Benzamide enaminone derivatives and methods of use thereof

Abstract

The present disclosure includes novel benzamide enaminone compounds and pharmaceutically acceptable salts thereof, as well as compositions comprising such compounds and pharmaceutically acceptable salts. The disclosure also includes methods of treating a subject at risk of an epileptic seizure and / or reducing or preventing the onset or severity of an epileptic seizure or an epileptic seizure disorder associated therewith by administering a compound, or a pharmaceutically acceptable salt thereof, or a composition thereof, to a subject in need thereof. In some embodiments, the invention includes compositions and pharmaceutical combinations that act synergistically to treat, prevent, or inhibit the onset of epileptic seizures or disorders of epileptic seizures.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 324,579, filed on March 28, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The field of the invention relates generally to novel benzamide enaminone compounds, their preparation, and their use, for example, in the treatment of epileptic seizures or epileptic seizure disorders. Background Art

[0004] Epilepsy is the fourth most common neurological disorder and is a chronic and usually progressive disease. It affects approximately 3 million people in the United States and 70 million people worldwide. Approximately 1 in 26 Americans is known to be diagnosed with epilepsy at some point in their lifetime. Epilepsy is characterized by brief spontaneous recurrent, convulsive and nonconvulsive seizures caused by excessive neuronal firing in the brain. Epileptic seizures are classified into two major categories, (a) generalized seizures and (b) focal seizures. Generalized seizures begin with neuronal firing that affects the entire brain, whereas in focal seizures, the abnormal neuronal firing is confined to one area of ​​the brain. Management of epilepsy can be challenging due to limited understanding of the pathophysiology of epileptic disorders. The goal of epilepsy treatment is complete freedom from seizures and the absence of major drug-induced side effects. Despite optimal use of available antiepileptic drugs (AEDs), 30-35% of patients are considered to have drug-resistant epilepsy (DRE). According to the International League Against Epilepsy, DRE is defined as "a patient's seizures that fail to respond to at least two appropriately selected antiepileptic drugs used for a sufficient period of time to achieve and maintain freedom from seizures." DRE is becoming an increasing burden in the epilepsy population with no known cure. Therefore, there is a growing need to develop new therapeutic agents for the management of DRE.

[0005] Because of the clinical need for therapies to address DRE, the present disclosure encompasses the design, synthesis, and evaluation of novel benzamide enaminones as potential anticonvulsant agents. Summary of the invention

[0006] The present disclosure includes novel benzamide enaminone derivatives and pharmaceutically acceptable salts thereof, and compositions comprising such compounds and pharmaceutically acceptable salts.

[0007] The present disclosure also includes methods of treating or preventing epileptic seizures or reducing the occurrence of epileptic seizures or epileptic seizure disorders or reducing the risk of the occurrence of epileptic seizures in a subject in need thereof by administering a fluorobenzamide enamine derivative or a pharmaceutically acceptable salt disclosed herein or a composition comprising such a compound derivative or salt thereof.

[0008] The present disclosure also includes methods of treating or preventing epileptic seizures or reducing the occurrence of epileptic seizures or epileptic seizure disorders or reducing the risk of the occurrence of epileptic seizures in a subject in need thereof by administering a chlorobenzamide enamine derivative or a pharmaceutically acceptable salt disclosed herein or a composition comprising such a compound derivative or salt thereof.

[0009] In some embodiments, the present disclosure provides compounds, compositions comprising the compounds, and methods of using the compounds and compositions for preventing and / or treating epileptic seizures and related disorders.

[0010] In some embodiments, the present disclosure provides novel fluorinated N-phenyl or N-benzyl enaminones. The compound may be in the form of a pharmaceutically acceptable salt of the compound. The composition includes a pharmaceutical preparation comprising one or a combination of the compounds and is suitable for administration to a subject in need (e.g., a mammal, preferably a human). In one embodiment, the present disclosure provides a composition comprising one or more of the compounds and a pharmaceutically acceptable carrier.

[0011] In some embodiments, the present disclosure provides novel chloro N-phenyl, 3-pyridyl or N-benzyl enaminones. The compound may be in the form of a pharmaceutically acceptable salt of the compound. The composition includes a pharmaceutical preparation comprising one or a combination of the compounds and is suitable for administration to a subject in need (e.g., a mammal, preferably a human). In one embodiment, the present disclosure provides a composition comprising one or more of the compounds and a pharmaceutically acceptable carrier.

[0012] In one embodiment, the compounds, compositions and methods of the invention include compounds of Formula (I) and Formula (Ia):

[0013]

[0014] in

[0015] X is O or S;

[0016] R1 is an aryl or heteroaryl ring having at least one halogen, alkyl, or alkyl substituted with 1 to 3 halogen groups, or R1 is a substituted heteroaryl (e.g., substituted 3-pyridine);

[0017] R2 is hydrogen or C1-C3 alkyl;

[0018] Each R3 is independently hydroxy, halogen, cyano, amino, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

[0019] n is an integer from 1 to 6,

[0020] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

[0021] In certain embodiments, one or both of R1 and R3 include a halogen substituent or an alkyl group substituted with one or more halogen substituents.

[0022] In another embodiment, the compounds, compositions and methods of the present invention include a compound of formula (II):

[0023]

[0024] Formula II

[0025] in

[0026] R1 is -OH, -CN, substituted or unsubstituted thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy or substituted or unsubstituted alkoxy;

[0027] Each of R2, R3, R4 or R5 is independently selected from -H, -OH, -CN, substituted or unsubstituted alkylthio, nitro, SCF3, OCF3, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy or substituted or unsubstituted alkoxy;

[0028] R6, R7, R8, R9, R 10 or R 11 Each of which is independently selected from -H, -OH, -CN, substituted or unsubstituted thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy or substituted or unsubstituted alkoxy;

[0029] R 12 is -H or substituted or unsubstituted alkyl;

[0030] X is O;

[0031] Y is -NR 13 ;and

[0032] Each R 13 independently selected from -H or substituted or unsubstituted alkyl (C1-C6 alkyl),

[0033] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof,

[0034] Among them, R3 and R8 / R9 are different.

[0035] In certain embodiments, at least one of R1-R5 is -F or -Cl, a substituted alkyl group containing one or more -F or -Cl groups, or a substituted alkoxy group containing one or more -F groups.

[0036] In certain embodiments, R7-R 12 At least one of is -F, a substituted alkyl containing one or more -F groups, or a substituted alkoxy containing one or more -F groups.

[0037] In another embodiment, the compounds, compositions and methods of the invention include a compound of formula (III) or formula (IIIa):

[0038]

[0039] in

[0040] R1 is halogen or alkyl substituted by 1 to 3 halogen groups;

[0041] R2 is hydrogen or C1-C3 alkyl;

[0042] R3 is independently hydroxy, halogen, cyano, amino, nitro or alkyl substituted with 1-3 halogen groups;

[0043] n, when present, is an integer from 1 to 6;

[0044] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

[0045] In another embodiment, the compounds, compositions and methods of the invention include a compound of formula (IV):

[0046]

[0047] Formula IV

[0048] in

[0049] R1 is halogen or alkyl substituted by 1 to 3 halogen groups;

[0050] R2 is hydrogen or C1-C3 alkyl; and

[0051] R3 is halogen or alkyl substituted by 1 to 3 halogen groups,

[0052] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

[0053] In certain embodiments, R1 is a halogen including fluorine or chlorine. In certain embodiments, R1 is fluorine.

[0054] In certain embodiments, R1 is a substituted alkyl group containing 1 to 3 fluoro or chloro substituents. In certain embodiments, R1 is trifluoromethyl.

[0055] The present invention relates to methods for treating a subject at risk of epileptic seizures and / or methods for reducing or preventing the occurrence or severity of epileptic seizures or epileptic seizure disorders associated therewith by administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof.

[0056] In various embodiments, administering a composition comprising a compound of Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof results in one or more of the following: preventing epileptic seizures in the subject; reducing the duration or intensity of epileptic seizures; reducing the number of epileptic seizures that occur per day; and / or preventing or reducing the severity of epileptic seizures.

[0057] The methods of the invention provide advantages such as greater overall efficacy, for example in achieving synergy or avoiding antagonism, and allow for reductions in the dosage of one or more individual agents, if desired, while reducing side effects. In addition, in cases where the epileptic seizure to be treated does not respond optimally to a given anti-epileptic agent, use of the pharmaceutical compositions of the invention in the methods may still provide effective treatment.

[0058] The disclosure also includes pharmaceutical compositions comprising a compound of formula (I), (II), (III) or (IV) and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions contemplated within the scope of the present invention include pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers. In various embodiments, the pharmaceutical composition can be administered by any suitable route of administration, such as parenteral, transmucosal, oral, nasal or rectal or transdermal. Preferably, administration is oral, such as by tablet or capsule. Alternative means of administration also include, but are not limited to, intra-arteriole, intramuscular, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration.

[0059] The pharmaceutical compositions of the present invention can be delivered in a controlled release system, for example, using intravenous infusion, an implantable osmotic pump, a transdermal patch, or other modes of administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 Exemplary illustrations of neural activity during an epileptic seizure and epileptic seizure characteristics are shown.

[0061] Figure 2 An exemplary chemical synthesis of 2-fluoro-N-(5-methyl-3-oxocyclohex-1-en-1-yl)benzamide is shown.

[0062] Figure 3 Shown is a structure activity study of compounds during lead compound optimization.

[0063] Figure 4 A dose response study of the lead compound is shown.

[0064] Figure 5 A description of the PGP assay analysis is shown.

[0065] Figure 6 PGP assay luminescence is shown for various exemplary compounds of the invention.

[0066] Figure 7 PGP assay results are shown for various exemplary compounds of the invention.

[0067] Figure 8 Shown are dose response analyses of various exemplary compounds of the invention. DETAILED DESCRIPTION

[0068] definition

[0069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0070] As used herein, the terms "about" or "approximately" mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to the practice in the art, "about" can mean within 3 or more standard deviations. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, more preferably up to 1% of a given value. Alternatively, particularly for biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, more preferably within 2-fold of a value.

[0071] As used herein, the term "alkyl" or "optionally substituted alkyl" refers to a C1-C6 unsubstituted alkyl group or an alkyl group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylamino-carbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonyl, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0072] The term "alkenyl" as used herein includes unsaturated aliphatic groups similar to the above-mentioned alkyl in length and possible substitution, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyls (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyls. In certain embodiments, a straight or branched alkenyl has six or less carbon atoms in its skeleton (e.g., C1-C6 for a straight chain and C3-C6 for a branched chain). The term "C2-C6" includes alkenyls containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyls containing 3 to 6 carbon atoms. The term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having a designated substituent replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonyl, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0073] The term "alkynyl" as used herein includes unsaturated aliphatic groups similar to the above-mentioned alkyl groups in length and possible substitution, but containing at least one triple bond. For example, the term "alkynyl" includes straight chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched chain alkynyl. In certain embodiments, a straight chain or branched chain alkynyl has six or less carbon atoms in its skeleton (e.g., C2-C6 for a straight chain and C3-C6 for a branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. The term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl group having a designated substituent replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonyl, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl includes heterocycloalkyl substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0074] As used herein, "amine" or "amino" refers to unsubstituted or substituted -NH2. "Alkylamino" includes compound groups in which the nitrogen of -NH2 is combined with at least one alkyl group. Examples of alkylamino include benzylamino, methylamino, ethylamino, phenethylamino, etc. "Dialkylamino" includes groups in which the nitrogen of -NH2 is combined with at least two additional alkyl groups. Examples of dialkylamino include, but are not limited to, dimethylamino and diethylamino. "Arylamino" and "diarylamino" include groups in which the nitrogen is combined with at least one or two aryl groups, respectively. "Aminoaryl" and "aminoaryloxy" refer to aryl and aryloxy groups substituted by amino. "Alkylarylamino", "alkylaminoaryl" or "arylaminoalkyl" refers to amino groups combined with at least one alkyl group and at least one aryl group. "Alkylaminoalkyl" refers to an alkyl, alkenyl or alkynyl group combined with a nitrogen atom, which is also combined with an alkyl group. "Acylamino" includes groups in which the nitrogen is combined with an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea.

[0075] The term "amide" or "aminocarboxyl" includes compounds or moieties containing a nitrogen atom bound to the carbon of a carbonyl or thiocarbonyl group. The term includes "alkylaminocarboxyl", which includes an alkyl, alkenyl or alkynyl group bound to an amino group, which is bound to the carbon of a carbonyl or thiocarbonyl group. It also includes "arylaminocarboxyl" groups, which include aryl or heteroaryl moieties bound to an amino group, which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxyl", "alkenylaminocarboxyl", "alkynylaminocarboxyl" and "arylaminocarboxyl" include moieties in which alkyl, alkenyl, alkynyl and aryl moieties are each bound to a nitrogen atom, which is in turn bound to the carbon of a carbonyl group. Amides can be substituted with substituents such as straight chain alkyl, branched chain alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. The substituents on the amide group can be further substituted.

[0076] The term "analog" as used herein refers to a compound that is structurally similar to another compound but has a slightly different composition (e.g., replacing an atom with an atom of a different element, or replacing a functional group with another functional group in the presence of a specific functional group). Therefore, an analog is a compound that is similar or comparable to a reference compound in function and appearance rather than in structure or origin. "Mimetic," "analog," and "derivative" are used interchangeably herein and refer to a compound that has the same core as the parent compound but may differ from the parent compound in terms of bond order, the absence or presence of one or more atoms and / or groups of atoms, and combinations thereof. The derivative may differ from the parent compound, for example, in terms of one or more substituents present on the core, which may include one or more atoms, functional groups, or substructures. In general, it is conceivable that a derivative is formed, at least in theory, from the parent compound by chemical and / or physical processes.

[0077] As used herein, the term "aryl" includes groups having aromatic properties, including "conjugated" or polycyclic systems having at least one aromatic ring, and not containing any heteroatoms in the ring structure. Examples include phenyl, benzyl, 1,2,3,4-tetrahydronaphthyl, etc. In addition, the terms "aryl" and "heteroaryl" include polycyclic aromatic and heteroaryl groups, such as tricyclic, bicyclic, such as naphthalene, benzophenone, etc. Azoles, benzophenone oxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine. In the case of a polycyclic aromatic ring, only one ring needs to be aromatic (e.g., 2,3-dihydroindole), although all rings can be aromatic (e.g., quinoline). The second ring can also be fused or bridged. The aryl or heteroaryl ring can be substituted at one or more ring positions (e.g., ring-forming carbon or heteroatoms such as N) with substituents as described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkyl Thiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonyl, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl).

