4-methoxyphenyl)quinolin-4-yl)propane-l,3-diamine; (1-(3-((2-(4-Methoxyphenyl)quinolin-4-yl)amino)propyl)piperidin-4-yl)methanol; l- (Diethylamino)-3-((3-((2-(4-methoxyphenyl)quinolin-4-yl)amino)propyl)amino)propan-2- ol; N1-(2-(4-Methoxyphenyl)quinolin-4-yl)-N3-((l-methyl-lH-pyrazol-5-yl)methyl)propane- 1,3-diamine; N1-(2-(4-methoxyphenyl)quinolin-4-yl)-N3-(2-(pyridin-2-yl)ethyl)propane-l,3- diamine; N1-(2-(4-Methoxyphenyl)quinolin-4-yl)-N3-(4-(piperidin-l-yl)phenyl)propane-l,3- diamine; N-((l-(3-Aminopropyl)piperidin-3-yl)methyl)-2-(4-methoxyphenyl)quinolin-4- amine; N-(3-(2-(6-Methoxy-lH-indol-3-yl)ethylamino)propyl)-2-(4- methoxyphenyl)quinolin-4-amine:tert-Butyl4-{[({l-[(tert-butoxy)carbonyl]piperidin-4- yl}methyl)(3-{[2-(4-methoxyphenyl)-quinolin-4-yl]amino}propyl)amino]methyl}piperidine-l- carboxylate; N-(3-(Bis((piperidin-4-yl)methyl)amino)propyl)-2-(4- methoxyphenyl)quinolin-4-amine; N1-(4-Methoxybenzyl)-N3-(2-(4- methoxyphenyl)quinolin-4-yl)-N1-methylpropane-1,3-diamine; tert-Butyl(3-((4-((2-(4- methoxyphenyl)quinolin-4-yl)amino)cyclohexyl)amino)propyl)carbamate; tert-Butyl4-{[(3- {[2-(4-methoxyphenyl)quinolin-4-yl]amino}propyl)amino]methyl}piperidine-1-carboxylate; N1-(2-(4-methoxyphenyl)quinolin-4-yl)-N3-(3-(pyridin-4-ylamino)propyl)propane-1,3- diamine; 2-(3-(4-((2-(4-Methoxyphenyl)quinolin-4-yl)amino)piperidin-l- yl)propyl)isoindoline-1,3-dione; 2-(3-(3-(((2-(4-Methoxyphenyl)quinolin-4- yl)amino)methyl)piperidin-1-yl)propyl)isoindoline-1,3-dione; N-(3-((3-((2-(4- Methoxyphenyl)quinolin-4-yl)amino)propyl)amino)propyl)methanesulfonamide; 2-(3-(2- (2-((2-(4-Methoxyphenyl)quinolin-4-yl)amino)ethyl)piperidin-l-yl)propyl)isoindoline-1,3- dione; N-(3-(Hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)propyl)-2-(4- methoxyphenyl)quinolin-4-amine; 2-(4-Methoxyphenyl)-N-(l'-methyl-[l,4'-bipiperidine]-4- yl)quinolin-4-amine; N1-(2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl)-N3-(2-(4- methoxyphenyl)quinolin-4-yl)propane-1,3-diamine; N1-((l-(Cyclopropylmethyl)piperidin- 4-yl)methyl)-N3-(2-(4-methoxyphenyl)\quinolin-4-yl)propane-l,3-diamine; 1-(3-((2-(4- Methoxyphenyl)quinolin-4-yl)amino)propyl)piperidine-4-carboxamide; 2-(4- Methoxyphenyl)-N-(3-(4-methylpiperazin-l-yl)propyl)quinolin-4-amine; 2-(4- Methoxyphenyl)-N-(2-(4-methylpiperazin-l-yl)ethyl)quinolin-4-amine; 2-(4- Methoxyphenyl)-N-(3-morpholinopropyl)quinolin-4-amine; 2-(7-Amino-4-methyl-2-oxo- 2H-chromen-3-yl)-N-(3-((3-((2-(4-methoxyphenyl)quinolin-4- yl)amino)propyl)(methyl)amino)propyl)acetamide; 5-(dimethylamino)-N-{3-[(3-{[2-(4- methoxyphenyl)quinolin-4yl]amino}propyl)(methyl)amino]propyl}naphthalene-l- sulfonamide; cis-N1-(6,7-dimethoxy-2-(4-(piperazin-l-yl)phenyl)quinolin-4-yl)cyclobutane- l,3-diamine; trans-/V1-(6,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinolin-4- yl)cyclobutane-1,3-diamine; trans-N1-(6,7-dimethoxy-2-(4-(piperazin-1- yl)phenyl)quinolin-4-yl)cyclohexane-1,4-diamine; N1-(6,7-dimethoxy-2-(4-(piperazin-1- yl)phenyl)quinolin-4-yl)propane-1,3-diamine; cis-N1-(2-(4-(piperazin-1-yl)phenyl)quinolin- 4-yl)cyclobutane-1,3-diamine; N1-(2-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)- yl)phenyl)quinolin-4-yl)propane-1,3-diamine; cis-N1-(6,7-dimethoxy-2-(4-(piperazin-1- yl)phenyl)quinolin-4-yl)cyclohexane-1,4-diamine; N1-(2-(4-(piperazin-1- yl)phenyl)quinolin-4-yl)propane-1,3-diamine; N1-(6,7-dimethoxy-2-(4-(piperazin-1- yl)phenyl)quinolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine; N1-(3-aminopropyl)-N1- methyl-N3-(2-(3-(piperazin-1-yl)phenyl)quinolin-4-yl)propane-1,3-diamine; N1-(6,7- dimethoxy-2-(4-methoxyphenyl)quinolin-4-yl)cyclohexane-1,4-diamine; N1-(2-(4- (piperazin-1-yl)phenyl)quinolin-4-yl)cyclohexane-1,4-diamine; 2-amino-1-(4-(4-(4-((3- (dimethylamino)propyl)amino)quinolin-2-yl)phenyl)piperazin-1-yl)-3-methylbutan-1-one; 2-amino-1-(4-(4-(4-((3-(dimethylamino)propyl)amino)quinolin-2-yl)phenyl)piperazin-1- yl)propan-1-one; N1-(2-(l-(1-methylpiperidin-4-yl)-lH-pyrazol-4-yl)quinolin-4-yl)propane- 1,3-diamine; N1-(3-aminopropyl)-N3-(6,7-dimethoxy-2-(4-methoxyphenyl)quinolin-4-yl)- N1-methylpropane-1,3-diamine; N1-(2-(4-(piperidin-4-yl)phenyl)quinolin-4-yl)propane- 1,3-diamine; N1-(2-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)quinolin-4-yl)propane-1,3-diamine; trans-N1-(6,7-dimethoxy-2-(4-methoxyphenyl)quinolin-4-yl)cyclobutane-1,3-diamine; - dimethyl-N3-(2-(3-(piperazin-1-yl)phenyl)quinolin-4-yl)propane-1,3-diamine; -dimethyl- N3-(2-(4-(piperazin-1-yl)phenyl)quinolin-4-yl)propane-1,3-diamine; -(2-(l-(2-(pyrrolidin-1- yl)ethyl)-lH-pyrazol-4-yl)quinolin-4-yl)propane-1,3-diamine; trans-N1-(6,7-dimethoxy-2- (4-methoxyphenyl)quinolin-4-yl)cyclohexane-1,4-diamine; N-(l-(4- aminocyclohexyl)piperidin-4-yl)-2-(4-methoxyphenyl)quinolin-4-amine; -(6-fluoro-2-(4- (piperazin-1-yl)phenyl)quinolin-4-yl)-N3-dimethylpropane-1,3-diamine; N-(1-(3- aminopropyl)piperidin-4-yl)-2-(4-methoxyphenyl)quinolin-4-amine; cis-N1-(6,7- dimethoxy-2-(4-methoxyphenyl)quinolin-4-yl)cyclohexane-1,4-diamine; 2-amino-N-(1- ((1-(4-(4-(4-((3-(dimethylamino)propyl)amino)quinolin-2-yl)phenyl)piperazin-1-yl)-3- methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-3-methylbutanamide; - dimethyl-N3-(2-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)quinolin-4-yl)propane-1,3- diamine; -(6,7-dimethoxy-2-(4-methoxyphenyl)quinolin-4-yl)-N3-dimethylpropane-1,3- diamine; -(6,7-dimethoxy-2-(4-methoxyphenyl)quinolin-4-yl)propane-1,3-diamine; - dimethyl-N3-(2-(4-(4-methylpiperazin-1-yl)phenyl)quinolin-4-yl)propane-1,3-diamine; 2- amino-N-(l-(4-(4-(4-((3-(dimethylamino)propyl)amino)quinolin-2-yl)phenyl)piperazin-1- yl)-3-methyl-1-oxobutan-2-yl)-3-methylbutanamide; cis-N1-(2-(4- methoxyphenyl)quinolin-4-yl)cyclobutane-1,3-diamine; -([2,6'-biquinolin]-4-yl)propane- 1,3-diamine; 4-(4-(4-((3-(dimethylamino)propyl)amino)quinolin-2-yl)phenyl)-1- methylpiperazin-2-one; N1-(2-(piperidin-4-yl)quinolin-4-yl)propane-1,3-diamine; N1-(2- (2,3-dihydrobenzofiiran-5-yl)quinolin-4-yl)propane-l,3-diamine; N1-(2-(4-(methoxy- d3)phenyl)quinolin-4-yl)propane-1,3-diamine; N1-([2,6'-biquinolin]-4-yl)-N3- dimethylpropane-1,3-diamine; N1-(2-(4-methoxyphenyl)quinolin-4-yl)cyclobutane-1,3- diamine; N1-(2-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-4-yl)propane-l,3-diamine; N1-(2- (4-methoxyphenyl)quinolin-4-yl)cyclohexane-1,4-diamine; 2-(4-methoxyphenyl)-N- (piperidin-4-yl)quinolin-4-amine; N1-(2-(4-(methoxy-d3)phenyl)quinolin-4-yl)-N3- dimethylpropane-1,3-diamine; N1-(2-(benzofiiran-5-yl)quinolin-4-yl)-N3- dimethylpropane-1,3-diamine; N1-(2-(l-methyl-lH-pyrazol-4-yl)quinolin-4-yl)propane-1,3- diamine; N1-(2-(1-(azetidin-3-y1)-1H-pyrazol-4-yl)quinolin-4-y1)-N3,N3-dimethylpropane- 1,3-diamine; N1-(2-(l-cyclopropyl-1H-pyrazol-4-yl)quinolin-4-yl)-N3-dimethylpropane-1,3- diamine; N1-(2-(cyclohex-1-en-1-yl)quinolin-4-yl)propane-1,3-diamine; (S)-2-amino-N- (3-((2-(4-methoxyphenyl)quinolin-4-yl)amino)propyl)-N-methylpropanamide; N1-(2-(4- methoxyphenyl)quinolin-4-yl)-N3-bis(methyl-d3)propane-1,3-diamine; N1-(2-(furan-2- yl)quinolin-4-yl)propane-1,3-diamine; N1-(5-fluoro-2-(4-methoxyphenyl)quinolin-4-yl)-N3- dimethylpropane-1,3-diamine; N1-(2-(l-(2-morpholinoethyl)-lH-pyrazol-4-yl)quinolin-4- yl)propane-1,3-diamine; 3-((2-(4-methoxyphenyl)quinolin-4-yl)amino)propan-l-ol; N1-(2- (2-methoxypyrimidin-5-yl)quinolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine; N3,N3- dimethyl-N3-(2-methylquinolin-4-yl)propane-1,3-diamine; 3-((2-(4- methoxyphenyl)quinolin-4-yl)amino)-N,N-dimethylpropanamide; N1-(2-(6- methoxypyridin-3-yl)quinolin-4-yl)-N3-dimethylpropane-1,3-diamine; N1-(2,2-difluoro-6- (4-methoxyphenyl)-[1,3]dioxolo[4,5-g]quinolin-8-yl)-N3-dimethylpropane-1,3-diamine; N- (4,4-difluorocyclohexyl)-2-(4-methoxyphenyl)quinolin-4-amine; tert-butyl3-((2-(4- methoxyphenyl)quinolin-4-yl)amino)propanoate; N1-(6-methoxy-2- (trifluoromethyl)quinolin-4-yl)-N3-dimethylpropane-1,3-diamine; N1-(6-methoxy-7-(3- (pyrrolidin-l-yl)propoxy)quinolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine; 2-cyclohexyl- N-(l-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(pyrrolidin-l-yl)propoxy)quinolin-4-amine; N1-(3-aminopropy1)-N3-(6,7-dimethoxyquinolin-4-y-methylpropane-1,3-diamine; 6- methoxy--N-(l-methylpiperidin-4-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-amine; N1- (6,7-dimethoxyquinolin-4-yl)-N3,N3-diethylpropane-1,3-diamine; 6,7-dimethoxy-N-(l'- methyl-[1,4'-bipiperidin]-4-yl)quinolin-4-amine; N1-(3-aminopropy1)-N3.(7-chloroquinolin- 4-yl)-N1-methylpropane-1,3-diamine; N1-(3-aminopropyl)-N3-(2-(4- (dimethylamino)phenyl)quinolin-4-yl)-N1-methylpropane-1,3-diamine,an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug, or a complex thereof. Formula 201 [0931] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 201. Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022, and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 201, these references incorporated by reference herein control. [0932] In an embodiment, the TDP-43 modulator is a compound according to Formula 201:
Figure imgf000609_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, X, Y, and Z are each independently N or CH; R2 is an amino(C3-Cv)cycloalkyl group or a (Ci- C5alkyl)2amino(C3-Cv)cycloalkyl group, wherein the (C i-C alkyl) attached to “amino” are optionally connected to form a ring; R3 is a substituted or unsubstituted phenyl group; and R4 is an amino(C3-Cv)cycloalkyl group, a (Ci-C5alkyl)2amino(C3-Cv)cycloalkyl group wherein the (C i-C alkyl) are optionally connected to form a ring, a heterocyclyl(C2- C5)alkyloxy group, or a heteroaryl(C2-C5)alkyloxy group, wherein “heterocyclyl” is a substituted or unsubstituted nitrogen-containing non-aromatic mono-heterocycle and wherein “heteroaryl” is a substituted or substituted nitrogen-containing aromatic mono- heterocycle. [0933] In further embodiments, X is CH, Y is CH, and Z is CH. [0934] In further embodiments, X is N, Y is CH, and Z is CH. [0935] In further embodiments, X is CH, Y is N, and Z is CH. [0936] In further embodiments, X is CH, Y is CH, and Z is N. [0937] In further embodiments, X is N, Y is N, and Z is CH. [0938] In further embodiments, X is CH, Y is N, and Z is N. [0939] In further embodiments, X is N, Y is CH, and Z is N. [0940] In further embodiments, X is N, Y is N, and Z is N. [0941] In further embodiments, R2 is an amino(C3-C7)cycloalkyl group selected from an aminocyclopropyl group, an aminocyclobutyl group, an aminocyclopentyl group, an aminocyclohexyl group, or an aminocycloheptyl group, each of which has either cis- configuration or trans-configuration. [0942] In further embodiments, R2 is a (C1-C5alkyl)2amino(C3-C7)cycloalkyl group selected from a (C1-C5alkyl)2aminocyclopropyl group, a (C1-C5alkyl)2aminocyclobutyl group, a (C1-C5alkyl)2aminocyclopentyl group, a (C1-C5alkyl)2aminocyclohexyl group, or a (C1- C5alkyl)2aminocycloheptyl group, each of which has either cis-configuration or trans configuration. [0943] In further embodiments, R3 is a substituted or unsubstituted phenyl group. [0944] In further embodiments, R3 is a phenyl group, a chlorophenyl group, or a methoxyphenyl group. [0945] In further embodiments, R4 is a (C0-C5alkyl)2amino(C2-C5)alkyloxy group selected from a (C1-C5alkyl)2aminoethyloxy group, a (C1-C5alkyl)2aminopropyloxy group, a (C1- C5alkyl)2aminobutyloxy group, and a (C1-C5alkyl)2aminopentyloxy group, wherein two “(C1- C5alkyl)” are optionally connected to form a ring. [0946] In further embodiments, the ring is a substituted or unsubstituted azetidine, a substituted or unsubstituted pyrrolidine, or a substituted or unsubstituted piperidine. [0947] In further embodiments, R4 is a (C0-C5alkyl)2amino(C2-C5)alkyl group selected from a (C1-C5alkyl)2aminoethyl group, a (C1-C5alkyl)2aminopentyl group, a (C1- C5alkyl)2aminobutyl group, and a (C1-C5alkyl)2aminopentyl group, wherein two “(Ci- Csalkyl)” are optionally connected to form a ring. [0948] In further embodiments, the ring is a substituted or unsubstituted azetidine, a substituted or unsubstituted pyrrolidine, or a substituted or unsubstituted piperidine. [0949] In further embodiments, R4 is a heterocyclyl(C2-C5)alkyloxy group or a heteroaryl(C2-C5)alkyloxy group, wherein “heterocyclyl” is a substituted or unsubstituted nitrogen-containing non-aromatic mono-heterocycle and wherein “heteroaryl” is a substituted or substituted nitrogen-containing aromatic mono-heterocycle. [0950] In further embodiments, “heterocyclyl” and the “heteroaryl” are connected to the “(C2-C5)alkyloxy” through a nitrogen atom. [0951] In further embodiments, R4 is a substituted or unsubstituted pyrrolidinoethyloxy group or substituted or unsubstituted pyrrolidinopropyloxy group. [0952] In further embodiments, the compound is according to formula 201, an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, X, Y, and Z are each independently N or CH; R2 is a substituted or unsubstituted C1-C20 linear, branched, or cyclic organic group including at least one nitrogen; and R3 and R4 are each independently hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted C0-C10 amino group, a substituted or unsubstituted Ci- C10 alkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C2-C10 alkynyl group, and a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C10 heterocycloalkyl group, a substituted or unsubstituted C3- C10 cycloalkenyl group, a substituted or unsubstituted C2- C10 heterocycloalkenyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C6- C20 aryloxy group, a substituted or unsubstituted C6-C20 arylthio group, a substituted or unsubstituted C2-C20 heteroaryl group, a substituted or unsubstituted C2- C20 heteroaryloxy group, or a substituted or unsubstituted C2-C20 heteroarylthio group. [0953] In further embodiments, Formula 202 [0954] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 202. Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022 and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 202, these references incorporated by reference herein control. [0955] In an embodiment, the TDP-43 modulator is a compound according to Formula 202:
