[go: up one dir, main page]

US20170355679A1 - Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives - Google Patents

Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives Download PDF

Info

Publication number
US20170355679A1
US20170355679A1 US15/618,937 US201715618937A US2017355679A1 US 20170355679 A1 US20170355679 A1 US 20170355679A1 US 201715618937 A US201715618937 A US 201715618937A US 2017355679 A1 US2017355679 A1 US 2017355679A1
Authority
US
United States
Prior art keywords
compound
butyl
substituted
mmole
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/618,937
Other languages
English (en)
Inventor
D. Scott Edwards
Ben C. Askew
Takeru Furuya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scifluor Life Sciences Inc
Original Assignee
Scifluor Life Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scifluor Life Sciences Inc filed Critical Scifluor Life Sciences Inc
Priority to US15/618,937 priority Critical patent/US20170355679A1/en
Assigned to SCIFLUOR LIFE SCIENCES, INC. reassignment SCIFLUOR LIFE SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ASKEW, BEN C., FURUYA, TAKERU, EDWARDS, D. SCOTT
Publication of US20170355679A1 publication Critical patent/US20170355679A1/en
Priority to US17/145,453 priority patent/US11858900B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles

Definitions

  • Epilepsy is one of the most common chronic neurological disorders, and affects approximately 50 million people worldwide. Epilepsy patients have significantly increased morbidity, including closed head injury, fractures, burns, dental injury and soft tissue injury. Decline in or worsening of memory, cognition, depression and sexual function and other lifestyle limitations occur frequently in epilepsy patients. Epilepsy patients also have an increased risk of mortality compared to the general population.
  • Ezogabine or retigabine also known as ethyl N-[2-amino-4-[(4-fluorophenyl) methylamino]phenyl]carbamate, is an anticonvulsant used as a treatment for partial epilepsies.
  • Ezogabine works primarily as a potassium channel opener, i.e., by activating KCNQ2/3 voltage-gated potassium channels in the brain.
  • Ezogabine was approved by the FDA and is marketed as PotigaTM and TrobaltTM.
  • U.S. Pat. No. 5,384,330 and WO 01/01970 describe ezogabine and its use.
  • the most common adverse events with ezogabine are central nervous system effects, particularly dizziness and somnolence. Occasional instances of urinary difficulty may require surveillance.
  • Ezogabine is predominantly metabolized via glucuronidation, with a half-life of 8 hours.
  • the application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the application also relates to a method of modulating a KCNQ2/3 potassium channel, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof.
  • the application also relates to a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, for use in modulating a KCNQ2/3 potassium channel.
  • the application also relates to a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for modulating a KCNQ2/3 potassium channel.
  • the present application also relates to use of a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for modulation of a KCNQ2/3 potassium channel.
  • the application further relates to a method of treating or preventing a disease or disorder which can be ameliorated by KCNQ2/3 potassium channel opening, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof.
  • the application also relates to a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing a disease or disorder which can be ameliorated by KCNQ2/3 potassium channel opening.
  • the application also relates to a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder which can be ameliorated by KCNQ2/3 potassium channel opening.
  • the present application also relates to use of a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder which can be ameliorated by KCNQ2/3 potassium channel opening.
  • the application further relates to a method of treating or preventing epilepsy, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof.
  • the application also relates to a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing epilepsy.
  • the application also relates to a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for treating or preventing epilepsy.
  • the present application also relates to the use of a compound of formula A, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of epilepsy.
  • FIG. 1 is a graph showing the schematic of voltage protocol and sweep settings for SyncroPatch Recordings in the assessment of exemplified compounds of the application.
  • FIG. 2A is a plot showing dose-dependent activation of Kv7.2/7.3 channels by Compound 4 as measured by the SyncroPatch platform.
  • FIG. 2B is a plot showing dose-dependent activation of Kv7.2/7.3 channels by Compound 6 as measured by the SyncroPatch platform.
  • FIG. 2C is a plot showing dose-dependent activation of Kv7.2/7.3 channels by Compound 7 as measured by the SyncroPatch platform.
  • FIG. 2D is a plot showing dose-dependent activation of Kv7.2/7.3 channels by Compound 8 as measured by the SyncroPatch platform.
  • FIG. 2E is a plot showing dose-dependent activation of Kv7.2/7.3 channels by Compound 10 (control) as measured by the SyncroPatch platform.
  • FIG. 2F is a plot showing dose-dependent activation of Kv7.2/7.3 channels by Compound 12 as measured by the SyncroPatch platform.
  • FIG. 2G is a plot showing dose-dependent activation of Kv7.2/7.3 channels by Compound X (control) as measured by the SyncroPatch platform.
  • a compound of the application refers to any compound disclosed herein, e.g., a compound of any of the formulae described herein, including formulae A, I, Ia, II, IIIa-IIIc, IVa-IVc, V, VI, and VII, and/or an individual compound explicitly disclosed herein.
  • a compound of the application refers to any compound disclosed herein, e.g., a compound of any of the formulae described herein, including formulae A, I, Ia, II, IIIa-IIIc, IVa-IVc, V, VI, and VII, and/or an individual compound explicitly disclosed herein.
  • the term is used in the context of the present application it is to be understood that the reference is being made to the free base, a deuterium labeled compound, and the corresponding pharmaceutically acceptable salts or solvates thereof, provided that such is possible and/or appropriate under the circumstances.
  • pharmaceutical or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient.
  • pharmaceutical formulation it is further meant that the carrier, solvent, excipient, and salt must be compatible with the active ingredient of the formulation (e.g., a compound of the application). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application.
  • Some of the compounds of the present application may exist in unsolvated as well as solvated forms such as, for example, hydrates.
  • Solidvate means a solvent addition form that contains either a stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate. In the hydrates, the water molecules are attached through secondary valencies by intermolecular forces, in particular hydrogen bridges.
  • Solid hydrates contain water as so-called crystal water in stoichiometric ratios, where the water molecules do not have to be equivalent with respect to their binding state.
  • Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally suitable are the hydrates of salts of the compounds of the application.
  • Physiologically acceptable, i.e., pharmaceutically compatible or pharmaceutically acceptable, salts can be salts of the compounds of the application with inorganic or organic acids.
  • inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid
  • organic carboxylic or sulphonic acids such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
  • salts with customary bases such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.
  • Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamottle
  • the compounds of the application may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers. It is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of the application. The application is meant to comprehend all such isomeric forms of these compounds.
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the present application includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.
  • “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture”.
  • Chiral isomer means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.
  • “Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques; it has been possible to separate mixtures of two atropic isomers in select cases.
  • Tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
  • keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism arises as a result of the aldehyde group (—CHO) in a sugar chain molecule reacting with one of the hydroxy groups (—OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine.
  • heterocyclic rings e.g., in nucleobases such as guanine, thymine and cytosine
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as contacting a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the diastereomeric mixture is often a mixture of diasteriomeric salts formed by contacting a racemic mixture of compounds with an enantiomerically pure acid or base.
  • the diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which are well known in the art.
  • the application also includes one or more metabolites of a compound of the application.
  • the present application also comprehends deuterium labeled compounds of each of the formulae described herein or the individual compounds specifically disclosed, wherein a hydrogen atom is replaced by a deuterium atom.
  • the deuterium labeled compounds comprise a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, e.g., 0.015%.
  • a compound of the application has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Deuterium labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium labeled compounds of each of the formulae described herein or the compounds listed in Table 1 can generally be prepared by carrying out the procedures described herein, by substituting a readily available deuterium labeled reagent for a non-deuterium labeled reagent.
  • a compound of the application or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the application. Further, substitution with deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life and/or reduced dosage requirements.
  • the term “treat”, “treating”, or “treatment” herein is meant decreasing the symptoms, markers, and/or any negative effects of a disease, disorder or condition in any appreciable degree in a patient who currently has the condition.
  • the term “treat”, “treating”, or “treatment” includes alleviating symptoms of a disease, disorder, or condition, e.g., alleviating the symptoms of epilepsy.
  • treatment may be administered to a subject who exhibits only early signs of the condition for the purpose of decreasing the risk of developing the disease, disorder, and/or condition.
  • prevention refers to any method to partially or completely prevent or delay the onset of one or more symptoms or features of a disease, disorder, and/or condition. Prevention may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • subject means a human or animal (in the case of an animal, more typically a mammal). In one embodiment, the subject is a human. In one embodiment, the subject is a male. In one embodiment, the subject is a female.
  • a “fluorinated derivative” is a derivative compound that has the same chemical structure as the original compound, except that at least one atom is replaced with a fluorine atom or with a group of atoms containing at least one fluorine atom.
  • the problem to be solved by the present application is the identification of novel compounds for the treatment and/or prevention of epilepsy and/or other diseases or disorders ameliorated by KCNQ2/3 potassium channel opening.
  • drugs for epilepsy and related disorders are available, these drugs are often not suitable for many patients for a variety of reasons.
  • Many epilepsy drugs are associated with adverse effects.
  • many of the available epilepsy drugs are believed to significantly increase the risk of birth defects if taken during the first trimester of pregnancy.
  • Other adverse side effects include urinary retention, neuro-psychiatric symptoms including hallucinations and psychosis, dizziness and somnolence, QT-prolonging effect, and increased risk of suicidal behavior and ideation.
  • Some epilepsy drugs require administration of high doses due to extensive metabolism into inactive or less potent metabolites.
  • the present application provides the solution of new fluorinated 2-amino-4-(benzylamino)phenylcarbamate compounds for treating epilepsy and other diseases or disorders ameliorated by KCNQ2/3 potassium channel opening.
  • the compounds described herein have the advantage of providing improved potency, selectivity, tissue penetration, half-life, and/or metabolic stability.
  • the present application relates to a compound of formula A:
  • X 1 , X 2 , X 3 , and X 9 are each independently H, deuterium, F, NH 2 , or a C 1 -C 4 alkyl optionally substituted with one or more F;
  • X 10 is C(O)(C 7 X 7 ) n X 6 or CO 2 (C 7 X 7 ) n X 6 ;
  • X 4 is H, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • X 5 is phenyl-(CX 8 X 8 ) m , wherein the phenyl is substituted with one or more substituents independently selected from deuterium, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 , and wherein at least one substituent is selected from C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 , or
  • X 4 and X 5 together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from deuterium, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 , wherein at least one substituent is selected from C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 , or two substituents attached to adjacent carbon atoms on the heterocyclic ring, together with the carbon atoms to which they are attached, form a phenyl substituted with one or more substituents independently selected from deuterium, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 , wherein the phenyl is substituted with at least one
