WO2025217596A1

WO2025217596A1 - Substituted 2,3-dihydro-4h-benzo[e][ 1,3] oxazin-4-one compounds and methods of use thereof

Info

Publication number: WO2025217596A1
Application number: PCT/US2025/024395
Authority: WO
Inventors: Eileen CARRY; Jacques Y. Roberge; Anastasiia Tsymbal; Ariane VASILATIS
Original assignee: Rutgers State University of New Jersey
Current assignee: Rutgers State University of New Jersey
Priority date: 2024-04-11
Filing date: 2025-04-11
Publication date: 2025-10-16
Anticipated expiration: 2026-10-11

Abstract

The disclosure provides certain GABA_AR positive modulator compounds of Formula (I) and methods of use thereof for treating, ameliorating, and/or preventing anxiety, opiate-related disorder(s), alcohol-related disorder(s), benzodiazepine-related disorder(s), seizure or seizure disorder(s), and/or pain. In another aspect, the compounds of the disclosure are suitable for sedating a subject.

Description

TITLE OF THE INVENTION

Substituted 2.3-Dihydro-4//-Benzo|c|| 1.3 |Oxazin-4-one Compounds and

Methods of Use Thereof

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant No. R43 DA058472 awarded by the National Institutes of Health. The government has certain rights in the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/632,655, filed April 11, 2024, which is incorporated herein by reference in its entirety.

BACKGROUND

Benzodiazepines (BZDs) are a class of y-aminobutyric acid A receptor (GABAAR) positive allosteric modulators. They are the most commonly prescribed acute anxiolytic agent, with an estimated 5.2% of the population having one or more active BZD prescription. While BZDs are highly effective in the short-term and safe if taken as prescribed, BZDs are highly addictive and commonly misused. A major risk of BZDs misuse is their synergistic and respiratory' depressants effects when combined with other central nervous system (CNS) depressants. Thus, while GABAAR positive modulators have demonstrated significant utility' and efficacy as acute anxiolytics, their potential toxicity if combined with opiates and/or ethanol limits their use, as they can lead to expensive hospital stays and overdose fatalities. The high incidents of overdoses involving BZD co-use led the FDA to release a black box warning in 2016 about risks of using such drugs.

Thus, there is a need in the art for safe and effective GABAAR positive modulators that do not pose potentially fatal risks of respiratory depression if misused. The present disclosure addresses this need.

BRIEF SUMMARY

In one aspect, the disclosure provides a compound of formula (I), or a salt, stereoisomer, tautomer, or isotopologue thereof, wherein R^la, R^lb, R^lc, R^ld, R², R³, and A are defined elsewhere herein.

In certain embodiments, the compound of formula (I) is a compound of formula (la): certain embodiments, the compound of formula (I) is a compound of formula ( certain embodiments, the compound of formula (I) is a compound of formula ( certain embodiments, the compound of formula (I) is a compound of formula (Id): compound of formula ( certain embodiments, the compound of formula (I) is a compound of formula certain embodiments, the compound of formula (I) is a compound of formula (Ig): certain embodiments, the compound of formula (I) is a compound of formula (

In another aspect, the compound of the disclosure is selected from the group consisting of 7-bromo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one, 6-chloro-2- (m-nitrophenyl)-2.3-dihydro-4H-l,3-benzoxazin-4-one. 6-iodo-2-(m-nitrophenyl)-2.3- dihydro-4H-l,3-benzoxazin-4-one, m-(6-bromo-4-oxo-2,3-dihydro-4H-l,3-benzoxazin-2- yl)benzonitrile, 6-bromo-2-(o-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one, 6-bromo- 2-(m-chlorophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one, 6-bromo-2-(m-fluorophenyl)-2,3- dihydro-4H-l,3-benzoxazin-4-one, 6-bromo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3- benzoxazin-4-one, or a salt, stereoisomer, tautomer, or isotopologue thereof.

In one aspect, the disclosure provides a method for treating, ameliorating, and/or preventing anxiety in a subject. In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing an opiate-related disorder in a subject. In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing an alcohol-related disorder in a subject. In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing a benzodiazepine-related disorder in a subject. In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing a seizure or seizure disorder in a subject. In another aspect, the disclosure provides a method for treating, ameliorating, or preventing pain in a subject. In another aspect, the disclosure provides a method for sedating a subject. In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

BRIEF DESCRIPTION OF THE FIGURES

The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application.

FIGs. 1A-1D: Open arms activity in mice following administration of compound EC2-118 assed using an open field test to evaluate anxiolytic-like behavior, wherein each scatter plot illustrates behavior measures in the open arms of the test arena at either 0.5 hours (FIGs. 1A-1B) or 1 hour (FIGs. 1C-1D). Mice were administered vehicle control, 8 mg/kg EC2-118, or 25 mg/kg EC2-118. FIG. 1A: number of entries into the open arms recorded 0.5 hours after administration. FIG. IB: time spent (in seconds) in the open arms 0.5 hours after administration. FIG. 1C: number of entries into the open arms recorded 1 hour after administration. FIG. ID: time spent (in seconds) in the open arms 1 hour after administration.

FIG. 2A: Breaths per minute (BPM) and minute ventilation (MVb) following oral alprazolam (77 mg/kg) or Ztx-001 (EC2-118) (25 mg/kg). Dotted line indicates oral gavage. ** indicates p < 0.005 from vehicle and Ztx-001. FIG. 2B: Respiratory' effects of fentanyl (0.25 m/kg IP), alprazolam (Img/kg IP). Ztx-001 (EC2-118) (25 mg/kg), fentanyl (0.25 mg/kg) + alprazolam (1 mg/kg), and fentanyl (0.25 mg/kg) + Ztx-001 (25 mg/kg IP).

FIG. 3: Effect of EC2-118 on breathing rate. Data represent mean ± SEM; ns = not significant compared to vehicle - saline; **p<0.01, **** p<0.0001 compared to fentanyl (0.25 mg/kg) - saline. Gorup size: n=20 gender balanced.

FIG. 4: Time course of impact on breathing rate.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "about 0. 1% to about 5%" or "about 0.1% to 5%" should be interpreted to include notjust about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g.. 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement "about X to Y" has the same meaning as "about X to about Y," unless indicated otherwise. Likewise, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z," unless indicated otherwise.

In this document, the terms "a." "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B." In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

Definitions

The term "about" as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term "substantially free of as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free of can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

The term "organic group" as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester: a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)₂, SR, SOR, SO2R, SO₂N(R)₂, SO3R, C(O)R, C(O)C(O)R, C(O)CH₂C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)₂, OC(O)N(R)₂, C(S)N(R)₂, (CH₂)O- ₂N(R)C(O)R, (CH₂)O-2N(R)N(R)₂, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)₂, N(R)SO₂R. N(R)SO₂N(R)₂, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)₂. N(R)C(S)N(R)₂, N(COR)COR, N(OR)R, C(=NH)N(R)₂, C(O)N(OR)R, and/or C(=NOR)R, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted.