[0078] As used herein, the term "arylalkyl" or "aralkyl" moiety is an alkyl group substituted with an aryl group (eg, phenylmethyl (benzyl)). An "alkylaryl" moiety is an aryl group substituted with an alkyl group (eg, methylphenyl).

[0079] The term "bioisostere" refers to a compound produced by exchanging one atom or group of atoms with another roughly similar atom or group of atoms. The purpose of bioisosteric substitution is to create a new compound with similar biological properties to the parent compound. Bioisosteric substitution may be based on physical chemistry or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0080] The term "carbonyl" includes compounds and moieties containing a carbon connected to an oxygen atom with a double bond. Examples of carbonyl-containing moieties include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.

[0081] The term "carboxyl" as used herein refers to -COOH or a C1-C6 alkyl ester thereof.

[0082] As used herein, compounds of the present invention include novel compounds encompassed by formula (I), (II), (III) and (IV). Disclosures of compounds of formula (I), (II), (III) and / or (IV) include compounds (I), (Ia), (II), (III), (IIIa) and (IV). Disclosures of compounds of formula (I) include both compounds of formula (I) and formula (Ia). Disclosures of compounds of formula (III) include both compounds of formula (III) and formula (IIIa).

[0083] The term "derivative" as defined herein refers to compounds having a common core structure and substituted by various groups described herein. For example, all compounds represented by formula (I), (II), (III) and (IV) are benzene compounds substituted by aryl or heteroaryl groups and have formula (I), (II), (III) and (IV) as a common core.

[0084] "Dose" as used herein is intended to include formulations expressed in μg / kg / day, μg / kg / hr, mg / kg / day or mg / kg / hr. Dose is the amount of a component administered according to a specific dosage regimen. "Dose" refers to the amount of a medicament administered to a mammal in a unit volume or mass, for example, an absolute unit dose expressed in mg or μg of medicament. The dose depends on the concentration of the medicament in the formulation, for example, in units of moles per liter (M), mass per unit volume (m / v) or mass per unit mass (m / m). The two terms are closely related because a specific dose is produced by an administration regimen of one or more formulations. In any case, its specific meaning will be apparent from the context.

[0085] As used herein, the phrase "effective amount" or "therapeutically effective amount" of a compound or pharmaceutical composition refers to an amount sufficient to achieve the intended purpose, such as preventing or reducing the number of epileptic seizures in mammals, especially humans, including but not limited to reducing the number or intensity of epileptic seizures or preventing the occurrence or duration of epileptic seizures in animals before administration, i.e., prophylactic administration. The term also refers to the amount of a compound or its salt or its composition that treats, improves or prevents an identified disease or condition or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount of the subject will depend on the subject's weight, size and health, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. In a preferred aspect, the disease or condition to be treated is an epileptic seizure or an epileptic seizure disorder.

[0086] The term "ester" includes compounds or moieties containing carbon or heteroatoms bonded to an oxygen atom bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and the like.

[0087] As used herein, "excipient" refers to a substance of a pharmaceutical composition other than the active drug substance (e.g., gaboxadol) whose safety has been appropriately evaluated and is included in a drug delivery system to aid in its processing during manufacture of the drug delivery system, to protect, support, enhance stability, bioavailability or patient acceptance, to aid in product identification, or any other attribute that enhances the overall safety and effectiveness of the drug delivery system during storage or use.

[0088] As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0089] The term "heteroaryl" as used herein is an aryl group as defined above, except that it has 1 to 4 heteroatoms in the ring structure, and may also be referred to as an "aryl heterocycle" or "heteroaromatic compound". The term "heteroaryl" as used herein is intended to include a stable 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocycle consisting of carbon atoms and one or more heteroatoms, such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or such as 1, 2, 3, 4, 5 or 6 heteroatoms, independently selected from nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N->O and S(O) p, wherein p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocyclic ring does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, Azoles, Isopropylamine Azole, pyridine, pyrazine, pyridazine, pyrimidine, etc.

[0090] The term "hydroxy" includes groups bearing the -OH group.

[0091] As used herein, "improvement" refers to treatment of a symptom or condition associated with epileptic seizures or an epileptic disorder as measured relative to at least one symptom or condition of a metabolic disease.

[0092] As used herein, "improvement in next-day function" or "wherein next-day function is improved" refers to improvement after waking up from an overnight sleep period, wherein the beneficial effect of administering a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is applicable to at least one symptom or condition associated with an epileptic disorder and can be discerned subjectively by the patient or objectively by an observer within a period of time after waking up, such as immediately, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc.

[0093] As used herein, the term "mitigation" is intended to describe a process of reducing the severity of a sign or symptom of a disorder. Importantly, a sign or symptom can be alleviated without being eliminated. In a preferred embodiment, administration of the pharmaceutical composition of the present invention results in the elimination of a sign or symptom, however, elimination is not required. An effective dose is expected to reduce the severity of a sign or symptom. For example, if the severity or frequency of a disorder such as an epileptic seizure is reduced, the sign or symptom of the epileptic seizure is alleviated.

[0094] As used herein, "pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe," e.g., they are physiologically tolerable and do not typically produce allergic or similar adverse reactions, such as stomach upset, etc., when administered to humans. In embodiments, the term refers to molecular entities and compositions approved by a regulatory agency of the federal or state government, such as the GRAS list or similar list under sections 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act, the U.S. Pharmacopeia, or another generally recognized pharmacopoeia, for use in animals, and more particularly in humans, subject to premarket review and approval by the FDA.

[0095] As used herein, the term "prevention" means administering a composition to a subject or system at risk or susceptible to one or more symptoms caused by a disease or disorder to promote the cessation of specific symptoms of the disease or disorder, reduce or prevent one or more symptoms of the disease or disorder, lessen the severity of the disease or disorder, completely eliminate the disease or disorder, stabilize or delay the progression of epilepsy or the disease or disorder.

[0096] As used herein, the term "epileptic seizure" and related "epileptic seizure disorders" that can be treated, prevented or alleviated by administering the compounds of the present invention include, but are not limited to, epilepsy and related disorders and their accompanying epileptic seizure symptoms. Non-limiting examples of epileptic seizure disorders include, but are not limited to, epilepsy (including, but not limited to, localized related epilepsy, generalized epilepsy, epilepsy with both generalized and / or focal seizures, etc.), seizures associated with Lennox-Gastaut syndrome, seizures as complications of a disease or condition (e.g., seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher disease, Unvericht-Lundborg progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, infection, brain cancer, essential tremor syndrome, and restless limb syndrome, etc.). In an embodiment, the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor syndrome, or restless limb syndrome. In an embodiment, the epileptic seizure disorder is a disease or condition mediated by a persistent increase in sodium current and / or other abnormalities in neural ion transport. As will be appreciated in the art, the feature that distinguishes the categories of epileptic seizures is whether the seizure activity is partial (e.g., focal) or systemic. In one embodiment, the compounds / compositions disclosed herein are used to treat partial and / or systemic epileptic seizures. Partial seizures are considered to be seizures in which the seizure activity is limited to discrete areas of the cerebral cortex. As is known in the art, if consciousness is fully maintained during the seizure, the seizure is considered to be a simple partial seizure. If consciousness is impaired, the seizure is considered to be a complex partial seizure. Included among these types of seizures are those that begin as partial seizures and subsequently extend to the cortex; these are considered to be partial seizures with secondary generalization. Generalized seizures involve distal areas of the brain simultaneously in a bilaterally symmetrical manner and can include sudden, transient loss of consciousness, such as in the case of absence or petit mal seizures, without loss of postural control. Atypical absence seizures typically include longer periods of loss of consciousness, as well as more gradual onset and termination. Generalized tonic-clonic or grand mal seizures, which are considered to be the main types of generalized seizures, are characterized by sudden onset without any warning. The initial stage of the epileptic seizure is usually a tonic contraction of muscles, impaired breathing, and a significant increase in sympathetic tone, resulting in an increase in heart rate, blood pressure, and pupil size. After 10-20 seconds, the tonic phase of the epileptic seizure usually evolves into a clonic phase, which is caused by the superposition of a muscle relaxation phase on the tonic muscle contraction. The duration of relaxation gradually increases until the end of the epileptic phase, usually lasting no more than one minute. The post-ictal stage is characterized by unresponsiveness, muscle relaxation, and excessive salivation, which can lead to respiratory wheezing and partial airway obstruction.Atonic seizures are characterized by a sudden loss of postural muscle tone, lasting 1-2 seconds. Consciousness is briefly impaired, but there is usually no post-ictal confusion. Myoclonic seizures are characterized by sudden and brief muscle contractions, which may involve a part of the body or the entire body. It is believed that the present disclosure is applicable to the prevention and / or treatment of any of the above-mentioned types of epileptic seizures, which are described for illustration, but are not meant to be limiting. In an embodiment, the present disclosure relates to the treatment of epilepsy. In an embodiment, the epilepsy is selected from idiopathic, cryptogenic, symptomatic, generalized and focal epilepsy. In an embodiment, the present disclosure relates to the treatment of drug-resistant epilepsy. The term drug-resistant epilepsy as used herein means epilepsy that is not controlled despite the use of at least two drugs suitable for the type of epilepsy and appropriate prescription at the maximum tolerated dose. In an embodiment, the drug-resistant epilepsy is an epilepsy in which three such drug trials have failed to eliminate epileptic seizures. Those skilled in the art will recognize that after the failure of the second or third anti-epileptic drug trial, the chance of controlling epilepsy drops sharply, so the present disclosure provides a method intended to address these failed treatment cases.

[0097] As used herein, the term "severity" is intended to describe the likelihood of a reduction in seizure severity or, for example, a reduction in the frequency of seizures.

[0098] In this specification, for convenience in some cases, the structural formula of the compound of formula (I), (II), (III) or (IV) represents a certain isomer, but the present invention includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, etc. In addition, the compound represented by the formula may have crystalline polymorphism. It should be noted that any crystal form, crystal form mixture or its anhydride or hydrate is included in the scope of the present invention. In addition, the so-called metabolites produced by the degradation of the compound of the present invention in the body are also included in the scope of the present invention. "Stereoisomer" as used herein refers to isomeric molecules having the same molecular formula and bonded atomic sequence (composition), but different three-dimensional orientations of their atoms in space. Examples of stereoisomers include enantiomers and diastereomers. Enantiomers as used herein refer to one of the two mirror-image forms of optically active or chiral molecules. Diastereomers (or diastereomers) are stereoisomers that are not enantiomers (mirrors that are not superimposable with each other). Chiral molecules contain chiral centers, also called stereogenic centers or stereogenic centers, which are any points in a molecule with groups, although not necessarily atoms, such that the interchange of any two groups results in stereoisomers. In organic compounds, chiral centers are usually carbon, phosphorus, or sulfur atoms, although other atoms may also be stereogenic centers in organic and inorganic compounds. A molecule can have multiple stereogenic centers, resulting in many stereoisomers. In compounds where stereoisomerism is caused by tetrahedral stereogenic centers (such as tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereogenic centers. Molecules with symmetry usually have fewer stereoisomers than the maximum possible number. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, an enantiomeric mixture can be enantioenriched so that one enantiomer is present in an amount greater than 50%. Enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. "Chirality" also includes axial and planar chirality. It should be understood that the structures and other compounds discussed in this invention include all atropisomers thereof. An "atropisomer" is a stereoisomer in which the atoms of the two isomers are arranged differently in space. The existence of atropisomers is due to restricted rotation caused by the hindrance of rotation of large groups around a central bond. Such atropisomers usually exist as a mixture, but due to recent advances in chromatographic techniques, a mixture of two atropisomers can be separated in some cases.

[0099] As used herein, a "subject in need" is a subject suffering from epileptic seizures or epileptic seizure-related disorders or a subject at increased risk of developing such disorders relative to the population as a whole. A subject in need may have a condition that makes them susceptible to epileptic seizures. "Subjects" include mammals. The mammal can be, for example, any mammal, such as a human, a primate, a bird, a mouse, a rat, poultry, a dog, a cat, a cow, a horse, a goat, a camel, a sheep or a pig. Preferably, the mammal is a human. The subjects of the present invention include any human subject who has been diagnosed with epileptic seizures or epileptic seizure disorders, has symptoms of epileptic seizures or epileptic seizure disorders, or is at risk of developing epileptic seizures or epileptic seizure disorders.

[0100] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in a formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer groups in solution. In solutions where tautomerism is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is known as tautomerism.

[0101] The compounds of formula (I), (II), (III) and (IV) disclosed herein include the compounds themselves, as well as their salts, their esters, their solvates and their prodrugs (if applicable). For example, salts can be formed between anions and positively charged groups (e.g., amino groups) on aryl or heteroaryl substituted benzene compounds. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthylidenesulfonate and acetate (e.g., trifluoroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between cations and negatively charged groups (e.g., carboxylates) on aryl or heteroaryl substituted benzene compounds. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions and ammonium cations such as tetramethylammonium ions. The aryl or heteroaryl substituted benzene compounds also include salts containing quaternary nitrogen atoms. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1 or any ratio other than 1:1, such as 3:1, 2:1, 1:2 or 1:3.

[0102] In addition, the compounds of the present invention, such as salts of the compounds, may exist in hydrated or unhydrated (anhydrous) forms, and may also exist as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0103] "Solvate" means a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap fixed molar ratios of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance, wherein the water remains in its molecular state as HO.

[0104] As used herein, the term "treatment" refers to reducing, attenuating or delaying the appearance of clinical symptoms of a disease or condition in a subject who may be suffering from or susceptible to a disease or condition, but has not yet experienced or shown clinical or subclinical symptoms of the disease or condition. In certain embodiments, "treatment" may refer to preventing the appearance of clinical symptoms of the disease or condition in a subject who may be suffering from or susceptible to a disease or condition, but has not yet experienced or shown clinical or subclinical symptoms of the disease or condition. "Treatment" may also refer to inhibiting the disease or condition, such as preventing or alleviating epilepsy or at least one clinical or subclinical symptom thereof. "Treatment" also refers to alleviating the disease or condition, such as causing the disease or condition or at least one clinical or subclinical symptom thereof to subside. The benefit to the subject to be treated may be statistically significant, mathematically significant, or at least perceptible to the subject and / or physician. However, preventive (prevention) and therapeutic treatment are two independent embodiments of the present disclosure. The inhibition is a measurable inhibition compared to a suitable control. In one embodiment, the inhibition is an inhibition of at least 10% compared to a suitable control. In other words, the rate of enzyme activity or the amount of product when the inhibitor is used is less than or equal to 90% of the corresponding rate or amount when the inhibitor is not used. In various other embodiments, inhibition is at least 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90% or 95% inhibition compared to a suitable control. In one embodiment, inhibition is at least 99% inhibition compared to a suitable control. In other words, the rate of enzyme activity or the amount of product when the inhibitor is used is less than or equal to 1% of the corresponding rate or amount when the inhibitor is not used.