  • X 6 is H or deuterium
  • each X 7 is independently H, C 1 -C 4 alkyl, or deuterium, or two X 7 , together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S;
  • each X 8 is independently H, deuterium, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, or F;
  • n 1, 2, or 3;
  • n 1, 2, or 3
  • X 1 , X 2 , X 3 , and X 6 are each H, n is 2, each X 7 is H, X 5 is 4-fluorobenzyl, X 9 is NH 2 , and X 10 is CO 2 (C 7 X 7 ) n X 6 , then X 4 is not propenyl or propynyl.
  • the compound of the present application is a compound of formula A, wherein when X 1 , X 2 , X 3 , and X 6 are each H, n is 2, each X 7 is H, and X 5 is 4-fluorobenzyl, then X 4 is not propenyl or propynyl.
  • the compound of the present application is a compound of formula A, wherein when X 10 is CO 2 (C 7 X 7 ) n X 6 , then X 4 is not H.
  • the compound of formula A is of formula I:
  • X 1 , X 2 , and X 3 are each independently H, deuterium, or F
  • X 4 , X 5 , X 6 , X 7 , X 8 , m, and n are each as defined above in formula A, wherein when X 1 , X 2 , X 3 , and X 6 are each H, n is 2, each X 7 is H, and X 5 is 4-fluorobenzyl, then X 4 is not propenyl or propynyl.
  • the compound of formula A is of formula Ia:
  • X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , m, and n are each as defined above in formula A.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , m, and n can each be, where applicable, selected from the groups described herein below, and any group described herein for any of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , m, and n can be combined, where applicable, with any group described herein for one or more of the remainder of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , m, and n.
  • At least one of X 1 , X 2 , X 3 , and X 9 is NH 2 . In one embodiment, one of X 1 , X 2 , X 3 , and X 9 is NH 2 . In one embodiment, X 9 is NH 2 .
  • one of X 1 , X 2 , X 3 , and X 9 is NH 2
  • the remainder of X 1 , X 2 , X 3 , and X 9 are each independently H, deuterium, F, C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • X 9 is NH 2
  • X 1 , X 2 , and X 3 are each independently H, deuterium, F, C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, propyl, butyl, i-butyl, or t-butyl), or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • X 9 is NH 2
  • X 1 , X 2 , and X 3 are each independently H, deuterium, or F.
  • X 9 is NH 2 , and X 3 is F. In one embodiment, X 9 is NH 2 , X 3 is F, and X 1 and X 2 are each independently H or deuterium.
  • At least one of X 1 , X 2 , X 3 , and X 9 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • At least two of X 1 , X 2 , X 3 , and X 9 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • X 1 and X 9 are each independently C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), and X 2 and X 3 are each independently H, deuterium, F, or NH 2 .
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-
  • X 1 and X 9 are each independently C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), and X 2 and X 3 are each independently H, deuterium, or F.
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
  • X 1 and X 9 are each independently methyl, CF 3 , CHF 2 , or CH 2 F, and X 2 and X 3 are each independently H, deuterium, or F. In one embodiment, at least one of X 1 and X 9 is methyl. In one embodiment, X 1 and X 9 are each methyl. In one embodiment, X 1 and X 9 are each methyl, and X 2 and X 3 are each independently H, deuterium, or F.
  • X 10 is CO 2 (C 7 X 7 ) n X 6 . In one embodiment, X 10 is C(O)(C 7 X 7 ) n X 6 .
  • X 1 , X 2 , and X 3 are each H.
  • At least one of X 1 , X 2 , and X 3 is deuterium or F.
  • X 1 is deuterium or F
  • X 2 and X 3 are each H.
  • X 1 is F
  • X 2 and X 3 are each H.
  • X 2 is deuterium or F
  • X 1 and X 3 are each H.
  • X 2 is F
  • X 1 and X 3 are each H.
  • X 3 is deuterium or F
  • X 1 and X 2 are each H.
  • X 3 is F
  • X 1 and X 2 are each H.
  • X 3 is F
  • X 1 and X 2 are each H.
  • At least two of X 1 , X 2 , and X 3 are deuterium or F.
  • X 1 and X 2 are each independently deuterium or F, and X 3 is H.
  • X 1 and X 2 are each F, and X 3 is H.
  • X 1 and X 3 are each independently deuterium or F, and X 2 is H.
  • X 1 and X 3 are each F, and X 2 is H.
  • X 2 and X 3 are each independently deuterium or F, and X 1 is H.
  • X 2 and X 3 are each F, and X 1 is H.
  • X 2 and X 3 are each F, and X 1 is H.
  • X 4 is H. In one embodiment, X 4 is H, only when X 10 is C(O)(C 7 X 7 ) n X 6 .
  • X 4 is C 1 -C 4 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl. In one embodiment, X 4 is C 1 -C 4 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, when X 10 is CO 2 (C 7 X 7 ) n X 6 .
  • X 4 is C 1 -C 4 alkyl selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, and t-butyl.
  • X 4 is C 2 -C 6 alkenyl or C 2 -C 6 alkynyl.
  • X 4 is C 2 -C 6 alkenyl selected from ethenyl, propenyl (e.g., 1-propenyl or 2-propenyl), butenyl (e.g., 1-butenyl, 2-butenyl, or 3-butenyl), pentenyl (e.g., 1-pentenyl, 2-pentenyl, 3-pentenyl, or 4-pentenyl), and hexenyl (e.g., 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl).
  • X 4 is 1-propenyl or 2-propenyl.
  • X 4 is C 2 -C 6 alkynyl selected from ethynyl, propynyl (e.g., 1-propynyl or 2-propynyl), butynyl (e.g., 1-butynyl, 2-butynyl, or 3-butynyl), pentynyl (e.g., 1-pentynyl, 2-pentynyl, 3-pentynyl, or 4-pentynyl), and hexynyl (e.g., 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl). In one embodiment, X 4 is 1-propynyl or 2-propynyl.
  • X 5 is phenyl-(CX 8 X 8 ), phenyl-(CX 8 X 8 ) 2 , or phenyl-(CX 8 X 8 ) 3 , wherein the phenyl is substituted with one or more substituents independently selected from deuterium, C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), F, and SF 5 .
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl,
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), and F.
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) and C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substitute
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F) and F.
  • the phenyl is substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the phenyl is substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F. In one embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F. In one embodiment, the phenyl is substituted with one or more substituents independently selected from CF 3 and F. In one embodiment, the substituent is attached at the para-position on the phenyl ring. In one embodiment, the substituent(s) are attached at the meta-position(s) on the phenyl ring.
  • X 5 is 4-fluoro-benzyl, 4-trifluoromethyl-benzyl, or 3-trifluoromethyl-benzyl.
  • each X 5 is H.
  • at least one X 5 is deuterium, C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), or F.
  • at least one X 5 is deuterium.
  • At least one X 8 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), or F.
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F
  • At least one X 8 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F.
  • At least one X 8 is C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F) or F.
  • at least one X 8 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl).
  • At least one X 8 is C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F). In one embodiment, at least one X 8 is F.
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F.
  • at least one X 8 is F.
  • X 4 and X 5 together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiapyranyl, dioxanyl, morpholinyl, oxazinanyl, thiazinanyl, or oxathianyl).
  • N, O, and S e.g., pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, isoxazolidinyl,
  • X 4 and X 5 together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring comprising 1 heteroatom selected from N, O, and S. In one embodiment, X 4 and X 5 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring comprising 1 heteroatom selected from N, O, and S. In one embodiment, X 4 and X 5 , together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring comprising 1 heteroatom selected from N and O. In one embodiment, X 4 and X 5 , together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidinyl ring.
  • X 4 and X 5 together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring substituted with one or more substituents independently selected from deuterium, C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), F, and SF 5 .
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl
  • the heterocyclic ring is substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), and F.
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of
  • the heterocyclic ring is substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) and C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is
  • the heterocyclic ring is substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F) and F.
  • the heterocyclic ring is substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the heterocyclic ring is substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F. In one embodiment, the heterocyclic ring is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F. In one embodiment, the heterocyclic ring is substituted with one or more substituents independently selected from CF 3 and F.
  • X 4 and X 5 together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring substituted with two or more substituents, wherein two substituents attached to adjacent carbon atoms on the heterocyclic ring, together with the carbon atoms to which they are attached, form a phenyl substituted with one or more substituents independently selected from deuterium, C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), F, and SF 5 .
  • C 1 -C 4 alkyl e.g., methyl,
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), and F.
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) and C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substitute
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F) and F.
  • the phenyl is substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the phenyl is substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F. In one embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F. In one embodiment, the phenyl is substituted with one or more substituents independently selected from CF 3 and F.
  • X 4 and X 5 together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from
  • X 6 is H. In one embodiment, X 6 is deuterium.
  • each X 7 is H. In one embodiment, at least one X 7 is deuterium. In one embodiment, at least one X 7 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl). In one embodiment, at least two X 7 , together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • a 3- to 6-membered carbocyclic ring e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • At least two X 7 together with the carbon atom to which they are attached, form a 3- to 6-membered heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S (e.g., aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiapyranyl, dioxanyl, morpholinyl, oxazinanyl, thiazinanyl, or oxathianyl).
  • N, O, and S e.g., aziridinyl, oxi
  • At least two X 7 together with the carbon atom to which they are attached, form a 3- to 6-membered heterocyclic ring comprising 1 heteroatom selected from N, O, and S. In one embodiment, at least two X 7 , together with the carbon atom to which they are attached, form a 3- or 4-membered heterocyclic ring comprising 1 heteroatom selected from N, O, and S. In one embodiment, at least two X 7 , together with the carbon atom to which they are attached, form a 3- or 4-membered heterocyclic ring comprising 1 heteroatom selected from N and 0.
  • m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • n is 1. In one embodiment, n is 2. In one embodiment, n is 3.
  • any of the substituent groups described above for any of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , m, and n can be combined with any of the substituent groups described above for one or more of the remainder of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , m, and n.
  • X 1 , X 2 , and X 3 are each H.
  • X 1 and X 2 are each H, and X 3 is deuterium or F.
  • X 1 and X 2 are each H, and X 3 is F.
  • X 1 and X 9 are each methyl, and X 3 is F.
  • X 6 is H.
  • X 6 is deuterium
  • each X 7 is H.
  • At least one X 7 is C 1 -C 4 alkyl.
  • At least two X 7 together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O, and S. In one embodiment, at least two X 7 , together with the carbon atom to which they are attached, form a 3- to 6-membered heterocyclic ring comprising 1 heteroatom selected from N, O, and S. In one embodiment, at least two X 7 , together with the carbon atom to which they are attached, form a 3- or 4-membered heterocyclic ring comprising 1 heteroatom selected from N, O, and S. In one embodiment, at least two X 7 , together with the carbon atom to which they are attached, form a 3- or 4-membered heterocyclic ring comprising 1 heteroatom selected from N and O.
  • n 1
  • n is 2.
  • n 3.
  • X 1 , X 2 , and X 3 are each as defined in (1a), and X 7 is as defined in (3a).
  • X 1 , X 2 , and X 3 are each as defined in (1b), and X 7 is as defined in (3a).
  • X 1 , X 2 , and X 3 are each as defined in (1c), and X 7 is as defined in (3a).
  • X 1 , X 3 , and X 9 are each as defined in (1d), and X 7 is as defined in (3a).
  • X 1 , X 2 , and X 3 are each as defined in (1a), and X 7 is as defined in (3b).
  • X 1 , X 2 , and X 3 are each as defined in (1b), and X 7 is as defined in (3b).
  • X 1 , X 2 , and X 3 are each as defined in (1c), and X 7 is as defined in (3b).
  • X 1 , X 3 , and X 9 are each as defined in (1d), and X 7 is as defined in (3b).
  • X 1 , X 2 , and X 3 are each as defined in (1a), and X 7 is as defined in (3c).
  • X 1 , X 2 , and X 3 are each as defined in (1b), and X 7 is as defined in (3c).
  • X 1 , X 2 , and X 3 are each as defined in (1c), and X 7 is as defined in (3c).
  • X 1 , X 3 , and X 9 are each as defined in (1d), and X 7 is as defined in (3c).