The term "substituted" as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term "functional group" or "substituent" as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g.. F. Cl. Br. and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)₂, CN, NO, NO₂, ONO₂, azido, CF3, OCF3. R, O (oxo), S (thiono). C(O), S(O), methylenedioxy, ethylenedioxy, N(R)₂, SR, SOR, SO₂R, SO₂N(R)₂, SO3R, C(O)R, C(O)C(O)R, C(O)CH₂C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)₂, OC(O)N(R)₂, C(S)N(R)₂, (CH₂)O- ₂N(R)C(O)R, (CH₂)O.₂N(R)N(R)₂, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)₂, N(R)SO₂R. N(R)SO₂N(R)₂, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)₂, N(R)C(S)N(R)₂, N(COR)COR, N(OR)R, C(=NH)N(R)₂, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaryl alkyl: or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl.

The term "alkyl" as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or. in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-buty l, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl.

Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH₃)2, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃), -C(CH₂CH₃)=CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

The term "alkynyl" as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms. 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to - C=CH. -C=C(CH₃). -C =C(CH2CH₃). -CH2OCH, -CH₂OC(CH₃), and -CH₂C^C(CH₂CH₃) among others.

The term "acyl" as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or is bonded to another carbon atom, which can be part of an alky l, aryl, aralky l cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acry loyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.

The term "cycloalkyl" as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloocty l groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4. 5. 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbomyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.

The term "halocycloalkyl" as used herein refers to a cycloalkyl group that has one or more C-H bonds replaced by C-X bond, where X is a F, Cl, Br, or I atom. When all such hydrogen atoms are replaced by a halogen, the halocycloalkyl is a perhalogenated halocycloalkyl. For example, and without limitation, a perfluorinated cycloalkyl. Mixed halogen (more than one time of halogen atom) halocycloakyls are also contemplated.

The term "heterocycloalkyl" as used herein refers to a cycloalkyl group in which one or more of the carbon atoms are replaced by a heteroatom such as, B, O, N. S, or P, as well as stable oxides of these heteroatoms. Heterocycloalkyl groups can also contain one or more degrees of unsaturation, such as carbon-carbon double bonds or carbon-heteroatom double bonds. Heterocycloalkyl groups can be optionally substituted by one or more of any of the substituents described herein.

The term "aryl" as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to. phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, ary l groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof.

The term "aralkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an ar l group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. The term heterocyclyl includes rings where a CH2 group in the ring is replaced by one or more C=O groups, such as found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing a C=O group include, but are not limited to, - propiolactam, y-butyrolactam, 5-valerolactam, and 8-caprolactam, as well as the corresponding lactones. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with tw o heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl. azaindolyl. indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl. isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein.

The term "heteroaryl" as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to. N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring designated Cx-_y can be any ring containing 'x' members up to 'y' members, including all intermediate integers between 'x' and 'y ' and that contains one or more heteroatoms, as defined herein. In a ring designated Cx-_y, all non-heteroatom members are carbon. Heterocyclyl rings designated Cx-_y can also be polycyclic ring systems, such as bicyclic or tricyclic ring systems. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl. pyrazolyl, triazolyl, tetrazolyl. oxazolyl, isoxazolyl. thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl. isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein.

Additional examples of ary l and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl. N- hydroxytriazolyl, N-hydroxyimidazolyl. anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2 -thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl. l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2 -thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl. 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1 -isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b] furanyl, 5-benzo[b]furanyl. 6-benzo[b] furanyl. 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2.3- dihydro-benzo[b] furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),

6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl). 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,

3-indolyl, 4-indolyl, 5-indolyl. 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl,

4-indazolyl, 5-indazolyl. 6-indazolyl, 7-indazolyl), benzimidazolyl (1 -benzimidazolyl.

2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1 -benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5 -benzothiazolyl, 6-benzothiazolyl,

7-benzothiazolyl), carbazolyl ( 1 -carbazolyl. 2-carbazolyl. 3-carbazolyl. 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f| azepin- 1 -yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f|azepine-3-yl, 5H-dibenz[b,f|azepine-4-yl, 5H-dibenz[b,f|azepine-5-yl),

10,1 l-dihydro-5H-dibenz[b,f| azepine (10,1 l-dihydro-5H-dibenz[b,f|azepine-l-yl,

10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f|azepine-3-yl.

10,1 l-dihydro-5H-dibenz[b,f|azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f|azepine-5-yl), and the like.

The term "heterocyclylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

The term "heteroarylalkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein. The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopenty loxy, isohexyloxy, and the like. Examples of cy clic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedi oxy group in a context where two adjacent atoms of a structure are substituted therewith.

The term "amine" as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)s wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and RsN wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

The term "amino group" as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3 . wherein each R is independently selected, and protonated forms of each, except for -NR? . which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes a monoalkydamino, dialkylamino, and trialkylamino group.

The terms "halo," "halogen," or "halide" group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

The term "haloalkyl" group, as used herein, includes mono-halo alkyl groups, polyhalo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyd groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl. 1,1 -dichloroethyl, 1.2-di chloroethyl, l,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. The term "solvent" as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

The term "independently selected from" as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase "X¹, X², and X³ are independently selected from noble gases" would include the scenario where, for example, X¹, X², and X³ are all the same, where X¹, X², and X³ are all different, where X¹ and X² are the same but X³ is different, and other analogous permutations.

The term "room temperature" as used herein refers to a temperature of about 15-28 °C.

The term "standard temperature and pressure" as used herein refers to 20 °C and 101 kPa.

As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary' and topical administration.

A "disease" is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.

In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

As used herein, the terms "effective amount," "pharmaceutically effective amount" and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the term "efficacy" refers to the maximal effect (Emax) achieved within an assay. As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, z.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in w hich it is contained.

As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic. heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic. sulfanilic, cyclohexylaminosulfonic, stearic, alginic, P-hy dr oxy butyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein w ithin or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed.. Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

The terms "patient," "subject," or "individual" are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

As used herein, the term "potency" refers to the dose needed to produce half the maximal response (ED50).

A "therapeutic" treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, i.e., a compound or compounds as described herein (alone or in combination w ith another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, or the symptoms of a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

Compounds

In one aspect, the disclosure provides a compound of formula (I), or a salt, stereoisomer, tautomer, or isotopologue thereof: wherein:

R^la. R^lb, R^lc. and R^ld are each independently selected from the group consisting of H, R, F, Cl, Br, I, OR, CN, NO₂, N(R)₂, SR, S(=O)R, SF₃, SFs, S(=O)₂R, S(=O)₂N(R)₂, P(=O)(OR)₂, C( O)R. C( O)OR. C(=O)N(R)₂, OC(=O)R, and OC(=O)N(R)₂;

R² is selected from the group consisting of H and optionally substituted C1-C6 alkyl;

R³ is selected from the group consisting of H and optionally substituted Ci-Cs alkyl;

A is selected from the group consisting of:

X¹ is CR^4C or N, X¹ is CR^4d or N, and X² is CR^4e or N, wherein one of X¹, X², and X³ is N;

R^4a. R^4b, R^4C, R^4d, and R^4e, if present, are each independently selected from the group consisting of R, F, Cl, Br, I, OR. CN, NO₂, N(R)₂, SR, S(=O)R. SF3, SF₅, S(=O)₂R, S(=O)₂N(R)₂, P(=O)(OR)₂, C(=O)R, C(=O)OR, C(=O)N(R)₂, OC(=O)R, and OC(=O)N(R)₂;

R⁵ is selected from the group consisting of H and optionally substituted Ci-Ce alkyl;

R^6a and R^6b are each independently selected from the group consisting of H, F, Cl, Br, I. OR, and optionally substituted Ci-Cs alkyl; and each occurrence of R is independently selected from the group consisting of hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3- Cs cycloalkenyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C2-C10 heteroaryl.