[0105] Compounds and compositions of the present invention

[0106] The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically suitable carrier or excipient, at a dosage for treating or preventing a disease or condition described herein (e.g., a disease or condition associated with epileptic seizures).

[0107] In one embodiment, the compounds, compositions and methods of the invention include a compound of formula (I):

[0108]

[0109] Formula I

[0110] in

[0111] X is O or S;

[0112] R1 is an aryl ring having at least one halogen, alkyl, or alkyl substituted with 1-3 halogen groups, or R1 is a substituted heteroaryl (e.g., substituted 3-pyridine);

[0113] R2 is hydrogen or C1-C3 alkyl;

[0114] R3 is hydroxy, halogen, cyano, amino, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

[0115] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

[0116] In certain embodiments, X is O.

[0117] In certain embodiments, X is S.

[0118] In certain embodiments, R1 is an aryl ring having at least one halogen. In certain embodiments, the halogen is -F. In certain embodiments, the halogen is -Cl. In certain embodiments, R1 is a benzene ring having one -F. In certain embodiments, R1 is a benzene ring having one -Cl.

[0119] In certain embodiments, R1 is an aryl ring having at least one alkyl group substituted with 1-3 halogen groups.

[0120] In certain embodiments, R1 is an aryl ring having at least one alkyl group substituted with 1 halogen group.

[0121] In certain embodiments, R1 is an aryl ring having at least one alkyl group substituted with 2 halo groups.

[0122] In certain embodiments, R1 is an aryl ring having at least one alkyl group substituted with 3 halo groups.

[0123] In certain embodiments, R1 is an aryl ring having at least one -CH2F.

[0124] In certain embodiments, R1 is an aryl ring having at least one -CHF2.

[0125] In certain embodiments, R1 is an aryl ring having at least one -CF3.

[0126] In certain embodiments, R1 is an aryl ring having at least one alkyl group.

[0127] In certain embodiments, R1 is an aryl ring having at least one -CH3.

[0128] In certain embodiments, R1 is an aryl ring having at least one -CH2CH3.

[0129] In certain embodiments, R1 is .

[0130] In certain embodiments, when R1 is When R3 is C1-C3-alkyl substituted by 1-3 halogen groups (e.g. CF3).

[0131] In certain embodiments, R1 is .

[0132] In certain embodiments, R1 is .

[0133] In certain embodiments, R1 is .

[0134] In certain embodiments, R1 is .

[0135] In certain embodiments, R1 is .

[0136] In certain embodiments, when R1 is When R3 is C1-C6 alkyl (eg CH3) or C1-C3-alkyl substituted by 1-3 halogen groups (eg CF3).

[0137] In certain embodiments, R1 is .

[0138] In certain embodiments, R1 is .

[0139] In certain embodiments, R1 is .

[0140] In certain embodiments, R2 is hydrogen.

[0141] In certain embodiments, R2 is C1-C3 alkyl.

[0142] In certain embodiments, R2 is methyl.

[0143] In certain embodiments, R2 is ethyl.

[0144] In certain embodiments, R2 is propyl.

[0145] In certain embodiments, R3 is hydroxy.

[0146] In certain embodiments, R3 is halogen.

[0147] In certain embodiments, R3 is cyano.

[0148] In certain embodiments, R3 is amino.

[0149] In certain embodiments, R3 is nitro.

[0150] In certain embodiments, R3 is substituted alkyl.

[0151] In certain embodiments, R3 is unsubstituted alkyl.

[0152] In certain embodiments, R3 is substituted alkenyl.

[0153] In certain embodiments, R3 is unsubstituted alkenyl.

[0154] In certain embodiments, R3 is substituted alkynyl.

[0155] In certain embodiments, R3 is unsubstituted alkynyl.

[0156] In certain embodiments, R3 is alkyl substituted with 1 halogen group.

[0157] In certain embodiments, R3 is alkyl substituted with 2 halo groups.

[0158] In certain embodiments, R3 is alkyl substituted with 3 halo groups.

[0159] In certain embodiments, R3 is -CH2F.

[0160] In certain embodiments, R3 is -CHF2.

[0161] In certain embodiments, R3 is -CF3.

[0162] In certain embodiments, R1 and R3 comprise a halogen substituent or an alkyl group substituted with one or more halogen substituents.

[0163] In one embodiment, the compounds, compositions and methods of the invention include a compound of formula (Ia):

[0164]

[0165] Formula Ia

[0166] in

[0167] X is O or S;

[0168] R1 is an aryl ring having at least one halogen, alkyl, or alkyl substituted with 1 to 3 halogen groups;

[0169] R2 is hydrogen or C1-C3 alkyl;

[0170] R3 is hydroxy, halogen, cyano, amino, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

[0171] n is an integer from 1 to 6 (wherein the a, b and / or c positions may each contain 1 or 2 R3 groups);

[0172] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

[0173] In certain embodiments, X is O.

[0174] In certain embodiments, X is S.

[0175] In certain embodiments, R1 is an aryl ring having at least one halogen. In certain embodiments, the halogen is -F. In certain embodiments, the halogen is -Cl. In certain embodiments, R1 is -F.

[0176] In certain embodiments, R1 is an aryl ring having at least one alkyl group.

[0177] In certain embodiments, R1 is an aryl ring having at least one alkyl group substituted with 1-3 halogen groups.

[0178] In certain embodiments, R1 is an aryl ring having at least one alkyl group substituted with 1 halogen group.

[0179] In certain embodiments, R1 is an aryl ring having at least one alkyl group substituted with 2 halo groups.

[0180] In certain embodiments, R1 is an aryl ring having at least one alkyl group substituted with 3 halo groups.

[0181] In certain embodiments, R1 is an aryl ring having at least one -CH2F.

[0182] In certain embodiments, R1 is an aryl ring having at least one -CHF2.

[0183] In certain embodiments, R1 is an aryl ring having at least one -CF3.

[0184] In certain embodiments, R1 is .

[0185] In certain embodiments, R1 is .

[0186] In certain embodiments, R1 is .

[0187] In certain embodiments, R1 is .

[0188] In certain embodiments, R1 is .

[0189] In certain embodiments, R2 is hydrogen.

[0190] In certain embodiments, R2 is C1-C3 alkyl.

[0191] In certain embodiments, R2 is methyl.

[0192] In certain embodiments, R2 is ethyl.

[0193] In certain embodiments, R2 is propyl.

[0194] In certain embodiments, R3 is hydroxy.

[0195] In certain embodiments, R3 is halogen.

[0196] In certain embodiments, R3 is cyano.

[0197] In certain embodiments, R3 is amino.

[0198] In certain embodiments, R3 is nitro.

[0199] In certain embodiments, R3 is substituted alkyl.

[0200] In certain embodiments, R3 is unsubstituted alkyl.

[0201] In certain embodiments, R3 is substituted alkenyl.

[0202] In certain embodiments, R3 is unsubstituted alkenyl.

[0203] In certain embodiments, R3 is substituted alkynyl.

[0204] In certain embodiments, R3 is unsubstituted alkynyl.

[0205] In certain embodiments, R3 is alkyl substituted with 1 halogen group.

[0206] In certain embodiments, R3 is alkyl substituted with 2 halo groups.

[0207] In certain embodiments, R3 is alkyl substituted with 3 halo groups.

[0208] In certain embodiments, R3 is -CH2F.

[0209] In certain embodiments, R3 is -CHF2.

[0210] In certain embodiments, R3 is -CF3.

[0211] In certain embodiments, R1 and R3 comprise a halogen substituent or an alkyl group substituted with one or more halogen substituents.

[0212] In certain embodiments, n is 1.

[0213] In certain embodiments, n is 2.

[0214] In certain embodiments, n is 3.

[0215] In certain embodiments, n is 4.

[0216] In certain embodiments, n is 5.

[0217] In certain embodiments, n is 6.

[0218] In another embodiment, the compounds, compositions and methods of the present invention include a compound of formula (II):

[0219]

[0220] Formula II

[0221] in

[0222] R1 is hydrogen, -OH, -CN, substituted or unsubstituted thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, or substituted or unsubstituted alkoxy;

[0223] Each of R2, R3, R4 or R5 is independently selected from -H, -OH, -CN, substituted or unsubstituted alkylthio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy or substituted or unsubstituted alkoxy, OCF3, SCF3 and NO2;

[0224] R6, R7, R8, R9, R 10 or R 11 Each of which is independently selected from -H, -OH, -CN, substituted or unsubstituted thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryloxy, or substituted or unsubstituted alkoxy;

[0225] R 12 is -H or substituted or unsubstituted alkyl;

[0226] X is O;

[0227] Y is -NR 13 ;and

[0228] Each R 13 independently selected from -H or substituted or unsubstituted alkyl (C1-C6 alkyl),

[0229] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof,

[0230] in

[0231] At least one of R1-R5 is -F, substituted alkyl containing one or more -F groups, or substituted alkoxy containing one or more -F groups, and

[0232] R7-R 12 is -F, a substituted alkyl group containing one or more -F groups, or a substituted alkoxy group containing one or more -F groups, and

[0233] Among them, R3 and R8 / R9 are different.

[0234] In certain embodiments, R1 is -H.

[0235] In certain embodiments, R1 is -OH.

[0236] In certain embodiments, R1 is -CN.

[0237] In certain embodiments, R1 is substituted thioalkyl.

[0238] In certain embodiments, R1 is unsubstituted thioalkyl.

[0239] In certain embodiments, R1 is substituted alkyl.

[0240] In certain embodiments, R1 is hydrogen.

[0241] In certain embodiments, R1 is CH2F.

[0242] In certain embodiments, R1 is CHF2.

[0243] In certain embodiments, R1 is CF3.

[0244] In certain embodiments, R1 is unsubstituted alkyl.

[0245] In certain embodiments, R1 is substituted alkenyl.

[0246] In certain embodiments, R1 is unsubstituted alkenyl.

[0247] In certain embodiments, R1 is substituted alkynyl.

[0248] In certain embodiments, R1 is unsubstituted alkynyl.

[0249] In certain embodiments, R1 is halogen.

[0250] In certain embodiments, R1 is -F.

[0251] In certain embodiments, R1 is -Cl.

[0252] In certain embodiments, R1 is substituted aryl.

[0253] In certain embodiments, R1 is unsubstituted aryl.

[0254] In certain embodiments, R1 is substituted heteroaryl.

[0255] In certain embodiments, R1 is unsubstituted heteroaryl.

[0256] In certain embodiments, R1 is substituted aryloxy.

[0257] In certain embodiments, R1 is unsubstituted aryloxy.

[0258] In certain embodiments, R1 is substituted alkoxy.

[0259] In certain embodiments, R1 is unsubstituted alkoxy.

[0260] In certain embodiments, R2 is -OH.

[0261] In certain embodiments, R2 is -CN.

[0262] In certain embodiments, R2 is substituted thioalkyl.

[0263] In certain embodiments, R2 is unsubstituted thioalkyl.

[0264] In certain embodiments, R2 is substituted alkyl.

[0265] In certain embodiments, R2 is CH2F.

[0266] In certain embodiments, R2 is CHF2.

[0267] In certain embodiments, R2 is CF3.

[0268] In certain embodiments, R2 is unsubstituted alkyl.

[0269] In certain embodiments, R2 is substituted alkenyl.

[0270] In certain embodiments, R2 is unsubstituted alkenyl.

[0271] In certain embodiments, R2 is substituted alkynyl.

[0272] In certain embodiments, R2 is unsubstituted alkynyl.

[0273] In certain embodiments, R2 is halogen.

[0274] In certain embodiments, R2 is -F.

[0275] In certain embodiments, R2 is -Cl.

[0276] In certain embodiments, R2 is substituted aryl.

[0277] In certain embodiments, R2 is unsubstituted aryl.

[0278] In certain embodiments, R2 is substituted heteroaryl.

[0279] In certain embodiments, R2 is unsubstituted heteroaryl.

[0280] In certain embodiments, R2 is substituted aryloxy.

[0281] In certain embodiments, R2 is unsubstituted aryloxy.

[0282] In certain embodiments, R2 is substituted alkoxy.

[0283] In certain embodiments, R2 is unsubstituted alkoxy.

[0284] In certain embodiments, R2 is -OCF3.

[0285] In certain embodiments, R2 is -SCF3.

[0286] In certain embodiments, R2 is -NO2.

[0287] In certain embodiments, R3 is -OH.

[0288] In certain embodiments, R3 is -CN.

[0289] In certain embodiments, R3 is substituted thioalkyl.

[0290] In certain embodiments, R3 is unsubstituted thioalkyl.

[0291] In certain embodiments, R3 is substituted alkyl.

[0292] In certain embodiments, R3 is CH2F.

[0293] In certain embodiments, R3 is CHF2.

[0294] In certain embodiments, R3 is CF3.

[0295] In certain embodiments, R3 is unsubstituted alkyl.

[0296] In certain embodiments, R3 is substituted alkenyl.

[0297] In certain embodiments, R3 is unsubstituted alkenyl.

[0298] In certain embodiments, R3 is substituted alkynyl.

[0299] In certain embodiments, R3 is unsubstituted alkynyl.

[0300] In certain embodiments, R3 is halogen.

[0301] In certain embodiments, R3 is -F.

[0302] In certain embodiments, R3 is -Cl.

[0303] In certain embodiments, R3 is substituted aryl.

[0304] In certain embodiments, R3 is unsubstituted aryl.

[0305] In certain embodiments, R3 is substituted heteroaryl.

[0306] In certain embodiments, R3 is unsubstituted heteroaryl.

[0307] In certain embodiments, R3 is substituted aryloxy.

[0308] In certain embodiments, R3 is unsubstituted aryloxy.

[0309] In certain embodiments, R3 is substituted alkoxy.

[0310] In certain embodiments, R3 is unsubstituted alkoxy.

[0311] In certain embodiments, R3 is -OCF3.

[0312] In certain embodiments, R3 is -SCF3.

[0313] In certain embodiments, R3 is -NO2.

[0314] In certain embodiments, R4 is -OH.

[0315] In certain embodiments, R4 is -CN.

[0316] In certain embodiments, R4 is substituted thioalkyl.

[0317] In certain embodiments, R4 is unsubstituted thioalkyl.

[0318] In certain embodiments, R4 is substituted alkyl.

[0319] In certain embodiments, R4 is CH2F.

[0320] In certain embodiments, R4 is CHF2.

[0321] In certain embodiments, R4 is CF3.

[0322] In certain embodiments, R4 is unsubstituted alkyl.

[0323] In certain embodiments, R4 is substituted alkenyl.

[0324] In certain embodiments, R4 is unsubstituted alkenyl.

[0325] In certain embodiments, R4 is substituted alkynyl.

[0326] In certain embodiments, R4 is unsubstituted alkynyl.

[0327] In certain embodiments, R4 is halogen.

[0328] In certain embodiments, R4 is -F.

[0329] In certain embodiments, R4 is -Cl.

[0330] In certain embodiments, R4 is substituted aryl.

[0331] In certain embodiments, R4 is unsubstituted aryl.

[0332] In certain embodiments, R4 is substituted heteroaryl.

[0333] In certain embodiments, R4 is unsubstituted heteroaryl.

[0334] In certain embodiments, R4 is substituted aryloxy.

[0335] In certain embodiments, R4 is unsubstituted aryloxy.

[0336] In certain embodiments, R4 is substituted alkoxy.

[0337] In certain embodiments, R4 is unsubstituted alkoxy.

[0338] In certain embodiments, R4 is -OCF3.

[0339] In certain embodiments, R4 is -SCF3.

[0340] In certain embodiments, R4 is -NO2.

[0341] In certain embodiments, R5 is -OH.

[0342] In certain embodiments, R5 is -CN.

[0343] In certain embodiments, R5 is substituted thioalkyl.

[0344] In certain embodiments, R5 is unsubstituted thioalkyl.

[0345] In certain embodiments, R5 is substituted alkyl.

[0346] In certain embodiments, R5 is CH2F.

[0347] In certain embodiments, R5 is CHF2.

[0348] In certain embodiments, R5 is CF3.

[0349] In certain embodiments, R5 is unsubstituted alkyl.

[0350] In certain embodiments, R5 is substituted alkenyl.

[0351] In certain embodiments, R5 is unsubstituted alkenyl.

[0352] In certain embodiments, R5 is substituted alkynyl.

[0353] In certain embodiments, R5 is unsubstituted alkynyl.

[0354] In certain embodiments, R5 is halogen.

[0355] In certain embodiments, R5 is -F.

[0356] In certain embodiments, R5 is -Cl.

[0357] In certain embodiments, R5 is substituted aryl.

[0358] In certain embodiments, R5 is unsubstituted aryl.

[0359] In certain embodiments, R5 is substituted heteroaryl.

[0360] In certain embodiments, R5 is unsubstituted heteroaryl.

[0361] In certain embodiments, R5 is substituted aryloxy.

[0362] In certain embodiments, R5 is unsubstituted aryloxy.

[0363] In certain embodiments, R5 is substituted alkoxy.

[0364] In certain embodiments, R5 is unsubstituted alkoxy.

[0365] In certain embodiments, R5 is -OCF3.

[0366] In certain embodiments, R5 is -SCF3.

[0367] In certain embodiments, R5 is -NO2.

[0368] In certain embodiments, R6 is -H.

[0369] In certain embodiments, R6 is -OH.

[0370] In certain embodiments, R6 is -CN.

[0371] In certain embodiments, R6 is substituted thioalkyl.

[0372] In certain embodiments, R6 is unsubstituted thioalkyl.

[0373] In certain embodiments, R6 is substituted alkyl.

[0374] In certain embodiments, R6 is CH2F.

[0375] In certain embodiments, R6 is CHF2.

[0376] In certain embodiments, R6 is CF3.

[0377] In certain embodiments, R6 is unsubstituted alkyl.

[0378] In certain embodiments, R6 is substituted alkenyl.

[0379] In certain embodiments, R6 is unsubstituted alkenyl.

[0380] In certain embodiments, R6 is substituted alkynyl.

[0381] In certain embodiments, R6 is unsubstituted alkynyl.

[0382] In certain embodiments, R6 is halogen.

[0383] In certain embodiments, R6 is -F.

[0384] In certain embodiments, R6 is -Cl.

[0385] In certain embodiments, R6 is substituted aryl.

[0386] In certain embodiments, R6 is unsubstituted aryl.

[0387] In certain embodiments, R6 is substituted heteroaryl.

[0388] In certain embodiments, R6 is unsubstituted heteroaryl.

[0389] In certain embodiments, R6 is substituted aryloxy.

[0390] In certain embodiments, R6 is unsubstituted aryloxy.

[0391] In certain embodiments, R6 is substituted alkoxy.

[0392] In certain embodiments, R6 is unsubstituted alkoxy.

[0393] In certain embodiments, R7 is -H.

[0394] In certain embodiments, R7 is -OH.

[0395] In certain embodiments, R7 is -CN.

[0396] In certain embodiments, R7 is substituted thioalkyl.

[0397] In certain embodiments, R7 is unsubstituted thioalkyl.

[0398] In certain embodiments, R7 is substituted alkyl.

[0399] In certain embodiments, R7 is CH2F.

[0400] In certain embodiments, R7 is CHF2.

[0401] In certain embodiments, R7 is CF3.

[0402] In certain embodiments, R7 is unsubstituted alkyl.

[0403] In certain embodiments, R7 is substituted alkenyl.

[0404] In certain embodiments, R7 is unsubstituted alkenyl.

[0405] In certain embodiments, R7 is substituted alkynyl.

[0406] In certain embodiments, R7 is unsubstituted alkynyl.

[0407] In certain embodiments, R7 is halogen.

[0408] In certain embodiments, R7 is -F.

[0409] In certain embodiments, R7 is -Cl.

[0410] In certain embodiments, R7 is substituted aryl.

[0411] In certain embodiments, R7 is unsubstituted aryl.

[0412] In certain embodiments, R7 is substituted heteroaryl.

[0413] In certain embodiments, R7 is unsubstituted heteroaryl.

[0414] In certain embodiments, R7 is substituted aryloxy.

[0415] In certain embodiments, R7 is unsubstituted aryloxy.

[0416] In certain embodiments, R7 is substituted alkoxy.

[0417] In certain embodiments, R7 is unsubstituted alkoxy.

[0418] In certain embodiments, R8 is -H.

[0419] In certain embodiments, R8 is -OH.

[0420] In certain embodiments, R8 is -CN.

[0421] In certain embodiments, R8 is substituted thioalkyl.

[0422] In certain embodiments, R8 is unsubstituted thioalkyl.

[0423] In certain embodiments, R8 is substituted alkyl.

[0424] In certain embodiments, R8 is CH2F.

[0425] In certain embodiments, R8 is CHF2.

[0426] In certain embodiments, R8 is CF3.

[0427] In certain embodiments, R8 is unsubstituted alkyl.

[0428] In certain embodiments, R8 is substituted alkenyl.

[0429] In certain embodiments, R8 is unsubstituted alkenyl.

[0430] In certain embodiments, R8 is substituted alkynyl.

[0431] In certain embodiments, R8 is unsubstituted alkynyl.

[0432] In certain embodiments, R8 is halogen.

[0433] In certain embodiments, R8 is -F.

[0434] In certain embodiments, R8 is -Cl.

[0435] In certain embodiments, R8 is substituted aryl.

[0436] In certain embodiments, R8 is unsubstituted aryl.

[0437] In certain embodiments, R8 is substituted heteroaryl.

[0438] In certain embodiments, R8 is unsubstituted heteroaryl.

[0439] In certain embodiments, R8 is substituted aryloxy.

[0440] In certain embodiments, R8 is unsubstituted aryloxy.

[0441] In certain embodiments, R8 is substituted alkoxy.

[0442] In certain embodiments, R8 is unsubstituted alkoxy.

[0443] In certain embodiments, R9 is -H.

[0444] In certain embodiments, R9 is -OH.

[0445] In certain embodiments, R9 is -CN.

[0446] In certain embodiments, R9 is substituted thioalkyl.

[0447] In certain embodiments, R9 is unsubstituted thioalkyl.

[0448] In certain embodiments, R9 is substituted alkyl.

[0449] In certain embodiments, R9 is CH2F.

[0450] In certain embodiments, R9 is CHF2.

[0451] In certain embodiments, R9 is CF3.

[0452] In certain embodiments, R9 is unsubstituted alkyl.

[0453] In certain embodiments, R9 is substituted alkenyl.

[0454] In certain embodiments, R9 is unsubstituted alkenyl.

[0455] In certain embodiments, R9 is substituted alkynyl.

[0456] In certain embodiments, R9 is unsubstituted alkynyl.

[0457] In certain embodiments, R9 is halogen.

[0458] In certain embodiments, R9 is -F.

[0459] In certain embodiments, R9 is -Cl.

[0460] In certain embodiments, R9 is substituted aryl.

[0461] In certain embodiments, R9 is unsubstituted aryl.

[0462] In certain embodiments, R9 is substituted heteroaryl.

[0463] In certain embodiments, R9 is unsubstituted heteroaryl.

[0464] In certain embodiments, R9 is substituted aryloxy.

[0465] In certain embodiments, R9 is unsubstituted aryloxy.

[0466] In certain embodiments, R9 is substituted alkoxy.

[0467] In certain embodiments, R9 is unsubstituted alkoxy.

[0468] In certain embodiments, R 10 Yes -H.

[0469] In certain embodiments, R 10 It is -OH.

[0470] In certain embodiments, R 10 Yes-CN.

[0471] In certain embodiments, R 10 It is a substituted thioalkyl group.

[0472] In certain embodiments, R 10 It is an unsubstituted thioalkyl.

[0473] In certain embodiments, R 10 is a substituted alkyl group.

[0474] In certain embodiments, R 10 It is CH2F.

[0475] In certain embodiments, R 10 It is CHF2.

[0476] In certain embodiments, R 10 It's CF3.

[0477] In certain embodiments, R 10 is an unsubstituted alkyl group.

[0478] In certain embodiments, R 10 is a substituted alkenyl.

[0479] In certain embodiments, R 10 is an unsubstituted alkenyl group.

[0480] In certain embodiments, R10 is a substituted alkynyl.

[0481] In certain embodiments, R 10 is an unsubstituted alkynyl group.

[0482] In certain embodiments, R 10 It's a halogen.

[0483] In certain embodiments, R 10 Yes -F.

[0484] In certain embodiments, R 10 It is -Cl.

[0485] In certain embodiments, R 10 is a substituted aryl group.

[0486] In certain embodiments, R 10 is an unsubstituted aryl group.

[0487] In certain embodiments, R 10 is a substituted heteroaryl.

[0488] In certain embodiments, R 10 is an unsubstituted heteroaryl.

[0489] In certain embodiments, R 10 is a substituted aryloxy group.

[0490] In certain embodiments, R 10 is an unsubstituted aryloxy group.

[0491] In certain embodiments, R 10 is a substituted alkoxy group.

[0492] In certain embodiments, R 10 is an unsubstituted alkoxy group.

[0493] In certain embodiments, R 11 Yes -H.

[0494] In certain embodiments, R 11 It is -OH.

[0495] In certain embodiments, R 11 Yes-CN.

[0496] In certain embodiments, R 11 It is a substituted thioalkyl group.

[0497] In certain embodiments, R 11 It is an unsubstituted thioalkyl group.

[0498] In certain embodiments, R 11 is a substituted alkyl group.

[0499] In certain embodiments, R 11 It is CH2F.

[0500] In certain embodiments, R 11 It is CHF2.

[0501] In certain embodiments, R 11 It's CF3.

[0502] In certain embodiments, R 11 is an unsubstituted alkyl group.

[0503] In certain embodiments, R 11 is a substituted alkenyl.

[0504] In certain embodiments, R 11 is an unsubstituted alkenyl group.

[0505] In certain embodiments, R 11 is a substituted alkynyl.

[0506] In certain embodiments, R 11 is an unsubstituted alkynyl group.

[0507] In certain embodiments, R 11 It's a halogen.

[0508] In certain embodiments, R 11 Yes -F.

[0509] In certain embodiments, R 11 It is -Cl.

[0510] In certain embodiments, R 11 is a substituted aryl group.

[0511] In certain embodiments, R 11 is an unsubstituted aryl group.

[0512] In certain embodiments, R 11 is a substituted heteroaryl.

[0513] In certain embodiments, R 11 is an unsubstituted heteroaryl.

[0514] In certain embodiments, R 11 is a substituted aryloxy group.

[0515] In certain embodiments, R 11 is an unsubstituted aryloxy group.

[0516] In certain embodiments, R 11 is a substituted alkoxy group.

[0517] In certain embodiments, R 11 is an unsubstituted alkoxy group.

[0518] In certain embodiments, R 12 Yes -H.

[0519] In certain embodiments, R 12 is a substituted alkyl group.

[0520] In certain embodiments, R 12 is an unsubstituted alkyl group.

[0521] In certain embodiments, R 13 Yes -H.

[0522] In certain embodiments, R 13 is a substituted alkyl group.

[0523] In certain embodiments, R 13 is an unsubstituted alkyl group.

[0524] In certain embodiments, when R1 is halogen or hydrogen, each of R2, R3, R4 and R5 is independently selected from halogen (e.g., F or Cl), alkyl (e.g., CH3), CF3, alkoxy, OCF3, CN, NO2 and SCF3.

[0525] In certain embodiments, when R1 is halogen, each of R2, R3, R4, and R5 is hydrogen, R6, R7, R 10 , R 11 and R 12 , and either R8 or R9 is -CF3.

[0526] In another embodiment, the compounds, compositions and methods of the invention include a compound of formula (III):

[0527]

[0528] Formula III

[0529] in

[0530] R1 is halogen or alkyl substituted by 1 to 3 halogen groups;

[0531] R2 is hydrogen or C1-C3 alkyl;

[0532] R3 is hydroxy, halogen, cyano, amino, nitro or alkyl substituted with 1-3 halogen groups, and one or more R3 is at position a, b or c or a combination thereof;

[0533] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

[0534] In certain embodiments, R1 is -F.

[0535] In certain embodiments, R1 is -Cl.

[0536] In certain embodiments, R1 is alkyl substituted with 1-3 halogen groups.

[0537] In certain embodiments, R1 is alkyl substituted with 1 halogen group.

[0538] In certain embodiments, R1 is alkyl substituted with 2 halo groups.

[0539] In certain embodiments, R1 is alkyl substituted with 3 halo groups.

[0540] In certain embodiments, R1 is -CH2F.

[0541] In certain embodiments, R1 is -CHF2.

[0542] In certain embodiments, R1 is -CF3.

[0543] In certain embodiments, R2 is hydrogen.

[0544] In certain embodiments, R2 is C1-C3 alkyl.

[0545] In certain embodiments, R2 is methyl.

[0546] In certain embodiments, R2 is ethyl.

[0547] In certain embodiments, R2 is propyl.

[0548] In certain embodiments, R3 is hydroxy.

[0549] In certain embodiments, R3 is halogen.

[0550] In certain embodiments, R3 is cyano.

[0551] In certain embodiments, R3 is amino.

[0552] In certain embodiments, R3 is nitro.

[0553] In certain embodiments, R3 is substituted alkyl.

[0554] In certain embodiments, R3 is unsubstituted alkyl.

[0555] In certain embodiments, R3 is substituted alkenyl.

[0556] In certain embodiments, R3 is unsubstituted alkenyl.

[0557] In certain embodiments, R3 is substituted alkynyl.

[0558] In certain embodiments, R3 is unsubstituted alkynyl.

[0559] In certain embodiments, R3 is alkyl substituted with 1 halogen group.

[0560] In certain embodiments, R3 is alkyl substituted with 2 halo groups.

[0561] In certain embodiments, R3 is alkyl substituted with 3 halo groups.

[0562] In certain embodiments, R3 is -CH2F.

[0563] In certain embodiments, R3 is -CHF2.

[0564] In certain embodiments, R3 is -CF3.

[0565] In certain embodiments, R3 is at the a position.

[0566] In certain embodiments, R3 is at position b.

[0567] In certain embodiments, R3 is at the c position.

[0568] In certain embodiments, one R3 is at the a position and one R3 is at the b position.

[0569] In certain embodiments, one R3 is at the a position and one R3 is at the c position.

[0570] In certain embodiments, one R3 is at the b position and one R3 is at the b position.

[0571] In certain embodiments, one R3 is at the a position, one R3 is at the b position, and one R3 is at the c position.

[0572] In certain embodiments, R1 and R3 comprise a halogen substituent or an alkyl group substituted with one or more halogen substituents.

[0573] In certain embodiments, R1 is -F, and R3 is -CF3.

[0574] In another embodiment, the compounds, compositions and methods of the invention include a compound of formula (IIIa):

[0575]

[0576] Formula IIIa

[0577] in

[0578] R1 is halogen or alkyl substituted by 1 to 3 halogen groups;

[0579] R2 is hydrogen or C1-C3 alkyl;

[0580] Each R3 is independently hydroxy, halogen, cyano, amino, nitro, or alkyl substituted with 1-3 halogen groups, and one or more R3 is at position a, b, or c, or a combination thereof;

[0581] n is an integer from 1 to 6 (wherein the a, b and / or c positions may each contain 1 or 2 R3 groups);

[0582] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

[0583] In certain embodiments, R1 is -F.

[0584] In certain embodiments, R1 is -Cl.

[0585] In certain embodiments, R1 is alkyl substituted with 1-3 halogen groups.

[0586] In certain embodiments, R1 is alkyl substituted with 1 halogen group.

[0587] In certain embodiments, R1 is alkyl substituted with 2 halo groups.

[0588] In certain embodiments, R1 is alkyl substituted with 3 halo groups.

[0589] In certain embodiments, R1 is -CH2F.

[0590] In certain embodiments, R1 is -CHF2.

[0591] In certain embodiments, R1 is -CF3.

[0592] In certain embodiments, R2 is hydrogen.

[0593] In certain embodiments, R2 is C1-C3 alkyl.

[0594] In certain embodiments, R2 is methyl.

[0595] In certain embodiments, R2 is ethyl.

[0596] In certain embodiments, R2 is propyl.

[0597] In certain embodiments, R3 is hydroxy.

[0598] In certain embodiments, R3 is halogen.

[0599] In certain embodiments, R3 is cyano.

[0600] In certain embodiments, R3 is amino.

[0601] In certain embodiments, R3 is nitro.

[0602] In certain embodiments, R3 is substituted alkyl.

[0603] In certain embodiments, R3 is unsubstituted alkyl.

[0604] In certain embodiments, R3 is substituted alkenyl.

[0605] In certain embodiments, R3 is unsubstituted alkenyl.

[0606] In certain embodiments, R3 is substituted alkynyl.

[0607] In certain embodiments, R3 is unsubstituted alkynyl.

[0608] In certain embodiments, R3 is alkyl substituted with 1 halogen group.

[0609] In certain embodiments, R3 is alkyl substituted with 2 halo groups.

[0610] In certain embodiments, R3 is alkyl substituted with 3 halo groups.

[0611] In certain embodiments, R3 is -CH2F.

[0612] In certain embodiments, R3 is -CHF2.

[0613] In certain embodiments, R3 is -CF3.

[0614] In certain embodiments, R3 is at the a position.

[0615] In certain embodiments, R3 is at position b.

[0616] In certain embodiments, R3 is at the c position.

[0617] In certain embodiments, one R3 is at the a position and one R3 is at the b position.

[0618] In certain embodiments, one R3 is at the a position and one R3 is at the c position.

[0619] In certain embodiments, one R3 is at the b position and one R3 is at the b position.

[0620] In certain embodiments, one R3 is at the a position, one R3 is at the b position, and one R3 is at the c position.

[0621] In certain embodiments, R1 and R3 comprise a halogen substituent or an alkyl group substituted with one or more halogen substituents.

[0622] In certain embodiments, R1 is -F, and R3 is -CF3.

[0623] In certain embodiments, n is 1.

[0624] In certain embodiments, n is 2.

[0625] In certain embodiments, n is 3.

[0626] In certain embodiments, n is 4.

[0627] In certain embodiments, n is 5.

[0628] In certain embodiments, n is 6.

[0629] In another embodiment, the compounds, compositions and methods of the invention include a compound of formula (IV):

[0630]

[0631] Formula IV

[0632] in

[0633] R1 is halogen, hydrogen or alkyl substituted by 1 to 3 halogen groups;

[0634] R2 is hydrogen or C1-C3 alkyl; and

[0635] R3 is halogen or alkyl substituted by 1 to 3 halogen groups,

[0636] or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

[0637] In certain embodiments, R1 is -F.

[0638] In certain embodiments, R1 is -Cl.

[0639] In certain embodiments, R1 is alkyl substituted with 1-3 halogen groups.

[0640] In certain embodiments, R1 is alkyl substituted with 1 halogen group.

[0641] In certain embodiments, R1 is alkyl substituted with 2 halo groups.

[0642] In certain embodiments, R1 is alkyl substituted with 3 halo groups.

[0643] In certain embodiments, R1 is -CH2F.

[0644] In certain embodiments, R1 is -CHF2.

[0645] In certain embodiments, R1 is -CF3.

[0646] In certain embodiments, R2 is hydrogen.

[0647] In certain embodiments, R2 is C1-C3 alkyl.

[0648] In certain embodiments, R2 is methyl.

[0649] In certain embodiments, R2 is ethyl.

[0650] In certain embodiments, R2 is propyl.

[0651] In certain embodiments, R3 is hydroxy.

[0652] In certain embodiments, R3 is halogen.

[0653] In certain embodiments, R3 is cyano.

[0654] In certain embodiments, R3 is amino.

[0655] In certain embodiments, R3 is nitro.

[0656] In certain embodiments, R3 is substituted alkyl.

[0657] In certain embodiments, R3 is unsubstituted alkyl.

[0658] In certain embodiments, R3 is substituted alkenyl.

[0659] In certain embodiments, R3 is unsubstituted alkenyl.

[0660] In certain embodiments, R3 is substituted alkynyl.

[0661] In certain embodiments, R3 is unsubstituted alkynyl.

[0662] In certain embodiments, R3 is alkyl substituted with 1 halogen group.

[0663] In certain embodiments, R3 is alkyl substituted with 2 halo groups.

[0664] In certain embodiments, R3 is alkyl substituted with 3 halo groups.

[0665] In certain embodiments, R3 is -CH2F.

[0666] In certain embodiments, R3 is -CHF2.

[0667] In certain embodiments, R3 is -CF3.

[0668] Exemplary, but non-limiting, compounds of the invention are shown in the following table:

[0669]

[0670] Scheme 1 illustrates an exemplary synthetic method that can be used to develop meta-substituted N-benzamide enaminone derivatives.

[0671]

[0672] Exemplary but non-limiting compounds of the present invention also include:

[0673]

[0674]

[0675]

[0676]

[0677] In another embodiment, the disclosure also provides a pharmaceutical composition comprising a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically suitable carrier or excipient at a dosage for treating or preventing a disease or condition described herein. The pharmaceutical composition of the present invention can also be combined with other therapeutic agents or treatment modalities for simultaneous, sequential or alternating administration.

[0678] The compositions of the present invention comprise a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof. The present invention provides administration of a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents or a pharmaceutically acceptable salt thereof as a co-formulation or a separate formulation, wherein the administration of the formulation is simultaneous, sequential or alternating. In certain embodiments, the other therapeutic agent may be an agent recognized in the art as being useful for treating a disease or condition treated by the composition of the present invention. In other embodiments, the other therapeutic agent may be an agent not recognized in the art as being useful for treating a disease or condition treated by the composition of the present invention. In one aspect, the other therapeutic agent may be an agent that imparts beneficial properties to the composition of the present invention (e.g., an agent that affects the viscosity of the composition). The beneficial properties of the compositions of the present invention include, but are not limited to, pharmacokinetic or pharmacodynamic synergy caused by the combination of a compound of formula (I), (II), (III) or (IV) and one or more other therapeutic agents. For example, the one or more other therapeutic agents may be anti-epileptic drugs.

[0679] The mixture of the compositions of the present invention can also be administered to a patient as a simple mixture or in a suitable formulated pharmaceutical composition. For example, one aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof, one or more other therapeutic agents, and a pharmaceutically acceptable diluent or carrier.

[0680] A pharmaceutical composition is a preparation containing a compound of formula (I), (II), (III) or (IV) in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any one of various forms, including, for example, a capsule, an IV bag, a tablet, a single pump or a vial on an aerosol inhaler. The amount of active ingredient (e.g., a preparation of a disclosed compound or its salt, hydrate, solvate or isomer) in the composition of the unit dose is an effective amount and varies according to the specific treatment involved. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that are required.

[0681] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0682] A pharmaceutically acceptable excipient is an excipient useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary use and human pharmaceutical use. "Pharmaceutically acceptable excipient" as used in this specification and claims includes both one and more than one such excipient.

[0683] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous applications may include the following components: a sterile diluent, such as water for injection, saline solution, non-volatile oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates, and agents for regulating osmotic pressure, such as sodium chloride or glucose. pH can be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. The parenteral formulation may be contained in an ampoule, a disposable syringe, or a multidose vial made of glass or plastic.

[0684] The compositions of the present invention can be administered to a subject in many well-known methods currently used for chemotherapy treatment. For example, to treat the disorders disclosed herein, the compounds of the present invention can be injected into the bloodstream or body cavity, or taken orally or applied through the skin with a patch. The dose selected should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The status of the disease condition (e.g., epileptic seizures or epileptic seizure disorders, etc.) and the health of the patient are preferably closely monitored during and for a reasonable period of time after treatment.

[0685] In certain embodiments, the therapeutically effective amount of each agent used in combination will be lower when used in combination compared to monotherapy with each drug alone. Such lower therapeutically effective amounts can reduce the toxicity of the treatment regimen.

[0686] For any compound, the therapeutically effective amount can be estimated initially in cell culture assays or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as LD 50 / ED 50 The ratio of . Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range, depending on the dosage form used, the sensitivity of the patient, and the route of administration.

[0687] Dosage and administration are adjusted to provide sufficient levels of a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combination, reaction sensitivity and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered once every 3 to 4 days, weekly or biweekly, depending on the half-life and clearance rate of the particular formulation.

[0688] Pharmaceutical compositions containing compounds of formula (I), (II), (III) or (IV) or pharmaceutically acceptable salts thereof can be prepared in a generally known manner, for example, using conventional mixing, dissolving, granulating, dragee preparation, grinding, emulsifying, encapsulating, embedding or lyophilizing processes. Pharmaceutical compositions can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, which include excipients and / or adjuvants that help process the active compound into a pharmaceutically usable preparation. Of course, suitable preparations depend on the selected route of administration.

[0689] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM(BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid for easy injection. It must be stable under the conditions of manufacture and storage and must be preserved to prevent the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the desired particle size in the case of dispersions, and using a surfactant. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents such as sugars, polyols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be caused by including agents that delay absorption such as aluminum monostearate and gelatin in the composition.

[0690] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound into an appropriate solvent having one or a combination of the above-mentioned ingredients as required, and then filtering and sterilizing. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other ingredients required from the above-mentioned ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and freeze drying, which obtain a powder of the active ingredient and any additional required ingredients from a previously sterile filtered solution.

[0691] Oral compositions typically contain an inert diluent or an edible pharmaceutically acceptable carrier. They can be placed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be blended with an excipient and used in the form of tablets, lozenges 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 administered orally and gargled, spit out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavorings, such as mint, methyl salicylate or orange flavoring.

[0692] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0693] Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are well known in the art and, for example, include detergents, bile salts and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gel or cream as known in the art.

[0694] The compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof can be prepared with a pharmaceutically acceptable carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art. The materials can also be purchased commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These suspensions can be prepared according to methods known to those skilled in the art, such as described in U.S. Patent No. 4,522,811.

[0695] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0696] In therapeutic applications, the compound of formula (I), (II), (III) or (IV) described herein, or a pharmaceutically acceptable salt thereof, and optionally one or more other therapeutic agents, or a pharmaceutical composition used in accordance with the present invention, the dosage varies according to the agent, the age, weight and clinical condition of the recipient patient, the experience and judgment of the clinician or practitioner administering the therapy, and other factors affecting the selected dosage. Typically, the dosage should be sufficient to cause a slowing, preferably regression of the growth of the tumor, and preferably also to cause complete regression of the cancer. The dosage may be in the range of about 0.001 mg / kg per day to about 5000 mg / kg per day. In preferred aspects, the dosage may be in the range of about 0.01 mg / kg per day to about 1000 mg / kg per day. In one aspect, the dosage will be in the range of about 0.1 mg / day to about 50 g / day, about 0.1 mg / day to about 25 g / day, about 0.1 mg / day to about 10 g / day, about 0.1 mg to about 3 g / day, or about 0.1 mg to about 1 g / day, in single, divided, or continuous doses (the dosage may be based on the patient's weight (kg), body surface area (m 2 ) and age (years) are adjusted). An effective amount of an agent is an amount that provides an objectively identifiable improvement noted by a clinician or other qualified observer. As used herein, the term "dosage effective manner" refers to the amount of active compound that produces a desired biological effect in a subject or cell.