Figure imgf000612_0001
, an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, X is N or CH; R1 and R2 are the same or different and are each independently H, halogen, C1-C4 alkyl, C1- C4 alkoxy, CF3, or CF3O, wherein C1-C4 alkyl and C1-C4 alkoxy are optionally substituted with at least one fluorine; R3 is H, C1-C7 alkyl, C4-C7 carbocyclic, aryl, heteroaryl, heterocyclic, heterocyclic alkyl, wherein R3 is optionally taken together with either A or B to form a ring consisting of 4-7 ring members; R4 = phenyl or phenyl substituted with C1- C4 alkyl, C1-C4 alkoxy, CF3, CF3O, halogen, amino, or sulfonamide; A = (CH2)n, wherein n is 2-4, wherein A and R3 are optionally taken together to form a ring consisting of 4-7 ring members; B = (CH2)n, wherein n is 2-6, wherein B and R3 are optionally taken together to form a ring consisting of 4-7 members, and wherein B is optionally substituted with one or more substituents selected from C1-C4 alkyl, hydroxy, C1- C4 alkoxy, CF3, and CF3O; and Z is OH, C1-C4 alkoxy, OCF3, or N with one or more of H, C1-C4 alkyl, heteroaryl, substituted heteroaryl, C1-C4 sulfonamido, substituted amido. [0956] In further embodiments, X = CH; R1 and R2 are each H, R3 is H or Me, R4 is 4- methoxyphenyl, A is (CH2)3, B is (CH2)n, wherein n is 2-4 and Z = N(R6)2, wherein each R6 is independently H, C1-C4 alkyl, heteroaryl, substituted heteroaryl, C1- C4 sulfonamido, or substituted amido. Formula 203 - 204 [0957] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to any one of Formula 203 - 204. Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022, and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 203 - 204, these references incorporated by reference herein control. [0958] In an embodiment, the TDP-43 modulator is a compound according to any one of Formula 203 - 204:
Figure imgf000613_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, R2 is a substituted or unsubstituted C1-C20 linear, branched, or cyclic organic group including at least one nitrogen; and R3, R4, R5, and R6 are each independently hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted C0-C10 amino group, a substituted or unsubstituted Ci- C10 alkyl group, a substituted or unsubstituted C2- C10 alkenyl group, a substituted or unsubstituted C2-C10 alkynyl group, and a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C10 heterocycloalkyl group, a substituted or unsubstituted C3-C10 cycloalkenyl group, a substituted or unsubstituted C2- C 10 heterocycloalkenyl group, a substituted or unsubstituted C6-C2o aryl group, a substituted or unsubstituted C6-C20 aryloxy group, a substituted or unsubstituted C6- C20 arylthio group, a substituted or unsubstituted C2-C20 heteroaryl group, a substituted or unsubstituted C2- C20 heteroaryloxy group, or a substituted or unsubstituted C2- C20 heteroarylthio group. Formula 205 [0959] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 205. Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022, and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 205, these references incorporated by reference herein control. [0960] In an embodiment, the TDP-43 modulator is a compound according to Formula 205:
Figure imgf000614_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, R2 is a substituted or unsubstituted C1-C20 linear, branched, or cyclic organic group including at least one nitrogen; and R1a, R1b, R1c, and Rld are each independently hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted C0- C10 amino group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C2-C10 alkynyl group, and a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C 10 heterocycloalkyl group, a substituted or unsubstituted C3-C10 cycloalkenyl group, a substituted or unsubstituted C2-C10 heterocycloalkenyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C6-C20 aryloxy group, a substituted or unsubstituted C6- C20 arylthio group, a substituted or unsubstituted C2-C20 heteroaryl group, a substituted or unsubstituted C2-C20 heteroaryloxy group, or a substituted or unsubstituted C2- C20 heteroarylthio group. Formula 206 [0961] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 206. Such compounds are described in International Publication No. WO2022178338A2, published August 25, 2022, and corresponding to International Application No. PCT/US2022/017116 filed February 20, 2022; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 206, these references incorporated by reference herein control. [0962] In an embodiment, the TDP-43 modulator is a compound according to Formula 206:
Figure imgf000615_0001
an enantiomer, a diastereomer, a hydrate, a solvate, a pharmaceutically acceptable salt, an isotopic analog, a prodrug or a complex thereof, wherein, R2 is a substituted or unsubstituted C1-C20 linear, branched, or cyclic organic group including at least one nitrogen; and R1a, R1b, 1lc, R1d, and R1e are each independently hydrogen, halogen, a hydroxyl group, a cyano group, a nitro group, a substituted or unsubstituted Co-Cio amino group, a substituted or unsubstituted Ci-Cio alkyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C2-C10 alkynyl group, and a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C 10 heterocycloalkyl group, a substituted or unsubstituted C3-C10 cycloalkenyl group, a substituted or unsubstituted C2-C10 heterocycloalkenyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C6-C20 aryloxy group, a substituted or unsubstituted C6- C20 arylthio group, a substituted or unsubstituted C2-C20 heteroaryl group, a substituted or unsubstituted C2-C20 heteroaryloxy group, or a substituted or unsubstituted C2- C20 heteroarylthio group. Formula 207 - 210 [0963] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to any one of Formulas 207 - 210. Such compounds are described in International Publication No. WO2022015997A2, published January 20, 2022, and corresponding to International Application No. PCT/US2021/041852 filed July 15, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of any one of Formulas 207 - 210, this reference incorporated by reference herein control. [0964] In an embodiment, the TDP-43 modulator is a compound according to Formula 207:
Figure imgf000616_0001
N-(2-(3-hydroxypiperidin-1-yl)ethyl)-5-((3-(trifluoromethyl)phenoxy)methyl)isoxazole-3- carboxamide, or a pharmaceutically acceptable salt thereof and/or a structurally similar compound. [0965] In an embodiment, the TDP-43 modulator is a compound according to Formula 208:
Figure imgf000617_0001
1-(9-hydroxy-7-(p-tolyl)-2,3-dihydrobenzo[ ^][1,4]oxazepin-4(5H)-yl)-3-(5-methyl-1H- 1,2,4-triazol-3-yl)propan-1-one or a pharmaceutically acceptable salt thereof and/or a structurally similar compound. [0966] In an embodiment, the TDP-43 modulator is a compound according to Formula 209:
Figure imgf000617_0002
, 6-(benzo[d][1,3]dioxol-5-yl)-N-((1-isobutylpyrrolidin-3-yl)methyl)nicotinamide or a pharmaceutically acceptable salt thereof and/or a structurally similar compound. [0967] In an embodiment, the TDP-43 modulator is a compound according to Formula 210:
Figure imgf000617_0003
3-(5-(1H-indol-3-yl)-1,3,4-oxadiazol-2-yl)-N-(1,2,3,4-tetrahydronaphthalen-1- yl)propenamide or a pharmaceutically acceptable salt thereof and/or a structurally similar compound. Formula 211 - 212 [0968] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to one of Formulas 211 - 212. Such compounds are described in US Patent No.11,147,795, issued October 19, 2021, and corresponding to US Application No.16/515,743 filed July 18, 2019; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of one of Formulas 211 - 212, this reference incorporated by reference herein control. [0969] In an embodiment, the TDP-43 modulator is a compound according to one of Formulas 211 - 212:
Figure imgf000618_0001
Figure imgf000619_0001
or a pharmaceutically acceptable salt thereof, or a combination thereof, wherein * denotes a chiral center; each of R and R3a is independently hydrogen or alkyl; Ra is — CF3, —ORa1, or —NRb1Rb2; Ra1 is H or alkyl; each of Rb1 and Rb2 is independently H or alkyl; R1a is hydrogen, alkyl, or a nitrogen protecting group; each of R1, R2 and R3 is independently hydrogen, alkyl, haloalkyl, halide, vinyl, alkynyl, —CHO, — C(═O)R1b (ketone), —CO2R1c (ester), —OR1d, OSO2R1e, aryl and heteroaryl, wherein each of R1b, R1c, R1d, and R1e is independently alkyl or aryl; R2a is hydrogen, alkyl, haloalkyl, aryl, aralkyl, alkenyl, aralkenyl, cycloalkyl, heteroalkyl, heteroaryl or ester functional group; R2b is alkyl, cycloalkyl, aralkyl, alkenyl, aralkenyl, heteroalkyl, or heteroaryl; and Z is a conjugated electron withdrawing group. [0970] In further embodiments, R1a, R1, and R3 are H, R2 is halide, and R is alkyl. [0971] In further embodiments, * is an (R)- or (S)-configuration and R2b is alkyl, Z is an ester, and R2a is alkenyl or heteroaryl. [0972] In further embodiments, diastereomeric excess of said compound is at least 90% d.e. [0973] In further embodiments, the TDP-43 modulator of formula 212 is selected from the group consisting of:
Figure imgf000620_0001
wherein R2a is alkenyl; and
Figure imgf000620_0002
wherein R2a is heteroaryl. [0974] In further embodiments, the TDP-43 modulator is selected from the group consisting of:
Figure imgf000620_0003
or a pharmacologically acceptable salt thereof. Formula 213 [0975] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 213. Such compounds are described in International Publication No. WO2021025723A1, published February 11, 2021, and corresponding to International Application No. PCT/US2020/000030 filed July 312020; US Publication No. US20210052519A1, published February 25, 2021, and corresponding to US Application No.16/873,866 filed July 31, 2020; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 213, these references incorporated by reference herein control. [0976] In an embodiment, the TDP-43 modulator is a compound according to Formula 213:
Figure imgf000621_0001
, wherein, R1 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R3 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R4 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R5 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R6 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R20 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R21 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R22 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R23 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R24 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R25 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R26 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R27 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R28 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; and R29 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. [0977] In further embodiments, R1 is hydrogen, alkyl or acyl. [0978] In further embodiments, R3-R6 are independently hydrogen or alkyl. [0979] In further embodiments, R20-R24 are independently hydrogen, alkyl or halogen. [0980] In further embodiments, R25-R29 are independently hydrogen, alkyl or halogen. Formula 214 [0981] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 214. Such compounds are described in International Publication No. WO2021025723A1, published February 11, 2021, and corresponding to International Application No. PCT/US2020/000030 filed July 312020; US Publication No. US20210052519A1, published February 25, 2021, and corresponding to US Application No.16/873,866 filed July 31, 2020; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 214, these references incorporated by reference herein control. [0982] In an embodiment, the TDP-43 modulator is a compound according to Formula 214:
Figure imgf000624_0001