  • X 1 , X 2 , X 3 , X 7 , and X 9 are each as defined in any one of (A1)-(A4), and X 6 is as defined in (2a) or (2b). In one embodiment, X 6 is as defined in (2a).
  • X 1 , X 2 , X 3 , X 7 , and X 9 are each as defined in any one of (B1)-(B4), and X 6 is as defined in (2a) or (2b). In one embodiment, X 6 is as defined in (2a).
  • X 1 , X 2 , X 3 , X 7 , and X 9 are each as defined in any one of (C 1 )-(C 4 ), and X 6 is as defined in (2a) or (2b). In one embodiment, X 6 is as defined in (2a).
  • X 1 , X 2 , X 3 , X 7 , and X 9 are each as defined in any one of (A1)-(A4), (B1)-(B4), or (C 1 )-(C 4 ), and n is as defined in (4a).
  • X 1 , X 2 , X 3 , X 7 , and X 9 are each as defined in any one of (A1)-(A4), (B1)-(B4), or (C 1 )-(C 4 ), and n is as defined in (4b).
  • X 1 , X 2 , X 3 , X 7 , and X 9 are each as defined in any one of (A1)-(A4), (B1)-(B4), or (C 1 )-(C 4 ), and n is as defined in (4c).
  • X 4 is C 1 -C 4 alkyl
  • X 5 is phenyl-(CX 8 X 8 ) m
  • the phenyl is substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 .
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, and F.
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one or more F. In one embodiment, the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 and F.
  • X 4 is C 2 -C 6 alkenyl
  • X 5 is phenyl-(CX 8 X 8 ) m
  • the phenyl is substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 .
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, and F.
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one or more F. In one embodiment, the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 and F.
  • X 4 is C 2 -C 6 alkynyl
  • X 5 is phenyl-(CX 8 X 8 ) m
  • the phenyl is substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 .
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, and F.
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one or more F. In one embodiment, the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F. In a further embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 and F.
  • X 4 and X 5 together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 .
  • the heterocyclic ring is optionally substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, and F.
  • the heterocyclic ring is optionally substituted with one or more substituents independently selected from C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one or more F. In one embodiment, the heterocyclic ring is optionally substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F and F. In one embodiment, the heterocyclic ring is optionally substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the heterocyclic ring is optionally substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F. In one embodiment, the heterocyclic ring is optionally substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F. In one embodiment, the heterocyclic ring is optionally substituted with one or more substituents independently selected from CF 3 and F.
  • X 4 and X 5 together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O, and S, substituted with two or more substituents, wherein two substituents attached to adjacent carbon atoms on the heterocyclic ring, together with the carbon atoms to which they are attached, form a phenyl substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 .
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, and F. In one embodiment, the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl and C 1 -C 4 alkyl substituted with one or more F. In one embodiment, the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F and F.
  • the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F.
  • the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F.
  • the phenyl is substituted with one or more substituents independently selected from CF 3 and F.
  • n 1
  • each X 5 is H.
  • At least one X 5 is deuterium.
  • At least one X 5 is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, or F.
  • X 4 and X 5 are each as defined in (5a), and m is as defined in any one of (6a)-(6c). In a further embodiment, m is as defined in (6a).
  • X 4 and X 5 are each as defined in (5b), and m is as defined in any one of (6a)-(6c). In a further embodiment, m is as defined in (6a).
  • X 4 and X 5 are each as defined in (5c), and m is as defined in any one of (6a)-(6c). In a further embodiment, m is as defined in (6a).
  • X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c), and X 5 is as defined in (7a).
  • X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c), and X 5 is as defined in (7b).
  • X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c), and X 5 is as defined in (7c).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , and X 3 are each as defined in (1a).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , and X 3 are each as defined in (1b).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , and X 3 are each as defined in (1c).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 3 , and X 9 are each as defined in (1d).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 7 is as defined in (3a).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 7 is as defined in (3b).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 7 is as defined in (3c).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (A1).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (A2).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (A3).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 3 , X 7 , and X 9 are each as defined (A4).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (B1).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (B2).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (B3).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 3 , X 7 , and X 9 are each as defined (B4).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (C 1 ).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (C 2 ).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , and X 7 are each as defined (C 3 ).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 3 , X 7 , and X 9 are each as defined (C 4 ).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , X 6 , X 7 , and X 9 are each as defined (D1).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , X 6 , X 7 , and X 9 are each as defined (D2).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , X 6 , X 7 , and X 9 are each as defined (D3).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , X 7 , X 9 , and n are each as defined (E1).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , X 7 , X 9 , and n are each as defined (E2).
  • X 4 and X 5 are each as defined in any one of (5a)-(5e), and X 1 , X 2 , X 3 , X 7 , X 9 , and n are each as defined (E3).
  • X 1 , X 2 , and X 3 are each as defined in (1a), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , and X 3 are each as defined in (1b), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , and X 3 are each as defined in (1c), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 3 , and X 9 are each as defined in (1d), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , and X 3 are each as defined in (1a), and X 4 , X 5 , X 8 , and m are each as defined in any one of (G1a)-(G1c).
  • X 1 , X 2 , and X 3 are each as defined in (1b), and X 4 , X 5 , X 8 , and m are each as defined in any one of (G1a)-(G1c).
  • X 1 , X 2 , and X 3 are each as defined in (1c), and X 4 , X 5 , X 8 , and m are each as defined in any one of (G1a)-(G1c).
  • X 1 , X 3 , and X 9 are each as defined in (1d), and X 4 , X 5 , X 8 , and m are each as defined in any one of (G1a)-(G1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (A1), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (A2), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (A3), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 3 , X 7 , and X 9 are each as defined (A4), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (B1), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (B2), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (B3), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 3 , X 7 , and X 9 are each as defined (B4), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (C 1 ), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (C 2 ), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , and X 7 are each as defined (C 3 ), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 3 , X 7 , and X 9 are each as defined (C 4 ), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , X 6 , X 7 , and X 9 are each as defined (D1), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , X 6 , X 7 , and X 9 are each as defined (D2), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , X 6 , X 7 , and X 9 are each as defined (D3), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , X 7 , X 9 , and n are each as defined (E1), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , X 7 , X 9 , and n are each as defined (E2), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , X 7 , X 9 , and n are each as defined (E3), and X 4 , X 5 , and m are each as defined in any one of (F1a)-(F1c).
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , m, and n are each, where applicable, as defined in any one of (1a)-(I1z), X 10 is C(O)(C 7 X 7 ) n X 6 .
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , m, and n are each, where applicable, as defined in any one of (1a)-(I1z), X 10 is CO 2 (C 7 X 7 ) n X 6 .
  • the compound of formula A is of formula II or VI:
  • X 3 , X 4 , X 5 , X 8 , and m can each be selected from any of the substituents described above in formula A, and any of the substituents described above for any of X 3 , X 4 , X 5 , X 8 , and m can be combined with any of the substituents described above for one or more of the remainder of X 3 , X 4 , X 5 , X 8 , and m.
  • the compound of formula A is of formula V or VII:
  • X 3 , X 4 , X 5 , X 8 , and m can each be selected from any of the substituents described above in formula A, and any of the substituents described above for any of X 3 , X 4 , X 5 , X 8 , and m can be combined with any of the substituents described above for one or more of the remainder of X 3 , X 4 , X 5 , X 8 , and m.
  • the compound of formula A is of formula IIIa:
  • X 3 , X 4 , and m are each as defined above in formula A;
  • t1 is 1, 2, 3, 4, or 5;
  • each Z 1 is independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, or SF 5 , wherein at least one Z 1 is C 1 -C 4 alkyl substituted with one or more F, F, or SF 5 , wherein when X 3 is H, t1 is 1, and Z 1 is 4-fluoro, then X 4 is not propenyl or propynyl.
  • the compound of formula A is of formula IIIb or IIIc:
  • X 3 , X 4 , and m are each as defined above in formula A;
  • t1 is 1, 2, 3, 4, or 5;
  • each Z 1 is independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, or SF 5 , wherein at least one Z 1 is C 1 -C 4 alkyl substituted with one or more F, F, or SF 5 .
  • t1 and Z 1 can each be, where applicable, selected from the groups described herein below, and any group described herein for any of t1 and Z 1 can be combined, where applicable, with any group described herein for the remainder of t1 and Z 1 .
  • t1 is 1, 2, or 3.
  • t1 is 1 or 2.
  • t1 is 1.
  • t1 is 2.
  • t1 is 3.
  • t1 is 4.
  • t1 is 5.
  • At least one Z 1 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), F, or SF 5 .
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more
  • At least one Z 1 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), or F.
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F
  • At least one Z 1 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F.
  • At least one Z 1 is C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F) or F.
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F
  • At least one Z 1 is CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, or SF 5 . In a further embodiment, at least one Z 1 is CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, or F. In a further embodiment, at least one Z 1 is CF 3 , CHF 2 , CH 2 F, or F. In a further embodiment, at least one Z 1 is CF 3 or F.
  • X 3 , X 4 , and m can each be selected from any of the substituents described above in formula A, and any of the substituents described above for any of X 3 , X 4 , and m can be combined with any of the substituents described above for one or more of the remainder of X 3 , X 4 , and m, and can further be combined with any of the substituents described for any of t1 and Z 1 .
  • t1 is 1, and Z 1 is CF 3 or F.
  • t1 is 1, Z 1 is CF 3 or F, and m is 1.
  • t1 is 1, Z 1 is CF 3 or F, and X 4 is propenyl or propynyl.
  • t1 is 1
  • Z 1 is CF 3 or F
  • m is 1
  • X 4 is propenyl or propynyl.
  • t1 is 1, Z 1 is CF 3 or F, X 4 is propenyl or propynyl, and X 3 is H or F.
  • t1 is 1
  • Z 1 is CF 3
  • m is 1
  • X 4 is propenyl or propynyl
  • X 3 is H or F.
  • t1 is 1, Z 1 is CF 3 or F, m is 1, X 4 is propenyl or propynyl, and X 3 is F.
  • the compound of formula A is of formula IVa, IVb, or IVc:
  • X 3 is as defined above in formula A;
  • q 1, 2, or 3;
  • t2 is 1, 2, 3, or 4;
  • each Z 2 is independently C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, or SF 5 , wherein at least one Z 2 is C 1 -C 4 alkyl substituted with one or more F, F, or SF 5 , or two Z 2 , together with adjacent carbon atoms to which they are attached, form a phenyl substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 , wherein the phenyl is substituted with at least one substituent selected from C 1 -C 4 alkyl substituted with one or more F, F, and SF 5 .
  • q, t2, and Z 2 can each be, where applicable, selected from the groups described herein below, and any group described herein for any of q, t2, and Z 2 can be combined, where applicable, with any group described herein for one or more of the remainder of q, t2, and Z 2 .
  • q is 1.
  • q is 2.
  • q is 3.
  • t2 is 1, 2, or 3.
  • t2 is 1 or 2.
  • t2 is 1.
  • t2 is 2.
  • t2 is 3.
  • t2 is 4.
  • At least one Z 2 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), F, or SF 5 .
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more
  • At least one Z 2 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), or F.