[0697] Many pharmaceutical compositions are administered regularly at fixed doses to achieve therapeutic efficacy. The duration of action is reflected by the plasma half-life of the active ingredient (e.g., a compound covered by formula (I), (II), (III) or (IV)). Since efficacy generally depends on adequate exposure within the central nervous system, the administration of CNS drugs with a short half-life may require frequent maintenance dosing. Advantageously, disclosed herein is a method for treating, preventing or alleviating epileptic seizures and epileptic seizure disorders by administering a pharmaceutical composition comprising a compound covered by formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating epileptic seizures or epileptic seizure disorders is provided, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising about 0.05 mg to about 2000 mg of a compound covered by formula (I), (II), (III) or (IV), wherein the composition provides an improvement of more than 6 hours after administration to the patient. For example, in an embodiment, a method of treating epileptic seizures or epileptic seizure disorders is provided, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising about 0.05 mg to about 75 mg of a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement for more than 6 hours after administration to the patient.

[0698] In an embodiment, the method of treating epileptic seizures or epileptic seizure disorders comprises administering to a patient in need thereof a pharmaceutical composition comprising about 0.05 mg to about 50 mg of a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof. In an embodiment, the method of treating epileptic seizures or epileptic seizure disorders comprises administering to a patient in need thereof a pharmaceutical composition comprising about 0.1 mg to about 30 mg of a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof. For example, a dosage may include an amount of a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, ranging from about, for example, 0.05 mg to 50 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.1 mg to 30 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, wherein 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7.5 mg, 8.5 mg, 9.5 mg, 10.5 mg, 11.5 mg, 12.5 mg, 13.5 mg, 14.5 mg, 15.5 mg, 16.5 mg, 17.5 mg, 18.5 mg, 19.5 mg, 20.5 mg, 21.5 mg, 22.5 mg, 23.5 mg, 24.5 mg, 25.5 mg, 26.5 mg, 27.5 mg, 28.5 mg, 29.5 mg, 30.5 mg, 31.5 mg, 32.5 mg, 33.5 mg, 34.5 mg, 35.5 mg, 36.5 mg, 37.5 mg, 3 Doses of 100 mg, 200 mg, 300 mg, 400 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 3000 mg, and 4000 mg are specific examples of dosages.

[0699] Typically, a dose of a compound encompassed by Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof is administered once or twice daily to a patient in need thereof. The methods and compositions described herein can provide reduced dosing frequency and reduced adverse events and / or improved efficacy. In an embodiment, the dosage is about, for example, 0.05-30 mg / day, 0.1-20 mg / day, 0.2-15 mg / day, 0.5-10 mg / day, or 0.75-5 mg / day, such as 0.1 mg / day, 0.2 mg / day, 0.5 mg / day, 0.75 mg / day, 1 mg / day, 1.5 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 22 mg / day, 23 mg / day, 24 mg / day, 25 mg / day, 26 mg / day, 27 mg / day, 28 mg / day, 29 mg / day, or 30 mg / day.

[0700] In an embodiment, a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, is administered once daily at a dose of 0.2 mg to 1 mg in infants or 1-20 mg in adults.

[0701] In an embodiment, the pharmaceutical composition comprises 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg of a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof.

[0702] In an embodiment, the pharmaceutical composition comprises 5 mg to 20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg or 18 mg to 20 mg of a compound encompassed by Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof.

[0703] In an embodiment, the pharmaceutical composition comprises 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. In some embodiments, the pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg of a compound covered by Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, or an amount that is a multiple of such a dose. In an embodiment, the pharmaceutical composition comprises 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg of a compound covered by Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof.

[0704] In an embodiment, the total amount of the compound covered by formula (I), (II), (III) or (IV) or its pharmaceutically acceptable salt administered to the subject within a 24-hour period is 1 mg to 100 mg. In an embodiment, the total amount of the compound covered by formula (I), (II), (III) or (IV) or its pharmaceutically acceptable salt administered to the subject within a 24-hour period is 1 mg to 50 mg. In an embodiment, the total amount of the compound covered by formula (I), (II), (III) or (IV) or its pharmaceutically acceptable salt administered to the subject within a 24-hour period is 1 mg to 20 mg. In an embodiment, the total amount of the compound covered by formula (I), (II), (III) or (IV) or its pharmaceutically acceptable salt administered to the subject within a 24-hour period is 5 mg, 10 mg, 15 mg or 20 mg. In an embodiment, the subject can start with a low dose, and the dose is gradually increased. In this way, it can be determined whether the drug is well tolerated in the subject. The dose for children can be lower than that for adults. In an embodiment, the dosage of a compound encompassed by Formula (I), (II), (III) or (IV) for children may be 0.1 mg / kg to 1 mg / kg.

[0705] In an embodiment, a method of treating epileptic seizures or an epileptic seizure disorder comprises administering to a patient in need thereof a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof. The compounds encompassed by Formula (I), (II), (III) or (IV), or pharmaceutically acceptable salts thereof, can be administered at a dose ranging from 10 mg / kg to 40 mg / kg, e.g., 11 mg / kg to 39 mg / kg, 12 mg / kg to 38 mg / kg, 13 mg / kg to 37 mg / kg, 14 mg / kg to 36 mg / kg, 15 mg / kg to 35 mg / kg, 16 mg / kg to 34 mg / kg, 17 mg / kg to 33 mg / kg, 18 mg / kg to 32 mg / kg, 19 mg / kg to 31 mg / kg, 20 mg / kg to 30 mg / kg, 21 mg / kg to 29 mg / kg, 22 mg / kg to 28 mg / kg, 23 mg / kg to 27 mg / kg, or 24 mg / kg to 26 mg / kg. In an embodiment, a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, can be administered in an amount of, for example, 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg 1225 mg mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, or 2000 mg.

[0706] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0707] The composition of the present invention can further form salts. The composition of the present invention can form more than one salt per molecule, such as monosalt, disalt, trisalt. All these forms are also contemplated within the scope of the claimed invention.

[0708] Exemplary pharmaceutically acceptable salts refer to derivatives of compounds covered by formula (I), (II), (III) or (IV), wherein the parent compound is modified by preparing its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as inorganic or organic acid salts of amines, acidic residues such as alkali or organic salts of carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as those formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, ethylene glycol p-aminophenylarsonic acid, hexylresorcinic acid, hybamine acid, hydrobromic acid, hydrochloric acid , hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethyl sulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthoic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0709] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, etc. The present invention also includes salts formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

[0710] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein of said salts.

[0711] The compositions of the present invention can also be prepared as esters, such as pharmaceutically acceptable esters. For example, the carboxylic acid functional group in the compound of formula (I), (II), (III) or (IV) or its pharmaceutically acceptable salt can be converted into its corresponding ester, such as methyl ester, ethyl ester or other ester. In addition, the alcohol group in the compound can be converted into its corresponding ester, such as acetate, propionate or other ester.

[0712] The composition of the present invention can also be prepared as a prodrug, such as a pharmaceutically acceptable prodrug. The terms "prodrug" and "prodrug" are used interchangeably herein and refer to any compound that releases an active parent drug in vivo. Since it is known that prodrugs enhance many desirable qualities of drugs (such as solubility, bioavailability, manufacturing, etc.), the compounds of the present invention can be delivered in the form of prodrugs. Therefore, the present invention is intended to cover the prodrugs of the compounds currently claimed, their delivery methods, and compositions containing them. "Prodrugs" are intended to include any covalently bound carriers that release the active parent drug of the present invention in vivo when such prodrugs are administered to a subject. Prodrugs in the present invention are prepared by modifying the functional groups present in the compound so that the modifications are cut into parent compounds in conventional operations or in vivo. Prodrugs include compounds of the present invention, wherein hydroxyl, amino, sulfhydryl, carboxyl or carbonyl are bonded to any group that can be cut in vivo to form free hydroxyl, free amino, free sulfhydryl, free carboxyl or free carbonyl, respectively.

[0713] Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formates, phosphates, sulfates and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyl functional groups in the compounds of the invention, esters (e.g., ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl), N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups, etc., see Bundegaard, H., Design of prodrugs, p1-92, Elesevier, New York-Oxford (1985).

[0714] The composition or its pharmaceutically acceptable salt, ester or prodrug is administered orally, nasally, transdermally, pulmonary, inhaled, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0715] The dosage regimen for using the compound is selected based on various factors, including the type, species, age, weight, sex and medical condition of the patient, the severity of the condition to be treated, the route of administration, the patient's renal and liver function, and the specific compound or salt thereof used. An ordinary skilled physician or veterinarian can easily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0716] The preparation and administration techniques of the compounds disclosed in the present invention can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, Pa (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such a pharmaceutical composition in an amount sufficient to provide the desired dosage within the range described herein.

[0717] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present invention are apparent from the various examples. The examples provided illustrate various components and methods that may be used to practice the present invention. The examples do not limit the claimed invention. Based on this disclosure, the skilled person may identify and use other components and methods that may be used to practice the present invention.

[0718] In various embodiments, the composition may include diluents of various buffer contents (e.g., Tris-HCl, acetate, phosphate), pH, and ionic strength; additives, such as detergents and solubilizers (e.g., Tween 80, polysorbate 80), antioxidants (e.g., ascorbic acid, sodium pyrosulfite), preservatives (e.g., thimerosal, benzyl alcohol), and bulking agents (e.g., lactose, mannitol); the material is incorporated into a granular formulation of a polymer compound (e.g., polylactic acid, polyglycolic acid, etc.) or into a liposome. Such compositions may affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the components of the pharmaceutical composition of the present invention. See, for example, Remington's Pharmaceutical Sciences, 18th edition (1990, Mack Publishing Co., Easton, Pa. 18042), pp. 1435-1712, which is incorporated herein by reference. The pharmaceutical composition of the present invention may be prepared, for example, in liquid form, or in dry powder, such as lyophilized form. Specific methods for administering such compositions are described below.

[0719] Methods of treating and preventing epileptic seizures and epileptic seizure disorders

[0720] The compounds and compositions disclosed herein are useful for treating, preventing, or alleviating epileptic seizures and various conditions associated with epileptic seizures. The present invention provides a method for treating, preventing and alleviating seizures associated with epilepsy disorders, including epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Ohtahara syndrome, Rasmussen syndrome, West syndrome, Lennox-Gastaut syndrome (LGS), Rett syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, Dravet syndrome, Doose syndrome, acute repetitive seizures, benign motor epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 childhood epilepsy, increased seizure activity or breakthrough seizures (increased seizure activity, also known as continuous or clustered seizures), and sodium channel protein type 1 subunit alpha (Scn1a) related disorders by administering a pharmaceutical composition containing a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0721] In an embodiment, a method of treating, preventing and alleviating epileptic seizures and epileptic seizures associated with epileptic disorders, including status epilepticus, benign motor epilepsy (BRE), refractory childhood epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome and Lennox-Gastaut syndrome (LGS) is provided by administering a pharmaceutical composition comprising a compound of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0722] In an embodiment, methods of treating, preventing and alleviating epileptic seizures and seizures associated with epilepsy disorders characterized by sodium channel protein type 1 subunit alpha (Scn1a)-related disorders are provided. Scn1a-related disorders include generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory partial seizures of infancy, myoclonic-restless epilepsy, severe myoclonic epilepsy of infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures.

[0723] In an embodiment, provided is a method of treating a sodium channel protein type 1 subunit alpha (Scn1a)-related disorder by administering to a patient in need thereof a pharmaceutical composition comprising a compound of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof.

[0724] The methods described herein may also be effective in subjects experiencing refractory epileptic seizures, status epilepticus, akinetic seizures, myoclonic seizures, absence seizures, or severe myoclonic epilepsy of infancy (SMEI). In embodiments, the disorder is characterized by refractory epileptic seizures. Refractory epileptic seizures (also referred to as "uncontrolled" or "refractory" seizures) are seizures that cannot be controlled with conventional treatments. For example, a subject may suffer from refractory epilepsy or another disorder characterized by refractory epileptic seizures or a disorder characterized by status epilepticus. Status epilepticus is a condition in which epileptic seizures occur continuously without recovery of consciousness during the period. Therefore, in embodiments, the disclosed methods are used to treat subjects who would otherwise be resistant to one or more conventional therapies.

[0725] The methods described herein may be particularly useful for treating children and infants, and for treating disorders with onset in infancy or childhood. In embodiments, the subject of the disclosed methods is a newborn, infant, toddler, preschooler, school-age child, 10 to 12-year-old, or teenage adolescent. In embodiments, the subject is 18 years of age or younger, 12 years of age or younger, 10 years of age or younger, 8 years of age or younger, 6 years of age or younger, 4 years of age or younger, 2 years of age or younger, 1 year of age or younger. In embodiments, the subject is an adult 18 years of age or older.

[0726] In an embodiment, the epileptic disorder is characterized by seizures associated with epilepsy. In an embodiment, the seizure is a non-epileptic seizure (NES) or a dissociative seizure distinguished from epilepsy. Non-epileptic seizures include organic non-epileptic seizures and psychogenic seizures.

[0727] Epilepsy is a neurological disorder that occurs when nerve cell activity in the brain is disrupted, resulting in seizures or periods of abnormal behavior, sensations, and sometimes even loss of consciousness. A subject is said to have epilepsy when they have two seizures without an apparent cause. Epilepsy can occur in adults and children and can be associated with specific syndromes. Thus, in an embodiment, the subject has a childhood epilepsy syndrome, such as benign motor epilepsy (BRE), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome, or Lennox-Gastaut syndrome (LGS).

[0728] In embodiments, the subject does not experience diagnosable epileptic seizures, but exhibits subclinical discharges, which means that there is a high rate of seizure-like activity when their brain waves are measured using an electroencephalogram. Epilepsy syndromes associated with these seizure-like discharges include Landau-Kleffner syndrome, Dravet syndrome, and continuous spike wave activity during slow wave sleep.

[0729] In embodiments, epileptic disorders treated by the methods and compositions described herein include Scn1A-associated seizure disorders. Scn1A-associated seizure disorders include mild simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+), as well as severe Dravet syndrome and refractory childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). Specific Scn1A-associated seizure disorders include, but are not limited to, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, refractory infantile partial seizures, myoclonic-restless epilepsy, severe myoclonic epilepsy of infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-associated encephalopathy.

[0730] In embodiments, the subject suffers from intellectual disability with epilepsy (IDD), such as autism spectrum disorder (ASD). In embodiments, the subject of the disclosed method suffers from epilepsy and IDD or ASD disorders. Common IDD and ASD comorbid with seizures and epilepsy include, but are not limited to, fragile X syndrome (FXS), Rett syndrome (RTT), Angelman syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, neuroligin mutations, and "interneuronal diseases" caused by mutations in the awnless-related homeobox, X-linked (ARX) and Nueropilin 2 (NRP2) genes.

[0731] Also provided herein are methods and compositions for treating epileptic seizures and epileptic seizure disorders by co-administering a composition comprising a compound encompassed by Formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, and an anti-epileptic drug, such as sodium valproate, carbamazepine, lamotrigine, levetiracetam, or topiramate, to a patient in need thereof.

[0732] The compounds of formula (I), (II), (III) or (IV) or pharmaceutically acceptable salts thereof and compositions thereof can be used to treat, prevent, and alleviate epileptic seizures and epileptic seizure disorders. An epileptic seizure is an uncontrolled burst of electrical activity between brain cells (also known as neurons or nerve cells) that causes temporary abnormalities in muscle tone or movement (rigidity, twitching, or weakness), behavior, sensation, or state of consciousness. Not all epileptic seizures are the same. An epileptic seizure may be a single event caused by an acute cause, such as a drug. When a person has recurrent epileptic seizures, this is called epilepsy. Symptoms of an epileptic seizure vary and can include sudden changes in consciousness or complete loss of consciousness, unusual sensations or thoughts, involuntary twitching or stiffness of the body, or severe stiffness and trembling of the limbs with loss of consciousness (convulsions).

[0733] Seizure disorders are disorders that can directly or indirectly cause seizures and include two major categories or groups of seizures: focal onset and generalized. A focal onset seizure starts in one area and can spread throughout the brain, causing mild or severe symptoms, depending on how the discharge spreads. Generalized seizures can start as a focal onset seizure that spreads to both sides of the brain. They may also occur as a "generalized onset" seizure, in which seizure activity starts on both sides of the brain at the same time. Generalized onset seizures often begin in childhood and are similar to a thermostat surge or a flashing light - abnormal regulation between parts of the brain causes the seizure.

[0734] Focal seizures are also called partial seizures because they start in one area of ​​the brain. They can be caused by any type of focal injury that leaves a tangle of scars. A medical history or MRI will identify the cause (such as trauma, stroke, or meningitis) in about half of people with focal seizures. Developmental scars—scars that occur as part of the fetus and early growth of the brain—are a common cause of focal seizures in children.

[0735] Focal seizures may start in one part of the brain and spread to other areas, causing mild or severe symptoms, depending on how much of the brain is involved.

[0736] At first, people may notice mild symptoms, which are called auras. People may have an altered sense or perception of what is about to happen (premonition). Some people who experience auras describe a rising feeling in the stomach, similar to riding a roller coaster. As the seizure spreads through the brain, more symptoms develop. If the abnormal electrical activity involves a large area of ​​the brain, people may feel confused or disoriented, or experience mild tremors, muscle stiffness, hesitating, or chewing movements. Focal seizures that cause altered consciousness are called focal involuntary seizures or complex partial seizures. The electrical activity of a seizure can remain in one sensory or motor area of ​​the brain, resulting in a focal conscious seizure (also called a simple partial seizure). The person is aware of what is happening and may notice unusual sensations and movements. Focal seizures can evolve into major events that spread throughout the brain and cause tonic-clonic seizures. Treating and preventing these seizures is important because they can cause respiratory problems and injuries.

[0737] A generalized onset seizure is a surge of abnormal neural discharges that occurs more or less simultaneously throughout the cerebral cortex. The most common cause is an imbalance in the "brakes" (inhibitory circuits) and "accelerators" (excitatory circuits) of electrical activity in the brain. Generalized seizures may have a genetic component, but only a few people with generalized seizures have a family member with the same condition. There is a slightly increased risk of developing a generalized seizure in children or other family members of a person affected by generalized seizures, but the severity of the seizure varies from person to person. Genetic testing may reveal the cause of generalized seizures. Sleep deprivation or heavy alcohol consumption can increase the excitatory response, increasing the risk of generalized onset seizures, especially in people who are genetically predisposed.

[0738] Childhood absence epilepsy manifests as a brief onset of seizures in children, usually starting between the ages of 4 and 6. Children usually outgrow the seizures. Juvenile absence epilepsy begins slightly later and may continue into adulthood; in addition to being seizure-free in adulthood, people with this type of epilepsy may also have tonic-clonic seizures.

[0739] Myoclonic seizures involve sudden body or limb jerks that may involve the arms, head, and neck. The spasms occur in groups on both sides of the body, especially in the morning. When these seizures develop during adolescence along with tonic-clonic seizures, they are part of a syndrome called juvenile myoclonic epilepsy. People may also have myoclonic seizures as part of other epilepsy-related conditions.

[0740] Some people, usually those with multiple brain injuries and intellectual disability, experience tonic seizures, which involve sudden stiffening of the arms and body, which can lead to falls and injuries. Many people who have tonic seizures have a syndrome called Lennox-Gastaut syndrome. This condition can involve intellectual disability and multiple seizure types, including tonic seizures. People with Lennox-Gastaut syndrome may have a distinctive EEG pattern called slow spikes and waves.

[0741] People with diffuse brain disorders may also have atonic seizures, which are characterized by a sudden loss of body tone, leading to collapse, often with injury. A series of brief tonic periods followed by an atonic seizure is called a tonic-atonic seizure. Tonic and atonic seizures are usually managed with specific medications and sometimes with neurostimulation and dietary therapy.

[0742] Tonic-clonic seizures can evolve from any focal or generalized seizure type. For example, a focal seizure can spread to both sides of the brain and result in a tonic-clonic seizure. A series of myoclonic seizures may become continuous and evolve into a tonic-clonic seizure. Generalized onset tonic-clonic seizures can occur alone or as part of another syndrome such as juvenile myoclonic epilepsy (JME) or juvenile absence epilepsy in adulthood.

[0743] The following examples are provided to illustrate certain embodiments of the present invention. They are not intended to limit the present invention in any way. Such modifications are intended to fall within the scope of the appended claims.

[0744] Example

[0745] Embodiment 1:

[0746] synthesis

[0747] Simple bioisosteric replacement of the 5-methyl hydrogen atom by a fluorine atom resulted in an increase in electronegativity. Optimization of the lipophilic properties of the enaminone intermediate building block ultimately led to an improvement in the overall drug-like properties of the target analog (7). (Scheme 1)

[0748]

[0749] Utilizing SimulationPlus® physicochemical property prediction tools MedChemDesigner and ADMET Predictor 10.0 during the drug design process has become an effective strategy used by medicinal chemists, with the most traditional predictor being Lipinski’s Rule of Five. The predicted values ​​are often indicators of the absorption, distribution, and bioactivity of potential drug molecules. The optimal LogP value for CNS drugs has a threshold of ~3, and the TPSA value for CNS drugs with the best penetration is less than 70Å. The new compound (7) has values ​​within these ranges. The predicted values ​​generated from the physicochemical property prediction tools further validate that our lead compound optimization is most beneficial for the development of potential anticonvulsant drugs.

[0750] The synthesis of diketones involves the condensation of a ketoester and a Michael acceptor, followed by ester hydrolysis and decarboxylation under acidic conditions. 31 This was carried out using tert-butyl ketoester (8c) instead of methyl and ethyl ketoesters with the same Michael acceptor ethyl 4,4,4-trifluorocrotonate (9). Following the Michael addition step, an intramolecular aldehyde condensation was carried out in the presence of a base. This intramolecular cyclization of the enolate anion proceeds via a Claisen condensation, and the use of 8c prevented the reverse Claisen reaction during the hydrolysis and decarboxylation steps. The reaction was refluxed in sodium tert-butoxide solution to afford the inorganic sodium enolate of 5-(trifluoromethyl)cyclohexane-1,3-dione (10) in high yield, as can be seen in Scheme 2.

[0751]

[0752] Reagents and conditions: a. NaOtBu, anhydrous tert-butyl alcohol, reflux for 2 h; b. H2O, HCl; c. 0.05N H2SO4, H2O, reflux for 1 h; d. ammonium acetate, acetic acid, benzene, dean stark trap, reflux for 1 h; e. (i) NaH, THF, reflux for 40-60 min; (ii) X = substituted acyl chloride, RT (~3 h)

[0753] The sodium enolate was acidified using concentrated hydrochloric acid to release the ester intermediate (4), which was subjected to acid-catalyzed hydrolysis and decarboxylation in 0.05N H2SO4 for two hours under reflux to provide the fluorodiketone (5) in high yield. (Scheme 2). The resulting diketone then underwent an amination reaction to afford the trifluoromethylated enaminone intermediate (6) in significantly high yield (Scheme 2). After the successful synthesis of the trifluoromethylated enaminone, an acylation reaction produced the bioisosteric analog of the lead compound THA40. The reaction was carried out in an N-acylation method, the first step being to generate the enaminone anion by refluxing in a mixture of anhydrous THF and sodium hydride (NaH) as a base, followed by N-acylation at room temperature.

[0754] Results and discussion

[0755] Friary's group identified the use of tert-butyl acetoacetate rather than ethyl or methyl acetoacetate as the Michael adduct of choice in the condensation reaction as a means of overcoming the retro-Claisen condensation. Previous reports highlighted the formation of unwanted ester byproducts when methoxide or ethoxide salts were used, but not when the stronger base tert-butyl alcohol was used as an alternative, due to the base being a poor nucleophile. The poor nucleophilicity of the tert-butyl group on both the chosen base (sodium tert-butoxide) and the Michael donor (8c) facilitated the rapid formation of the sodium enolate precipitate in 80% yield after two hours of reflux. We believe this is due to the tert-butyl diketoester (4) being less susceptible to nucleophilic attack by the alkoxide base, resulting in a more stable intermediate.

[0756] We focused on the extraction of organic esters (4) from inorganic sodium enolates by simply dissolving the inorganic salts in water and acidifying the aqueous mixture with concentrated hydrochloric acid, which resulted in the formation of the ester as a white precipitate, which was extracted in 73% yield. Next, the tert-butyl ester group was removed by simple hydrolysis followed by decarboxylation in dilute aqueous sulfuric acid. We were able to replicate this approach and obtain (5) as white crystals in 75% yield. The integrity of the cyclic product was preserved as confirmed by NMR and GCMS analysis. To investigate the novelty of our synthetic strategy, a SciFinder search was performed for the synthesis of 4-carboxy-tert-butoxy-5-trifluoromethylcyclohexane-1,3-dione (4) and N-(3-oxo-5-(trifluoromethyl)cyclohex-1-en-1-yl)-4-(trifluoromethane)benzamide (7). Results for compound (7) yielded no synthetic method. However, a search for compound (4) revealed a previous synthetic method reported by Jackson et al. with different reaction conditions and low yield. Therefore, to date, no other research group has attempted the method reported in this paper to release fluorodione esters. This ester intermediate has other applications, for example, it is used as a building block for the synthesis of other potential therapeutic agents in cases where an ester intermediate is required. In this work, we were able to utilize the ester intermediate as a building block for an improved and efficient synthesis of dione intermediates (5).

[0757] Baraldi et al. have determined that 1,3-diketones are converted to enaminones in significant yields. 9-12,14,32-35 We successfully transformed compound 5 into 6 by refluxing it in benzene using ammonium acetate as the amine source and azeotropic removal of water using a Dean-Stark trap. After recrystallization from benzene / MeOH, the enaminone 6 was formed in 95% yield.

[0758] A comparison of the reaction conditions used to derivatize the fluorinated intermediates is shown in Table 1.

[0759] Table 1: Table of drug-like properties

[0760]

[0761] a Molecular weight (<500 g / mol); b Morugichi LogP (<4.15); c The number of rotatable bonds (<10); d the number of hydrogen bond acceptors (<10 for O, N, and F atoms); e The number of hydrogen bond donors (OH and NH groups < 5); f Topological surface area (<70); g Number of violations; h Molar refractive index between 40-130

[0762] In addition to the formation of unwanted byproducts in the reaction, the yields of ketoesters (8a) and (8b) and their corresponding alkoxide bases were relatively low despite the long reaction times as summarized in Table 1. As shown in Table 1, switching to the less reactive and stronger base tert-butoxide improved the yields regardless of the starting ketoester and the length of the reaction time. Using (8c) as the starting material for the ketoester, we were able to produce the sodium enolate (10) in higher yields and successfully synthesized a new diketoester.

[0763] Table 2: Comparative Synthesis of Fluorinated Cyclohexanedione Intermediates

[0764]

[0765] The enaminone (6) was successfully transformed into the target analog (7) using 3 molar equivalents of sodium hydride base. One of the chemical properties of the enaminone system is a "push-pull system" of vinyl-spaced amides, thus resulting in poor nucleophilicity of the primary amine. As a result, a strong base such as NaH was used for the N-deprotonation step of the reaction. After N-deprotonation, N-acylation was carried out by adding 4-trifluoromethylbenzoyl chloride in a dropwise manner and the reaction was monitored by TLC and GCMS until there was a sign of completion of the reaction, followed by work-up to extract the final product in a good yield of 54.6%.

[0766] From this novel drug series, the target analog (7) was evaluated by ETSP in a preliminary identification of anticonvulsant screening assays. Compared to the lead compound THA40, the CF3 bioisosteric analog (7) was less effective in protecting against seizures in an acute seizure rodent model. However, as previously reported, a moderate dose of 150 mg / kg of THA40 was able to elicit a pharmacological response and suppress seizures in the 6 Hz 44 mA animal model. Compared to the lead compound THA40, this new analog produced a pharmacological response at a higher dose of 300 mg / kg, and only 25% protection was observed. Interestingly, while THA40 showed no activity in the maximum electric shock (MES) model, which is the gold standard for screening anticonvulsant activity, compound 7 showed moderate activity at 100 mg / kg, with 25% after 2 h. At a higher dose of 300 mg / kg, 25% of the animals were protected at both 0.5 h and 2 h.

[0767] Chemical

[0768] All chemicals and reagents were purchased from Sigma Aldrich, USA and used without further purification. NMR spectra were recorded on a Bruker Advance series instrument (400 MHz) at room temperature. GC-MS analysis was performed on a Shimadzu QP-2010SE instrument. Melting point analysis was performed on a ThermoFisher IA9000 series digital melting point instrument. Elemental analysis was outsourced to Micro-Analysis Inc., Wilmington DE.

[0769] Synthesis of 4-carboxy-tert-butoxy-5-trifluoromethylcyclohexane-1,3-dione sodium (10)

[0770] To a freshly prepared sodium tert-butoxide solution (prepared from anhydrous tert-butanol and sodium metal (67 mmol) in mineral oil) was added tert-butyl acetoacetate (67 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 15 min. A solution of ethyl 4,4,4-trifluorocrotonate (67 mmol) in tert-butanol was added dropwise to the reaction mixture. The mixture was warmed to room temperature and stirred for another 30 min. The reaction mixture was refluxed for 2 h, where the formation of a white solid precipitate was observed. The product was collected by vacuum filtration and washed with anhydrous hexane to afford 16.5 g (80%) of (10) as a white powder, which was dried for the next step, i.e., acidification of the salt.

[0771] Synthesis of 4-carboxy-tert-butoxy-5-trifluoromethylcyclohexane-1, 3-dione (4)

[0772] The inorganic salt (16 g) was dissolved in 87 ml of water, filtered to remove impurities, and acidified with 8.7 ml of hydrochloric acid. The resulting white precipitate was washed with water and air-dried to give 73% of 4-carboxy-tert-butoxy-5-trifluoromethyl-cyclohexane-1,3-dione (9): MP. 135-136.2°C (literature value 133-137°C) 12 );¹H NMR (400 MHz, DMSO): d, ppm 11.80 (1H, s), 5.32 (1H, s), 3.43 (2H, d, J = 25.7 Hz), 2.61 (2H, d, J = 17.1 Hz),1.38 (9H, s); Anal. Calcd. for C12H15F3O4: C, 51.43; H, 5.40; F, 20.34; Found: C, 51.48; H, 5.33; F, 20.26. The sample was dried for the next step, i.e., hydrolysis and decarboxylation of the ester, to afford the target compound.

[0773] Synthesis of 5-(trifluoromethyl)cyclohexane-1,3-dione (5)

[0774] To 300 ml of stirred and boiling 0.05N sulfuric acid, 15 g of tert-butyl ester were added in small portions over a period of 40 min. Slow addition was necessary to avoid loss of material due to excessive formation of CO2 gas. The mixture was refluxed for 60 min and allowed to cool to room temperature. After cooling to room temperature, the reaction mixture was stored at 4°C overnight to give white crystals, which were collected by vacuum filtration. The crude sample was recrystallized from ethyl acetate to give 75% of 5-trifluoromethylcyclohexane-1,3-dione as white long needle-like crystals. MP. 140.4-142.2°C (literature value 140-142°C 10 ); ¹H NMR (400 MHz, DMSO): d, ppm 11.49 - 11.45 (1H, m), 5.27 (1H, s), 3.22 - 3.09 (1H, m), 2.43 -2.38 (4H, m); Anal. Calcd. for C7H7F3O: C, 46.68; H, 3.92; F, 31.64; Found: C, 46.62; H, 3.87; F, 31.52.

[0775] Synthesis of 3-amino-5-(trifluoromethyl)cyclohex-2-en-1-one (6)

[0776] To a 250 ml two-necked round bottom flask equipped with a condenser, Dean-Stark trap and magnetic stirrer was added 100 ml of anhydrous benzene under nitrogen. The reaction flask was cooled to 0 °C and then 5-trifluoromethylcyclohexane-1, 3-dione (4) (12 g, 67 mmol) and ammonium acetate (10.329 g, 134 mmol) were added. After stirring for 10 min, 5 ml of acetic acid was added dropwise and the reaction mixture was warmed to room temperature and allowed to stir for 30 min. The mixture was refluxed for 1 h and allowed to stir overnight at room temperature after cooling. The crude product precipitated as a light yellow solid which was collected by vacuum filtration and allowed to air dry. After drying, the crude product was recrystallized from benzene / MeOH to give the title compound at 95%. MP. 168.5-169.6 °C (literature value 160-162 °C 10 ). ¹H NMR (400 MHz, DMSO): d, ppm 6.97 (2H, d, J = 89.8 Hz), 4.98 (1H, s),3.02 (1H, s), 2.47 - 2.38 (2H, m), 2.16 (1H, d, J = 10.2 Hz), 1.87 (1H, s); Anal. Calcd. for C7H8F3NO: C, 46.93; H, 4.50; N, 7.82; F, 31.82; Found: C, 45.78; H,4.70; N, 7.74; F, 31.82.

[0777] Synthesis of N-(3-oxo-5-(trifluoromethyl)cyclohex-1-en-1-yl)-4(trifluoro-methyl)-benzamide (7)

[0778] To a 250 ml two-necked round-bottom flask equipped with a condenser and a magnetic stirrer was added 40 mL of anhydrous tetrahydrofuran (THF) under nitrogen. After cooling on an ice bath, sodium hydride (402 mg, 25.2 mmol) was slowly added, followed by an additional 20 mL of anhydrous THF. 3-amino-5-(trifluoromethyl)cyclohex-2-en-1-one (1.5 g, 8.7 mmol) was slowly added over the course of 5 min, followed by 10 mL of anhydrous THF. The reaction mixture was allowed to reflux for 40 min. After cooling to room temperature, the mixture was placed on an ice bath for 5 min, and then 15 mL of substituted benzoyl chloride (1.24 mL, 8.7 mmol) in anhydrous THF was added via a dropping funnel. The dropping funnel was rinsed with an additional 10 mL of anhydrous THF. The reaction mixture was stirred in an ice bath for about 10 min. Before the reaction mixture was removed from the ice bath, the first aliquot was removed and analyzed. The reaction mixture was stirred at room temperature and monitored by TLC and GCMS until completion. After confirming the reaction was complete, the reaction mixture was quenched with 80 mL of deionized (DI) water and acidified with 8 mL of concentrated HCl. The aqueous solution was extracted with dichloromethane (2 x 75 mL) and the organic layer was washed with 75 mL of 10% NaHCO3 and 75 mL of DI water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid residue, which was triturated with anhydrous ether. The product was collected by vacuum filtration to give the title compound as a white powder in 54.7% yield (1.609 g). MP 206.8 – 208 °C. 1H-NMR (400 MHz, DMSO) d 10.37(s, 1H), 8.13 - 8.09 (m, 2H), 7.93 - 7.89 (m, 2H), 6.88 (d, 1H, J = 1.4 Hz),3.00 (dd, 1H, J = 4.6, 17.3 Hz), 2.81 - 2.72 (m, 1H). Anal. Calcd. for C15H11F6NO2: C, 51.29; H, 3.16; N, 3.99; F, 32.45; Found: C, 51.15; H, 3.15; N, 3.85; F, 32.30.

[0779] General Synthesis of N-(5-methyl-3-oxocyclohex-1-en-1-yl)-3-((trifluoromethyl)thio)benzamide

[0780]

[0781] Synthesis of 3-((trifluoromethyl)thio)benzoyl chloride: The reaction is carried out under an inert N2 atmosphere. Anhydrous toluene is used as the reaction environment. It is expected that water will be produced in the reaction, so any anhydrous byproducts are removed by azeotropic conditions. The reaction mixture will contain 3-(trifluoromethylthio)benzoic acid, dimethylformamide, and thionyl chloride. Thionyl chloride is slowly added dropwise to the reaction. The reaction is heated and refluxed for approximately 5 hours. The completion of the reaction is monitored by TLC and GC-MS techniques. Acylation reaction using 3-((trifluoromethyl)thio)benzoyl chloride is performed using methods known in the chemical art to provide the target N-benzamide enaminone analog.

[0782] Synthesis of Pyridine Analogs of the Invention. This general method can be extended to the synthesis of pyridine derivatives of the compounds of the invention. The starting material for the synthesis is an acyl chloride. Similar one-pot acylation reactions can be used to prepare these compounds, and the above synthesis can be modified using known techniques.

[0783] Pharmacology

[0784] Preliminary evaluation of anticonvulsant activity was completed by the Epilepsy Therapeutics Screening Program Branch of the National Institute of Neurological Disorders and Stroke. The first phase of evaluation included three tests: maximum electric shock (MES), 6 Hz, and rotarod tests of neurotoxicity (Tox). The studies were conducted in normal adult male Carworth Farms No. 1 (CF1) mice, using four or more mice for each test. Test compounds were administered intraperitoneally (ip) as a suspension in 0.5% methylcellulose. The compounds were tested at doses ranging from 30 mg / kg to 300 mg / kg. Animals were pretreated with test compounds at intervals of 0.5 h and 2 h. Rotarod neurotoxicity testing was completed at each dose and time point. The MES test is a high-frequency (60 Hz), short-duration (0.3 s) stimulus delivered through corneal electrodes in normal rodents, while the 6 Hz 44 mA psychomotor test has a long duration (3 s) and low frequency (6 Hz). Compounds that are active in the MES Identification Phase test are screened for their ability to block induced seizures in the 6 Hz psychomotor focal seizure animal model. Compounds that are effective in the 6-Hz model during the Identification Phase become candidates for advanced screening in the Differentiation Phase.

[0785] Example 2

[0786] The PTZ seizure model can be used to evaluate the novel N-benzamide enaminone compounds of the present invention.

[0787] In vivo target validation studies using the pentylenetetrazol (PTZ) zebrafish model

[0788] Mussulini et al. previously described a pentylenetetrazol (PTZ) seizure model using adult zebrafish. See Mussulini, BH M et al., Seizures induced by pentylenetetrazole in the adult zebrafish: a detailed behavioral characterization, PloS one 2013, 8 (1), e54515-e54515. The PTZ seizure model can be used to validate the compounds of the present invention using the following general method:

[0789] The test zebrafish are immersed in various concentrations of PTZ (e.g., 2.5 mM-7.5 mM). Behavioral activity is monitored, for example, using video recording software, over a 20-minute test period and compared to a control group (no PTZ exposure). See Cachat et al., Measuring behavioral and endocrine responses to novelty stress in adult zebrafish, Nature Protocols 2010, 5 (11), 1786-1799.

[0790] The software was used to equally divide the observation area into virtual lower and upper zones and determine the following endpoints as the fish moved; a) distance traveled (cm); b) average speed (cm / s); c) time spent in the upper zone of the observation tank; and d) time spent in the lower zone.

[0791] Example 3

[0792] PGP assay analysis

[0793] The PGP-Glo™ assay detects the effects of compounds on recombinant human Pgp in the cell membrane fraction. See Amaye et al., Int. J. Environ. Res. Public Health 2018, 15, 1784. The assay relies on the ATP dependence of the light-generating reaction of firefly luciferase. ATP is first incubated with Pgp; the Pgp ATPase reaction is then stopped, and the remaining unmetabolized ATP is detected as a luminescent signal generated by the luciferase.

[0794] The PGP-dependent decrease in luminescence reflects the consumption of ATP by PGP; thus the greater the decrease in signal, the higher the Pgp activity. Thus, samples containing compounds that stimulate the Pgp ATPase will have significantly lower signals than untreated samples.

[0795] This assay system is valuable for screening drugs and new chemical entities for their ability to modulate P-glycoprotein ATPase activity. Figure 6 and Table 1.

[0796]

[0797] Table 1: Chemical properties of fluoro-substituted N-benzamide enaminones

[0798]

[0799] It is to be understood that the words used are words of description rather than limitation and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the invention in its broader aspects.

[0800] Although the present invention has been described with some detail and specificity with respect to several described embodiments, it is not intended that it should be limited to any such details or embodiments or to any particular embodiment, but rather should be interpreted with reference to the appended claims so that such claims are interpreted as broadly as possible in light of the prior art to effectively cover the intended scope of the present invention.

[0801] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification (including definitions) will control. In addition, section headings, materials, methods, and examples are for illustrative purposes only and are not intended to be limiting.

Claims

1. A compound of formula (II): or a pharmaceutically acceptable salt thereof, in R1 is -H, -OH, -CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy or substituted or unsubstituted alkoxy; Each of R2, R3, R4 or R5 is independently selected from -H, -OH, -CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, OCF3, SCF3, NO2 or substituted or unsubstituted alkoxy; R6, R7, R8, R9, R 10 or R 11 Each of which is independently selected from -H, -OH, -CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy or substituted or unsubstituted alkoxy; R 12 is -H or substituted or unsubstituted alkyl; X is O, S or -NR 13 ;and R 13 are independently selected from -H or substituted or unsubstituted alkyl, wherein at least one of R1-R5 is -F, a substituted alkyl group containing one or more -F groups, or a substituted alkoxy group containing one or more -F groups, and Among them R7-R 12 is -F, a substituted alkyl group containing one or more -F groups, or a substituted alkoxy group containing one or more -F groups, and Among them, R3 and R8 / R9 are different.

2. A compound of formula (III): Formula III in R1 is halogen or alkyl substituted by 1 to 3 halogen groups; R2 is hydrogen or C1-C3 alkyl; R3 is hydroxy, halogen, cyano, amino, nitro, unsubstituted alkyl or alkyl substituted by 1 to 3 halogen groups; or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof.

3. The compound according to claim 2, wherein R1 is halogen.

4. The compound according to claim 3, wherein the halogen is F or Cl. The compound according to claim 3 , wherein the halogen is F.

6. The compound according to claim 2, wherein R1 is halogen, and R3 is a substituted alkyl group having 1 to 3 halogen groups. The compound according to claim 6 , wherein the substituted alkyl group is substituted with 1 halogen group.

8. The compound according to claim 6, wherein the substituted alkyl group is substituted with 2 halogen groups.

9. The compound according to claim 6, wherein the substituted alkyl group is substituted with 3 halogen groups.

10. The compound of claim 2, wherein R1 is -F, and R3 is an alkyl group substituted with 1 to 3 halogen groups.

11. The compound of claim 2, wherein R1 is -F and R3 is -CF3.

12. The compound of claim 2, wherein R2 is H.

13. The compound of claim 2, wherein R2 is -CH3.

14. The compound of claim 2, wherein R1 is -F, R2 is -H, and R3 is -CF3.

15. The compound of claim 2, wherein R3 is at position b.

16. The compound of claim 2, wherein R1 is halogen, R3 is CF3, and R3 is at position b.

17. The compound according to claim 2, wherein the compound has the following structure. 。 18. A pharmaceutical composition comprising the compound according to claim 2 and a pharmaceutically acceptable carrier or excipient.

19. A pharmaceutical composition comprising the compound according to claim 17 and a pharmaceutically acceptable carrier or excipient.

20. A method of reducing the occurrence or severity of epileptic seizures in a subject, the method comprising administering to a subject in need thereof a pharmaceutical composition according to claim 18.

21. A method of treating a subject at risk for an epileptic seizure, the method comprising administering to a subject in need thereof a pharmaceutical composition according to claim 18.

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