wherein, R1 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R3 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R4 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R5 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R6 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R7 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R8 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R20 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R21 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R22 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R23 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R24 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R25 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R26 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R27 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; R28 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon; and R29 is hydrogen, acyl, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, arylalkyl, aryloxy, aryloxyalkyl, electron withdrawing group, halogen, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, hydroxy, mercapto, saturated cyclic hydrocarbon, substituted alkenyl, substituted alkyl, substituted alkynyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted heterocyclic, or unsaturated cyclic hydrocarbon. [0983] In further embodiments, R1 is hydrogen, alkyl or acyl. [0984] In further embodiments, R3-R6 are independently hydrogen or alkyl. [0985] In further embodiments, R20-R24 are independently hydrogen, alkyl or halogen. [0986] In further embodiments, R25-R29 are independently hydrogen, alkyl or halogen. Formula 215 [0987] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 215. Such compounds are described in US Publication No. US20170369474A1, published December 28, 2017, and corresponding to US Application No.15/533,339 filed December 4, 2015; International Publication No. WO2016090313A1, published June 9, 2016, and corresponding to International Application No. PCT/US2015/064103 filed December 4, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 215, these references incorporated by reference herein control. [0988] In an embodiment, the TDP-43 modulator is a compound according to Formula 215:
Figure imgf000628_0001
, wherein, Ring A is heteroaryl; R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —NRBC(O)RD, or —SRE, each of which is optionally substituted with 1-5 R7; R2 is H, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1- C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —ORA, or — SRE, each of which is optionally substituted with 1-5 R8; each of R3 and R4 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —NRBC(O)RD, —NRBC(O)NRBRC, —SRE, — S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —ORA, —C(O)RD, —C(O)ORA, —C(O)NRBRC, or —SRE, each of which is optionally substituted with 1-5 R9; or R5, together with the nitrogen atom to which it is attached, forms a heterocyclyl or heteroaryl ring with Ring A, optionally substituted with 1-3 R9; each R6 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cyano, hydroxy, halo, — ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, — NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9; each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, each of which is optionally substituted with 1-4 occurrences of R7; or RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7; each R7, R8, or R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —ORa, —NRbRc, —C(O)Rd, —C(O)ORa, —C(O)NRbRc, —NRbC(O)Rd, — NRbC(O)NRbRc, —SRe, —S(O)Re, —S(O)2Re, —NRbS(O)2Re, or —S(O)2NRbRc, each of which is optionally substituted with 1-5 R10; each R10 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, hydroxy, cyano, or nitro, each of which is optionally substituted with 1-4 R11; each Ra, Rb, Rc, Rd, or Re is H, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R11; or RB and RC, together with the atoms to which each is attached, form a cycloalkyl or heterocyclyl ring optionally substituted with 1-4 R11; each R11 is independently C1- C6 alkyl, halo, hydroxy, cycloalkyl, alkoxy, keto, cyano, or nitro; and n is 0, 1, 2, 3, 4, or 5. [0989] In further embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, cycloalkyl, —ORA, or — NRBRC, and RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7. [0990] In further embodiments, R1 is —NRBRC, and RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7. [0991] In further embodiments, R1 is selected from the group consisting of
Figure imgf000630_0001
[0992] In further embodiments, R2 is H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R8. [0993] In further embodiments, each of R3 and R4 is independently H, C1-C6 alkyl, C2- C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, or —NRBC(O)RD, each of which is optionally substituted with 1-5 R9. [0994] In further embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R9. [0995] In further embodiments, Ring A is a monocyclic or bicyclic heteroaryl. [0996] In further embodiments, Ring A is a 5- or 6-membered monocyclic heteroaryl. [0997] In further embodiments, R6 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —S(O)2RE, — NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9. [0998] In further embodiments, R6 is C1-C6 alkyl, cyano, hydroxy, halo, —ORA, or — NRBRC. [0999] In further embodiments, n is 0, 1, or 2. [1000] In further embodiments, the TDP-43 modulator is a compound of formula 215 or a pharmaceutically acceptable salt thereof, wherein, Ring A is aryl; R1 is C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —NRBC(O)RD, or —SRE, each of which is optionally substituted with 1-5 R7; R2 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —C(O)RD, — C(O)ORA, —C(O)NRBRC, —ORA, or —SRE, each of which is optionally substituted with 1-5 R8; each of R3 and R4 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —NRBC(O)RD, — NRBC(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —ORA, —C(O)RD, —C(O)ORA, —C(O)NRBRC, or —SRE, each of which is optionally substituted with 1-5 R9; or R5, together with the nitrogen atom to which it is attached, forms a heterocyclyl or heteroaryl ring with Ring A, optionally substituted with 1-3 R9; each R6 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —SRE, — S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9; each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1- C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, each of which is optionally substituted with 1-4 occurrences of R7; or RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7; each R7, R8, or R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1- C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —ORa, —NRbRc, —C(O)Rd, —C(O)ORa, —C(O)NRbRc, —NRbC(O)Rd, —NRbC(O)NRbRc, —SRe, —S(O)Re, —S(O)2Re, —NRbS(O)2Re, or — S(O)2NRbRc, each of which is optionally substituted with 1-5 R10; each R10 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, hydroxy, cyano, or nitro, each of which is optionally substituted with 1-4 R11; each Ra, Rb, Rc, Rd, or Re is H, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R11; or RB and RC, together with the atoms to which each is attached, form a cycloalkyl or heterocyclyl ring optionally substituted with 1-4 R11; each R11 is independently C1- C6 alkyl, halo, hydroxy, cycloalkyl, alkoxy, keto, cyano, or nitro; and n is 0, 1, 2, 3, 4, or 5; provided that when R2 is CH3, Ring A is not
Figure imgf000632_0001
[1001] In further embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, cycloalkyl, —ORA, or — NRBRC and RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7. [1002] In further embodiments, R1 is —NRBRC, and RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7. [1003] In further embodiments, R1 is selected from the group consisting of
Figure imgf000632_0002
[1004] In further embodiments, R2 is H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R8. [1005] In further embodiments, each of R3 and R4 is independently H, C1-C6 alkyl, C2- C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, or —NRBC(O)RD, each of which is optionally substituted with 1-5 R9. [1006] In further embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R9. [1007] In further embodiments, Ring A is a monocyclic fused aryl. [1008] In further embodiments, R6 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —S(O)2RE, — NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9. [1009] In further embodiments, R6 is C1-C6 alkyl, cyano, hydroxy, halo, —ORA, or — NRBRC. [1010] In further embodiments, n is 0, 1, or 2. [1011] In further embodiments, Ring A is selected from the group consisting of:
Figure imgf000633_0001
[1012] In further embodiments, Ring A is
Figure imgf000633_0002
[1013] In further embodiments, the compound is
Figure imgf000634_0001
or a pharmaceutically acceptable salt thereof. [1014] In further embodiments, the compound is
Figure imgf000634_0002
or a pharmaceutically acceptable salt thereof. Formula 216 [1015] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 216. Such compounds are described in US Publication No. US20170360726A1, published December 21, 2017 and corresponding to US Application No.15/533,354 filed December 4, 2015; International Publication No. WO2016090317A1, published June 9, 2016 and corresponding to International Application No. PCT/US2015/064107 filed December 4, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 216, these references incorporated by reference herein control. [1016] In an embodiment, the TDP-43 modulator is a compound according to Formula 216:
Figure imgf000634_0003
or a pharmaceutically acceptable salt thereof, wherein, Ring A is aryl or heteroaryl; Ring B is 6-membered aryl or 5- or 6-membered heteroaryl; R″ is H or C(O)R1; R1 is C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1- C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —NRBC(O)RD, or —SRE, each of which is optionally substituted with 1-5 R7; each R is independently H, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, — C(O)NRBRC, —NRBC(O)RD, —NRBC(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, — NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R8; R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1- C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, — C(O)RD, —C(O)ORA, —C(O)NRBRC, —ORA, or —SRE, each of which is optionally substituted with 1-5 R9; or R5, together with the nitrogen atom to which it is attached, forms a heterocyclyl or heteroaryl ring with Ring A, optionally substituted with 1-3 R9; each R6 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, — C(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9; each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, each of which is optionally substituted with 1-4 occurrences of R7; or RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7; each R7, R8, or R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —ORa, —NRbRc, —C(O)Rd, — C(O)ORa, —C(O)NRbRc, —NRbC(O)Rd, —NRbC(O)NRbRc, —SRe, —S(O)Re, — S(O)2Re, —NRbS(O)2Re, or —S(O)2NRbRc, each of which is optionally substituted with 1-5 R10; each R10 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, hydroxy, cyano, or nitro, each of which is optionally substituted with 1-4 R11; each Ra, Rb, Rc, Rd, or Re is H, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R11; or RB and RC, together with the atoms to which each is attached, form a cycloalkyl or heterocyclyl ring optionally substituted with 1-4 R11; each R11 is independently C1-C6 alkyl, halo, hydroxy, cycloalkyl, alkoxy, keto, cyano, or nitro; n is 0, 1, 2, 3, 4, or 5; and p is 0, 1, or 2; provided that Ring B is not
Figure imgf000636_0001
wherein the connection to C(O)R1 and N(R5)S(O)2— is as shown. [1017] In further embodiments, R″ is H or C(O)R1. [1018] In further embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, cycloalkyl, —ORA, or — NRBRC, and RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4R7. [1019] In further embodiments, R1 is —NRBRC, and RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7. [1020] In further embodiments, R1 is selected from the group consisting of
Figure imgf000636_0002
[1021] In further embodiments, each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, or — NRBC(O)RD, each of which is optionally substituted with 1-5 R8. [1022] In further embodiments, each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halo, each of which is optionally substituted with 1-5 R8. [1023] In further embodiments, R is H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R8. [1024] In further embodiments, R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-5 R9. [1025] In further embodiments, Ring A is a monocyclic or bicyclic aryl or heteroaryl. [1026] In further embodiments, Ring A is phenyl or a 5- or 6-membered heteroaryl. [1027] In further embodiments, R6 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —S(O)2RE, — NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9. [1028] In further embodiments, Ring A is selected from the group consisting of:
Figure imgf000637_0001
[1029] In further embodiments, Ring A is
Figure imgf000637_0002
and R6 is C1-C6 alkyl or halo. [1030] In further embodiments, Ring B is phenyl. [1031] In further embodiments, Ring B is selected from:
Figure imgf000637_0003
[1032] In further embodiments, Ring B is a 5- or 6-membered heteroaryl. [1033] In further embodiments, Ring B is selected from:
Figure imgf000638_0001
wherein the connectivity to —S(O)2 is indicated by a wavy line and the connectivity to R″ is as shown. [1034] In further embodiments, n is 0, 1, or 2 and p is 0 or 1. Formula 217 [1035] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 217. Such compounds are described in US Publication No. US20170360726A1, published December 21, 2017, and corresponding to US Application No.15/533,354 filed December 4, 2015; International Publication No. WO2016090317A1, published June 9, 2016, and corresponding to International Application No. PCT/US2015/064107 filed December 4, 2015; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 217, these references incorporated by reference herein control. [1036] In an embodiment, the TDP-43 modulator is a compound according to Formula 217:
Figure imgf000638_0002
, or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or C(RD)2, and Ring A, R, R″, R5, R6, RD, n, p and subvariables thereof are defined as for Formula 216. [1037] In further embodiments, the TDP-43 modulator is selected from the group consisting of:
Figure imgf000639_0001
or a pharmaceutically acceptable salt thereof. Formula 218 [1038] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 218. Such compounds are described in International Publication No. WO2012162249A1, published November 29, 2012, and corresponding to International Application No. PCT/US2012/038861 filed May 21, 2012; US Patent No.9,359,363, issued June 7, 2016, and corresponding to US Application No.14/118,628 filed May 21, 2012; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 218, these references incorporated by reference herein control. [1039] In an embodiment, the TDP-43 modulator is a compound according to Formula 218:
Figure imgf000639_0002
and analogs, derivatives, isomers, prodrugs, and pharmaceutically acceptable salts thereof wherein, R11 and R12 are independently H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, C(O)R17, or C(O)OR17, each of which can be optionally substituted. In some embodiments, R11 is an optionally substituted aryl or heteroaryl; R13 and R14 are independently H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, OR17, C(O)R17, or C(O)OR17, N(R17)2, each of which can be optionally substituted; R15 is independently, halo, alkyl, alkenyl, cyclyl, heterocyclyl, aryl, heteroaryl, NO2, OR17, OC(O)R17, OC(O)OR17, N(R17)2, NHC(O)R17, NHC(O)OR17, C(O)R17, C(O)OR17, SR17, or SO2R17, each of which can be optionally substituted; b is 0, 1, 2, 3, or 4; c is 0, 1, 2, 3, 4, or 5; and when present a R16 substituent can be located at the 2, 3, 4, 5, or 6 position of the phenyl group. [1040] In further embodiments, the TDP-43 modulator is selected from the group consisting of:
Figure imgf000641_0001
Figure imgf000642_0001
Formula 219 [1041] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 219. Such compounds are described in US Publication No. US20220160699A1, published May 26, 2022 and corresponding to US Application No.17/310,971 filed March 16, 2020; International Publication No. WO2020190866A1, published September 24, 2020 and corresponding to International Application No. PCT/US2020/022972 filed March, 16, 2020; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 219, these references incorporated by reference herein control. [1042] In an embodiment, the TDP-43 modulator is a compound according to Formula 219:
Figure imgf000643_0001
wherein, R1 is H, OH, or lower alkyl; R2 is an optionally substituted aromatic ring of four, five, or six carbons, wherein the aromatic ring is carbocyclic or heterocyclic, and wherein each position on the aromatic ring is independently H, halo, lower alkyl, OH, lower alkoxy, NH2, lower alkylamino, di(lower alkyl)amino, SH, lower alkylthio, NO2, or two residues together form a heterocyclic ring; R3 and R8 are each independently H, lower alkyl, ═O, ═S, OH, NH2, aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH2, lower alkyl, lower alkoxy, SH, lower alkylthio, and lower alkylamino R4, R5, R6, and R7 are each independently H, lower alkyl, OH, NH2, aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH2, lower alkyl, lower alkoxy, SH, lower alkylthio, and lower alkylamino; at least one of R9 and R10, R10 and R11, or R11 and R12, together form an optionally substituted benzene ring, wherein the benzene ring is optionally substituted with H, halo, lower alkyl, OH, lower alkoxy, or NO2; and wherein any one of the carbon atoms on any one of fused rings of Formula 219 is optionally replaced with a nitrogen atom. [1043] In further embodiments, the TDP-43 modulator is selected from the group consisting of:
Figure imgf000644_0001
Figure imgf000645_0001
Figure imgf000646_0001
, or a pharmaceutically acceptable salt thereof. [1044] In further embodiments, the compound is according to Formula 219 wherein the compound is according to any one of the subformulas:
Figure imgf000646_0002
, wherein, R1 is H, OH, or lower alkyl; R2, is an optionally substituted aromatic ring of four, five, or six carbons, wherein the aromatic ring is carbocyclic or heterocyclic, and wherein each position on the aromatic ring is independently H, halo, lower alkyl, OH, lower alkoxy, NH2, lower alkylamino, di(lower alkyl)amino, SH, lower alkylthio, NO2, or two residues together form a heterocyclic ring; R3 and R8 are each independently H, lower alkyl, ═O, ═S, OH, NH2, aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH2, lower alkyl, lower alkoxy, SH, lower alkylthio, and lower alkylamino; R4, R5, R6, and R7 are each independently H, lower alkyl, OH, NH2, aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH2, lower alkyl, lower alkoxy, SH, lower alkylthio, and lower alkylamino; R8, R9, R10, R11, R12, R13, R14 are each independently H, halo, lower alkyl, OH, lower alkoxy, or NO2; and wherein any one of the carbon atoms on any one of fused rings is optionally replaced with a nitrogen atom. [1045] In further embodiments, the compound is according to Formula 219 wherein the compound is according to the subformulas:
Figure imgf000647_0001
wherein, R1 is H, OH, or lower alkyl; R2 is an optionally substituted aromatic ring of four, five, or six carbons, wherein the aromatic ring is carbocyclic or heterocyclic, and wherein each position on the aromatic ring is independently H, halo, lower alkyl, OH, lower alkoxy, NH2, lower alkylamino, di(lower alkyl)amino, SH, lower alkylthio, NO2, or two residues together form a heterocyclic ring; R3, R4, R5, R6, and R7 are each independently H, lower alkyl, OH, NH2, aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH2, lower alkyl, lower alkoxy, SH, lower alkylthio, and lower alkylamino; at least one of R8 and R9, R9 and R10, or R10 and R11 together form an optionally substituted benzene ring, wherein the benzene ring is optionally substituted with H, halo, lower alkyl, OH, lower alkoxy, or NO2; and wherein any one of the carbon atoms on any one of fused rings is optionally replaced with a nitrogen atom. [1046] In further embodiments, the compound is according to Formula 219 wherein the compound is according to any one of the subformulas:
Figure imgf000648_0001
wherein, R1 is H, OH, or lower alkyl; R2 is an optionally substituted aromatic ring of four, five, or six carbons, wherein the aromatic ring is carbocyclic or heterocyclic, and wherein each position on the aromatic ring is independently H, halo, lower alkyl, OH, lower alkoxy, NH2, lower alkylamino, di(lower alkyl)amino, SH, lower alkylthio, NO2, or two residues together form a heterocyclic ring; R3, R4, R5, R6, and R7 are each independently H, lower alkyl, OH, NH2, aryl, or aralkyl, where aryl and aralkyl are substituted with 0-3 moieties selected from the group consisting of halo, OH, NH2, lower alkyl, lower alkoxy, SH, lower alkylthio, and lower alkylamino; R8, R9, R10, R11, R12, and R13 are each independently H, halo, lower alkyl, OH, lower alkoxy, or NO2; and wherein any one of the carbon atoms on any one of fused rings is optionally replaced with a nitrogen atom. Formula 220 [1047] In an embodiment, the TDP-43 modulator is AIM4, a compound according to formula 220 described in Prasad, A., Raju, G., Sivalingam, V. et al. An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models. Sci Rep 6, 39490 (2016), which is incorporated by reference in its entirety herein:
Figure imgf000649_0001
Formula 221 [1048] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 221. Such compounds are described in International Publication No. WO2022049377A1, published March 10, 2022, and corresponding to International Application No. PCT/GB2021/052262 filed September 1, 2021; 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 control. [1049] In an embodiment, the TDP-43 modulator is a compound according to Formula 221:
Figure imgf000649_0002
wherein, R1a is H or methyl; R1b is H or fluoro; A is group (Aa), (Ab), (Ac) or (Ad): wherein group (Aa) is:
Figure imgf000650_0001
Aa); wherein: R2 is H, C1-4alkyl, C1- 4alkylene(aryl), C1-4alkylene(OH), C1-4alkylene(C3-6cycloalkyl), C1- 4alkylene(4-7 membered heterocycloalkyl), C1-4alkoxy, OC1-4alkylene(aryl), C1- 4alkyleneOC1-4alkyl, C1-4alkyleneOC3-6cycloalkyl, C1-4alkyleneO(4-7 membered heterocycloalkyl), C1- 4alkyleneO(aryl), C3-6alkynyl and C1-4alkyleneO(C3-6alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl are optionally substituted by 1, 2 or 3 substituents each independently selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1- 4haloalkyl, halo, CN, OH, NR2aR2b, SO2R2c and NHSO2R2c; R2a is selected from H and C1-4alkyl; R2b is selected from H, C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R2c is selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1- 4haloalkyl, aryl and 4-7 membered heterocycloalkyl; each R3 is independently halo, methyl, ethyl or n-propyl; m is 0, 1, 2, 3 or 4; wherein group (Ab) is:
Figure imgf000650_0002
wherein: R4 is H, C1-4alkyl or C1-4alkylene(aryl); wherein said aryl is optionally substituted by 1, 2 or 3 substituents each independently selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1-4haloalkyl, halo, CN, OH, NR4aR4b, SO2R4c and NHSO2R4c; R4a is selected from H and C1-4alkyl; R4b is selected from H, C1-4alkyl, C3- 6cycloalkyl, C1-4alkoxy, C1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R4c is selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R5 is H or C1-4alkyl; each R6 is independently C1-4alkyl or halo; n is 0, 1, 2 or 3; wherein group (Ac) is: (Ac); wherein: R7 is C1-4alkyl, C1-
Figure imgf000650_0003
4alkylene(OH) or C1-4alkyleneOC1-4alkyl; o is 1 or 2; wherein group (Ad) is:
Figure imgf000651_0001
(Ad); wherein: X is a bond, O or CH2; each R8 is independently halo, C1-4alkyl, C1-4alkoxy OC1-4haloalkyl, OC1-4alkylene(C3- 6cycloalkyl), OC1-4alkylene(4-7 membered heterocycloalkyl) or OH; wherein said heterocycloalkyl and cycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1-4haloalkyl, halo, CN, OH, NR8aR8b, SO2R8c and NHSO2R8c; R8a is selected from H and C1-4alkyl; R8b is selected from H, C1- 4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; R8c is selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1-4haloalkyl, aryl and 4-7 membered heterocycloalkyl; each R9 is independently halo or C1-4alkyl; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; wherein B is:
Figure imgf000651_0002
erein: R10 is H, halo or C1-4alkyl; D, E and F are each independently C(R10); or one of D, E and F is N and the two remaining D, E and F groups are independently C(R10); and provided that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H- indazol-6-yl)acrylamide; or a pharmaceutically acceptable salt and/or solvate thereof. [1050] In further embodiments, R1a is H or methyl; R1b is H or fluoro; A is group (Aa), (Ab), (Ac) or (Ad): wherein group (Aa) is:
Figure imgf000651_0003
(Aa); wherein: R2 is H, C1- 4alkyl, C1-4alkylene(aryl), C1-4alkylene(OH), C1-4alkylene(C3-6cycloalkyl), C1- 4alkylene(4- 7 membered heterocycloalkyl), C1-4alkoxy, OC1-4alkylene(aryl), C1- 4alkyleneOC1-4alkyl, C1-4alkyleneOC3-6cycloalkyl, C1-4alkyleneO(4-7 membered heterocycloalkyl), C1- 4alkyleneO(aryl), C3-6alkynyl or C1-4alkyleneO(C3-6alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl may be optionally substituted by up to 3 substituents each independently selected from C1-4alkyl, C3-6cycloalkyl, C1-4alkoxy, C1- 4haloalkyl, halo and CN; each R3 is independently halo, methyl, ethyl or n-propyl; m is 0, 1, 2, 3 or 4; wherein group (Ab) is:
Figure imgf000652_0001
(Ab); wherein: R4 is H, C1-4alkyl or C1- 4alkylene(aryl); wherein said aryl may be optionally substituted by up to 3 substituents each independently selected from C1-4alkyl, C3-6cycloalkyl, C1- 4alkoxy, C1-4haloalkyl, halo and CN; R5 is H or C1-4alkyl; each R6 is independently C1-4alkyl or halo; n is 0, 1, 2 or 3; wherein group (Ac) is:
Figure imgf000652_0002
(Ac); wherein: R7 is C1-4alkyl, C1- 4alkylene(OH) or C1-4alkyleneOC1-4alkyl; o is 1 or 2; wherein group (Ad) is:
Figure imgf000652_0003
(Ad); wherein: X is a bond, O or CH2; each R8 is independently halo, C1-4alkyl, C1-4alkoxy or OH; each R9 is independently halo or C1- 4alkyl; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; wherein B is: ein: R10 is
Figure imgf000652_0004