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F
  • At least one Z 2 is C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F.
  • At least one Z 2 is C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F) or F.
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F
  • At least one Z 2 is CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, or SF 5 . In a further embodiment, at least one Z 2 is CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, or F. In a further embodiment, at least one Z 2 is CF 3 , CHF 2 , CH 2 F, or F. In a further embodiment, at least one Z 2 is CF 3 or F.
  • two Z 2 together with adjacent carbon atoms to which they are attached, form a phenyl substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), F, and SF 5 .
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl,
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F), and F.
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) and C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F).
  • C 1 -C 4 alkyl e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl
  • F e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substitute
  • the phenyl is substituted with one or more substituents independently selected from C 1 -C 4 alkyl substituted with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted with one or more F) and F.
  • the phenyl is substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, F, and SF 5 .
  • the phenyl is substituted with one or more substituents independently selected from CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, and F. In one embodiment, the phenyl is substituted with one or more groups independently selected from CF 3 , CHF 2 , CH 2 F, and F. In one embodiment, the phenyl is substituted with one or more substituents independently selected from CF 3 and F.
  • any of the substituents described above for any of q, t2, and Z 2 can be combined with any of the substituents described above for any of the remainder of q, t2, and Z 2 , and can further be combined with any of the substituents described above for X 3 .
  • a compound of the present application is selected from the compounds in Tables 1a and 1b.
  • a compound of the application is a pharmaceutically acceptable salt. In one embodiment, a compound of the application is a solvate. In one embodiment, a compound of the application is a hydrate.
  • the present application relates to pharmaceutical compositions comprising one of the compounds of the application as an active ingredient.
  • the application provides a pharmaceutical composition comprising at least one compound of formula A, I, Ia, II, IIIa, IIIb, IIIc, IVa, IVb, IVc, V, VI, or VII, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carrier or excipient.
  • the application provides a pharmaceutical composition comprising at least one compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carrier or excipient.
  • the present application relates to a method of synthesizing a compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • a compound of the application can be synthesized using a variety of methods known in the art, such as those described in U.S. Pat. No. 8,916,133, the contents of which are incorporated by reference in their entirety.
  • the schemes and description below depict general routes for the preparation of a compound of the application.
  • compounds of the present application can be synthesized by following the steps outlined in Schemes 1-6 which comprise different sequences of assembling intermediates 3a, 3b, 3c, 3d, 3e, 4a, 4b, 4c, 5a, 5b, 5c, 5d, 5e, 7a, 7b, 7c, 7d, 7e, 7f, 8a, 8b, 8c, 8d, 8e, 8f, 9a, 9b, 9c, 9d, 9e, and 9f.
  • Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
  • Nucleophilic addition of 3c to fluoride 3d in the presence of a base, e.g., triethylamine (Et 3 N), in a solvent, e.g., dimethylsulfoxide (DMSO), and optionally at an elevated temperature provides intermediate 3e.
  • a base e.g., triethylamine (Et 3 N)
  • a solvent e.g., dimethylsulfoxide (DMSO)
  • a metal catalyst e.g., Zinc (Zn), and ammonium chloride (NH 4 C 1 )
  • a base e.g., DIPEA
  • a solvent e.g., methanol (MeOH)
  • an agent e.g., ethyl chloroformate
  • DIPEA diisopropylethylamine
  • a metal catalyst e.g., Zinc (Zn), and ammonium chloride (NH 4 C 1 )
  • DIPEA i.e., DIPEA
  • a solvent i.e., methanol (MeOH)
  • an agent e.g., ethyl chloroformate
  • DIPEA diisopropylethylamine
  • amine 5c with bromide 5d i.e., an alkyl bromide, allyl bromide, etc.
  • a base e.g., diisopropylethylamine (DIPEA)
  • DIPEA diisopropylethylamine
  • DMF dimethylformamide
  • a metal catalyst e.g., Zinc (Zn), and ammonium chloride (NH 4 C 1 )
  • DIPEA diisopropylethylamine
  • DIPEA diisopropylethylamine
  • a metal catalyst e.g., Zinc (Zn), and ammonium chloride (NH 4 C 1 ) in the presence of a base, e.g., DIPEA and in a solvent, e.g., methanol (MeOH), and consequent protection using BOC 2 O in the presence of a base, e.g., NaHCO 3 , provides intermediate 7d.
  • a metal catalyst e.g., Zinc (Zn)
  • NH 4 C 1 ammonium chloride
  • amine 7d with bromide 7e i.e., an alkyl bromide, allyl bromide, etc.
  • a base e.g., diisopropylethylamine (DIPEA)
  • DIPEA diisopropylethylamine
  • DMF dimethylformamide
  • Acetylation of 8e with tert-butylacetyl chloride in the presence of a base, e.g., diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane (DCM), and optionally at an elevated temperature provides intermediate 8f.
  • a base e.g., diisopropylethylamine (DIPEA)
  • DIPEA diisopropylethylamine
  • DCM dichloromethane
  • Deprotection of 7f in the presence of an acid, e.g., hydrochloric acid (HCL), in a solvent, e.g., DCM and/or diethyl ether (Et 2 O), and optionally at an elevated temperature provides compounds of formula VIa.
  • Reduction of 9b using a metal catalyst, e.g., Zinc (Zn), and ammonium chloride (NH 4 C 1 ), in a solvent, e.g., water and ethyl acetate (EtOAc), and optionally at an elevated temperature provides intermediate 9c.
  • a metal catalyst e.g., Zinc (Zn), and ammonium chloride (NH 4 C 1 )
  • a solvent e.g., water and ethyl acetate (EtOAc)
  • EtOAc ethyl acetate
  • Bromination of 9c with N-bromosuccinimide (NBS) in the presence of an acid, e.g., acetic acid, and optionally at an elevated temperature provides intermediate 9d.
  • NBS N-bromosuccinimide
  • Coupling 9e with 9f in the presence of a metal catalyst e.g., tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), and in the presence of a base, e.g., potassium tert-butoxide (t-BuOK), in a solvent, e.g., toluene, and optionally at an elevated temperature provides compounds of formula VII.
  • a metal catalyst e.g., tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3
  • a base e.g., potassium tert-butoxide (t-BuOK)
  • solvent e.g., toluene
  • the present application also comprehends deuterium labeled compounds, wherein one or more hydrogen atoms is replaced by a deuterium atom having an abundance of deuterium at that position that is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • Deuterium labeled compounds can be prepared by using any of a variety of art-recognized techniques. For example, deuterium labeled compounds of any of the formulae described herein and compounds listed in Table 1 of this application can be prepared.
  • a deuterium labeled compound of the application is a pharmaceutically acceptable salt. In one aspect, a deuterium labeled compound of the application is a solvate. In one aspect, a deuterium labeled compound of the application is a hydrate.
  • the present application relates to pharmaceutical compositions comprising one of the deuterium labeled compounds of the application as an active ingredient.
  • the application provides a pharmaceutical composition comprising at least one deuterium labeled compound of any of the formulae described herein or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carrier or excipient.
  • the present application relates to a method of synthesizing a deuterium labeled compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • the deuterium labeled compounds of the application can be prepared using any of a variety of art-recognized techniques, such as those described in U.S. Pat. No. 8,916,133, the contents of which are incorporated by reference in their entirety.
  • a deuterium labeled compound can be prepared by starting with deuterium labeled Compound 1 and/or substituting a readily available deuterium labeled reagent for a non-deuterium labeled reagent.
  • Scheme 1A outlines a preparation for a deuterium labeled compound of the application.
  • the preparation begins with Compound A (from Scheme 1A described herein).
  • Step 1 the nitro group of Compound A is reduced and then the deuterium label is introduced via formation of a carbamate containing one or more deuterium.
  • the nitro group of Compound A can be reduced using zinc powder and ammonium chloride in methanol and the carbamate can be formed using ethyl-d 5 chloroformate to provide a deuterium labeled compound.
  • temporary protecting groups may be used to prevent other reactive functionality, such as amines, thiols, alcohols, phenols, and carboxylic acids, from participating or interfering in the fluorination reaction.
  • Representative amine protecting groups include, for example, tert-butoxycarbonyl and trityl (removed under acid conditions), Fmoc (removed by the use of secondary amines such as piperidine), and benzyloxycarbonyl (removed by strong acid or by catalytic hydrogenolysis).
  • the trityl group may also be used for the protection of thiols, phenols, and alcohols.
  • the carboxylic acid protecting groups include, for example, tert-butyl ester (removed by mild acid), benzyl ester (usually removed by catalytic hydrogenolysis), and alkyl esters such as methyl or ethyl (usually removed by mild base). All protecting groups may be removed at the conclusion of the synthesis using the conditions described above for the individual protecting groups, and the final product may be purified by techniques which would be readily apparent to one of ordinary skill in the art, in combination with the teachings described herein.
  • Biological activities of the compounds of the application can be assessed by using various methods known in the art.
  • the KCNQ2/3 channel activation activity of the compounds of the application can be evaluated through an in vitro assay described below.
  • the in vitro effects of a compound of the application on cloned KCNQ2/3 potassium channels are evaluated using a patch clamp system.
  • Compounds of the application are tested at various concentrations (e.g., 0.01, 0.1, 1, 10 and 100 ⁇ M) for a certain duration of exposure (e.g., 5 min).
  • the baseline for each recording is established.
  • a single test compound concentration is applied for a certain duration of exposure after the vehicle.
  • Each recording ends with treatment with a supramaximal dose of linopirdine.
  • the % activation is calculated using the following equation by using leak subtracted responses:
  • a maximal seizure in a test animal includes four distinct phases that includes, hind leg flexor component tonic phase (Phase I), hind leg extensor component of the tonic phase (Phase II), intermittent, whole-body clonus (Phase III), and muscular relaxation (Phase IV) followed by seizure termination (Woodbury & Davenport, 1952; Racine et al., 1972).
  • Test compounds are tested for their ability to abolish hind limb tonic extensor component that indicates the compound's ability to inhibit MES-induced seizure spread.
  • Compounds are pre-administered (i.p) and tested at various time points for the abolishment of hind limb tonic extensor component after electrical stimulus.
  • mice are kindled electrically with stimulation delivered through corneal electrodes primed with tetracaine hydrochloride in saline, twice daily, until 5 consecutive stage V seizures are induced.
  • Mice are considered kindled when they display at least 5 consecutive stage V seizures according to the Racine scale (Racine et al., 1972) including, mouth and facial clonus (stage I), Stage I plus head nodding (Stage II), Stage II plus forelimb clonus (Stage III), Stage III plus rearing (Stage IV), and stage IV plus repeated rearing and falling (Stage V) (Racine et al., 1972).
  • mice are permitted a 3-day stimulation-free period prior to any drug testing.
  • mice are pre-administered (i.p) with increasing doses of the test compound and challenged with the corneal kindling stimulus. Mice are scored as protected (seizure score of ⁇ 3) or not protected, (seizure score ⁇ 4) based on the Racine scoring (Racine et al., 1972).
  • the present application relates to pharmaceutical compositions comprising a compound of the application as an active ingredient.
  • the application provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the application provides a pharmaceutical composition comprising at least one compound selected from Table 1.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the compounds of the application can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of the application can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present application may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.
  • Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.
  • solubility enhancing agent examples include cyclodextrin, such as those selected from the group consisting of hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, randomly methylated- ⁇ -cyclodextrin, ethylated- ⁇ -cyclodextrin, triacetyl- ⁇ -cyclodextrin, peracetylated- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, sulphated ⁇ -cyclodextrin (S- ⁇ -CD), maltosyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin sulfobutyl ether, branched-
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.
  • a preservative examples include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium
  • the aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure).
  • the tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the aqueous vehicle may also contain a viscosity/suspending agent.
  • Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols—such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • Carbopols such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • the aqueous vehicle may also contain a buffering agent to stabilize the pH.
  • the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ⁇ -aminocaproic acid, and mixtures thereof.
  • the formulation may further comprise a wetting agent.
  • wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the present application relates to methods for the use of compounds of the application.
  • the compounds of the application have a useful pharmacological activity spectrum and are therefore particularly suitable for the prophylaxis and/or treatment of diseases or disorders.
  • the present application provides a method of treating or preventing diseases or disorders, comprising administering a therapeutically effective amount of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for the treatment or prevention of diseases or disorders.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing diseases or disorders.
  • the disease or disorder is a condition which can be ameliorated by KCNQ2/3 potassium channel opening.
  • the disease or disorder is selected from epilepsy, neurotransmission disorder, CNS disorder, neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration, or glaucoma), cognitive disorder (e.g., degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, and Creutzfeldt-Jakob disease); vascular dementia (including multi-infarct dementia); dementia associated with intracranial space occupying lesions, trauma, infections or related conditions (including HIV infection), metabolism, toxins, anoxia, or vitamin deficiency; mild cognitive impairment associated with ageing, particularly Age Associated Memory Loss, or learning deficiencies), bipolar disorder (e.g., Type I or II bipolar disorder), unipolar depression, anxiety, migraine, ataxia, myokimia, tin
  • the application provides a method of producing an anti-epileptic, muscle relaxing, fever reducing, peripherally analgesic, and/or anti-convulsive effect in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for producing an anti-epileptic, muscle relaxing, fever reducing, peripherally analgesic, and/or anti-convulsive effect.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for producing an anti-epileptic, muscle relaxing, fever reducing, peripherally analgesic, and/or anti-convulsive effect.
  • the application provides compounds that are useful as an anticonvulsant. They are therefore useful in treating or preventing epilepsy.
  • Compounds of the application may be used to improve the condition of a host, typically a human being, suffering from epilepsy. They may be employed to alleviate the symptoms of epilepsy in a host.
  • “Epilepsy” is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalized seizures, generalized seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures. Partial-onset seizures are the most common type of seizure in adult patients.
  • Partial seizures there is a focal epileptic zone (site of seizure onset), and seizure activity is initially limited to one hemisphere. Partial seizures can be further sub-divided into simple partial (without impairment of consciousness), complex partial (with impairment of consciousness with or following a simple partial onset) and secondarily generalized (i.e., partial seizures, either simple or complex, which evolve to generalized tonic-clonic seizures). Simple partial seizures, depending on the anatomical site of origin of the seizure, may have motor, somatosensory or special sensory, autonomic or psychic signs or symptoms.
  • the application provides a method of treating a subject suffering from or susceptible to epilepsy, comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject suffering from or susceptible to epilepsy for the treatment of epilepsy.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for treating a subject suffering from or susceptible to epilepsy.
  • the application provides a method for the adjunctive treatment of adults with partial-onset seizures, comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt thereof.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for adjunctive treatment of adults with partial-onset seizures.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for adjunctive treatment of adults with partial-onset seizures.
  • the present application provides a method of treating or preventing epilepsy, comprising administering a therapeutically effective amount of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for the treatment or prevention of epilepsy.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing epilepsy.
  • a compound of the application is administered in combination with one or more anti-epileptic drugs (AEDs).
  • AEDs anti-epileptic drugs
  • narrow-spectrum AEDs include phenytoin (Dilantin), phenobarbital, carbamazepine (Tegretol), oxcarbazepine (Trileptal), gabapentin (Neurontin), pregabalin (Lyrica), lacosamide (Vimpat), and vigabatrin (Sabril).
  • Broad spectrum AEDs include valproic acid (Depakote), lamotrigine (Lamictal), topiramate (Topamax), zonisamide (Zonegran), levetiracetam (Keppra), clonazepam (Klonopin), and rufinamide (Banzel).
  • the AED is any AED.
  • the AED is a narrow spectrum AED.
  • the AED is a broad spectrum AED.
  • the application provides compounds that are useful as analgesics.
  • the compounds are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically a human being, suffering from pain. They may be employed to alleviate pain in a host.
  • the compounds may be used as a pre-emptive analgesic to treat acute pain such as musculoskeletal pain, post-operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g., rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g., post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia.
  • acute pain such as musculoskeletal pain, post-operative pain and surgical pain
  • chronic pain such as chronic inflammatory pain (e.g., rheumatoid arthritis and osteoarthritis)
  • neuropathic pain e.g., post herpetic neuralgia, tri
  • the compounds may also be used in the treatment or prevention of pain associated with migraine.
  • the compounds may also be used in the treatment of the pain (both chronic and acute), fever and inflammation of conditions such as rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
  • the application provides a method of producing an analgesic effect in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for producing an analgesic effect.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for producing an analgesic effect.
  • the analgesic effect is a neuroprotective effect.
  • the analgesic effect is a centrally acting analgesic effect.
  • the application provides a method of treating or preventing a neurotransmission disorder, CNS disorder, neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration and glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II bipolar disorder), unipolar depression, or anxiety in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • a neurotransmission disorder e.g., CNS disorder, neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration and glaucoma)
  • cognitive disorder e.g., a cognitive disorder, bipolar disorder (e.g., Type I or II bipolar disorder), unipolar depression, or anxiety in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for treating or preventing a neurotransmission disorder, CNS disorder, neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration and glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II bipolar disorder), unipolar depression, or anxiety.
  • a neurotransmission disorder CNS disorder
  • neurodegenerative disease e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration and glaucoma
  • cognitive disorder e.g., bipolar disorder (e.g., Type I or II bipolar disorder), unipolar depression, or anxiety.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing a neurotransmission disorder, CNS disorder, neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration and glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II bipolar disorder), unipolar depression, or anxiety.
  • a neurotransmission disorder e.g., CNS disorder, neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration and glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II bipolar disorder), unipolar depression, or anxiety.
  • a neurotransmission disorder e.g., CNS disorder, neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration and glaucoma), cognitive disorder, bi
  • the application provides a method of treating or preventing migraine, ataxia, myokimia, tinnitus, and functional bowel disorders (e.g., non-ulcer dyspepsia, non-cardiac chest pain, or irritable bowel syndrome) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • bowel disorders e.g., non-ulcer dyspepsia, non-cardiac chest pain, or irritable bowel syndrome
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for treating or preventing migraine, ataxia, myokimia, tinnitus, and functional bowel disorders (e.g., non-ulcer dyspepsia, non-cardiac chest pain, or irritable bowel syndrome).
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing migraine, ataxia, myokimia, tinnitus, and functional bowel disorders (e.g., non-ulcer dyspepsia, non-cardiac chest pain, or irritable bowel syndrome).
  • the application provides compounds that are useful in the treatment of CNS disorders such as bipolar disorder, alternatively known as manic depression.
  • the compounds may thus be used to improve the condition of a human patient suffering from bipolar disorder. They may be used to alleviate the symptoms of bipolar disorder in a host.
  • the compounds may also be used in the treatment of unipolar depression, ataxia, myokimia and anxiety.
  • the application provides compounds that are useful in the treatment of neurodegenerative diseases, such as Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease, macular degeneration and glaucoma.
  • the compounds of the application may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • compounds of the application are further useful in the treatment of tinnitus.
  • the application provides compounds that are useful in the treatment of functional bowel disorders which include non-ulcer dyspepsia, non-cardiac chest pain and in particular irritable bowel syndrome.
  • Irritable bowel syndrome is a gastrointestinal disorder characterized by the presence of abdominal pain and altered bowel habits without any evidence of organic disease. The compounds may thus be used to alleviate pain associated with irritable bowel syndrome. The condition of a human patient suffering from irritable bowel syndrome may thus be improved.
  • the application provides a method of preventing or reducing dependence on, or preventing or reducing tolerance, or reverse tolerance, to a dependence-inducing agent in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for preventing or reducing dependence on, or preventing or reducing tolerance, or reverse tolerance, to a dependence-inducing agent.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for preventing or reducing dependence on, or preventing or reducing tolerance, or reverse tolerance, to a dependence-inducing agent.
  • dependence inducing agents include opioids (e.g., morphine), CNS depressants (e.g., ethanol), psychostimulants (e.g., cocaine) and nicotine.
  • the application provides a method of treating or preventing cancer, inflammatory disease, or ophthalmic disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for treating or preventing cancer, inflammatory disease, or ophthalmic disease.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing cancer, inflammatory disease, or ophthalmic disease.
  • the application provides compounds that inhibit cellular and neoplastic transformation and metastatic tumor growth and hence are useful in the treatment of certain cancerous diseases, such as colonic cancer.
  • the application provides compounds that inhibit inflammatory processes and therefore are of use in the treatment of asthma, allergic rhinitis and respiratory distress syndrome; gastrointestinal conditions such as inflammatory bowel disease, Chron's disease, gastritis, irritable bowel syndrome and ulcerative colitis; and the inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, conjunctivitis and myocardial ischemia.
  • vascular disease migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome
  • the application provides compounds that are useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis, and acute injury to the eye tissue.
  • ophthalmic diseases such as retinitis, retinopathies, uveitis, and acute injury to the eye tissue.
  • the application provides compounds that are useful for the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Loss; and learning deficiencies.
  • dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age
  • the application provides a method of producing an anxiolytic effect in a subject in need thereof comprising administering to the subject an effective amount of a compound of the application or a pharmaceutically acceptable salt or solvate thereof.
  • the application provides a method for the treatment of anxiety and its related psychological and physical symptoms. Anxiolytics have been shown to be useful in the treatment of anxiety disorders.
  • the present application also provides the use of a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for administration to a subject for producing an anxiolytic effect.
  • the present application also provides a compound of the application, or a pharmaceutically acceptable salt or solvate thereof, for producing an anxiolytic effect.
  • the application provides compounds for treatment. In one embodiment, the application provides compounds for prophylaxis. In one embodiment, the application provides compound for alleviation of established symptoms.
  • Administration may for example be in the form of tablets, capsules, pills, coated tablets, suppositories, ointments, gels, creams, powders, dusting powders, aerosols or in liquid form.