In certain embodiments, R^la is H. In certain embodiments, R^lb is H. In certain embodiments, R^lc is H. In certain embodiments. R^ld is H. In certain embodiments, R^la is halogen. In certain embodiments, R^lb is halogen. In certain embodiments, R^lc is halogen. In certain embodiments, R^ld is halogen. In certain embodiments, R^la is Ci-Ce alkyl. In certain embodiments, R^lb is Ci-Ce alkyl. In certain embodiments, R^lc is Ci-Ce alkyl. In certain embodiments, R^ld is Ci-Ce alkyl. In certain embodiments, R^,a is F. In certain embodiments, R^lb is F. In certain embodiments, R^lc is F. In certain embodiments, R^ld is F. In certain embodiments, R^la is Cl. In certain embodiments, R^lb is Cl. In certain embodiments, R^lc is Cl. In certain embodiments, R^ld is Cl. In certain embodiments, R^la is Br. In certain embodiments, R^lb is Br. In certain embodiments, R^lc is Br. In certain embodiments, R^ld is Br. In certain embodiments, R^la is zPr. In certain embodiments, R^lb is zPr. In certain embodiments, R^lc is zPr. In certain embodiments, R^ld is zPr. In certain embodiments, R^la is CF3. In certain embodiments, R^lb is CFs. In certain embodiments, R^lc is CF3. In certain embodiments, R^ld is CF3.

In certain embodiments, three of R^la, R^lb, R^lc, and R^ld are H, and one of R^la, R^lb. R^lc, and R^ld is a halogen.

In certain embodiments, R² is H. In certain embodiments, R² is CH3.

In certain embodiments, R³ is H.

In certain embodiments, R^4a is H. In certain embodiments, R^4a is CH3. In certain embodiments, R^4a is CH2CH3. In certain embodiments, R^4a is CF3. In certain embodiments, R^4a is F. In certain embodiments, R^4a is Cl. In certain embodiments, R^4a is Br. In certain embodiments, R^4a is OH. In certain embodiments, R^4a is OCH3. In certain embodiments, R^4a is OCF3. In certain embodiments, R^4a is CN. In certain embodiments, R^4a is NO2. In certain embodiments, R^4a is S(=O)2CH3. In certain embodiments. R^4b is H. In certain embodiments, R^4b is CH3. In certain embodiments. R^4b is CH2CH3. In certain embodiments. R^4b is CF3. In certain embodiments, R^4b is F. In certain embodiments, R^4b is Cl. In certain embodiments, R^4b is Br. In certain embodiments, R^4b is OH. In certain embodiments, R^4b is OCHs. In certain embodiments, R^4b is OCF3. In certain embodiments, R⁴¹’ is CN. In certain embodiments, R^4b is NO2. In certain embodiments. R^4b is S(=O)2CH3. In certain embodiments, R^4c is H. In certain embodiments, R^4c is CH3. In certain embodiments, R^4c is CH2CH3. In certain embodiments, R^4c is CF3. In certain embodiments, R^4c is F. In certain embodiments, R^4c is Cl. In certain embodiments, R^4c is Br. In certain embodiments, R^4c is OH. In certain embodiments, R^4c is OCH3. In certain embodiments, R^4c is OCF3. In certain embodiments, R^4C is CN. In certain embodiments, R^4c is NO2. In certain embodiments, R^4c is S(=O)2CH3. In certain embodiments, R^4d is H. In certain embodiments, R^4d is CH3. In certain embodiments, R^4d is CH2CH3. In certain embodiments. R^4d is CF3. In certain embodiments, R^4d is F. In certain embodiments, R^4d is Cl. In certain embodiments, R^4d is Br. In certain embodiments, R^4d is OH. In certain embodiments, R^4d is OCH3. In certain embodiments, R^4d is OCF3. In certain embodiments, R^4d is CN. In certain embodiments, R^4d is NO2. In certain embodiments, R^4d is S(=O)2CH3. In certain embodiments, R^4e is H. In certain embodiments, R^4e is CH3. In certain embodiments, R^4e is CH2CH3. In certain embodiments. R^4e is CF3. In certain embodiments, R^4e is F. In certain embodiments, R^4e is Cl. In certain embodiments, R^4e is Br. In certain embodiments, R^4e is OH. In certain embodiments, R^4e is OCHs. In certain embodiments, R^4e is OCF3. In certain embodiments, R^4e is CN. In certain embodiments, R^4e is NO2. In certain embodiments, R^4e is S(=O)2CH3.

In certain embodiments, R³ is H. In certain embodiments, R³ is CH3. In certain embodiments, R^6a is H. In certain embodiments, R^6b is H. In certain embodiments, the compound of formula (I) is a compound of formula (la):

In certain embodiments, the compound of formula (I) is a compound of formula (Ic):

In certain embodiments, the compound of formula (I) is a compound of formula (Id): ents, the compound of formula (I) is a compound of formula (le):

In certain embodiments, the compound of formula (I) is a compound of formula (If) :

In certain embodiments, the compound of formula (I) is a compound of formula (Ih):

In certain embodiments, R^lb is Br.

In certain embodiments, R^4a is CH3. In certain embodiments, R^4b is CH3. In certain embodiments, R^4b is F. In certain embodiments, R^4b is Br. In certain embodiments, R^4c is F. In certain embodiments, R^4c is Cl. In certain embodiments, R^4c is CH2CH3. In certain embodiments, R^4d is F. In certain embodiments. R^4d is CH3.

In certain embodiments, A is . In certain embodiments, A is In certain embodiments, A is . In certain embodiments, A is F . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, . In certain embodiments, A is

In certain embodiments, the compound of the disclosure is a compound of formula (I). In certain embodiments, the compound of the disclosure is selected from the group consisting of:

6-bromo-2-(5-bromo-2-fluoro-3-pyridyl)-2,3-dihydro-4H-l ,3-benzoxazin-4-one;

6-bromo-2-(5-fluoro-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one hydrogen chloride;

6-bromo-2-(6-fluoro-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(5-bromo-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(5-methyl-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(4-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(5-chloro-4,6-difluoro-2-pyridyl)-2,3-dihydro-4H-1.3-benzoxazin-4-one;

6-bromo-2-(5-ethyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(3-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(6-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; and

6-bromo-2-methyl-2-(2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one.

In another aspect, the compound of the disclosure is selected from the group consisting of:

7-bromo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-chloro-2-(m-nitrophenyl)-2,3-dihydro-4H-1.3-benzoxazin-4-one;

6-iodo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; m-(6-bromo-4-oxo-2,3-dihydro-4H-1.3-benzoxazin-2-yl)benzonitrile;

6-bromo-2-(o-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(m-chlorophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; 6-bromo-2-(m-fluorophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; and

6-bromo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; or a salt, stereoisomer, tautomer, or isotopologue thereof. Table 1. Exemplary compounds of the disclosure

Table 2. Exemplary characterization data for certain compounds of the disclosure

In one aspect, the disclosure relates to partial GABAAR modulators. Without wishing to be limited by any theory⁷, in certain embodiments, the compounds of the disclosure are allosteric modulators which bind outside of the typical binding site for benzodiazepines (BZDs). Electrophysiology⁷ studies in Xenopus Oocytes expressing a2p3/2 GABAARs with and without flumazenil, a known BZD competitive binder, reveals the absence of the compounds of the present disclosure binding at typical BZD binding site. In certain embodiments, the compounds of the disclosure, which may' represent flavonoid derivatives, the chemical structures of which appear in Table 1, include functional activity⁷ as per electrophysiology studies expressing a2p2y2L GABAA receptor subtype expressed in Xenopus Oocytes.