H, halo or C1-4alkyl; and D, E and F are each independently C(R10); or one of D, E and F is N and the two remaining D, E and F groups are independently C(R10); provided that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H- indazol-6- yl)acrylamide; or a pharmaceutically acceptable salt and/or solvate thereof. [1051] In further embodiments, R2 is C1-4alkyl, C1- 4alkylene(aryl), C1-4alkylene(OH), C1- 4alkyleneOC1-4alkyl, C1-4alkyleneOC3-6cycloalkyl, C1- 4alkyleneO(aryl), C1-4alkylene(4-7 membered heterocycloalkyl), C1-4alkyleneO(4-7 membered heterocycloalkyl) and C1- 4alkyleneO(C3-6alkynyl); wherein said aryl, heterocycloalkyl or cycloalkyl may be optionally substituted by up to 3 substituents each independently selected from C1- 4alkyl, C3-6cycloalkyl; C1-4alkoxy, C1-4haloalkyl, halo and CN. [1052] In further embodiments, the aryl is unsubstituted. [1053] In further embodiments, the aryl is substituted by 1, 2 or 3 substituents independently selected from methyl, chloro and fluoro. [1054] In further embodiments, the heterocycloalkyl is unsubstituted. [1055] In further embodiments, the heterocycloalkyl is substituted by 1, 2 or 3 substituents independently selected from CH2CH2F and fluoro. [1056] In further embodiments, each R3 is independently fluoro or methyl. [1057] In further embodiments, m is 1 or 2. [1058] In further embodiments, m is 1 and R3 is in the 3- position. [1059] In further embodiments, m is 1 and R3 is in the 6- position. [1060] In further embodiments, m is 2, one R3 is in the 3-position, and the other R3 is in the 6-position. [1061] In further embodiments, R4 is H, methyl or benzyl. [1062] In further embodiments, R5 is H. [1063] In further embodiments, each R6 is independently fluoro or methyl. [1064] In further embodiments, n is 0. [1065] In further embodiments, R7 is methyl, CH2OH or CH2OMe. [1066] In further embodiments, o is 2. [1067] In further embodiments, X is a bond or O. [1068] In further embodiments, R8 is independently methyl, OMe or fluoro. [1069] In further embodiments, p is 0 or 1. [1070] In further embodiments, each R9 is independently fluoro. [1071] In further embodiments, q is 1 or 2. [1072] In further embodiments, D, E and F are C(R10). [1073] In further embodiments, D is N, and E and F are C(R10). [1074] In further embodiments, E is N, and D and F are C(R10). [1075] In further embodiments, F is N, and D and E are C(R10). [1076] In further embodiments, each R10 is independently H, fluoro, chloro or methyl. [1077] In further embodiments, the TDP-43 modulator is selected from the group consisting of: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro- 1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2- methylcyclohexyl) acrylamide (racemic mixture); (E) 3 (1H indazol 6 yl) N ((1R2R) 2 methylcyclohexyl) acrylamide (enantiomer 1); (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2- methylcyclohexyl) acrylamide (enantiomer 2); (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1- yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H- indazol-6-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6- yl)acrylamide; (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3- dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H- inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide; (E)-3-(5-chloro-1H-indazol-6-yl)-N- (2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro- 1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1- yl)acrylamide (mixture of stereoisomers); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3- dihydro-1H-inden-1-yl)acrylamide (stereoisomer 1); (E)-3-(1H-indazol-6-yl)-N-(2-methyl- 2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 2); (E)-3-(1H-indazol-6-yl)-N-(2- methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 3); (E)-3-(1H-indazol-6-yl)- N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 4); (E)-3-(1H-indazol- 6-yl)-N-(3-methylchroman-4-yl)acrylamide (mixture of stereoisomers); (E)-3-(1H-indazol- 6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 1); (E)-3-(1H-indazol-6-yl)-N- (3-methylchroman-4-yl)acrylamide (stereoisomer 2); (E)-3-(1H-indazol-6-yl)-N-(3- methylchroman-4-yl)acrylamide (stereoisomer 3); (E)-3-(1H-indazol-6-yl)-N-(3- methylchroman-4-yl)acrylamide (stereoisomer 4); (E)-N-(2-(benzyloxy)phenyl)-3-(1H- indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2- (phenoxymethyl)phenyl)acrylamide; (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol- 6-yl)acrylamide; (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3- (1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(m- tolyl)acrylamide; (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3- fluorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol- 6-yl)acrylamide; (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6- yl)acrylamide (mixture of stereoisomers); (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden- 1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 1); (E)-N-((1R,3S)-3-fluoro-2,3- dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 2); (E)-N-(2- (hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2,6- dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2- (methoxymethyl)phenyl)acrylamide; (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3- yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride; (E)-N-(2-((3- fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-(2-(3- fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-fluoro-6- methylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1H- pyrazolo[4,3-b]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H- pyrazolo[4,3-c]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H- pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy- 2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro- 1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1- yl)acrylamide; and (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1- yloxy)methyl)phenyl)acrylamide; or a pharmaceutically acceptable salt and/or solvate of any one thereof. Formula 222 [1078] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 222. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1079] In an embodiment, the TDP-43 modulator is a compound according to Formula 222:
Figure imgf000656_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halo, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, and optionally substituted C1- 9 heterocyclyl; each of X1 and X2 is independently selected from O, S, N, and C; W is a bond; O; S; (CH2)n; S(O); SO2; NRa; C(O); C(O)NRa; NRaC(O); SO2NRa; NRaSO2; CRa=CRb; C=NRa; or NRa=CRb, wherein n is 1-5 and each of Ra and Rb is independently H, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; each of R2 and R3 is optionally present depending on the valence of the atom to which each is attached, and if present, each of R2 and R3 is independently hydrogen, halo, hydroxyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, and optionally substituted C1-9 heterocyclyl; R4 is hydrogen, optionally substituted C1-6 alkyl, C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, and optionally substituted C1-9 heterocyclyl; U is hydrogen, wherein m is 0-3, a 5 6 7 8
Figure imgf000656_0002
nd each of R , R , R, R , and R9 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, and optionally substituted C1-9 heterocyclyl; or R3 and U, together with the nitrogen atom to which they are attached, form 4- to 6- membered heterocyclyl or heteroaryl optionally substituted by one or more substituents selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, and optionally substituted C1-9 heterocyclyl; one of the two is a single bond, and the other is a double bond; or each of the two are aromatic bonds; each of V and Z is independently N or CH; and A is optionally substituted C3-8 carbocyclyl, optionally substituted C1-9 heterocyclyl, and optionally substituted C1-9 heteroaryl. [1080] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000658_0001
Figure imgf000659_0001
Figure imgf000660_0001
Figure imgf000661_0001
Figure imgf000662_0001
Figure imgf000663_0001
Figure imgf000664_0001
Figure imgf000665_0001
Figure imgf000666_0001
Figure imgf000667_0001
Figure imgf000668_0001
Formula 223 [1081] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 223. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1082] In an embodiment, the TDP-43 modulator is a compound according to Formula 223:
Figure imgf000669_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; each of Q1, Q2, Q3, and Q4 is independently C or N, and at least one of Q1, Q2, Q3, and Q4 is N; W is a bond; O; S; (CH2)n; S(O); SO2; NRa; C(O); C(O)NRa; NRaC(O); SO2NRa; NRaSO2; CRa=CRb; C=NRa; or NRa=CRb, wherein n is 1-5, and each of Ra and Rb is independently H, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3- 8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; each of R2 and R3 is optionally present depending on the valence of the atom to which each is attached, and if present, each of R2 and R3 is independently hydrogen, halo, hydroxyl, optionally substituted C6- 10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; R4 is hydrogen, optionally substituted C1-6 alkyl, C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or optionally substituted C1-9 heterocyclyl; U is hydrogen, wherein m is 0-3, and each of R5, R6, R7, R8, and
Figure imgf000669_0002
R9 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; or R3 and U, together with the nitrogen atom to which they are attached, form 4- to 6- membered heterocyclyl or heteroaryl optionally substituted by one or more substituents selected from hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; wherein each is a single bond or a double bond and at least one is a double bond; or each is an aromatic bond; each of V and Z is independently N or CH; and A is optionally substituted C3-8 carbocyclyl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1-9 heteroaryl. [1083] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000671_0001
Figure imgf000672_0001
Figure imgf000673_0001
Figure imgf000674_0001
Formula 224 [1084] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 224. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1085] In an embodiment, the TDP-43 modulator is a compound according to Formula 224:
Figure imgf000675_0001
or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C1-9 heterocyclyl, optionally substituted C6-10 aryl, or optionally substituted C1-9 heteroaryl; R2 is optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, -N=CHRa, or -N=CHRbRc, wherein Ra is optionally substituted C1-6 alkyl or optionally substituted C1-9 heteroaryl; Rb is optionally substituted C6-10 arylene; and Rc is hydrogen or NHSO2Me; and each of R3 and R4 is independently H, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; or R3 and R4, together with the nitrogen to which they are attached, form optionally substituted C1-9 heterocyclyl. [1086] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000676_0001
Figure imgf000677_0001
Formula 225 [1087] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 225. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1088] In an embodiment, the TDP-43 modulator is a compound according to Formula 225:
Figure imgf000678_0001
or a pharmaceutically acceptable salt thereof, wherein each bond denoted as is either a single bond or a double bond, provided that the bonds denoted as are not both simultaneously double bonds; X1 is selected from N and CRA; X2 is selected from N and CRA; X3 is selected from N and CRA; each RA is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; Ar is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R7; each R7 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc2Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1 and S(O)2NRc1Rd1; R1 is selected from the group consisting of H and C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; R2 is C1-6 alkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; or R1 and R2 together with the N to which they are attached form a 4-7 membered non-aromatic heterocyclyl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected R8; each R8 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; R3 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; R4 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; Y is selected from N, C, and CRA; when the bond between R5 and Y is a single bond, R5 is 5-10 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, Rc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3 and S(O)2NRc3Rd3; when the bond between R5 and Y is a double bond, R5 is CRBRc; RB is selected from H, C1-6 alkyl, and C1-6 haloalkyl; Rc is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3 and S(O)2NRc3Rd3; or R4 and R5 together with Y and N to which R4 is attached form a 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R9; each R9 is independently selected from halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; wherein said Ci-e alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2 or 3 substituents independently selected from halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)2Rb3 and S(O)2NRc3Rd3; R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or R6 is absent; each Ra1, Rb1, Ra2, Rb2, Ra3, and Rb3 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Rc1, Rd1, Rc2, Rd2, Rc3, and Rd3 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, and S(O)2NRc7Rd7; wherein said Ci-e alkyl, C2-6 alkenyl, and C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; each Ra7, Rb7, Rc7, and Rd7 is in dependently selected from H, C1-6 alkyl, Ci-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Rg, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered non-aromatic heterocyclyl group optionally substituted with 1, 2, or 3 substituents independently selected from Rg; or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered non-aromatic heterocyclyl group optionally substituted with 1, 2, or 3 substituents independently selected from Rg; or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered non-aromatic heterocyclyl group optionally substituted with 1, 2, or 3 substituents independently selected from Rg; each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO-C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfamyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 acyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino. [1089] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000682_0001
Figure imgf000683_0001
Formula 226 [1090] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 226. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1091] In an embodiment, the TDP-43 modulator is a compound according to Formula 226:
Figure imgf000684_0001
or a pharmaceutically acceptable salt thereof, wherein R1 is hydroxy, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; each occurrence of R2 is independently optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; R3 is a nitrogen- or oxygen-containing moiety; Ring A is (i) a 5 or 6-membered heteroaryl or 5-6 or 6-5 membered bicyclic heteroaryl, each having at least one nitrogen or oxygen ring atom, or (ii) phenyl; L1 is absent, C1-C2 alkylene, -NRC-, -O-, -S-, -C(O)-, -NHC(O)-, or - C(O)NH-; L2 is -O-(CRaRb)m-, -(CRaRb)m-, -NRc-(CRaRb)m-, or -S-(CRaRb)m-; X1 is CH, N, or CRC; each occurrence of Ra and Rb are independently hydrogen, hydroxy, hydroxy(Ci-4)alkyl, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3- 8 cycloalkyl, or optionally substituted C1-9 heterocyclyl, halogen, nitro, NRcC(O)Rd, - NORd, -SRd, -NRdRe, -C(O)Rd, -C(S)Rd, -OC(O)Rd, -SC(O)Rd, OC(S)Rd, SC(S)Rd, - NRcC(S)Rd, -SO2Rc, -S(O)Rc, -NRcSO2Rd, -OS(O)2Rd, -OP(O)RdRe, or -P(O)RdRe; Rc is a hydrogen or C1-6 alkyl; each occurrence of Rd and Re are independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-9 heterocyclyl; m is 1-4; and p is 1 or 2. [1092] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000686_0001
Formula 227 [1093] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 227. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1094] In an embodiment, the TDP-43 modulator is a compound according to Formula 227
Figure imgf000687_0001
, or a pharmaceutically acceptable salt thereof, wherein Q1 and Q2 are each independently CH or N, wherein Q1 and Q2 are not both N; each R1 is independently hydroxy, C1-4 alkyl, or C1-4 alkoxy; n is 0, 1, or 2; each R2 is independently C1-4 alkyl or C1-4 alkoxy; and m is 0 or 1. [1095] In further embodiments, the TDP-43 modulator compound is
Figure imgf000687_0002
or a pharmaceutically acceptable salt thereof. Formula 228 [1096] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 228. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1097] In an embodiment, the TDP-43 modulator is a compound according to Formula 228:
Figure imgf000688_0001
or a pharmaceutically acceptable salt thereof, wherein Ar1 is phenyl or pyridyl, with each optionally independently substituted with 1 or 2 C1-4 alkoxy; Ar2 is phenyl, pyridyl, or pyrimidyl with each optionally independently substituted with halo, C1-4 alkyl, C1-4 alkoxy, or C(O)NR2aR2b; and R2a and R2 are each independently H or C1-4 alkyl. [1098] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000689_0001
Formula 229 [1099] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 229. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of Formula 229, this reference incorporated by reference herein control. [1100] In an embodiment, the TDP-43 modulator is a compound according to Formula 229:
Figure imgf000690_0001
or a pharmaceutically acceptable salt thereof, wherein R1 is hydroxy, C1-4 alkoxy, or H(CO)R1a; and R1a is phenyl or pyridyl, optionally substituted with amino, alkylamino, or dialkylamino. [1101] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000690_0002
Formula 230 [1102] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 230. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1103] In an embodiment, the TDP-43 modulator is a compound according to Formula 230:
Figure imgf000691_0001
or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl or pyridyl, with each optionally independently substituted with 1 or 2 alkyl, aminoalkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; R1 is hydrogen or alkyl; and R2 is hydrogen or halo. [1104] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000691_0002
Formula 231 [1105] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 231. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1106] In an embodiment, the TDP-43 modulator is a compound according to Formula 231:
Figure imgf000692_0001
or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently hydrogen or C1-4 alkyl; R3 is hydrogen or C1-3 alkyl substituted with morpholinyl. [1107] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000693_0001
Formula 232 [1108] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 232. Such compounds are described in International Publication No. WO2021252895A2, published December 16, 2021, and corresponding to International Application No. PCT/US2021/037008 filed June 11, 2021; 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 control. [1109] In an embodiment, the TDP-43 modulator is a compound according to Formula 232:
Figure imgf000694_0001
or a pharmaceutically acceptable salt thereof, wherein X is selected from:
Figure imgf000694_0002
[1110] In further embodiments, the TDP-43 modulator compound is
Figure imgf000694_0003
Formulas 233 - 237 [1111] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to any one of Formulas 233 - 237. Such compounds are described in International Publication No. WO2021247921A1, published December 9, 2021, and corresponding to International Application No. PCT/US2021/035778 filed June 3, 2021; which is incorporated by reference in its entirety herein. In the case of any conflict of terminology in the context of any one of Formulas 233 - 237, this reference incorporated by reference herein control. [1112] In an embodiment, the TDP-43 modulator is a compound according to any one of Formulas 233 - 237:
Figure imgf000695_0001
Figure imgf000696_0001
wherein n is 0, 1, 2, 3, or 4; X is S or O; each R1 is, independently, halo, cyano, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, - SO2-optionally substituted C1-C6 alkyl, or -CO2-optionally substituted C1-C6 alkyl; R2 is optionally substituted C2-C9 heteroaryl; and R3 is optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heterocyclyl, optionally substituted C1-C6 alkyl C3-C8 cycloalkyl, optionally substituted C1-C6 heteroalkyl C3-C8 cycloalkyl, optionally substituted C1-C6 alkyl C2-C9 heteroaryl, optionally substituted C1-C6 heteroalkyl C2-C9 heteroaryl, optionally substituted C1-C6 alkyl C2-C9 heterocyclyl, optionally substituted C1-C6 heteroalkyl C2-C9 heterocyclyl, optionally substituted C1-C6 alkyl C6-C10 aryl, or optionally substituted C1-C6 heteroalkyl C6-C10 aryl. [1113] In further embodiments, X is S. [1114] In further embodiments, X is O. [1115] In further embodiments, n is 0. [1116] In further embodiments, n is 1. [1117] In further embodiments, R1 is halo. [1118] In further embodiments, halo is fluoro. [1119] In further embodiments, R1 is cyano. [1120] In further embodiments, R1 is hydroxy. [1121] In further embodiments, R1 is optionally substituted C1-C6 alkyl. [1122] In further embodiments, optionally substituted C1-C6 alkyl is methyl, ethyl, trifluoromethyl, or hydroxymethyl. [1123] In further embodiments, R1 is optionally substituted C1-C6 heteroalkyl. [1124] In further embodiments, optionally substituted C1-C6 heteroalkyl is ethoxy or trifluoromethoxy. [1125] In further embodiments, R1 is -SO2-optionally substituted C1-C6 alkyl. [1126] In further embodiments, -SO2-optionally substituted C1-C6 alkyl is -SO2-methyl. [1127] In further embodiments, R1 is -CO2-optionally substituted C1-C6 alkyl. [1128] In further embodiments, -CO2-optionally substituted C1-C6 alkyl is -CO2-methyl or -CO2-ethyl. [1129] In further embodiments, R2 is a 5-membered optionally substituted C2-C9 heteroaryl. [1130] In further embodiments, R2 is
Figure imgf000697_0001
Figure imgf000697_0002
[1131] In further embodiments, R2 is a 6-membered optionally substituted C2-C9 heteroaryl.25. The compound of claim 24, wherein R2 is
Figure imgf000697_0003
[1132] In further embodiments, R3 is optionally substituted C3-C8 cycloalkyl. [1133] In further embodiments, R3 is cyclohexyl. [1134] In further embodiments, R3 is optionally substituted C2-C9 heterocyclyl. [1135] In further embodiments, R3 is
Figure imgf000697_0004
wherein R4 is -C(O)R5; R5 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C1-C6 alkyl C3-C8 cycloalkyl, or optionally substituted C1-C6 heteroalkyl C3-C8 cycloalkyl. [1136] In further embodiments, R3 is optionally substituted C6-C10 aryl. [1137] In further embodiments, R3 is phenyl, 4-cyano-phenyl, or 4-fluoro-phenyl. [1138] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of (where the structure numbers are independent from the Formula numbers utilized herein):
Figure imgf000699_0001
Figure imgf000700_0001
Figure imgf000701_0001
Figure imgf000702_0001
Figure imgf000703_0001
Figure imgf000704_0001
Figure imgf000705_0001
Figure imgf000706_0001
Figure imgf000707_0001
Figure imgf000708_0001
Figure imgf000709_0001
Figure imgf000710_0001
Figure imgf000711_0001
Figure imgf000712_0001
Figure imgf000713_0001
Figure imgf000714_0001
Figure imgf000715_0001
Figure imgf000716_0001
Figure imgf000717_0001
Figure imgf000718_0001
Formula 238 [1139] In an embodiment, the TDP-43 modulator may be selected from one of the following compounds according to Formula 238. Such compounds are described in International Publication No. WO2021239915A1, published December 2, 2021, and corresponding to International Application No. PCT/EP2021/064274 filed May 27, 2021; US Patent No.8,133,882, issued March 13, 2012 and corresponding to US Application No.12/293,055 filed March 14, 2007; which are incorporated by reference in their entirety herein. In the case of any conflict of terminology in the context of Formula 238, these references incorporated by reference herein control. [1140] In an embodiment, the TDP-43 modulator is a compound according to Formula 238: Formula 238
Figure imgf000718_0002
or a pharmaceutically acceptable salt thereof: wherein R1: a cycloalkyl or lower alkylene-cycloalkyl, wherein the cycloalkyl in R1 may be substituted; R2: — H or a halogen; R3: — H, a halogen, — OR0 or — O-lower alkylene-aryl; R°: the same or different from each other and each represents — H or a lower alkyl R4: a lower alkyl, halogeno-lower alkyl, lower alkylene-cycloalkyl, cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic group in R4may respectively be substituted; R5: — NO2, — CN, a lower alkyl, lower alkenyl, halogeno-lower alkenyl, -L-Ra, — C(0)R°, — O — Rb, — N(R6)2, lower alkylene-N(R6)(Rc), — N(R6)C(0) — Rd, lower alkylene- N(R6)C(0) — Rd, lower) alkylene-N(R0)C(O)O-lower alkyl, — N(R°)C(0)N(R°) — Re, lower alkylene-N(R°)C(0)N(R°)— Re, — N(R0)S(O)2N(R°)C(O)— Rd, — CH=NOH, cycloalkyl, heterocyclic group, (2,4-dioxo-l,3-thiazolidin-5-ylidene)methyl or (4-oxo-2- thioxo-l,3- thiazolidin-5-ylidene)methyl, wherein the cycloalkyl and heterocyclic group in R5 may respectively be substituted; R6: H, a lower alkyl, lower alkylene-C02R° or lower alkylene-P(0)(ORp)2, wherein the lower alkylene in R6 may be substituted; L: a lower alkylene or lower alkenylene which may respectively be substituted; Ra: — OR0, — CN, — O-lower alkylene-aryl, — O-lower alkylene-C02R°, — C(0)R°, — C02R°, — C(0)NH0H, — C(0)N(R6)2, — C(0)N(R°)-aryl, — C(0)N(R°)— S(0)2-lower alkyl, — C(0)N(R°) — S(0)2-aryl, — C(0)N(R°) — S(0)2-heterocyclic group, — NH2OH, — 0C(0)R°, — OC(0)-halogeno-lower alkyl, — P(0)(0Rp)2, an aryl or heterocyclic group, wherein the aryl and heterocyclic group in Ramay be substituted; Rp: R°, a lower alkylene-OC(0)-lower alkyl, lower alkylene-OC(0)-cycloalkyl, lower alkylene-OC(0)0- lower alkyl, lower alkylene-OC(0)0-cycloalkyl, or lower alkylene- heterocyclic group, wherein the heterocyclic group in Rp may be substituted; Rb: H, a cycloalkyl, aryl, heterocyclic group, lower alkylene-Rba or lower alkenylene-Rba, wherein the lower alkylene, lower alkenylene, cycloalkyl, aryl and heterocyclic group in Rb may be substituted; Rba: —OR0, — O— Si(lower alkyl)3, — C02R°, — C(0)NH0H, — C(0)N(R°)2, — C(0)N(R°) — S(0)2-lower alkyl, — C(0)N(R°)— S(0)2-aryl, =C(NH2)=NOH, — C(NH2)=N0— C(0)R°, — C(NH2)=N0— C(0)-lower alkylene-C(O)R0, — C02-lower alkylene-aryl, — P(0)(0Rp)2, — C(0)R°, — C(0)-aryl, a cycloalkyl, aryl or heterocyclic group, wherein the aryl and heterocyclic group in Rba may be substituted; Rc: H, a lower alkyl, lower alkylene-OR0, lower alkylene-C02R°, lower alkylene- C(0)NH0H, lower)alkylene-C(0)N(R°)2, lower alkylene-P(0)(ORp)2, lower alkylene-aryl, lower alkylene-heterocyclic group, aryl or heterocyclic group, wherein the lower alkylene, aryl and heterocyclic group in Rc may be substituted; Rd: a Ci -7 alkyl, lower alkenyl, halogeno-lower alkyl, lower alkylene-Rda, lower alkenylene- Rda, cycloalkyl, aryl or heterocyclic group, wherein the lower alkylene, lower alkenylene, cycloalkyl, aryl and heterocyclic group in Rdmay be substituted; Rda: — CN, —OR0, — 0C(0)R°, -O-lower alkylene-C02R°, -O-aryl, — C02R°, — C(0)NH0H, — C(0)N(R°)2, — C02-lower alkylene- N(R°)2, — P(0)(0Rp)2, — N(R6)2, — N(R°)C(0)R°, — C(0)N(R°)-aryl, — C(0)N(R°)-(lower alkylene which may be substituted with — C02R°)-aryl, — N(R°)C(0)-aryl, — N(R°)C(0)— OR0, —N(R°)C(0)— O-lower alkylene-aryl, — N(R°)S(0)2-aryl, — S- heterocyclic group, — C(O)N(R0)-heterocyclic group, — N(R°)C(0)-heterocyclic group, a cycloalkyl, aryl or heterocyclic group, wherein the cycloalkyl, aryl and heterocyclic group in Rda may be substituted; Re: lower alkylene-C02R°, lower alkylene-C(0)NHOH, lower)alkylene-C(0)N(R°)2, a lower alkylene-heterocyclic group, aryl, heterocyclic group, — S(0)2-aryl or — S(0)2-heterocyclic group, wherein the aryl and heterocyclic group in Re may be substituted; X: CH; A: C(R7); R7: — H or a lower alkyl, or R4 and R' may together form a lower alkylene which may be substituted. [1141] In further embodiments, the TDP-43 modulator compound is selected from the group consisting of:
Figure imgf000720_0001
Further TDP-43 modulator embodiments [1142] The TDP-43 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 at levels higher than natural abundance include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), nC, 13C, 14C, 15N, 18F, 31P, 32P, 35S, CI and I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H, 13C and 14C 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. [1143] 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. [1144] 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 18F 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. [1145] 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 Ή" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. PHARMACEUTICAL COMPOSITIONS [1146] In an embodiment, provided is a pharmaceutical composition comprising a metal channel activator and a TDP-43 modulator. [1147] In another embodiment, the metal channel activator in said pharmaceutical composition is a potassium channel activator. [1148] In another embodiment, the potassium channel activator in said pharmaceutical composition is a Kv7 channel activator. [1149] 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. [1150] In another embodiment, the Kv7 channel activator in said pharmaceutical composition is a Kv7.2/7.3 channel activator. [1151] 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 170 and the compounds disclosed in the “further embodiments” under the “METAL CHANNEL ACTIVATORS” subheading. [1152] In another embodiment, the TDP-43 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 238. [1153] In another embodiment, the TDP-43 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 238, 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 170 and the compounds disclosed in the “further embodiments” under the “METAL CHANNEL ACTIVATORS” subheading. [1154] In another embodiment, the TDP-43 modulator or a pharmaceutically acceptable salt thereof in said pharmaceutical composition is in a form of a prodrug. METHODS OF TREATING DISEASES [1155] The combination therapies disclosed herein are useful for treating or preventing various neurological and neurodegenerative disorders. In an embodiment, disclosed is a method for treating or preventing a disease that involves TDP-43, including administering to a subject any of the above pharmaceutical compositions. The disease may be selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), chronic traumatic encephalopathy (CTE), hippocampal sclerosis of aging (CARTS), inclusion body myositis (IBM), Alzheimer’s disease (AD), Alzheimer’s disease (AD) related disorders, or any combination thereof. [1156] In another embodiment, disclosed is a method for treating or preventing a disease associated with TDP-43 proteinopathies, including administering to a subject any of the above pharmaceutical compositions. [1157] In another embodiment, disclosed is a method for treating or preventing a disease associated with TDP-43 proteinopathies and/or that can benefit from Kv7 channel activation, including administering to a subject any of the above pharmaceutical compositions. [1158] In another embodiment, disclosed is a method for treating or preventing a disease that can benefit from Kv7 channel activation, including administering to a subject any of the above pharmaceutical compositions. [1159] In another embodiment, disclosed is a method for treating or preventing diseases that involve excess amounts of TDP-43 in the cytosol, including administering to a subject any of the above pharmaceutical compositions. [1160] In another embodiment, disclosed is a method of use of the TDP-43 modulators of the present invention as positron emission tomography (PET) imaging agents, including administering to a subject any of the pharmaceutical compositions. [1161] In another embodiment, disclosed is a method of use of the TDP-43 modulators of the present invention as single-photon emission computed tomography (SPECT) imaging agents, wherein the method includes administering to a subject any of the above pharmaceutical compositions including an isotopically labeled metal channel activator, an isotopically labeled TDP-43 modulator, or any combination thereof. The pharmaceutical composition may be administered in a combination with at least one other agent known to treat amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), chronic traumatic encephalopathy (CTE), hippocampal sclerosis of aging (CARTS), inclusion body myositis (IBM), Alzheimer’s disease (AD), Alzheimer’s disease (AD) related disorders, or any combination thereof. [1162] In another embodiment, the combination of Kv7 opener and TDP-43 modulator further includes at least one other agent. In some embodiments, the at least one other agent is riluzole, troriluzole, and/or edavarone. [1163] In further embodiments, a kit is provided for treating a patient afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the metal channel activator; and (b) instructions for administering said metal channel activator in combination with [1164] In further embodiments, a kit is provided for treating a patient wherein the patient is afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the metal channel activator; and (b) instructions for administering said metal channel activator in combination with a TDP-43 modulator by one of the aforementioned methods. [1165] In further embodiments, a kit is provided for treating a patient wherein the patient is afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the TDP-43 modulator; and (b) instructions for administering said TDP-43 modulator with a metal channel activator by one of the aforementioned methods. [1166] 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. [1167] 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 [1168] 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 – 180, Formulas 200 – 238, 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. [1169] The TDP-43 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 TDP-43 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 TDP-43 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 TDP-43 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. [1170] 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 TDP-43 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 TDP-43 modulator e.g., within 1 week, 1 day, 1 hour, 1 minute before or after the TDP-43 modulator or simultaneously with the metal channel activator. [1171] The dose of the TDP-43 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 TDP-43 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 TDP-43 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. [1172] Some of the TDP-43 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 TDP-43 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. [1173] A sublingual formulation useful in the present invention comprises an effective amount of a TDP-43 modulator, metal channel activator, or pharmaceutically acceptable salts, solvates, anomers, enantiomers, hydrates, or prodrugs thereof. The formulation provides sufficient solubility for a TDP-43 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 TDP-43 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 TDP-43 modulator and/or a metal channel activator, which have 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 TDP-43 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 TDP- 43 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 TDP- 43 modulator may also have improved properties. [1174] In one aspect of the invention, the TDP-43 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 TDP-43 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 TDP-43 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; 6,982,25l; 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. [1175] The clinical or therapeutic effect of the sublingually formulated TDP-43 modulator may have an improved pharmacokinetic profile for the pharmaceutical agent as measured by standard testing parameters. When the TDP-43 modulator is administered sublingually, the Tmax, 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 TDP-43 modulator may have a greater Cmax than the orally administered TDP-43 modulator to provide a therapeutically beneficial effect. The sublingual formulation of the TDP-43 modulator may have an earlier or lesser Tmax than the orally administered TDP-43 modulator to provide a therapeutically beneficial effect and in some instances, a more rapid therapeutic effect. Alternatively, the sublingual formulation of the TDP-43 modulator may have a greater AUC per milligram of the agent than the orally administered TDP-43 modulator. In addition, as the TDP-43 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 of the inherent side effects. [1176] 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 Tmax, 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 TDP-43 modulator more effective, lesser amounts of the TDP-43 modulator may be needed to achieve the same results lessening of the inherent side effects. [1177] 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
Figure imgf000730_0001
Figure imgf000731_0001
Figure imgf000732_0001
Figure imgf000733_0001
Figure imgf000734_0001
Figure imgf000735_0001
Figure imgf000736_0001
Figure imgf000737_0001
Figure imgf000738_0001
Figure imgf000739_0001
[1178] In some embodiments, the route of administration may be oral, intranasal, inhalation, intravenous, sublingual, topical, injectable and/or transdermal. [1179] The pharmaceutical compositions of the present invention comprising the TDP- 43 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. [1180] 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. [1181] 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. [1182] 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. TDP-43 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 TDP-43 modulators 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. [1183] The TDP-43 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. [1184] 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., corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like. [1185] 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. [1186] 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. A TDP-43 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. [1187] 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. [1188] 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. [1189] 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. [1190] 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. [1191] 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. [1192] 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. [1193] 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). [1194] 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. [1195] 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. [1196] 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 [1197] In some embodiments, a method of treating a neurological disease may be characterized by one or more pharmacokinetic parameters such as AUC, Cmax, Tmax, 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 TDP-43 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. [1198] In some embodiments, a method of treating a neurological disease may be characterized by an AUC for a TDP-43 and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 238, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof. In some embodiments, the AUC0-t and/or AUC0-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. [1199] In some embodiments, a method of treating a neurological disease may be characterized by a Cmax for a TDP-43 and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 238, 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. [1200] 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 TDP-43 and/or metal channel activator compound according to Formulas 1 – 180, Formulas 200 – 238, 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. [1201] In some embodiments, the Tmax may 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 Tmax of a compound according to Formulas 1 – 180, Formulas 200 – 238, 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 – 180, Formulas 200 – 238, compounds disclosed in the “further embodiments section” under the “METAL CHANNEL ACTIVATOR” subheading, and/or pharmaceutically acceptable salts thereof may alter the Tmax value by making it larger or smaller than a pharmaceutical composition having the excipient or carrier excluded. [1202] 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. [1203] 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. [1204] 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 TDP- 43 modulator according to any one of Formulas 1 – 180, and/or a metal channel activator according to any one of Formulas 200 – 238, 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 TDP-43 modulator according to any one of Formulas 1 – 180, and/or a metal channel activator according to any one of Formulas 200 – 238, 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.

Claims

CLAIMS 1. A pharmaceutical composition comprising a metal channel activator and a TDP-43 modulator. 2. The pharmaceutical composition of claim 1, wherein the metal channel activator is a potassium channel activator. 3. The pharmaceutical composition of claim 2, wherein the potassium channel activator is a Kv7 channel activator. 4. The pharmaceutical composition of claim 3, wherein the Kv7 channel activator 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.
5. The pharmaceutical composition of claim 3 or 4, wherein the Kv7 channel activator is a Kv7.2/7.3 channel activator.
6. The pharmaceutical composition of any one of claims 1 to 5, wherein the metal channel activator is selected from one or more of the disclosed compounds according to any one or more of formulas 1 to 171.
7. The pharmaceutical composition of any one of claims 1 to 6, wherein the TDP-43 modulator is selected from one or more of the disclosed compounds according to any one or more of formulas 200 to 238.
8. The pharmaceutical composition of any one of claims 1 to 5, wherein the TDP-43 modulator is selected from one or more of the disclosed compounds according to any one or more of formulas 200 to 238, and wherein the metal channel activator is selected from one or more of the disclosed compounds according to any one or more of formulas 1 to 171.
9. The pharmaceutical composition of any one of the preceding claims, wherein the TDP-43 modulator or a pharmaceutically acceptable salt thereof is in a form of a prodrug.
10. A method for treating or preventing a neurological disease that involves TDP-43, comprising administering to a subject the pharmaceutical composition of any one of claims 1 to 9.
11. The method of Claim 10, wherein the disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), chronic traumatic encephalopathy (CTE), hippocampal sclerosis of aging (CARTS), inclusion body myositis (IBM), Alzheimer’s disease (AD), Alzheimer’s disease (AD) related disorders, or any combination thereof.
12. A method for treating or preventing a disease associated with TDP-43 proteinopathies and/or that can benefit from Kv7 channel activation, comprising administering to a subject the pharmaceutical composition of any one of claims 1 to 9.
13. A method for treating or preventing diseases that involve excess amounts of TDP-43 in the cytosol, comprising administering to a subject the pharmaceutical composition of any one of claims 1 to 9.
14. A method of use of the TDP-43 modulators of the present invention as positron emission tomography (PET) imaging agents, comprising administering to a subject the pharmaceutical composition of any one of claims 1 to 9.
15. A method of use of the TDP-43 modulators of the present invention as single-photon emission computed tomography (SPECT) imaging agents, wherein the method comprises administering to a subject the pharmaceutical composition of any one of claims 1 to 9 comprising an isotopically labeled metal channel activator, an isotopically labeled TDP-43 modulator, or any combination thereof.
16. A method for treating or preventing a disease that can benefit from Kv7 Channel activation, comprising administering to a subject the pharmaceutical composition of any one of claims 1 to 9.
17. A method for treating of preventing a disease associated with TDP-43 proteinopathies, comprising administering to a subject the pharmaceutical composition of any one of claims 1 to 9.
18. The method of any one of claims 9 to 17, wherein the pharmaceutical composition is administered in a combination with at least one other agent known to treat amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), chronic traumatic encephalopathy (CTE), hippocampal sclerosis of aging (CARTS), inclusion body myositis (IBM), Alzheimer’s disease (AD), and Alzheimer’s disease (AD) related disorders. 19. The method of claim 18, wherein the at least one other agent is riluzole, troriluzole, or edavarone.
19. A kit for treating a patient afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the metal channel activator or TDP-43 modulator; and (b) instructions for administering said metal channel activator in combination with a TDP-43 modulator by one of the methods of claims 9 to 19.
20.The kit of claim 19 wherein the patient is afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the metal channel activator; and (b) instructions for administering said metal channel activator in combination with a TDP-43 modulator by one of the methods of claims 9-19.
21.The kit of claim 19 wherein the patient is afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the TDP-43 modulator; and (b) instructions for administering said TDP-43 modulator with a metal channel activator by one of the methods of claims 9 to 19.
22. The pharmaceutical composition of any one of claims 1 – 9, wherein the metal channel activator is the following compound, or a pharmaceutically acceptable salt thereof:
Figure imgf000752_0001
23. The pharmaceutical composition of any one of claims 1 – 9, wherein the metal channel activator is the following compound, or a pharmaceutically acceptable salt thereof:
Figure imgf000753_0001
24. The pharmaceutical composition of any one of claims 1 – 9, wherein the metal channel activator is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition of any one of claims 1 – 9, wherein the metal channel activator is a compound according to Formula 2, or a pharmaceutically acceptable salt thereof.
26. The pharmaceutical composition of any one of claims 22 – 25, wherein the TDP-43 modulator is selected from one or more of the disclosed compounds according to any one or more of formulas 200 to 238.
27. A method for treating or preventing a neurological disease that involves TDP-43, comprising administering to a subject the pharmaceutical composition of claim 26.
28. The method of claim 27, wherein the disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), chronic traumatic encephalopathy (CTE), hippocampal sclerosis of aging (CARTS), inclusion body myositis (IBM), Alzheimer’s disease (AD), Alzheimer’s disease (AD) related disorders, or any combination thereof.
29. A method for treating or preventing a disease associated with TDP-43 proteinopathies and/or that can benefit from Kv7 channel activation, comprising administering to a subject the pharmaceutical composition of claim 26.
30. A method for treating or preventing diseases that involve excess amounts of TDP-43 in the cytosol, comprising administering to a subject the pharmaceutical composition of claim 26.
31. A method of use of the TDP-43 modulators of the present invention as positron emission tomography (PET) imaging agents, comprising administering to a subject the pharmaceutical composition of claim 26.
32. A method of use of the TDP-43 modulators of the present invention as single-photon emission computed tomography (SPECT) imaging agents, wherein the method comprises administering to a subject the pharmaceutical composition of claim 26 comprising an isotopically labeled metal channel activator, an isotopically labeled TDP- 43 modulator, or any combination thereof.
33. A method for treating or preventing a disease that can benefit from Kv7 Channel activation, comprising administering to a subject the pharmaceutical composition of claim 26.
34. A method for treating of preventing a disease associated with TDP-43 proteinopathies, comprising administering to a subject the pharmaceutical composition of claim 26.
35. The method of any one of claims 27 to 34, wherein the pharmaceutical composition is administered in a combination with at least one other agent known to treat amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), chronic traumatic encephalopathy (CTE), hippocampal sclerosis of aging (CARTS), inclusion body myositis (IBM), Alzheimer’s disease (AD), and Alzheimer’s disease (AD) related disorders.
36. The method of claim 35, wherein the at least one other agent is riluzole, troriluzole, or edavarone.
37. A kit for treating a patient afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the metal channel activator or TDP-43 modulator; and (b) instructions for administering said metal channel activator in combination with a TDP-43 modulator by one of the methods of claims 27 to 34 38.The kit of claim 19 wherein the patient is afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the metal channel activator; and (b) instructions for administering said metal channel activator in combination with a TDP-43 modulator by one of the methods of claims 27 to 34. 39.The kit of claim 19 wherein the patient is afflicted with a disorder involving metal channel dysfunction and TDP-43, said kit comprising: (a) the TDP-43 modulator; and (b) instructions for administering said TDP-43 modulator with a metal channel activator by one of the methods of claims 27 to 34
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070293476A1 (en) * 2006-05-19 2007-12-20 Smith-Swintosky Virginia L Co-therapy for the treatment of epilepsy and related disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070293476A1 (en) * 2006-05-19 2007-12-20 Smith-Swintosky Virginia L Co-therapy for the treatment of epilepsy and related disorders

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DE SARRO GIOVAMBATTISTA, DI PAOLA EUGENIO DONATO, CONTE GIUSEPPE, PASCULLI MARIA PATRIZIA, DE SARRO ANGELA: "Influence of retigabine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, SPRINGER, DE, vol. 363, no. 3, 14 February 2001 (2001-02-14), DE , pages 330 - 336, XP093149609, ISSN: 0028-1298, DOI: 10.1007/s002100000361 *
EMANUELE BURATTI: "Targeting TDP‐43 proteinopathy with drugs and drug‐like small molecules", BRITISH JOURNAL OF PHARMACOLOGY, WILEY-BLACKWELL, UK, vol. 178, no. 6, 30 June 2020 (2020-06-30), UK , pages 1298 - 1315, XP071089448, ISSN: 0007-1188, DOI: 10.1111/bph.15148 *
JAROGNIEW J. LUSZCZKI ; JIM Z. WU ; GRZEGORZ RASZEWSKI ; STANISLAW J. CZUCZWAR: "Isobolographic characterization of interactions of retigabine with carbamazepine, lamotrigine, and valproate in the mouse maximal electroshock-induced seizure model", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, SPRINGER, BERLIN, DE, vol. 379, no. 2, 5 September 2008 (2008-09-05), Berlin, DE , pages 163 - 179, XP019702056, ISSN: 1432-1912 *

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