  • Liquid application forms that may for example be considered are: oils or alcoholic or aqueous solutions as well as suspensions and emulsions.
  • the application provides forms of application that are tablets that contain between 30 and 60 mg or solutions that contain between 0.1 to 5 percent by weight of active substance.
  • a compound of the application is used in human medicine. In one embodiment, the compound of the application is used in veterinary medicine. In one embodiment, a compound of the application is used in agriculture. In one embodiment, a compound of the application is used alone or mixed with other pharmacologically active substances.
  • Step 1 Synthesis of Compound a
  • Step 1 Synthesis of 2-Fluoro-N 1 -(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine
  • 2,3-Difluoro-6-nitroaniline (10.0 g, 79.9 mmole) was dissolved in anhydrous dimethylsulfoxide (90 mL). 4-fluorobenzylamine (9.3 g, 53.3 mmole) was added triethylamine (17.7 mL) and solid iodine (80 mg) were added and the mixture was heated at reflux for 4 h. under argon. The reaction was dissolved in ethyl acetate (200 mL) and extracted with water (3 ⁇ 100 mL). A yellow solid precipitated out of the organic layer to give 2-fluoro-N 1 -(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (13.6 g, 91% yield).
  • Step 2 Synthesis of di-tert-butyl (3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate
  • Step 3 Synthesis of di-tert-butyl (4-(allyl(4-fluorobenzyl)amino)-3-fluoro-1,2-phenylene)dicarbamate
  • Di-tert-butyl (3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (2.03 g, 4.52 mmole) was dissolved in anhydrous dimethylformamide (10 mL).
  • Diisopropylethylamine (1.6 mL, 9.0 mmole) was added followed by allyl bromide (0.710 mg, 5.87 mmole).
  • the mixture was heated in an 110° C. oil bath under argon for 6h.
  • the reaction was diluted in ethyl acetate (100 mL) and extracted with water (100 mL). The aqueous layer was washed with ethyl acetate (100 mL).
  • the organic layers were washed with water, 2 ⁇ 50 mL and then brine (50 mL) and filtered through a 1PS filter to dry and evaporated to dryness.
  • the crude material was chromatographed on a silica gel column (25 g) packed in hexanes. The column polarity was increased to 9% ethyl acetate over 4 CV, held at 9% ethyl acetate over 7 CV and then increased to 33% ethyl acetate over 12 CV.
  • the flow rate was 25 mL/min.
  • Step 4 Synthesis of ethyl (4-(allyl(4-fluorobenzyl)amino)-2-amino-3-fluorophenyl)carbamate (Compound 1)
  • Step 2 Synthesis of N 1 -allyl-2-fluoro-4-nitro-N 1 -(4-(trifluoromethyl)benzyl)benzene-1,3-diamine
  • Step 3 Synthesis of ethyl (4-(allyl(4-(trifluoromethyl)benzyl)amino)-2-amino-3-fluorophenyl)carbamate (Compound 2)
  • N 1 -allyl-2-fluoro-4-nitro-N 1 -(4-(trifluoromethyl)benzyl)benzene-1,3-diamine (0.392 g, 1.06 mmole) was dissolved in methanol (10 mL).
  • Zinc powder (347 mg, 5.30 mmole) was added followed by ammonium chloride (284 mg, 5.30 mmole) in DI water (1.0 mL). The mixture was stirred under argon at ambient temperature for 2 h. and then cooled to 10° C. in an ice bath.
  • N, N-diisopropylethylamine (0.221 mL, 1.27 mmole) was added, followed by ethyl chloroformate, dropwise (285 mg, 2.66 mmole) and the reaction was stirred at ambient temperature for 18 h.
  • the reaction was dissolved in ethyl acetate (10 mL) and extracted with water (10 mL). The organic layer was washed with 2 ⁇ 10 mL water and then dried through a 1PS filter and evaporated to dryness.
  • the crude material was chromatographed on a silica gel column (25 g) packed in chloroform. The column polarity was increased to 20% ethyl acetate/chloroform over 10 CV, at 25 mL/min.
  • Step 2 Synthesis of N′-allyl-2-fluoro-4-nitro-N 1 -(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
  • 2,3-Difluoro-6-nitroaniline (270 mg, 2.32 mmole) was dissolved in anhydrous dimethylsulfoxide (5 mL). N-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine (0.500 g, 2.32 mmole) was added triethylamine (0.708 mL) and solid iodine (1 mg). The mixture was heated at reflux for 18 h. under argon. The reaction was dissolved in dichloromethane (20 mL) and extracted with water (20 mL). The aqueous layer was washed with dichloromethane (20 mL). The organic layers were washed with water, 2 ⁇ 20 mL brine and evaporated to dryness.
  • Step 3 Synthesis of ethyl (4-(allyl(3-(trifluoromethyl)benzyl)amino)-2-amino-3-fluorophenyl)carbamate (Compound 3)
  • N 1 -allyl-2-fluoro-4-nitro-N 1 -(3-(trifluoromethyl)benzyl)benzene-1,3-diamine (0.305 g, 0.826 mmole) was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL).
  • Zinc powder 0.540 g, 8.26 mmole
  • ammonium chloride 442 mg, 8.26 mmole
  • Step 1 Synthesis of di-tert-butyl (4-(allyl(4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate
  • Di-tert-butyl (4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (0.937 g, 2.17 mmole) was dissolved in anhydrous dimethylformamide (10 mL).
  • Diisopropylethylamine (0.755 mL, 4.34 mmole) was added followed by allyl bromide (0.237 mL, 2.82 mmole).
  • the mixture was heated in an 110° C. oil bath under argon for 2h.
  • the reaction was diluted in ethyl acetate (100 mL) and extracted with water (100 mL). The aqueous layer was washed with ethyl acetate (100 mL).
  • the organic layers were washed with water, 2 ⁇ 50 mL and then brine (50 mL) and filtered through a 1PS filter to dry and evaporated to dryness.
  • the crude material was chromatographed on a silica gel column (25 g) packed in hexanes. The column polarity was increased to 12% ethyl acetate over 6 CV, held at 12% ethyl acetate over 2 CV and then increased to 40% ethyl acetate over 14 CV. The flow rate was 25 mL/min.
  • Step 2 Synthesis of ethyl (4-(allyl(4-fluorobenzyl)amino)-2-aminophenyl)carbamate (Compound 4)
  • Step 1 Synthesis of N 1 -allyl-4-nitro-N 1 -(4-(trifluoromethyl)benzyl)benzene-1,3-diamine
  • Step 2 Synthesis of ethyl (4-(allyl(4-(trifluoromethyl)benzyl)amino)-2-aminophenyl)carbamate (Compound 5)
  • N 1 -allyl-4-nitro-N 1 -(4-(trifluoromethyl)benzyl)benzene-1,3-diamine (0.182 g, 0.518 mmole) was dissolved in methanol (3 mL).
  • Zinc powder (169 mg, 2.59 mmole) was added followed by ammonium chloride (139 mg, 2.59 mmole) in DI water (1.0 mL).
  • the mixture was stirred under argon at ambient temperature for 30 min., and then zinc powder (169 mg, 2.59 mmole) was added followed by ammonium chloride (139 mg, 2.59 mmole) in DI water (1.0 mL) and tetrahydrofuran (3 mL).
  • Step 1 Synthesis of 4-Nitro-N 1 -(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
  • Step 2 Synthesis of di-tert-butyl (4-((tert-butoxycarbonyl)(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
  • Step 3 Synthesis of di-tert-butyl (4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
  • the solid was dissolved in dioxane (125 mL) and di-tert-butyldicarbonate (10.24 g, 46.94 mmole) was added followed by solid sodium bicarbonate (7.51 g, 89.4 mmole) and then DI water (50 mL).
  • the reaction was heated to 40° C. with stirring for 18 h., under argon.
  • the reaction was evaporated and ethyl acetate (200 mL) was added.
  • the organic layer was extracted with 3M NH 4 OH (2 ⁇ 100 mL) and brine (50 mL), dried through a 1PS filter and evaporated to dryness.
  • Step 4 Synthesis of di-tert-butyl (4-(allyl(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
  • Di-tert-butyl (4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate (2.0 g, 4.2 mmole) was dissolved in anhydrous dimethylformamide (20 mL).
  • Diisopropylethylamine (2.2 mL, 12.5 mmole) was added followed by allyl bromide (0.803 mL, 9.55 mmole).
  • the mixture was heated in an 110° C. oil bath under argon for 2h.
  • the reaction was diluted in ethyl acetate (200 mL) and extracted with water (200 mL), and then brine (50 mL) and filtered through a 1PS filter to dry and evaporated to dryness.
  • Step 5 Synthesis of ethyl (4-(allyl(3-(trifluoromethyl)benzyl)amino)-2-aminophenyl)carbamate (Compound 6)
  • Step 1 Synthesis of 2-Fluoro-N 1 -(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine
  • 2,3-Difluoro-6-nitroaniline (10.0 g, 79.9 mmole) was dissolved in anhydrous dimethylsulfoxide (90 mL). 4-fluorobenzylamine (9.3 g, 53.3 mmole) was added triethylamine (17.7 mL) and solid iodine (80 mg) were added and the mixture was heated at reflux for 4 h. under argon. The reaction was dissolved in ethyl acetate (200 mL) and extracted with water (3 ⁇ 100 mL). A yellow solid precipitated out of the organic layer to give 2-fluoro-N 1 -(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (13.6 g, 91% yield).
  • Step 2 Synthesis of di-tert-butyl (3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate
  • Step 3 Synthesis of di-tert-butyl (3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-1,2-phenylene)dicarbamate
  • Di-tert-butyl (3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (2.00 g, 4.45 mmole) was dissolved in anhydrous dimethylformamide (20 mL), 80% propargyl bromide in toluene (0.618 mL, 5.78 mmole) and diisopropylethylamine (1.50 mL, 8.90 mmole). The mixture was heated in a 90° C. oil bath, under argon, for 0.5 h.
  • the reaction was diluted in ethyl acetate (100 mL) and extracted with water (100 mL) and brine (50 mL), filtered through a 1PS filter and evaporated to dryness.
  • the crude material was chromatographed on a silica gel column (25 g) packed in hexanes. The column polarity was increased to 40% ethyl acetate over 15 CV, at 25 mL/min.
  • Step 4 Synthesis of ethyl (2-amino-3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)phenyl)carbamate (Compound 7)
  • Step 2 Synthesis of 2-Fluoro-4-nitro-N 1 -(prop-2-yn-1-yl)-N 1 -(4-(trifluoromethyl)benzyl)benzene-1,3-diamine
  • 2,3-Difluoro-6-nitroaniline (0.681 g, 3.91 mmole) was dissolved in anhydrous dimethylsulfoxide (5 mL). N-(4-(trifluoromethyl)benzyl)prop-2-yn-1-amine (1.75 g, 8.21 mmole)) was added followed by triethylamine (2.3 mL) and solid iodine (2 mg). The mixture was heated at reflux for 18 h. under argon. The reaction was dissolved in dichloromethane (10 mL) and extracted with water (10 mL). The aqueous layer was washed with 2 ⁇ 10 mL dichloromethane.
  • Step 3 Synthesis of ethyl (2-amino-3-fluoro-4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)phenyl)carbamate (Compound 8)
  • Step 2 Synthesis of 2-Fluoro-4-nitro-N 1 -(prop-2-yn-1-yl)-N 1 -(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
  • Step 3 Synthesis of ethyl (2-amino-3-fluoro-4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino)phenyl)carbamate (Compound 9)
  • Step 1 Synthesis of 4-Nitro-N 1 -(4-(trifluoromethyl)benzyl)benzene-1,3-diamine
  • Step 2 Synthesis of di-tert-butyl (4-((4-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
  • Step 3 Synthesis of di-tert-butyl (4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
  • Step 4 Synthesis of ethyl (2-amino-4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)phenyl)carbamate (Compound 11)
  • Step 1 Synthesis of 4-Nitro-N 1 -(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
  • Step 2 Synthesis of di-tert-butyl (4-((tert-butoxycarbonyl)(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
  • Step 3 Synthesis of di-tert-butyl (4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
  • the solid was dissolved in dioxane (125 mL) and di-tert-butyldicarbonate (10.24 g, 46.94 mmole) was added followed by solid sodium bicarbonate (7.51 g, 89.4 mmole) and then DI water (50 mL).
  • the reaction was heated to 40° C. with stirring for 18 h., under argon.
  • the reaction was evaporated and ethyl acetate (200 mL) was added.
  • the organic layer was extracted with 3M NH 4 OH (2 ⁇ 100 mL) and brine (50 mL), dried through a 1PS filter and evaporated to dryness.
  • Step 4 Synthesis of Di-tert-butyl (4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
  • Di-tert-butyl (4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate (2.00 g, 4.15 mmole) was dissolved in anhydrous dimethylformamide (20 mL).
  • Diisopropylethylamine (2.20 mL, 12.5 mmole) was added followed by 80% propargyl bromide in toluene (1.50 mL, 14.3 mmole).
  • the mixture was heated in a 110° C. oil bath under argon for 2h.
  • the reaction was diluted in ethyl acetate (200 mL) and extracted with water (200 mL). The organic layer was evaporated to dryness.
  • Step 5 Synthesis of ethyl (2-amino-4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino) phenyl)carbamate (Compound 12)
  • Step 2 Synthesis of ethyl (2-amino-3-fluoro-4-(5-(trifluoromethyl)isoindolin-2-yl)phenyl)carbamate (Compound 14)
  • Triethylamine (0.55 mL, 3.96 mmole) was added, followed by ethyl chloroformate dropwise (265 mg, 2.48 mmole) and the reaction was stirred at ambient temperature for 105 min. The reaction was filtered and evaporated. The crude oil was dissolved in ethyl acetate (10 mL) and extracted with water (10 mL). the organic layer was then dried through a 1PS filter and evaporated to dryness. It was chromatographed on a silica gel column (10 g) packed in chloroform. The column was washed with 13 CV of chloroform and then polarity was increased to 45% ethyl acetate/chloroform over 14 CV, at 12 mL/min.
  • 5-Fluoro-2-nitroaniline (0.237 g, 1.52 mmole) was dissolved in anhydrous dimethylsulfoxide (6 mL).
  • 5-(trifluoromethyl)isoindoline hydrochloride (0.510 g, 2.28 mmole) was added triethylamine (0.72 mL) and solid iodine (1 mg).
  • the mixture was heated at reflux for 12 h. under argon.
  • the reaction was dissolved in dichloromethane (10 mL) and extracted with water (10 mL).
  • the reaction was dissolved in dichloromethane (10 mL) and extracted with water (10 mL).
  • Step 2 Synthesis of ethyl (2-amino-4-(5-(trifluoromethyl)isoindolin-2-yl)phenyl)carbamate (Compound 16)
  • Ethyl chloroformate was added dropwise (150 mg, 1.40 mmole) and the reaction was stirred at ambient temperature for 2 h. The reaction was filtered and evaporated. The crude oil was dissolved in ethyl acetate (10 mL) and extracted with water (10 mL). the organic layer was then dried through a 1PS filter and evaporated to dryness. It was chromatographed on a silica gel column (10 g) packed in chloroform. The column was washed with 12 CV of chloroform and then polarity was increased to 50% ethyl acetate/chloroform over 20 CV, at 12 mL/min.