The disclosure provides an exemplary synthetic method for the preparation of certain compounds of the disclosure, including compounds of formula (1-3), wherein Z¹ is CR^4c or N, Z² is CR^4e or N, Z^? is CR^4e or N, and R^la, R^lb, R^1c, R^ld, R^4a, R^4b, R^4c, R^4d, and R^4e are defined elsewhere herein. In certain embodiments, a compound of formula (1-3) is prepared by contacting salicylamide (1-1) with aryl or heteroaryl aldehyde or ketone (1-2), as depicted in Scheme 1.

Scheme 1.

In certain embodiments, the corresponding salicylamide (1.0 eq.) and aldehyde or ketone (1.5 eq.) were dissolved in toluene with a catalytic amount of piperidine and reacted in the microwave at 165 °C for 10 minutes. Samples were then extracted three times with ethyl acetate and isolated through either crystallization or silica gel chromatograph. Non-limiting examples of compounds of the disclosure prepared according to Scheme 1, and the corresponding salicylamides and benzaldehydes used, are provided in Table 3.

Table 3. Exemplary⁷ compounds prepared according to Scheme 1

The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry⁷ of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons. 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc.. 1989), March, Advanced Organic Chemistry 4^th Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry⁷ 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure).

General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources or are prepared using procedures described herein.

In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means.

Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl, triisopropylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t- butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. The silyl group are also selectively removable with fluoride ions.

In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively -removable protective groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically- active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

The methods and formulations described herein include the use of N-oxides (if appropriate), cry stalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts (i.e., a salt known to be non-toxic and commonly used in the pharmaceutical literature) of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same ty pe of activity⁷. When the compounds have a basic group as a substituent group, pharmaceutically acceptable salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and other mineral acids, salts with formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid, and other organic carboxylic acids or salts with methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, hydroxybenzenesulfonic acid, and other sulfonic acids, etc. may be mentioned. When the compounds have an acid group, pharmaceutically acceptable salts with sodium, potassium, or other alkali metal salt, calcium, magnesium or other alkali earth metal salt, a salt with or ammonia, triethylamine, or ethylenediamine, propanediamine, pyrrolidine, piperidine, piperadine, pyridine, lysine, choline, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine, N-methylglucamine, or other organic bases may be mentioned and droxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may be used. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form.

In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

Compounds described herein also include isotopically -labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to ²H. ³H. ¹³C, ¹⁴C, ³⁶C1, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵0, ¹⁷O, ¹⁸0, ³²P, and ³⁵S.

In certain embodiments, isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as nc, ¹⁸F, ¹⁵0 and ¹³N. is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to. the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

Compositions

The compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapul monary. intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Methods

In one aspect, the disclosure provides a method for treating, ameliorating, and/or preventing anxiety in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the compound of the disclosure or a pharmaceutical composition thereof. In certain embodiments, the anxiety is selected from the group consisting of generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), and major depressive disorder (MDD). In certain embodiments, the subject is administered at least one additional therapeutic agent. In certain embodiments, the therapeutic agent is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), benzodiazepine, and beta-blocker.

In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing an opiate-related disorder in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the compound of the disclosure or a pharmaceutical composition thereof. In certain embodiments, the opiate- related disorder is selected from the group consisting of opioid use disorder, opioid dependence, and opioid withdrawal syndrome. In certain embodiments, the subject is administered at least one additional therapeutic agent. In certain embodiments, the therapeutic agent is selected from the group consisting of naloxone, buprenorphine, methadone, and naltrexone.

In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing an alcohol-related disorder in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the compound of the disclosure or a pharmaceutical composition thereof. In certain embodiments, the alcohol- related disorder is selected from the group consisting of alcohol use disorder (AUD). alcohol withdrawal syndrome, alcohol dependence, alcohol intoxication, and alcohol-induced anxiety disorder. In certain embodiments, the subject is administered at least one additional therapeutic agent. In certain embodiments, the therapeutic agent is selected from the group consisting of disulfiram, acamprosate. naltrexone, and gabapentin.

In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing a benzodiazepine-related disorder in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the compound of the disclosure or a pharmaceutical composition thereof. In certain embodiments, the benzodiazepine-related disorder is selected from the group consisting of benzodiazepine use disorder, benzodiazepine withdrawal syndrome, benzodiazepine dependence, and benzodiazepine intoxication. In certain embodiments, the subject is administered at least one additional therapeutic agent. In certain embodiments, the therapeutic agent is selected from the group consisting of flumazenil. pregabalin. gabapentin, and a selective serotonin reuptake inhibitor (SSRI).

In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing a seizure or seizure disorder in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the compound of the disclosure or a pharmaceutical composition thereof. In certain embodiments, the seizure or seizure disorder is selected from the group consisting of a seizure, epilepsy, generalized tonic-clonic seizure, focal (partial) seizure, seizure associated with Lennox-Gastaut syndrome, febrile seizure, or a seizure associated with alcohol withdrawal syndrome. In certain embodiments, the subject is administered at least one additional therapeutic agent. In certain embodiments, the therapeutic agent is selected from the group consisting of valproic acid, levetiracetam, lamotrigine, and clonazepam.

In another aspect, the disclosure provides a method for treating, ameliorating, and/or preventing pain in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the compound of the disclosure or a pharmaceutical composition thereof.

In another aspect, the disclosure provides a method for sedating a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the compound of the disclosure or a pharmaceutical composition thereof.

In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

Combination Therapies

The compounds useful within the methods described herein can be used in combination with one or more additional therapeutic agents useful for treating, ameliorating, and/or preventing AUD, anxiety and/or distress. These additional therapeutic agents may comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additional therapeutic agents are know n to treat or reduce the symptoms of AUD or anxiety⁷.

In various embodiments, a synergistic effect is observed when a compound as described herein is administered with one or more additional therapeutic agents or compounds. A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926. Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

Administration/Dosage/Formulations

The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a AUD, anxiety or distress. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions described herein to a patient, may be earned out using known procedures, at dosages and for periods of time effective to treat AUD or anxiety in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat AUD or anxiety in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level depends upon a variety' of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex. weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound 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 patients to be treated: each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound.

In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or poly alcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may⁷ be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every⁷ day, every⁷ two, days, every⁷ three days to once a week, and once every⁷ two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account.

The compound(s) described herein for administration may be in the range of from about 1 pg to about 10,000 mg, about 20 pg to about 9,500 mg, about 40 pg to about 9,000 mg, about 75 pg to about 8,500 mg, about 150 pg to about 7,500 mg. about 200 pg to about 7,000 mg, about 350 pg to about 6,000 mg, about 500 pg to about 5,000 mg, about 750 pg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg. about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg. or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg. or less than about 15 mg. or less than about 10 mg, or less than about 5 mg. or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of AUD and/or anxiety in a patient.

Formulations may be employed in admixtures with conventional excipients, z.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route. such as for oral or parenteral, for example, transdermal, transmucosal (e.g, sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g, trans- and perivaginally). (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, nano-encapsulations, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose: granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g, polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropyl methylcellulose); fdlers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc, or silica); disintegrates (e.g, sodium starch gly collate); or wetting agents (e.g, sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g, OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K.18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g, methyl or propyl p-hydroxy benzoates or sorbic acid).

Compositions as described herein can be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. A tablet that includes a compound as described herein can, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, dispersing agents, surface-active agents, disintegrating agents, binding agents, and lubricating agents.

Suitable dispersing agents include, but are not limited to, potato starch, sodium starch gly collate, pol oxamer 407. or poloxamer 188. One or more dispersing agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more dispersing agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%. 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%. 50%. 55%. 60%. 65%. 70%. 75%. 80%. 85%. or 90% w/w relative to weight of the dosage form.

Surface-active agents (surfactants) include cationic, anionic, or non-ionic surfactants, or combinations thereof. Suitable surfactants include, but are not limited to, behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbethopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen bromide, lauryl methyl gluceth-10 hydroxypropyl dimonium chloride, tetramethylammonium hydroxide, thonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-l,3-propanediamine, 2-acrylamido-2 -methylpropane sulfonic acid, alkylbenzene sulfonates, ammonium lauryl sulfate, ammonium perfluorononanoate, docusate, disodium cocoamphodiacetate. magnesium laureth sulfate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate esters, cetomacrogol 1000. cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, cocamide monoethanolamine, decyl glucoside, decyl polyglucose, glycerol monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypolyethoxyethanol P-40, Nonoxynol-9, Nonoxynols, nonyl phenoxypolyethoxylethanol (NP-40), octaethylene glycol monododecyl ether, N-octyl beta- D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG- 10 sunflower glycerides, pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan. sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100. and Tween 80. One or more surfactants can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to w eight of the dosage form. One or more surfactants can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%. 0.1%, 0.5%, 1%. 2%, 3%, 4%. 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w/w relative to weight of the dosage form.

Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose ® 80 (75 % a- lactose monohydrate and 25 % cellulose powder), mannitol, pre-gelatinized starch, starch, sucrose, sodium chloride, talc, anhydrous lactose, and granulated lactose. One or more diluents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w /w relative to weight of the dosage form. One or more diluents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%. 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%. 60%. 65%. 70%. 75%. 80%. 85%. or 90% w/w relative to weight of the dosage form. Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, com starch, microcrystalline cellulose, methyl cellulose, sodium starch gly collate, pregelatinized starch, povidone, sodium carboxy methyl cellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, colloidal silicone dioxide, crosspovidone and alginic acid. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%. 85%. or 90% w/w relative to weight of the dosage form.

Suitable binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamides, sucrose, dextrose, maltose, gelatin, polyethylene glycol. One or more binding agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more binding agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%. 10%. 15%. 20%. 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%. 70%. 75%. 80%. 85%. or 90% w/w relative to weight of the dosage form.

Suitable lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glycery l behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricating agents can each be individually present in the composition in an amount of about 0.01% w/w to about 90% w/w relative to weight of the dosage form. One or more lubricating agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%. 3%, 4%, 5%. 10%. 15%, 20%, 25%, 30%, 35%. 40%. 45%. 50%. 55%. 60%. 65%. 70%. 75%. 80%. 85%. or 90% w/w relative to weight of the dosage form.

Tablets can be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patent Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation.

Tablets can also be enterically coated such that the coating begins to dissolve at a certain pH. such as at about pH 5.0 to about pH 7.5. thereby releasing a compound as described herein. The coating can contain, for example, EUDRAGIT ® L, S, FS, and/or E polymers with acidic or alkaline groups to allow release of a compound as described herein in a particular location, including in any desired section(s) of the intestine. The coating can also contain, for example, EUDRAGIT ® RL and/or RS polymers with cationic or neutral groups to allow for time controlled release of a compound as described herein by pH-independent swelling.

Parenteral Administration

For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formal atory agents such as suspending, stabilizing and/or dispersing agents may be used.

Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as such as laury l, stearyl, or oleyl alcohols, or similar alcohol.

Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos. 6,340.475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in PCT Applications Nos. WO 03/35041; WO 03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO 02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO 98/11879; WO 97/47285; WO 93/18755; and WO 90/11757.

Controlled Release Formulations and Drug Delivery Systems

In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release, slow release and pulsatile release formulations.

The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may. although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.

For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profde in varying proportions. Suitable controlled-release formulations known to those of ordinary' skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the compositions and dosage forms described herein.

Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.

Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled-release component" is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In one embodiment, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. In one embodiment, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.

As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

Dosing

The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of AUD or anxiety in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.

A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (z.e., a "drug holiday “). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days. 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-l 00%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary’. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.

The compounds described herein can be formulated in unit dosage form. The term “unit dosage form“ refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined uantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity⁷. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

EXAMPLES

Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein.

Example 1: Electrophysiology studies in Xenopus oocyte expressing subtype specific GABAA receptors In one aspect, the disclosure provides certain compounds comprising flavonoid derivatives and functional activity thereof for modulation of GABAA receptors. In certain embodiments, GABAA modulation was evaluated in vitro by performing electrophysiology studies in Xenopus oocytes expressing the a2|32y2L GABAA receptor subtype (Table 4). Certain exemplary compounds of the disclosure were subjected to electrophysiology studies in Xenopus oocytes expressing subtype specific GABAA receptors. The activity of certain compounds of the disclosure was examined with or without administration of flumazenil, which is a competitive ligand for the benzodiazepine (BZD) binding site.

Activity was measured in the presence of GABA, indicative of allosteric modulator (PAM) mode using the SyncroPatch automated platform at room temperature. Compounds were initially screened for activity at 1000 nM concentrations. Compounds identified to be positive modulators were then tested at 6 concentrations (1, 10, 30, 100, 300, 3000 nM, with and without Flumazenil (10 pM), an established ligand of the benzodiazepine binding site of GABAARs. This data was then utilized to determine the ECso, the concentration at which compound is 50% effective and representative of the potency of each molecule. Intrinsic efficacy for each compound is reported as percent change in activity as compared to that of vehicle control. All samples were run in duplicate.

Thus, in certain embodiments, addition of flumazenil did not inhibit activity⁷ of the compounds of the disclosure. Thus, the data provided herein demonstrate that compounds of the disclosure are allosteric GABAA modulators which do not bind to the BZD binding site (Table 4).

Table 4. Exemplary⁷ GABAA modulation data for certain compounds of the disclosure

^a% Change in activity; ^bWithout flumazenil; ^cWith flumazenil. ND = not determined

Based on the foregoing, the data suggests that the compounds of the disclosure are allosteric modulators which do not bind at the BZD binding site, as evidenced by electrophysiology studies with the compounds of the disclosure with and without flumazenil, a competitive ligand of the BZD site. Flumazenil did not impact the activity' of the compounds, and rather, appeared to be slightly additive to the activity’ of certain exemplary’ compounds. Without wishing to be bound by any theory, these data suggest that the compounds of the disclosure are binding to an alternate allosteric site on the GABAARs.

Example 2: Plasma pharmacokinetic data for certain exemplary compounds

The disclosure provides plasma pharmacokinetic data for certain exemplary’ compounds of the disclosure. Studies were conducted using a single intraperitoneal and oral dose administration in male Sprague Dayvley rats, the results for which are provided in Table 5. Severe sedation was observed for 2 hours in rats given 10 mg/kg IP doses of ZT-15 and

ZT-22. Table 5. Exemplary plasma pharmacokinetic data for certain compounds of the disclosure

Example 3: In vivo studies with EC2-118

In accordance with Examples 5 and 6 of PCT International Patent Application No. W02023/059802, which is hereby incorporated herein by reference, in vivo studies in rats were conducted for activity of EC2-118. Male and female rats were exposed to an open field test (OFT) and elevated plus maze (EPM) 7 days apart. Each group (n = 8/group, total = 24) received IP injection 30 min prior to IP dosing of EC2-118 or vehicle control. OFT and EPM were performed in 52 adult SD rats (26 male/26 female). The groups were as follow vehicle (0.9% Saline, 4% Tween 80. and 4% DMSO; n = 9 males; n = 10 females). 3.95 mg/kg (n=10 males; n=8 females), 12.5 mg/kg (n = 7 males, females n= 8). Statistical analysis was completed using TWO-ANOVA with Treatment and Sex as factors and showed significant differences between 3.95 mg/kg dose and vehicle control.

Rats were given EC2-118 (3.95 mg/kg IP) and alcohol (3 g/kg) and assessed for duration of loss-of-righting-reflex (LORR). EC2-118 (3.95 mg/kg, 12.95 IP) did not induce an LORR Further, EC2-118 3.95 mg/kg did not have a significant impact on alcohol induced LORR. The effects of EC2-118 (12.5 mg/kg IP) on alcohol-induced LORR were not determined.

In summary, EC2-118 displayed statistically significant anxiolytic effects at a dose of 3.95 mg/kg IP in male and female rats. It is hypothesized herein that, like compound EC2- 118, other exemplary' compounds of the disclosure likewise display anxiolytic effects. A dose of 12.5 mg/kg EC2-118 IP did not exhibit a significant effect in the open field test (OFT), but the observation of increased lethargy’ at 12.5 mg/kg IP coupled with enhanced motor impairment at 12.5 mg/kg IP suggest a dose-dependent increase in sedative effects, as is expected with GABAAR PAMs.

In vivo studies were conducted in male and female mice to screen for anxiolytic-like behavior, as evidenced by the open field test (OFT). A significant effect was observed 30 minutes post oral administration of 25 mg/kg EC2-118 but not one hour post administration (FIGs. 1A-1D).

Example 4: Pharmacokinetic studies with EC2-118

This is a pharmacokinetics and tissue distribution (brain) study with EC2-118 in Male Sprague Dawley Rats. Following a Single Intravenous and Oral Administration (Dose: 2.5 mg/kg. IV and 10 mg/kg, PO, twenty-one rats were divided into three groups as Group 1 (3 rats), Group 2 (3 rats) and Group 3 (15 rats). Animals in Group 1 and Group 3 were administered intravenously as slow bolus injection through the tail vein, with solution formulation of EC2-118 at 2.5 mg/kg dose. The formulation vehicle used for intravenous administration was 100% DMSO. Animals in Group 2 were administered through oral route with a solution formulation of EC2-118 at 10 mg/kg dose. The formulation vehicle used for oral administration was 10% NMP, 10% Solutol HS 15, 40% PEG 400 and 40% Normal saline. Blood samples (approximately 120 pL) were collected under light isoflurane anesthesia (Surgivet®) from retro orbital plexus from a set of three rats at Pre-dose (only for PO), 0.08 (only for IV), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h. Immediately after blood collection, plasma was harvested by centrifugation at 10000 rpm, 10 min at 40 °C and samples were stored at -70±10°C until bioanalysis. Following blood and CSF collection from Group 3, the animals were sacrificed, perfused using 10 mL of PBS. Brain samples were collected from set of three rat at 0.25, 0.5, 1, 4 and 8 h (IP). After isolation, brain samples were rinsed three times in ice cold PBS (for 5-10 seconds/rinse using -5-10 mL normal saline in disposable petri dish for each rinse) and dried on blotting paper and weighed. Brain samples were homogenized using ice-cold phosphate buffer saline (pH-7.4). Total homogenate volume was three times the tissue weight. All homogenates were stored below -70±10 °C until bioanalysis. All samples were processed for analysis by protein precipitation method and analyzed with fit-for-purpose LC-MS/MS method (LLOQ = 2 ng/mL for plasma and brain and 5.01 ng/mL for CSF). The pharmacokinetic parameters were estimated using noncompartmental analysis tool of Phoenix® WinNonlin software (Ver 8.3) and parameters are summarized in Tables 6A-6B.

Table 6A. Exemplary pharmacokinetic data for EC2-118

Table 6B. Exemplary' pharmacokinetic data for EC2-118 ^aBack extrapolated concentration in IV group; Brain Cmax and AUCiast are expressed as ng/g and h*ng/g, respectively. Density of brain tissue was considered as 1 which is equivalent to plasma density.

It was found that EC2-1 18 was 91 % orally bioavailable in rats and was detected in the brain for up to 4 hours after administration. Brain samples w ere diluted (1-part of tissue: 2- part of buffer) and homogenized. The homogenate was submitted for bioanalysis and the concentrations (ng/mL) received were corrected with dilution factor (3x) and the final reported concentrations were represented in ng/g.

Example 5: Respiratory studies using EC2-118

The whole-body plethysmograph assay in mice is used to assess various parameters of respiratory functions. Specialized whole-body plethysmographs (Data Sciences International, item 601-1425-001) were used to measure ventilation in conscious, unrestrained animals. These chambers allow⁷ the animals to move freely and provide continuous monitoring of temperature and humidity. The chamber floor is perforated to facilitate the passage of urine and feces. Mice were habituated to the chamber for approximately 15 minutes before recording began. Ventilation parameters, including average breath duration, breathing rate, tidal volume, minute tidal volume, and enhanced pauses, w ere measured for one hour following injection.

Data was analyzed by analysis of variance (ANOVA) followed by Bonferroni’s multiple comparisons post-hoc test where appropriate. The following post-hoc comparisons were performed when appropriate: (1) Test Compound (25 mg/kg)-Saline group vs. Vehicle- Saline group (to examine the effect of the test compound alone on respiration measures); (2) Fentanyl (0.25 mg/kg)-Saline vs. Vehicle-Saline (to examine the effect of fentanyl alone respiration measures; (3) Test Compound (25 mg/kg)-Fentanyl (0.25 mg/kg) vs. Fentanyl (0.25 mg/kg)-Saline (to examine the effect of fentanyl on respiration in the presence of the compound); (4) Alprazolam (0.5 mg/kg)-Fentanyl (0.25 mg/kg) vs. Fentanyl (0.25mg/kg)- Saline (to examine the effect of fentanyl on respiration in the presence of Alprazolam). An effect was considered significant p < .05. Data are represented as the mean and standard error to the mean (s.e.m)

Fentanyl 0.25 mg/kg was dissolved in saline and injected i.p.at a dose volume of 10 mL/kg. Test compound (25 mg/kg dose) was prepared in in 10% NMP. 10% Solutol HS 15,40% PEG 400 and 40% Normal saline and administered at a dose volume of 10 ml/kg. Alprazolam (0.5 mg/kg) was dissolved in saline and injected IP at a dose volume of 10 mL/kg. Treatments was administered as two separate IP injections immediately following each other. Injection one will occur on the animal's left side. Injection two will occur on the animal’s right side. Dosing will occur 30 min prior to test session initiation (i.e., 15 min prior to chamber habituation). Animals in the alprazolam (0.5 mg/kg)-Fentanyl group were monitored carefully during the session for indications of respiratory depression.

Enumerated Embodiments

The following exemplar}’ embodiments are provided, the numbering of which is not to be construed as designating levels of importance:

Embodiment 1 provides a compound of formula (I), or a salt, stereoisomer, tautomer, or isotopologue thereof: wherein:

R^la, R^lb, R^lc, and R^ld are each independently selected from the group consisting of H, R, F, Cl, Br, I, OR, CN, NO₂, N(R)₂, SR, S(=O)R, SF₃, SF₅, S(=O)₂R, S(=O)₂N(R)₂, P(=O)(OR)₂, C(=O)R, C(=O)OR, C(=O)N(R)₂, OC(=O)R, and OC(=O)N(R)₂;

R³ is selected from the group consisting of H and optionally substituted Ci-Ce alkyl;

A is selected from the group consisting of

X¹ is CR^4C or N, X¹ is CR^4d or N, and X² is CR^4e or N, wherein one of X¹, X², and X³, if present, is N;

R^4a. R^4b, R^4C. R^4d, and R^4e, if present, are each independently selected from the group consisting of R, F, Cl, Br, I, OR, CN, NO2, N(R)₂, SR, S(=O)R, SF3, SFs, S(=O)₂R, S(=O)₂N(R)₂, P(=O)(OR)₂, C(=O)R, C(=O)OR, C(=O)N(R)₂, OC(=O)R, and OC(=O)N(R)₂;

R^6a and R^6b are each independently selected from the group consisting of H, F, Cl, Br, I, OR, and optionally substituted Ci-Ce alkyl; and each occurrence of R is independently selected from the group consisting of hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted C₂-Ce alkenyl, optionally substituted C₂-Ce alkynyl, optionally substituted Ch-Cs cycloalkyl, optionally substituted C3- Cs cycloalkenyl, optionally substituted C₂-Cs heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C₂-Cio heteroaryl.

Embodiment 2 provides the compound of Embodiment 1, wherein R^la, R^lb, R^lc, and R^ld are each independently selected from the group consisting of H, halogen, and Ci-Ce alkyl, optionally wherein R^la, R^lb. R^lc, and R^ld are each independently selected from the group consisting of H, F, Cl, Br, zPr, and CF3.

Embodiment 3 provides the compound of Embodiment 1 or 2, wherein three of R^la, R^lb, R^lc, and R^ld are H, and one of R^la, R^lb, R^lc, and R^ld is a halogen.

Embodiment 4 provides the compound of any one of Embodiments 1-3, wherein R² is selected from the group consisting of H and CH3.

Embodiment 5 provides the compound of any one of Embodiments 1-4, wherein R’ is H.

Embodiment 6 provides the compound of any one of Embodiments 1-5, wherein R^4a. R^4b, R^4C, R^4d. and R^4e are each independently selected from the group consisting of H, CH3, CH₂CH₃, CF3, F, Cl, Br, OH, OCH3, OCF3, CN, NO₂, and S(=O)₂CH₃.

Embodiment 7 provides the compound of any one of Embodiments 1-6, wherein R⁵ is selected from the group consisting of H and CH3.

Embodiment 8 provides the compound of any one of Embodiments 1-7, wherein R^6a and R^6b are each independently H. Embodiment 9 provides the compound of any one of Embodiments 1-8, wherein the compound of formula (I) is selected from the group consisting of:

Embodiment 10 provides the compound of any one of Embodiments 1-9. wherein R^lb is Br.

Embodiment 11 provides the compound of Embodiment 9 or 10, wherein at least one of the following applies:

(a) R^4a is CH₃;

(b) R^4b is selected from the group consisting of CH?, F, and Br;

(c) R^4C is selected from the group consisting of F, Cl, and CH2CH3; and

(d) R^4d is selected from the group consisting of F and CH3. Embodiment 12 provides the compound of any one of Embodiments 1-11, wherein A is selected from the group consisting of:

Embodiment 13 provides the compound of any one of Embodiments 1-12, which is selected from the group consisting of:

6-bromo-2-(5-bromo-2-fluoro-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(6-fluoro-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(5-bromo-3-pyridyl)-2.3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(5-methyl-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(4-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(5-chloro-4,6-difluoro-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(5-ethyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(3-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(6-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; and

6-bromo-2-methyl-2-(2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one.

Embodiment 14 provides the compound selected from the group consisting of:

7-bromo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-chloro-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-iodo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; m-(6-bromo-4-oxo-2,3-dihydro-4H-l,3-benzoxazin-2-yl)benzonitrile;

6-bromo-2-(o-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(m-chlorophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(m-fluorophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; and

6-bromo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; or a salt, stereoisomer, tautomer, or isotopologue thereof.

Embodiment 15 provides the pharmaceutical composition comprising the compound of any one of Embodiments 1-14 and at least one pharmaceutically acceptable carrier.

Embodiment 16 provides a method for treating, ameliorating, and/or preventing anxiety in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-14 or the pharmaceutical composition of Embodiment 15.

Embodiment 17 provides the method of Embodiment 16, wherein the anxiety is selected from the group consisting of generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), and major depressive disorder (MDD).

Embodiment 18 provides the method of Embodiment 16 or 17, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), benzodiazepine, and beta-blocker.

Embodiment 19 provides a method for treating, ameliorating, and/or preventing an opiate-related disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-14 or the pharmaceutical composition of Embodiment 15.

Embodiment 20 provides the method of Embodiment 19, wherein the opiate-related disorder is selected from the group consisting of opioid use disorder, opioid dependence, and opioid withdrawal syndrome.

Embodiment 21 provides the method of Embodiment 19 or 20, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of naloxone, buprenorphine, methadone, and naltrexone.

Embodiment 22 provides a method for treating, ameliorating, and/or preventing an alcohol-related disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-14 or the pharmaceutical composition of Embodiment 15.

Embodiment 23 provides the method of Embodiment 22, wherein the alcohol-related disorder is selected from the group consisting of alcohol use disorder (AUD), alcohol withdrawal syndrome, alcohol dependence, alcohol intoxication, and alcohol-induced anxiety disorder.

Embodiment 24 provides the method of Embodiment 22 or 23, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of disulfiram, acamprosate, naltrexone, and gabapentin. Embodiment 25 provides a method for treating, ameliorating, and/or preventing a benzodiazepine-related disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-14 or the pharmaceutical composition of Embodiment 15.

Embodiment 26 provides the method of Embodiment 25, wherein the benzodiazepine- related disorder is selected from the group consisting of benzodiazepine use disorder, benzodiazepine withdrawal syndrome, benzodiazepine dependence, and benzodiazepine intoxication.

Embodiment 27 provides the method of Embodiment 25 or 26, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of flumazenil. pregabalin. gabapentin, and a selective serotonin reuptake inhibitors (SSRI).

Embodiment 28 provides a method for treating, ameliorating, and/or preventing a seizure or seizure disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-14 or the pharmaceutical composition of Embodiment 15.

Embodiment 29 provides the method of Embodiment 28, wherein the seizure or seizure disorder is selected from the group consisting of a seizure, epilepsy, generalized tonic-clonic seizure, focal (partial) seizure, seizure associated with Lennox-Gastaut syndrome, febrile seizure, or a seizure associated with alcohol withdrawal syndrome.

Embodiment 30 provides the method of Embodiment 28 or 29, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of valproic acid, levetiracetam, lamotrigine, and clonazepam.

Embodiment 31 provides a method for treating, ameliorating, and/or preventing pain in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-14 or the pharmaceutical composition of Embodiment 15.

Embodiment 32 provides a method for sedating a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-14 or the pharmaceutical composition of Embodiment 15.

Embodiment 33 provides the method of any one of Embodiments 16-32, wherein the subject is a mammal, optionally wherein the mammal is a human. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features show n and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application.

Claims

CLAIMS What is claimed is:

1. A compound of formula (I), or a salt, stereoisomer, tautomer, or isotopologue thereof: wherein:

R^1a. R^1b, R^lc, and R^1d are each independently selected from the group consisting of H, R, F, Cl, Br, I, OR. CN, NO₂, N(R)₂, SR, S(=O)R, SF3, SF₅, S(=O)₂R, S(=O)₂N(R)₂, P(=O)(OR)₂, C(=O)R, C(=O)OR, C(=O)N(R)₂, OC(=O)R, and OC(=O)N(R)₂;

R² is selected from the group consisting of H and optionally substituted Ci-Ce alkyl;

A is selected from the group consisting of

R^4a, R^4b, R^4C, R^4d, and R^4e, if present, are each independently selected from the group consisting of R, F, Cl, Br, I, OR, CN, NO2, N(R)₂, SR, S(=O)R. SF₃, SF₅, S(=O)₂R, S(=O)₂N(R)₂, P(=O)(OR)₂, C(=O)R. C(=O)OR. C(=O)N(R)₂. OC(=O)R, and OC(=O)N(R)₂;

R⁵ is selected from the group consisting of H and optionally substituted Ci-Cs alkyl;

R^6a and R^6b are each independently selected from the group consisting of H, F, Cl, Br, I, OR, and optionally substituted Ci-Ce alky l; and each occurrence of R is independently selected from the group consisting of hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3- Cs cycloalkenyl, optionally substituted C₂-Cs heterocycloalkyl, optionally substituted Ce-Cio aryl, and optionally substituted C₂-Cio heteroary l.

2. The compound of claim 1, wherein R^la, R^lb, R^lc, and R^ld are each independently selected from the group consisting of H. halogen, and Ci-Ce alkyl, optionally wherein R^la, R^lb, R^lc, and R^ld are each independently selected from the group consisting of H, F, CL Br, zPr, and CF3.

3. The compound of claim 1 or 2, wherein three of R^la, R^lb, R^lc, and R^ld are H, and one of R^la, R^lb. R^lc, and R^ld is a halogen.

4. The compound of any one of claims 1-3, wherein R² is selected from the group consisting of H and CH3.

5. The compound of any one of claims 1-4, wherein R³ is H.

6. The compound of any one of claims 1-5, wherein R^4a, R^4b, R^4c, R^4d, and R^4e are each independently selected from the group consisting of H, CH3, CH2CH3, CF3, F, Cl, Br, OH, OCH3, OCF3, CN, NO2, and S(=O)₂CH3.

7. The compound of any one of claims 1-6, wherein R⁵ is selected from the group consisting of H and CH3.

8. The compound of any one of claims 1 -7, wherein R^6a and R^6b are each independently

H.

9. The compound of any one of claims 1-8. wherein the compound of formula (I) is selected from the group consisting of:

10. The compound of any one of claims 1-9, wherein R^lb is Br.

11. The compound of claim 9 or 10, wherein at least one of the following applies:

(a) R^4a is CH₃;

(b) R^4b is selected from the group consisting of CHs, F, and Br;

(c) R^4C is selected from the group consisting of F, Cl, and CH2CH3; and

(d) R^4d is selected from the group consisting of F and CH3.

12. The compound of any one of claims 1-11, wherein A is selected from the group consisting of:

13. The compound of any one of claims 1-12, which is selected from the group consisting of:

6-bromo-2-(5-bromo-2-fluoro-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(6-fluoro-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; 6-bromo-2-(5-bromo-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(5-methyl-3-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(4-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; 6-bromo-2-(5-chloro-4,6-difluoro-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; 6-bromo-2-(5-ethyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(3-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(6-methyl-2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; and

6-bromo-2-methyl-2-(2-pyridyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one.

14. A compound selected from the group consisting of:

7-bromo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-chloro-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(o-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one;

6-bromo-2-(m-chlorophenyl)-2,3-dihydro-4H-1.3-benzoxazin-4-one;

6-bromo-2-(m-fluorophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; and 6-bromo-2-(m-nitrophenyl)-2,3-dihydro-4H-l,3-benzoxazin-4-one; or a salt, stereoisomer, tautomer, or isotopologue thereof.

15. A pharmaceutical composition comprising the compound of any one of claims 1 -14 and at least one pharmaceutically acceptable carrier.

16. A method for treating, ameliorating, and/or preventing anxiety in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

17. The method of claim 16, wherein the anxiety is selected from the group consisting of generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), and major depressive disorder (MDD).

18. The method of claim 16 or 17, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), benzodiazepine, and beta-blocker.

19. A method for treating, ameliorating, and/or preventing an opiate-related disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

20. The method of claim 19, wherein the opiate-related disorder is selected from the group consisting of opioid use disorder, opioid dependence, and opioid withdrawal syndrome.

21. The method of claim 19 or 20, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of naloxone, buprenorphine, methadone, and naltrexone.

22. A method for treating, ameliorating, and/or preventing an alcohol-related disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

23. The method of claim 22, wherein the alcohol-related disorder is selected from the group consisting of alcohol use disorder (AUD), alcohol withdrawal syndrome, alcohol dependence, alcohol intoxication, and alcohol-induced anxiety disorder.

24. The method of claim 22 or 23, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of disulfiram, acamprosate, naltrexone, and gabapentin.

25. A method for treating, ameliorating, and/or preventing a benzodiazepine-related disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

26. The method of claim 25, wherein the benzodiazepine-related disorder is selected from the group consisting of benzodiazepine use disorder, benzodiazepine withdrawal syndrome, benzodiazepine dependence, and benzodiazepine intoxication.

27. The method of claim 25 or 26, wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of flumazeml, pregabalin, gabapentin, and a selective serotonin reuptake inhibitors (SSRI).

28. A method for treating, ameliorating, and/or preventing a seizure or seizure disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

29. The method of claim 28, wherein the seizure or seizure disorder is selected from the group consisting of a seizure, epilepsy, generalized tonic-clonic seizure, focal (partial) seizure, seizure associated with Lennox-Gastaut syndrome, febrile seizure, or a seizure associated with alcohol withdrawal syndrome.

30. The method of claim 28 or 29. wherein the subject is administered at least one additional therapeutic agent, optionally wherein the therapeutic agent is selected from the group consisting of valproic acid, levetiracetam, lamotrigine, and clonazepam.

31. A method for treating, ameliorating, and/or preventing pain in a subj ect, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

32. A method for sedating a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

33. The method of any one of claims 16-32, wherein the subject is a mammal, optionally wherein the mammal is a human.