  • Step 2 Synthesis of ethyl (2-amino-3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate (Compound 17)
  • Step 1 Synthesis of 2-Fluoro-6-nitro-3-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)aniline
  • 2,3-Difluoro-6-nitroaniline (0.238 g, 1.37 mmole) was dissolved in anhydrous dimethylsulfoxide (6 mL). 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.487 g, 2.05 mmole) was added triethylamine (0.643 mL) and solid iodine (1 mg). The mixture was heated at reflux for 12 h. under argon. The reaction was dissolved in dichloromethane (10 mL) and extracted with water (10 mL).
  • Step 1 Synthesis of 2-Fluoro-6-nitro-3-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)aniline
  • 2,3-Difluoro-6-nitroaniline (0.238 g, 1.37 mmole) was dissolved in anhydrous dimethylsulfoxide (6 mL). 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.49 g, 2.05 mmole) was added triethylamine (0.64 mL) and solid iodine (1 mg). The mixture was heated at reflux for 2 h. under argon. The reaction was dissolved in dichloromethane (10 mL) and extracted with water (10 mL).
  • Step 2 Synthesis of ethyl (2-amino-3-fluoro-4-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate (Compound 19)
  • 2,3-Difluoro-6-nitroaniline (0.310 g, 1.78 mmole) was dissolved in anhydrous dimethylsulfoxide (6 mL). 7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.50 g, 2.66 mmole) was added triethylamine (0.840 mL) and solid iodine (1 mg). The mixture was heated at reflux for 12 h. under argon. The reaction was dissolved in dichloromethane (10 mL) and extracted with water (10 mL).
  • Step 2 Synthesis of ethyl (2-amino-3-fluoro-4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate (Compound 20)
  • N, N-diisopropylethylamine (0.666 mL, 3.77 mmole) was added, followed by ethyl chloroformate dropwise (298 mg, 2.80 mmole) and the reaction was stirred at ambient temperature for 12 h. The reaction was cooled in an ice bath. N, N-diisopropylethylamine (0.350 mL) was added, followed by ethyl chloroformate dropwise (162 mg,). The reaction was stirred at ambient temperature for 1 h. It was filtered and evaporated. The crude oil was dissolved in ethyl acetate (10 mL) and extracted with water (10 mL).
  • 5-Fluoro-2-nitroaniline (0.278 g, 1.78 mmole) was dissolved in anhydrous dimethylsulfoxide (6 mL). 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.50 g, 2.7 mmole) was added triethylamine (0.837 mL) and solid iodine (1 mg). The mixture was heated at reflux for 1.5 h. under argon. The reaction was dissolved in ethyl acetate (10 mL) and extracted with water (10 mL). The organic layer was washed with 3 ⁇ 30 mL water and then dried through a 1PS filter and evaporated to dryness.
  • Step 2 Synthesis of ethyl (2-amino-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate (Compound 21)
  • Step 2 Synthesis of ethyl (2-amino-4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate (Compound 22)
  • Step 2 Synthesis of ethyl (2-amino-4-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate (Compound 23)
  • 5-Fluoro-2-nitroaniline (0.278 g, 1.78 mmole) was dissolved in anhydrous dimethylsulfoxide (6 mL). 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.50 g, 2.7 mmole) was added triethylamine (0.837 mL) and solid iodine (1 mg). The mixture was heated at reflux for 1.5 h. under argon. The reaction was dissolved in ethyl acetate (10 mL) and extracted with water (10 mL). The organic layer was washed with 3 ⁇ 30 mL water and then dried through a 1PS filter and evaporated to dryness.
  • Step 2 Synthesis of ethyl (2-amino-4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate (Compound 24)
  • N, N-diisopropylethylamine (0.593 mL, 3.43 mmole) was added, followed by ethyl chloroformate dropwise (271 mg, 2.53 mmole) and the reaction was stirred at ambient temperature for 12 h. The reaction was filtered and evaporated. The crude oil was dissolved in ethyl acetate (10 mL) and extracted with water (10 mL). the organic layer was then dried through a 1PS filter and evaporated to dryness. It was chromatographed on a silica gel column (10g) packed in chloroform. The column polarity was increased to 20% ethyl acetate/chloroform over 8 CV, at 12 mL/min.
  • N-(4-bromo-3-fluoro-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (316 mg, 1.00 mmol, 1.00 equiv) in toluene (5 mL) at 23° C. were added N-(4-fluorobenzyl)prop-2-yn-1-amine (180 mg, 1.10 mmol, 1.10 equiv), DavePhos (47 mg, 0.12 mmol, 12 mol %), Pd 2 (dba) 3 (37 mg, 0.040 mmol, 4.0 mol %), and t-BuOK (168 mg, 1.50 mmol, 1.50 equiv). After stirring for 2 d at 110° C., the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 25 mg the title compound (6% yield).
  • Step 2 Synthesis of tert-Butyl N-[3-[bis(tert-butoxycarbonyl)amino]-2-fluoro-4-nitro-phenyl]-N-[(4-fluorophenyl)-methyl]carbamate
  • Step 3 Synthesis of tert-Butyl N-[4-amino-3-[bis(tert-butoxycarbonyl)amino]-2-fluoro-phenyl]-N-[(4-fluorophenyl)methyl]carbamate
  • Step 4 Synthesis of tert-Butyl N-[3-[bis(tert-butoxycarbonyl)amino]-4-(3, 3-dimethylbutanoylamino)-2-fluoro-phenyl]-N-[(4-fluorophenyl)methyl]carbamate
  • Step 5 Synthesis of N-[2-amino-3-fluoro-4-[(4-fluorophenyl)methylamino]phenyl]-3, 3-dimethyl-butanamide (Compound 29)
  • Step 2 Synthesis of tert-Butyl N-tert-butoxycarbonyl-N-[2-fluoro-3-[(4-fluorophenyl)methylamino]-6-nitro-phenyl]carbamate
  • Step 3 Synthesis of tert-Butyl N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[(4-fluorophenyl)methyl-prop-2-ynyl-amino]phenyl]carbamate
  • Step 4 Synthesis of N-(2-amino-3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)phenyl)-3,3-dimethylbutanamide (Compound 30)
  • Step 1 Synthesis of tert-Butyl N-tert-butoxycarbonyl-N-[2-fluoro-6-nitro-3-[[4-(trifluoromethyl)phenyl]-methylamino]phenyl]carbamate
  • Step 2 Synthesis of tert-Butyl N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[prop-2-ynyl-[[4-(trifluoromethyl)phenyl]methyl]amino]phenyl]carbamate
  • Step 3 Synthesis of N-[2-amino-3-fluoro-4-[prop-2-ynyl-[[4-(trifluoromethyl)phenyl]methyl]amino]phenyl]-3,3-dimethyl-butanamide (Compound 31)
  • Step 2 Synthesis of tert-Butyl N-tert-butoxycarbonyl-N-[3-[ethyl-[(4-fluoro-2-methyl-phenyl)methyl]amino]-2-fluoro-6-nitro-phenyl]carbamate
  • Step 3 Synthesis of tert-Butyl N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)phenyl]carbamate
  • Step 4 Synthesis of ethyl (3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-carbamate (Compound 32)
  • Step 1 Synthesis of tert-Butyl N-tert-butoxycarbonyl-N-[2-fluoro-6-nitro-3-[6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]phenyl]carbamate
  • Step 2 Synthesis of tert-Butyl N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]phenyl]carbamate
  • Step 3 Synthesis of N-[2-amino-3-fluoro-4-[6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]phenyl]-3,3-dimethyl-butanamide (Compound 33)
  • Step 4 Synthesis of ethyl (4-bromo-3-fluoro-2,6-dimethylphenyl)carbamate
  • Step 5 Synthesis of N-(3-fluoro-4-((4-fluorobenzyl)amino)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound 34)
  • the baseline for each recording is established using a 5-10 minute vehicle application (HBPS+0.3% DMSO). A single test compound concentration is applied for a period of 5 minutes after the vehicle, followed by a 3 minute application of 30 ⁇ M flupirtine. Each recording ends with a supramaximal dose of 30 ⁇ M linopirdine.
  • the % activation is calculated using the following equation by using leak subtracted responses:
  • HEK293T cells are transfected with recombinant DNA (3-5 ⁇ g) using Lipofectamine 2000 (Invitrogen, Carlsbad, Calif.) and recorded 48 hours after transfection. All experiments are performed at room temperature using conventional whole-cell patch clamp technique. Recording electrodes are filled with internal solution containing (in mM): 132 K-Gluconate, 10 KCl, 4 Mg.ATP, 20 HEPES, and 1 EGTA.KOH, pH 7.2-7.3, and have resistances of 3-5 M ⁇ .
  • the standard bath solution contains (in mM): 144 NaCl, 2.5 KCl, 2.25 CaCl 2 , 1.2 MgCl 2 , 10 HEPES, and 22 D-Glucose, pH 7.2-7.3. Series resistance is compensated by 75%. Osmolarity is adjusted to 300-305 mOsm and pH to 7.2-7.3 with NaOH. Voltage pulses are applied at 30s intervals from a holding potential of ⁇ 85 mV to various test pulses before jumping down to ⁇ 70 mV. These values are adjusted for the calculated junction potential of ⁇ 15 mV.
  • MES test the ability of different doses of the test compound in preventing seizure induced by an electrical stimulus of 0.2 s in duration (50 mA at 60 Hz), delivered through the corneal electrodes primed with a drop of anesthetic/electrolyte solution (0.5% tetracaine hydrochloride in 0.9% saline) is tested. Mice are restrained by hand and released immediately following corneal stimulation that allows for the observation of the entire seizure episode.
  • a maximal seizure in a test animal includes four distinct phases that includes, hind leg flexor component tonic phase (Phase I), hind leg extensor component of the tonic phase (Phase II), intermittent, whole-body clonus (Phase III), and muscular relaxation (Phase IV) followed by seizure termination (Woodbury & Davenport, 1952; Racine et al., 1972).
  • Test compounds are tested for their ability to abolish hind limb tonic extensor component that indicates the compound's ability to inhibit MES-induced seizure spread.
  • Compounds are pre-administered (i.p) and tested at 0.25, 0.5, 1 and 4 h time points for the abolishment of hind limb tonic extensor component after electrical stimulus.
  • mice are kindled electrically with 3 s stimulation, 8 mA, 60 Hz delivered through corneal electrodes primed with 0.5% tetracaine hydrochloride in 0.9% saline, twice daily, until 5 consecutive stage V seizures are induced.
  • Mice are considered kindled when they display at least 5 consecutive stage V seizures according to the Racine scale (Racine et al., 1972) including, mouth and facial clonus (stage I), Stage I plus head nodding (Stage II), Stage II plus forelimb clonus (Stage III), Stage III plus rearing (Stage IV), and stage IV plus repeated rearing and falling (Stage V) (Racine et al., 1972).
  • mice are permitted a 3-day stimulation-free period prior to any drug testing.
  • fully kindled mice are pre-administered (i.p) with increasing doses of the test compound and challenged with the corneal kindling stimulus of 3 mA for 3 seconds 15 min.
  • Mice are scored as protected (seizure score of ⁇ 3) or not protected, (seizure score ⁇ 4) based on the Racine scoring (Racine et al., 1972).
  • CHO cells stably expressing human Kv7.2/7.3 channels were cultured in Ham's F-12 media (Hyclone, Cat #SH30022.02) supplemented with 10% Fetal Bovine Serum, 1 ⁇ MEM non-essential amino acids, and 400 ⁇ g/ml G418 at 37° C. in 5% CO 2 .
  • Ham's F-12 media Ham's F-12 media
  • Fetal Bovine Serum 1 ⁇ MEM non-essential amino acids
  • 400 ⁇ g/ml G418 400 ⁇ g/ml G418 at 37° C. in 5% CO 2 .
  • the cells were washed once in DPBS (Hyclone, Cat #SH30028.03) for approximately 30 seconds.
  • the cells were then diluted to a concentration of 5 ⁇ 10 5 /ml and placed into the “cell hotel” on the deck of the Syncropatch at 10° C. for about 1 hour to recover. 40 ⁇ L of the cell suspension was dispensed into each well of a 384-well Syncropatch chip by the onboard pipettor at the beginning of each Syncropatch assay.
  • the compounds to be tested were dissolved in DMSO to give 10 mM stock solutions.
  • Eight-point dose response curves were created by performing semi-log serial dilutions from 10 mM compound stock solutions in 100% DMSO. Concentration-response curves were transferred to assay plates to give two-fold final compound concentration to account for the two-fold dilution with drug addition on the SyncroPatch.
  • Final DMSO concentration in the assay was 0.3%.
  • Final assay test concentrations were 30 ⁇ M to 0.01 ⁇ M or 1 ⁇ M to 0.0003 ⁇ M.
  • Negative (0.3% DMSO) and positive (30 ⁇ M ML213) controls were included in each test run to assess pharmacological responsiveness.
  • Kv7 channels were evaluated using a voltage protocol in which cells were voltage-clamped at a holding potential of ⁇ 110 mV. Potassium currents were activated with a series of voltage steps from ⁇ 110 mV to +50 mV in 10 mV intervals with 5.5 seconds between successive voltage steps. Each voltage step was 3 seconds in duration and immediately followed by a 1 second voltage step to ⁇ 120 mV to generate an inward “tail” current to allow construction of activation (G-V) curves by plotting normalized peak tail current versus the potential of the activating voltage step. To obtain normalized values, peak current amplitudes for successive depolarizing pulses were normalized against the maximum tail current amplitude generated at +50 mV (Tatulian et al., Journal of Neuroscience 2001, 21 (15)).
  • Exemplary compounds of the present application were tested for their ability to produce a concentration-dependent hyperpolarizing shift in the midpoint of activation for heteromeric Kv7.2/7.3 channels. Eight of the compounds produced a quantifiable hyperpolarizing shift in activation as determined by a concentration-dependent shift in the midpoint that could be fit with a 3-parameter logistic equation. These data were combined with the initial 8-point concentration-response data in a single fit. Potency and efficacy data for each compound are summarized in Table 2 and FIGS. 2A-2F .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
US15/618,937 2016-06-10 2017-06-09 Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives Abandoned US20170355679A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/618,937 US20170355679A1 (en) 2016-06-10 2017-06-09 Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives
US17/145,453 US11858900B2 (en) 2016-06-10 2021-01-11 Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662348481P 2016-06-10 2016-06-10
US15/618,937 US20170355679A1 (en) 2016-06-10 2017-06-09 Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US201916599203A Continuation 2016-06-10 2019-10-11

Publications (1)

Publication Number Publication Date
US20170355679A1 true US20170355679A1 (en) 2017-12-14

Family

ID=60572305

Family Applications (2)

Application Number Title Priority Date Filing Date
US15/618,937 Abandoned US20170355679A1 (en) 2016-06-10 2017-06-09 Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives
US17/145,453 Active US11858900B2 (en) 2016-06-10 2021-01-11 Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives

Family Applications After (1)

Application Number Title Priority Date Filing Date
US17/145,453 Active US11858900B2 (en) 2016-06-10 2021-01-11 Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives

Country Status (12)

Country Link
US (2) US20170355679A1 (ru)
EP (1) EP3468947A4 (ru)
JP (1) JP2019518754A (ru)
KR (1) KR20190008411A (ru)
CN (1) CN109641836A (ru)
AU (1) AU2017278093B8 (ru)
BR (1) BR112018075597A2 (ru)
CA (1) CA3023340A1 (ru)
IL (1) IL262855A (ru)
MX (1) MX2018015251A (ru)
RU (1) RU2018147263A (ru)
WO (1) WO2017214539A1 (ru)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10676437B2 (en) 2017-12-13 2020-06-09 Scifluor Life Sciences, Inc. Fluorinated 4-(substituted amino)phenyl carbamate derivatives
WO2020148617A1 (en) 2019-01-14 2020-07-23 Pi Industries Ltd. 3-substituted phenylamidine compounds, preparation and use thereof
WO2022113033A1 (en) 2020-11-30 2022-06-02 Pi Industries Ltd. Agrochemical composition comprising 3-substituted phenylamidine compounds and use thereof
US11858900B2 (en) 2016-06-10 2024-01-02 Ocuterra Therapeutics, Inc. Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20240208896A1 (en) * 2021-03-19 2024-06-27 Xyzagen, Inc. Prodrugs of kv7 channel openers
EP4393907A4 (en) * 2021-08-26 2024-11-20 Neushen Therapeutics (Shanghai) Co., Ltd POTASSIUM CHANNEL MODULATOR, COMPOSITION AND APPLICATION
CN113698345B (zh) * 2021-10-27 2022-02-01 上海挚盟医药科技有限公司 作为钾通道调节剂的化合物及其制备和应用
JP7294734B2 (ja) * 2021-10-27 2023-06-20 シャンハイ ジムン バイオファーマ，インコーポレーテッド カリウムチャネル調節剤としての化合物ならびにその調製および応用
WO2023125935A1 (zh) * 2021-12-31 2023-07-06 上海翰森生物医药科技有限公司 苯并哌啶衍生物调节剂、其制备方法和应用
CN116478068A (zh) * 2022-01-14 2023-07-25 中国科学院上海药物研究所 一种高选择性kcnq4钾通道激动剂、其制备方法和用途
CN116535353A (zh) * 2022-01-25 2023-08-04 上海挚盟医药科技有限公司 作为钾通道调节剂的酰胺类化合物及其制备和应用
WO2024067819A1 (zh) * 2022-09-30 2024-04-04 上海翰森生物医药科技有限公司 含哌啶多环类衍生物调节剂、其制备方法和应用

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4200259A1 (de) * 1992-01-08 1993-07-15 Asta Medica Ag Neue 1,2,4-triaminobenzol-derivate und verfahren zu deren herstellung
GB9915414D0 (en) 1999-07-01 1999-09-01 Glaxo Group Ltd Medical use
AU2001270167A1 (en) 2000-06-30 2002-01-14 Fmc Corporation Steam injection heater and method
WO2003106454A1 (en) * 2002-06-12 2003-12-24 Orchid Chemicals & Pharmaceuticals Ltd 1h-isoquinoline-oxazolidinone derivaties and their use as antibacterial agents
UA89503C2 (ru) 2004-09-13 2010-02-10 Х. Луннбек А/С Замещенные производные анилина
US8790623B2 (en) 2005-01-18 2014-07-29 Il'Oreal Composition for treating keratin fibers, comprising at least one aromatic alcohol, at least one aromatic carboxylic acid, and at least one protecting agent
US8993593B2 (en) 2006-08-23 2015-03-31 Valeant Pharmaceuticals International N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide as potassium channel modulators
MX2009002002A (es) * 2006-08-23 2009-07-22 Valeant Pharmaceuticals Int Derivados de 4-(n-azacicloalquil) anilidas como moduladores de canal de potasio.
JP2011513196A (ja) * 2007-08-01 2011-04-28 ハー・ルンドベック・アクチエゼルスカベット ドーパミン作動系が破壊された障害もしくは状態の症状を軽減するためまたはその障害もしくは状態を処置するためのｋｃｎｑカリウムチャネル開口薬の使用
AU2008300827B2 (en) * 2007-09-19 2013-04-04 4Sc Ag Novel tetrahydrofusedpyridines as histone deacetylase inhibitors
CN103073455B (zh) * 2011-10-25 2015-08-19 中国科学院上海药物研究所 一类新型的kcnq钾通道激动剂、其制备方法和用途
CN103373941B (zh) * 2012-04-11 2016-08-17 浙江九洲药物科技有限公司 瑞替加滨及其中间体的制备方法
US8916133B2 (en) * 2012-04-30 2014-12-23 Scifluor Life Sciences, Llc Fluorinated 2-amino-4-(benzylamino)phenylcarbamate derivatives
CN108250128A (zh) 2012-09-27 2018-07-06 江苏先声药业有限公司 作为钾通道调节剂的化合物
CN105017085B (zh) 2014-04-28 2018-06-29 中国科学院上海药物研究所 一类kcnq钾通道激动剂、其制备方法和用途
WO2016077724A1 (en) * 2014-11-13 2016-05-19 University Of Pittsburgh - Of The Commonwealth System Of Higher Education (2-amino-4(arylamino)phenyl) carbamates
WO2017214539A1 (en) 2016-06-10 2017-12-14 Scifluor Life Sciences, Inc. Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives
JP2021506810A (ja) 2017-12-13 2021-02-22 サイフルーア ライフ サイエンシズ インコーポレイテッド フッ素化４−（置換アミノ）フェニルカルバメート誘導体

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11858900B2 (en) 2016-06-10 2024-01-02 Ocuterra Therapeutics, Inc. Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives
US10676437B2 (en) 2017-12-13 2020-06-09 Scifluor Life Sciences, Inc. Fluorinated 4-(substituted amino)phenyl carbamate derivatives
WO2020148617A1 (en) 2019-01-14 2020-07-23 Pi Industries Ltd. 3-substituted phenylamidine compounds, preparation and use thereof
EP4647426A2 (en) 2019-01-14 2025-11-12 PI Industries Ltd. 3-substituted phenylamidine compounds, preparation and use thereof
WO2022113033A1 (en) 2020-11-30 2022-06-02 Pi Industries Ltd. Agrochemical composition comprising 3-substituted phenylamidine compounds and use thereof

Also Published As

Publication number Publication date
CA3023340A1 (en) 2017-12-14
IL262855A (en) 2018-12-31
AU2017278093A1 (en) 2018-11-22
JP2019518754A (ja) 2019-07-04
RU2018147263A (ru) 2020-07-10
BR112018075597A2 (pt) 2019-03-26
US20210309612A1 (en) 2021-10-07
WO2017214539A1 (en) 2017-12-14
US11858900B2 (en) 2024-01-02
AU2017278093B8 (en) 2021-12-23
CN109641836A (zh) 2019-04-16
EP3468947A4 (en) 2020-01-08
AU2017278093B2 (en) 2021-12-16
KR20190008411A (ko) 2019-01-23
MX2018015251A (es) 2019-04-25
EP3468947A1 (en) 2019-04-17

Similar Documents

Publication Publication Date Title
US11858900B2 (en) Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives
US7750025B2 (en) Derivatives of N-phenyl (piperidine-2-yl) methyl benzamide, preparation method thereof and applications of same in therapeutics
JP6700293B2 (ja) リルゾールプロドラッグおよびそれらの使用
KR0179661B1 (ko) N-페닐알킬 치환된 알파-아미노 카복스아미드 유도체 및 이를 포함하는 약제학적 조성물 및 이의 제조방법
CA2168432C (en) Piperazine compounds used in therapy
US6949574B2 (en) (Oxime)carbamoyl fatty acid amide hydrolase inhibitors
US20080312237A1 (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US9556114B2 (en) Fluorinated 2-amino-4-(benzylamino)phenylcarbamate derivatives
CA2199621A1 (en) Substituted aryl piperazines as neurokinin antagonists
US10676437B2 (en) Fluorinated 4-(substituted amino)phenyl carbamate derivatives
ES2201105T3 (es) Derivados del bencimidazol con actividad dopaminergica.
US20180127357A1 (en) (2-amino-4-(arylamino)phenyl) carbamates
US10519143B2 (en) Substituted-indole-compounds as estrogen receptor down-regulators
TW202304864A (zh) 1,3-取代的環丁基衍生物及其用途
JPWO1994001392A1 (ja) （−）−リトドリン
JPH0725749B2 (ja) Ｎ‐ピリジニル‐９ｈ‐カルバゾール‐９‐アミン類
KR100188902B1 (ko) [(1-아릴피롤리딘-2-일)메틸]피페라진 유도체, 그들의 제법 및 치료학적 용도
CN116710463A (zh) 用于抑制nav1.8电压门控钠通道和治疗nav1.8介导的疾病的化学化合物
TW202402284A (zh) 治療神經病變之方法
US20250084112A1 (en) Chemical Compounds Useful for Inhibiting Nav1.8 Voltage-Gated Sodium Channels and Treating Nav1.8 Mediated Diseases

Legal Events

Date Code Title Description
AS Assignment

Owner name: SCIFLUOR LIFE SCIENCES, INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:EDWARDS, D. SCOTT;ASKEW, BEN C.;FURUYA, TAKERU;SIGNING DATES FROM 20170614 TO 20170616;REEL/FRAME:042732/0613

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION