Compositions and methods for sleep maintenance

Abstract

Disclosed herein are compositions, uses, and methods for improving sleep maintenance by providing to a subject one or more compounds of the disclosure and a carrier. Some embodiments provided include methods for treating sleep maintenance insomnia or reducing, modulating, or ameliorating one or more conditions or symptoms of sleep maintenance insomnia by providing a sufficient amount of the composition of the disclosure to the subject.

Description

BSEED.056WO PATENT COMPOSITIONS AND METHODS FOR SLEEP MAINTENANCE Field of the Disclosure

[0001] The present disclosure relates to compositions and their uses. More particularly, the present disclosure relates to compositions and methods for sleep maintenance by administering a therapeutically effective amount of the composition and a carrier. BACKGROUND

[0002] The orexin system, comprising orexin-A and orexin-B peptides and their receptors, Orexin Receptor 1 (OX1R) and Orexin Receptor 2 (OX2R), play an important role in regulating wakefulness and arousal. Dysregulation of this system has been implicated in various sleep disorders, including sleep maintenance insomnia. The orexin receptors have thus emerged as promising drug targets for the development of therapeutic agents aimed at treating these conditions. Despite the potential of targeting orexin receptors, only three drugs have received FDA approval for this purpose: suvorexant, lemborexant, and daridorexant.

[0003] Suvorexant (marketed as Belsomra®) was the first orexin receptor antagonist approved by the FDA in 2014. It works by inhibiting the activity of both OX1R and OX2R, thereby promoting sleep onset and maintenance. However, suvorexant has several limitations, including a relatively high incidence of next-day residual effects, such as drowsiness and impaired driving ability, which can pose significant safety risks. Additionally, its efficacy varies among patients, and some individuals may experience tolerance or dependency with prolonged use.

[0004] Lemborexant (marketed as Dayvigo®), approved in 2019, also targets both OX1R and OX2R but has shown a different pharmacokinetic profile, with a faster onset of action and shorter half-life compared to suvorexant. While lemborexant has demonstrated efficacy in improving sleep onset and maintenance, it too can cause next-day drowsiness and impaired driving performance. Furthermore, like suvorexant, lemborexant may not be effective for all patients, and its long-term safety profile remains to be fully established.

[0005] Daridorexant (marketed as Quviviq®), the most recent addition to the orexin receptor antagonist class, received FDA approval in 2022. It exhibits high selectivity for OX2R, which is believed to reduce the risk of certain side effects associated with dual orexin receptor-1-antagonists. Despite this improvement, daridorexant still poses challenges, including potential next-day residual effects and the need for individualized dosing to minimize adverse reactions. The long-term effects of daridorexant also require further investigation to ensure its safety and efficacy for chronic use.

[0006] Given the limitations of the currently approved orexin receptor antagonists, there is a pressing need to identify additional compounds with improved safety and efficacy profiles for the treatment of sleep maintenance insomnia, including highly potent structure- activity-relationship compounds derived from natural sources. These new compounds could provide more effective management of sleep disorders, enhancing the quality of life for patients suffering from chronic insomnia and reducing the associated health risks. Clearly, there remains an unmet need to develop highly potent compounds capable of improving sleep maintenance. SUMMARY OF THE DISCLOSURE

[0007] Aspects of the disclosure relate to a composition. In some embodiments, the composition is an oral composition. In some embodiments, the oral composition includes at least one carrier and one or more compounds from Table A. In some embodiments, the oral composition is formulated as a dietary supplement, food ingredient or additive, a medical food or functional food, nutraceutical or pharmaceutical composition. In some embodiments, the oral composition is in a dosage form configured as one of a soft-gel capsule, a hard capsule, liquid, powder, granule, and a tablet. In some embodiments, the oral composition is formulated as a functional food. In some embodiments, the oral composition comprises 0.01% to 99% w / w of the one or more compounds. In some embodiments, the one or more compounds is derived from a plant extract. In some embodiments, the oral composition comprises 0.01% to 99% w / w of the plant extract. In some embodiments, the oral composition further comprises a preservative. In some embodiments, the preservative is from about 0.01% to about 5% by weight of the oral composition. In some embodiments, the oral composition further comprises a sweetener. In some embodiments, the oral composition further comprises a coloring agent. In some embodiments, the oral composition further comprises an additive. In some embodiments, the oral composition further comprises a flavoring agent. In some embodiments, the one or more compounds is unbound to a lignocellulosic material. In some embodiments, with a proviso that the oral composition does not comprise lignin, cellulose, or pectin. In some embodiments, the with a proviso that the one or more compounds is-2-not an extract from a natural source. In some embodiments, the oral composition comprises an orexin receptor 2 antagonist. In some embodiments, the oral composition an orexin receptor 1 antagonist.

[0008] Some aspects of the disclosure relate to a method for treating insomnia or reducing, modulating, or ameliorating one or more conditions of insomnia in a subject in need thereof. In some embodiments, the method includes providing an oral composition as described herein, wherein the oral composition is administered in an amount sufficient to treat insomnia or reduce, modulate, or ameliorate one or more conditions of insomnia in the subject in need thereof. In some embodiments, the one or more conditions associated with insomnia is selected from the group consisting of difficulty falling asleep at the beginning of the night, difficulty staying asleep, waking up frequently during the night, waking up too early in the morning, being unable to fall back asleep, or a combination thereof. In some embodiments, the insomnia is sleep onset insomnia. In some embodiments, the insomnia is sleep maintenance insomnia. In some embodiments, the insomnia is early morning awakening insomnia. In some embodiments, the subject is suffering from depression. In some embodiments, the subject is suffering from psychosis. In some embodiments, the subject is suffering from Parkinson’s disease. In some embodiments, providing the composition to the subject provides total sleep time and restores normal sleep architecture in the subject’s with insomnia by increasing slow wave sleep early in the night. In some embodiments, providing the composition increases stage 2 sleep late in the night in the subject. In some embodiments, providing the composition does not suppress REM sleep. In some embodiments, providing the composition does not increase rebound insomnia. In some embodiments, the oral composition is administered as a timed-release capsule that releases the one or more compounds gradually throughout the night to maintain consistent therapeutic levels thereby treating insomnia. In some embodiments, the oral composition is administered sublingually to ensure rapid absorption and quick onset of action thereby treating insomnia. In some embodiments, the method further includes providing the subject cognitive behavioral therapy (CBT) techniques to enhance the overall efficacy of the oral composition. In some embodiments, the method further includes administering light therapy. In some embodiments, the treating insomnia provides the subject a full night’s sleep. In some embodiments, the treating insomnia provides the subject a restful night’s sleep. In some embodiments, the treating insomnia provides the subject an increase in Slow-Wave-Sleep 1-4. In some embodiments, the treating insomnia-3-provides the subject an increase in REM sleep. In some embodiments, the treating insomnia decreases the time to sleep onset in the subject. In some embodiments, the time to sleep onset is from about 15 minutes to about 180 minutes. In some embodiments, the treating insomnia increases the average sleep length in the subject. In some embodiments, the average sleep length is increased from about 15 minutes to about 180 minutes. In some embodiments, the oral composition is administered to the subject prior to sleep.

[0009] Some aspects of the disclosure relate to a method for providing improved sleep maintenance in a subject in need thereof. In some embodiments, the method includes providing an oral composition as described herein, wherein the oral composition is administered in an amount sufficient to improve sleep maintenance in the subject in need thereof. In some embodiments, the oral composition is administered as a timed-release capsule that releases the one or more compounds gradually throughout the night to maintain consistent therapeutic levels thereby providing improved sleep maintenance. In some embodiments, the oral composition is administered sublingually to ensure rapid absorption and quick onset of action thereby providing improved sleep maintenance. In some embodiments, the method further includes providing the subject cognitive behavioral therapy (CBT) techniques to enhance the overall efficacy of the oral composition. In some embodiments, the method further includes administering light therapy. In some embodiments, improving sleep maintenance provides the subject a full night’s sleep. In some embodiments, improving sleep maintenance provides the subject a restful night’s sleep. In some embodiments, the improving sleep maintenance provides the subject an increase in Slow-Wave- Sleep 1-4. In some embodiments, improving sleep maintenance provides the subject an increase in REM sleep. In some embodiments, improving sleep maintenance decreases the time to sleep onset in the subject. In some embodiments, the time to sleep onset is from about 15 minutes to about 180 minutes. In some embodiments, improving sleep maintenance increases the average sleep length in the subject. In some embodiments, the average sleep length is increased from about 15 minutes to about 180 minutes. In some embodiments, the oral composition is administered to the subject prior to sleep.

[0010] Some aspects of the disclosure relate to a method for inducing sedation, inducing sleep, reducing locomotor activity, inducing somnolence, or treating insomnia in a mammal. In some embodiments, the method includes providing an oral composition comprising at least one carrier and at least one compound selected from Table A. In some embodiments, the-4-one or more compounds is selected from compounds 19, 22, or 23, or a salt thereof. In some embodiments, the one or more compounds is compound 19, or a salt thereof. In some embodiments, the one or more compounds is compound 22, or a salt thereof. In some embodiments, the one or more compounds is selected from compounds 1, 6, 7, 8, 9, 11, 13, 14, 15, 16, 17, 25, or a salt thereof. In some embodiments, the one or more compounds is compound 1, or a salt thereof. In some embodiments, the one or more compounds is compound 24, or a salt thereof. In some embodiments, the one or more compounds is compound 25, or a salt thereof. In some embodiments, the one or more compounds is compound 26, or a salt thereof. In some embodiments, the oral composition is formulated as a dietary supplement, a food ingredient or an additive, a medical food, a functional food, a nutraceutical or a pharmaceutical composition. In some embodiments, the oral composition is in a dosage form configured as one of a soft-gel capsule, a hard capsule, liquid, powder, granule, and a tablet. In some embodiments, the oral composition comprises 0.01% to 99% w / w of the one or more compounds. In some embodiments, the one or more compounds is derived from a plant extract. In some embodiments, the oral composition comprises 0.01% to 99% w / w of the plant extract. In some embodiments, the plant source is Capparis spinosa or Citrus Aurantium Dulcis. In some embodiments, the oral composition further comprises a preservative, a sweetener, a coloring agent, an additive, a flavoring agent, or a combination thereof. In some embodiments, the preservative is from about 0.01% to about 5% by weight of the oral composition. In some embodiments, the one or more compounds is unbound to a lignocellulosic material or does not comprise lignin, cellulose, or pectin. In some embodiments, with a proviso that the one or more compounds is not an extract from a natural source. In some embodiments, the at least one compound is an orexin receptor 2 antagonist. In some embodiments, the oral composition an orexin receptor 1 antagonist. In some embodiments, the oral composition comprises between 1 mg to about 5000 mg of the at least one compound. In some embodiments, the one or more conditions associated with insomnia is selected from the group consisting of difficulty falling asleep at the beginning of the night, difficulty staying asleep, waking up frequently during the night, waking up too early in the morning, being unable to fall back asleep, or a combination thereof. In some embodiments, providing the oral composition to the subject provides total sleep time and restores normal sleep architecture in the subject’s with insomnia by increasing slow wave sleep early in the night. In some embodiments, administering the composition increases stage 2 sleep late in the night in the subject. In some embodiments,-5-administering the composition does not suppress REM sleep. In some embodiments, administering the composition does not increase rebound insomnia. In some embodiments, the oral composition is administered as a timed-release capsule that releases the oral composition gradually throughout the night to maintain consistent therapeutic levels thereby treating insomnia. In some embodiments, the oral composition is administered sublingually to ensure rapid absorption and quick onset of action thereby treating insomnia. The method of any one of claims 1 to 28, further comprising providing the subject cognitive behavioral therapy (CBT) techniques to enhance the overall efficacy of the oral composition. In some embodiments, further comprising administering light therapy. In some embodiments, treating insomnia provides the subject a full night’s sleep. In some embodiments, treating insomnia provides the subject a restful night’s sleep. In some embodiments, treating insomnia provides the subject an increase in Slow-Wave-Sleep 1-4. In some embodiments, treating insomnia provides the subject an increase in REM sleep.

[0011] Some aspects of the disclosure relate to a method for providing improved sleep maintenance in a subject in need thereof. In some embodiments, the method includes providing a compound selected from Table A. In some embodiments, the one or more compounds is selected from compounds 19, 22, or 23, or a salt thereof. In some embodiments, the one or more compounds is compound 19, or a salt thereof. In some embodiments, the one or more compounds is compound 22, or a salt thereof. In some embodiments, the one or more compounds is selected from compounds 1, 6, 7, 8, 9, 11, 13, 14, 15, 16, 17, 25, or a salt thereof. In some embodiments, the one or more compounds is compound 1, or a salt thereof. In some embodiments, the one or more compounds is compound 24, or a salt thereof. In some embodiments, the one or more compounds is compound 25, or a salt thereof. In some embodiments, the one or more compounds is compound 26, or a salt thereof. In some embodiments, the oral composition is formulated as a dietary supplement, a food ingredient or an additive, a medical food, a functional food, a nutraceutical or a pharmaceutical composition. In some embodiments, the oral composition is in a dosage form configured as one of a soft-gel capsule, a hard capsule, liquid, powder, granule, and a tablet. In some embodiments, the oral composition is administered as a timed-release capsule that releases the oral composition gradually throughout the night to maintain consistent therapeutic levels thereby providing improved sleep maintenance. In some embodiments, improving sleep maintenance comprises sustaining sleep for at least a predetermined minimum duration following sleep onset without significant interruption. In some embodiments, improving sleep maintenance-6-comprises reducing the number of nocturnal awakenings experienced by the subject. In some embodiments, improving sleep maintenance comprises reducing the frequency of transitions from deeper sleep stages to lighter sleep stages or wakefulness. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The features and advantages of the compositions and methods described herein will become apparent from the following description, taken in conjunction with the accompanying drawings. These drawings depict certain aspects of the compositions and methods described in the present application, and thus, are not to be considered limiting. In the drawings, similar reference numbers or symbols typically identify similar components, unless context dictates otherwise. The drawings may not be drawn to scale.

[0013] FIG.1 illustrates a graph depicting in vitro bioactivity of compounds as orexin2 receptor antagonists of the disclosure.

[0014] FIG.2 illustrates a graph depicting in vitro bioactivity of compound 1 against orexin receptor 2 and orexin receptor 1.

[0015] FIG.3 illustrates a graph depicting in vitro bioactivity of compound 5 against orexin receptor 2 and orexin receptor 1.

[0016] FIG.4 illustrates a graph depicting in vitro bioactivity of compound 6 against orexin receptor 2 and orexin receptor 1.

[0017] FIG.5 illustrates a graph depicting in vitro bioactivity of compound 1 against orexin receptor 2 and orexin receptor 1.

[0018] FIG.6 illustrates a graph depicting in vitro bioactivity of compound 21 against orexin receptor 2 and orexin receptor 1.

[0019] FIG.7 illustrates a graph depicting in vitro bioactivity of compound 22 against orexin receptor 2 and orexin receptor 1.

[0020] FIG.8 illustrates a graph depicting in vitro bioactivity of compound 23 against orexin receptor 2 and orexin receptor 1.

[0021] FIG.9 illustrates a graph depicting in vitro bioactivity of compound 24 against orexin receptor 2 and orexin receptor 1.

[0022] FIG.10 illustrates a graph depicting in vitro bioactivity of compound 25 against orexin receptor 2 and orexin receptor 1.-7-

[0023] FIG.11 illustrates graphs depicting in vitro bioactivity of compound 26 against orexin receptor 2 and orexin receptor 1.

[0024] FIG.12 illustrates graphs depicting in vitro bioactivity of compound 27 against orexin receptor 2 and orexin receptor 1.

[0025] FIG.13 illustrates graphs depicting in vitro bioactivity of compound 28 against orexin receptor 2 and orexin receptor 1.

[0026] FIG.14 illustrates a decision-making tree from a tolerability study.

[0027] FIG.15 illustrates a graph depicting body weight change. DETAILED DESCRIPTION OF THE DISCLOSURE

[0028] This disclosure provides, among other things, the discovery of compounds, compositions, and methods for improving, restoring, modulating, or maintaining sleep in a subject. In some aspects, the compositions include one or more compounds as described herein and a carrier. In some aspects, methods include orally administering one or more compounds as described herein or a composition as described herein, thereby improving, restoring, modulating, or maintaining sleep in a subject. In some embodiments, the composition may, for example, promote the maintenance of sleep leading to a restful night’s sleep, further improving the quality of a person’s sleep, or treating insomnia. The compounds and compositions described herein employed in various embodiments of the present disclosure have been shown to be antagonists to certain receptors that may relate to the induction and modulation of sleep.

[0029] Moreover, the compounds and compositions disclosed herein may also be useful in treating, or modulating sleep maintenance insomnia. Definitions

[0030] Unless expressly defined otherwise, technical and / or scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The use of either the conjunction “or” or “and” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is-8-not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term “comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0031] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0032] While the disclosure has been illustrated and described in detail in the foregoing description, such description is to be considered illustrative or exemplary and not restrictive. The disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the disclosure and the appended claims.

[0033] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

[0034] Compounds disclosed herein having at least one chiral center they may exist as a racemate or as each enantiomer, and may exist as enantiomeric-enriched mixtures of the enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present invention. Furthermore, the crystalline forms for the compounds disclosed herein may exist as alternative polymorphs. Such polymorphs are included in one embodiment of the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are included in one embodiment of the present invention.

[0035] The term “pharmaceutically acceptable salt,” as used herein, refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some-9-embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine, lysine, and the like.

[0036] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient,” as used herein, includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0037] By “effective amount” it is meant an amount sufficient that when administered to the patient an amount of the drug is provided to achieve an effect. In the case of a therapeutic method, this effect may be the treatment of the sleep disorder. Therefore, the “effective amount” may be a “therapeutically effective amount”. By “therapeutically effective amount” it is meant an amount sufficient that when administered to the subject an amount of drug is provided to treat the disease or a symptom of the disease.

[0038] As used herein, the terms “treating”, “treatment”, “treat” and the like mean affecting a subject, tissue or cell to obtain a desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partially preventing, or reducing the-10-severity of, a disease or associated symptom, and / or may be therapeutic in terms of a partial or complete cure of a disease. For example, a reference to “treating” a sleep disorder therefore could encompasses: (a) assisting the subject to fall asleep; (b) assisting the subject remain asleep once sleep has been achieved; (c) relieving or ameliorating the effects of the sleep disorder, e.g. enhancing wakefulness during non-sleep periods; or (d) preventing the sleep disorder from occurring in a subject predisposed to, or at risk of, the sleep disorder, so that the sleep disorder does not develop or occur in the subject, or develops in a less severe form.

[0039] The term “halogen,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine.

[0040] Any amine, hydroxyl, or carboxyl side chain on the compounds disclosed herein can be esterified or amidified. The procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.

[0041] As used herein, “Ca to Cb” or “Ca-Cb” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C1 to C4 alkyl” group or a “C1-C4alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. Likewise, for example, cycloalkyl group may contain from “a” to “b”, inclusive, total atoms, such as a C3-C8 cycloalkyl group, 3 to 8 carbon atoms in the ring(s). If no “a” and “b” are designated with regard to an alkyl, cycloalkyl, or cycloalkenyl, the broadest range described in these definitions is to be assumed. Similarly, a “4 to 7 membered heterocyclyl” group refers to all heterocyclyl groups with 4 to 7 total ring atoms, for example, azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine, morpholine, and the like. As used herein, the term “C1-C6” includes C1, C2, C3, C4, C5and C6, and a range defined by any of the two preceding numbers. For example, C1-C6 alkyl includes C1, C2, C3, C4, C5 and C6 alkyl, C2-C6 alkyl, C1-C3 alkyl, etc. Similarly, C3-C8 carbocyclyl or cycloalkyl each includes hydrocarbon ring containing 3, 4, 5, 6, 7 and 8 carbon atoms, or a range defined by any of the two numbers, such as C3-C7cycloalkyl or-11-C5-C6cycloalkyl. As another example, 3 to 10 membered heterocyclyl includes 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, or a range defined by any of the two preceding numbers, such as 4 to 6 membered or 5 to 7 membered heterocyclyl.

[0042] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

[0043] The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Wherever a substituent is described as being “optionally substituted” that substituent may be substituted with one of the above substituents.

[0044] As used herein, “cycloalkyl” refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups may-12-range from C3to C10, in other embodiments it may range from C3to C6. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated. When substituted, substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including an aryl and a heteroaryl.

[0045] As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group of the compounds may be designated as “C1-4 heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “C1-4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0046] As used herein, the term “amino” refers to a “-NRARB” group in which RAand RBare each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0047] As used herein, “aryl” refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and-13-amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. When substituted, substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0048] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine. A heteroaryl group may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. When substituted, substituents on a heteroayl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0049] As used herein, “heterocyclyl” refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as “3-6-14-membered heterocyclyl” or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2- oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3- dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0050] The terms “purified,” “substantially purified,” and “isolated” as used herein, refer to compounds disclosed herein being free of other, dissimilar compounds with which the compounds of the invention are normally associated in their natural state, so that the compounds of the invention comprise at least 0.5%, 1%, 5%, 10%, or 20%, and most preferably at least 50% or 75% of the mass, by weight, of a given sample.

[0051] Substituted groups are based upon or derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be “substituted,” or “optionally substituted,” the group is substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), C3-C7- carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heterocyclyl- C1-C6-alkyl (optionally substituted with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1- C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heteroaryl (optionally substituted-15-with halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., –CF3), halo(C1-C6)alkoxy (e.g., –OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O- carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0052] The term “subject,” as used herein, refers to a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0053] The term “sleep maintenance insomnia” as used herein refers to the inability to stay asleep or to resume sleep after waking in the middle of the sleep cycle.

[0054] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens and / or deuteriums.

[0055] The term “about,” as used herein, refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. When a value is preceded by the term about, the component is not intended to be limited strictly to that value, but it is intended to include amounts that vary from the value. Compounds

[0056] In some aspects, the disclosure provides for a compound of Formula (I)-16-

[0057] Incribed herein. In some embodiments, the salt is suitable for oral consumption. In some embodiments, the salt is a pharmaceutically acceptable salt.

[0058] In some embodiments, Formula (I) is represented by Formula (IA)

[0059] In some emo ments, ormua () s represente y ormula (IB)-17-

[0060] In some aspects, the disclosure provides for a compound Formula (II)

[0061] In some em a (I), (IA), (IB), or (II), R1may be selected from H, deuterium, hydroxyl, halogen, cyano, optionally substituted amino, optionally substituted –C1-C6alkyl, optionally substituted –O-C1-C6alkyl, optionally substituted –C3-C8cycloalkyl, optionally substituted –C3-C8heteroalkyl, optionally substituted –C3-C8heterocyclyl, optionally substituted –C6-C10 aryl, or optionally substituted –O-C6-C10 aryl. In some embodiments, R1is H. In some embodiments, R1is hydroxyl. In some embodiments, R1is optionally substituted –O-C1-C6alkyl.

[0062] In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), R2may be selected from H, deuterium, hydroxyl, halogen, cyano, optionally substituted amino, optionally substituted –C1-C6alkyl, optionally substituted –O-C1-C6alkyl, optionally substituted –C3-C8 cycloalkyl, optionally substituted –C3-C8 heteroalkyl, optionally substituted –C3-C8 heterocyclyl, optionally substituted –C6-C10 aryl, or optionally substituted –O-C6-C10 aryl. In some embodiments, R2is H. In some embodiments, R2is hydroxyl. In some embodiments, R2is optionally substituted –O-C1-C6alkyl.

[0063] In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), R3may be selected from H, deuterium, hydroxyl, halogen, cyano, optionally substituted amino, optionally substituted –C1-C6alkyl, optionally substituted –O-C1-C6alkyl, optionally substituted –C3-C8 cycloalkyl, optionally substituted –C3-C8 heteroalkyl, optionally substituted –C3-C8 heterocyclyl, optionally substituted –C6-C10 aryl, or optionally substituted –O-C6-C10 aryl. In some embodiments, R3is H. In some embodiments, R3is hydroxyl.-18-

[0064] In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), R4may be selected from H, deuterium, hydroxyl, halogen, cyano, optionally substituted amino, optionally substituted –C1-C6 alkyl, optionally substituted –C1-C6 alkenyl, optionally substituted –O-C1-C6alkyl, optionally substituted –C3-C8cycloalkyl, optionally substituted –C3-C8heteroalkyl, optionally substituted –C3-C8 heterocyclyl, optionally substituted –C6-C10 aryl, or optionally substituted –O-C6-C10 aryl. In some embodiments, R4is H. In some embodiments, R4is hydroxyl. In some embodiments, R4is optionally substituted –C1-C6alkenyl. In some embodiments, R2is optionally substituted –O-C1-C6 alkyl.

[0065] In some embodiments of the compounds of Formula (I), (IA), or (IB), R5may be selected from H, deuterium, hydroxyl, halogen, cyano, optionally substituted amino, optionally substituted –C1-C6alkyl, optionally substituted –C1-C6alkenyl, optionally substituted –O-C1-C6alkyl, optionally substituted –C3-C8 cycloalkyl, optionally substituted –C3-C8 heteroalkyl, optionally substituted –C3-C8 heterocyclyl, optionally substituted –C6-C10 aryl, or optionally substituted –O-C6-C10aryl. In some embodiments, R5is H. In some embodiments, R5is hydroxyl. In some embodiments, R5is optionally substituted –C1-C6 alkenyl.

[0066] In some embodiments of the compounds of Formula (I), (IA), or (IB), R6may be selected from H, deuterium, hydroxyl, halogen, cyano, optionally substituted amino, optionally substituted –C1-C6alkyl, optionally substituted –C1-C6alkenyl, optionally substituted –O-C1-C6alkyl, optionally substituted –C3-C8 cycloalkyl, optionally substituted –C3-C8 heteroalkyl, optionally substituted –C3-C8heterocyclyl, optionally substituted –C6-C10aryl, or optionally substituted –O-C6-C10aryl. In some embodiments, R6is H. In some embodiments, R6is hydroxyl. In some embodiments, R6is optionally substituted –C1-C6 alkenyl.

[0067] In some embodiments of the compounds of Formula (I), (IA), or (IB), R7may be selected from H, deuterium, hydroxyl, halogen, cyano, optionally substituted amino, optionally substituted –C1-C6 alkyl, optionally substituted –C1-C6 alkenyl, optionally substituted –O-C1-C6 alkyl, optionally substituted –C3-C8 cycloalkyl, optionally substituted –C3-C8 heteroalkyl, optionally substituted –C3-C8heterocyclyl, optionally substituted –C6-C10aryl, or optionally substituted –O-C6-C10aryl. In some embodiments, R7is H. In some embodiments, R7is hydroxyl. In some embodiments, R7is optionally substituted –C1-C6 alkenyl.

[0068] In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), X is a bond or optionally substituted –C1-C6alkyl. In some embodiments of the compounds of Formula-19-(I), (IA), (IB), or (II), X is a bond. In some embodiments of the compounds of Formula (I), (IA), (IB), or (II),X is –C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), X is methylene.

[0069] In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), each dashed bond is independently present or absent. In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), one dashed bond is present and one dashed bond is absent. In some embodiments In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), both dashed bonds are absent.

[0070] In some embodiments, the optionally substituted C3-C8 heterocyclyl is . In some embodiments, the optionally substituted C3-C8ide. In some embodiments, the optionally substituted C3-C8 heterocyclyl is selected from the group consisting of glucose, mannose, fructose, and xylose, and rhamnose. In some embodiments, the optionally substituted C3-C8 heterocyclyl is an enantiomer, and may be D-glucose. In some embodiments, the optionally substituted C3-C8 heterocyclyl is . In some embodiments, the optionally substituted C3-C8-20--C8ndto a naturally occurring source, but may, for example, not be a naturally occurring compound. In some embodiments, a compound according to Formula (I), (IA), (IB), or (II), may be chemically modified from a naturally occurring compound. For example, a compound according to Formula (I), (IA), (IB), or (II), may be deuterated at one or more locations to replace a hydrogen, and is not itself a naturally occurring compound.

[0071] In some embodiments of the compounds of Formula (I), (IA), (IB), or (II), are selected from Compounds of Table A, salt thereof, or pharmaceutically acceptable salts thereof. Table A depicts compounds according to the disclosure, and may include isomers and stereoisomers of the compounds portrayed. Table A Cmpd ID Structure-21--22--23--24--25--26--27--8-

[0072] In some embodiments, the compound of Formula (I) does not include Compound 1, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 24, 25, 26, or a combination thereof. In some embodiments, the compound of Formula (I) does not include Compound 1, 18, 24, 25, 26, or a combination thereof.

[0073] In some embodiments, the disclosed chemical structures may contain glucosides, or other structures where the sugar part is selected from the nonlimiting examples of glucose, fructose, galactose, mannose, xylose, rhamnose, sialic acid, and a sugar derivative. The metabolites of such structures may vary depending on the specific sugar / glucoside; however, a primary metabolic reaction for glucosides is hydrolysis. This process involves the breaking of the-29-glycosidic bond between the glucose unit and the aglycone (the non-sugar part of the molecule). Enzymes called glucosidases, which are present in various organisms, facilitate this reaction. The hydrolysis yields a sugar component (glucose) and the aglycone. Accordingly, the disclosure provides for aglycones for any of the disclosed compounds listed in Table A. In some embodiments, the disclosure provides for substituted flavonoids, substituted flavanones, substituted flavones, substituted chalcones, and substituted anthraquinones. In some embodiments, a flavonoid core molecule may be produced from a chalcone by isomerization with the enzyme chalcone isomerase (CHI) for the generation of the flavanone group.

[0074] A salt of a compound of this disclosure refers to a compound that possesses the desired pharmacological activity of the parent compound and includes: (1) an acid addition salt, formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic camphorsulfonic acid, acid, 4- toluenesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1- carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or ( 2) a salt formed when an acidic proton present in the parent compound is replaced.

[0075] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or may be stereoisomeric mixtures, and include all diastereomeric, and enantiomeric forms. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. Likewise, it-30-is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0076] It is understood that the compounds described herein can be labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0077] It is understood that the compounds described herein can be labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0078] It is understood that the oral compositions, formulations, and methods described herein include the use of crystalline forms, amorphous phases, and / or pharmaceutically acceptable salts, solvates, hydrates, and conformers of compounds of some embodiments, as well as metabolites and active metabolites of these compounds having the same type of activity. A conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) of atoms about a rotating bond. In specific embodiments, the compounds described-31-herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Other forms in which the compounds of some embodiments can be provided include amorphous forms, milled forms and nano-particulate forms.

[0079] Likewise, it is understood that the compounds described herein, such as compounds of some embodiments, include the compound in any of the forms described herein (e.g., pharmaceutically acceptable salts, prodrugs, crystalline forms, amorphous form, solvated forms, enantiomeric forms, tautomeric forms, and the like). Compositions

[0080] In aspects, disclosed herein are compositions comprising one or more compounds described herein and a carrier. In some embodiments, the one or more compounds are plant-derived. In some embodiments, the one or more compounds are derived from a cell. In some embodiments, the one or more compounds are synthetically produced. In some embodiments, the composition is an oral composition.

[0081] In some embodiments, the composition includes a plant extract including one or more compounds as described herein and a carrier. As used herein, an “extract” refers a composition containing a desired compound of interest which is separated from other substances present in the natural source material from which the oral composition was obtained. Plant extracts can be obtained from any plant tissue including a whole plant; plant part such as shoot vegetative organs / structures (for example, leaves, stems and tubers), roots, flowers and floral organs / structures (for example, bracts, sepals, petals, stamens, carpels, anthers and ovules), seed (including embryo, endosperm, and seed coat) and fruit (the mature ovary); plant tissue (for example, vascular tissue, ground tissue, and the like); or cell (for example, guard cells, egg cells, and the like), and progeny and cultures or cell lines of the same. In some embodiments, the extract-32-is generally recognized as safe for human consumption. Accordingly, in certain embodiments the extract is from an edible source. In this respect, the extract is an edible extract. Extracts can be prepared by freezing, grinding, macerating, pulverizing and / or fermenting the source material of interest, subjecting the source material to solvent extraction, and separating the insoluble material from soluble material. In this respect, an “extract” of the disclosure can be crude, fractionated, sub- fractionated, separated, isolated, enriched or purified, without being limited thereto.

[0082] In some embodiments, the plant extract may be a crude extract. As used herein, “crude” refers to compounds or molecules that have not been entirely separated from the components of the original composition in which it was present. In embodiments pertaining to fractions or sub- fractions, a molecule in crude extract may be subjected to partial separation to provide a less crude extract containing other substances. By comparison, the term “isolated” means that a compound or molecule is substantially enriched or purified with respect to the complex cellular milieu in which it naturally occurs, such as in a crude extract. When an isolated molecule is enriched or purified, the absolute level of purity is not critical and those skilled in the art can readily determine appropriate levels of purity according to the use to which the material is to be put. In some circumstances, the isolated molecule forms part of a composition (for example a more or less crude extract containing many other substances), which may for example contain other components. In other circumstances, the isolated molecule may be purified to essential homogeneity, for example as determined spectrophotometrically, by NMR or by chromatography (for example LC-MS).

[0083] Suitable solvents for preparing an extract include, e.g., n-pentane, hexane, butane, chloroform, dichloromethane, di-ethyl ether, acetonitrile, water, butanol, isopropanol, ethanol, methanol, glacial acetic acid, acetone, norflurane (HFA134a), ethyl acetate, dimethyl sulfoxide, heptafluoropropane (HFA227), and subcritical or supercritical fluids such as liquid carbon dioxide and water, or a combination thereof in any proportion. When solvents such as those listed above are used, the resultant extract typically contains non-specific lipid-soluble material. This can be removed by a variety of processes including “winterization”, which involves chilling to a specified temperature, typically -20° C followed by filtration or centrifugation to remove waxy ballast, extraction with subcritical or supercritical carbon dioxide or non-polar solvents (e.g., hexane) and by distillation.-33-

[0084] In some embodiments, the plant extract includes Platymiscium praecox. In some embodiments, the plant extract includes a purified or crude extract of Platymiscium praecox. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0085] In some embodiments, the plant extract includes Berberis dictyota. In some embodiments, the plant extract includes a purified or crude extract of Berberis dictyota. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0086] In some embodiments, the plant extract includes Ceratiola ericoides. In some embodiments, the plant extract includes a purified or crude extract of Ceratiola ericoides. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0087] In some embodiments, the plant extract includes Crinum asiaticum. In some embodiments, the plant extract includes a purified or crude extract of Crinum asiaticum. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived-34-directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0088] In some embodiments, the plant extract includes Cryptocarya chinensis. In some embodiments, the plant extract includes a purified or crude extract of Cryptocarya chinensis. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0089] In some embodiments, the plant extract includes Dalbergia cochinchinensis. In some embodiments, the plant extract includes a purified or crude extract of Dalbergia cochinchinensis. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0090] In some embodiments, the plant extract includes Caeslpinia sappan. In some embodiments, the plant extract includes a purified or crude extract of Caeslpinia sappan. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a-35-temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0091] In some embodiments, the plant extract includes Vaccinium myrtillus. In some embodiments, the plant extract includes a purified or crude extract of Vaccinium myrtillus. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0092] In some embodiments, the plant extract includes Dodonaea viscosa. In some embodiments, the plant extract includes a purified or crude extract of Dodonaea viscosa. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0093] In some embodiments, the plant extract includes Onychium siliculosum. In some embodiments, the plant extract includes a purified or crude extract of Onychium siliculosum. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0094] In some embodiments, the plant extract includes Miliusa balansae. In some embodiments, the plant extract includes a purified or crude extract of Miliusa balansae. In some-36-embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0095] In some embodiments, the plant extract includes Andrographis paniculata. In some embodiments, the plant extract includes a purified or crude extract of Andrographis paniculata. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. I In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0096] In some embodiments, the plant extract includes Oroxylum indicum. In some embodiments, the plant extract includes a purified or crude extract of Oroxylum indicum. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0097] In some embodiments, the plant extract includes Eucalyptus globulus. In some embodiments, the plant extract includes a purified or crude extract of Eucalyptus globulus. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the-37-seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0098] In some embodiments, the plant extract includes Capparis spinosa. In some embodiments, the plant extract includes a purified or crude extract of Capparis spinosa. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0099] In some embodiments, the plant extract includes Citrus Aurantium Dulcis. In some embodiments, the plant extract includes a purified or crude extract of Citrus Aurantium Dulcis. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from leaves. In some embodiments, the extract may be derived directly from whole seeds. In some embodiments, the extract may be derived directly from flowers. In some embodiments, the extract may be derived directly from roots. In some embodiments, the seeds, leaves, flowers and / or roots may be ground into a powder, which is then heated to a temperature selected from a range of about 30 to 100° C., to remove oils prior to proceeding with an extraction step.

[0100] In some embodiments, the oral composition includes an extract from one or more plant source. In some embodiments, the oral composition includes an extract from two or more plant sources. In some embodiments, the oral composition includes an extract from three or more plant sources.

[0101] In some embodiments, the extract as described herein includes juices, infusions, and fermentation residues. The products fermentation plant-derived extracts or processed fractions thereof find use in consumable compositions such as health-promoting compositions or tonics for human and animals.

[0102] In some embodiments, the composition includes one or more compounds or an extract of the present disclosure at about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40,-38-45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% w / w, or ranges including and / or spanning the aforementioned values. In some embodiments, the composition includes from about 0.1% to about 10% of one or more compounds or an extract as described herein. In some embodiments, the composition includes from about 0.1% to about 5% of one or more compounds or an extract as described herein. In some embodiments, the composition includes from about 1% to about 10% of one or more compounds or an extract as described herein. In some embodiments, when one or more compounds or an extract of the present disclosure is provided or administered as pharmaceuticals, nutraceuticals, or dietary supplements to humans and animals, they can be given per se or as a composition containing, for example, 0.1 to 99% active ingredient in combination with an acceptable carrier. In some embodiments, the compound or extract of the present disclosure may be provided or administered at about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 % w / w, or ranges including and / or spanning the aforementioned values. In some embodiments, the plant extracts described herein include one or more compounds selected from Table A. In some embodiments, the compositions described herein include one or more compounds selected from Table A. In some embodiments, the one or more compounds selected from Table A include Compounds 1, 19, 20, 21, 22, 23, 24, 25, 26, or a combination thereof.

[0103] In some embodiments, the composition may include one or more compounds as described herein and a suitable carrier or excipient. In some embodiments, the one or more compounds described herein may be in a ratio from about 10:1 to about 1:10, or ranges including and / or spanning the aforementioned values. In some embodiments, the one or more compounds described herein may be in a ratio from about 10:1, 9.5:1, 8.5:1, 8.0:1, 7.5:1, 7:1, 6.5:1, 6:1, 5.5:1, 5:1, 4.5:1, 4:1, 3.5:1, 3.0:1, 2.5:1, 2.0:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10. In some embodiments, the composition includes one or more compounds described in Table A. In some embodiments, the one or more compounds selected from Table A include Compounds 1, 19, 20, 21, 22, 23, 24, 25, 26, or a combination thereof.

[0104] In some embodiments, the disclosure provided herein provides for a composition comprising one or more compounds as described herein and a carrier. In some embodiments, the carrier is an acceptable carrier suitable for oral consumption. In some embodiments, the acceptable carrier is a pharmaceutically acceptable carrier. In some-39-embodiments, the acceptable carrier is a food grade carrier. In some embodiments, the one or more compounds are substantially pure compounds. In some embodiments, the composition is an oral composition. The term “carrier” as used herein means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier should be compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials that can serve as carriers include: (1) sugars, such as lactose, glucose, fructose, maltose, and sucrose; (2) starches, such as corn starch, tapioca starch, rice starch, wheat starch, and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, microcrystalline cellulose, methylcellulose, ethyl cellulose, cellulose acetate, and hydroxyl propyl methyl cellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter, carnauba wax, beeswax, paraffin wax, candelilla wax, shellac wax, rice bran wax, and suppository waxes; (9) oils, such as vegetable oil, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol and glycerol (glycerin); (11) polyols, such as glycerin, xylitol, erythritol, maltitol, isomalt, lactitol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; (22) lipids and / or phospholipids; and (23) other nontoxic compatible substances employed in conventional formulations. Examples of food grade carriers include vegetable proteins, soy proteins, ion exchangers, soft gels, oils, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, PEG, maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, rice flour, magnesium stearate, stearic acid, croscarmellose sodium, sodium starch glycolate, crospovidone, sucrose, vegetable gums, lactose, methylcellulose, povidone, carboxymethylcellulose, corn starch, and-40-mixtures thereof. Other examples of pharmaceutically acceptable carriers may be found, for example, in AN’EL'S PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS (9th Ed., Lippincott Williams and Wilkins (2010)), PHARMACEUTICAL SCIENCES (8th Ed., Mack Publishing Co. (1990) or REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (1st Ed., Lippincott Williams & Wilkins (2005)), which are incorporated in their entirety. In some embodiments, the carrier is about 0.5% to about 80% (w / w) of the composition. In some embodiments, the carrier is about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 7.5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 70%, about 75%, about 80% (w / w) of the composition, or ranges including, between, and / or spanning the aforementioned values.

[0105] In some embodiments, the oral composition may further include a preservative. In some embodiments, the preservative may be in an amount from about 0.01%, 0.05%, 0.1%, 0.15%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0% w / w, or ranges including and / or spanning the aforementioned values. In some embodiments, the preservative may be, but not limited to, the group selected from sodium benzoate, methyl parabens, propyl parabens, sodium nitrite, sulfur dioxide, sodium sorbate, ascorbic acid, tocopherols, calcium propionate, citric acid, sorbic acid, butylated hydroxtoluene (BHT), butylated hydroxyanisole (BHA), alcohol, such as ethyl alcohol, rosemary extract, and potassium sorbate. Other suitable preservatives include, but are not limited to, salts of edetate, (also known as salts of ethylenediaminetetraacetic acid, or EDTA, such a disodium EDTA).

[0106] In some embodiments, the oral composition may further include a sweetener. In some embodiments, the sweetener may be in an amount from about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or ranges including and / or spanning the aforementioned values. In some embodiments, the sweetener may include a natural sweetener. In some embodiments, the sweetener may include a synthetic sweetener. Non-limiting examples of sweeteners include sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose, high fructose corn syrup, levulose, galactose, corn syrup solids, tagatose, polyols (e.g., sorbitol, mannitol, xylitol, lactitol, erythritol,-41-and maltitol), hydrogenated starch hydrolysates, isomalt, trehalose, stevia, sucralose, aspartame, saccharina, acesulfame potassium, and mixtures thereof.

[0107] In some embodiments, the oral composition may further include a flavoring agent. In some embodiments, the flavoring agent may be in an amount from about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or ranges including and / or spanning the aforementioned values. In some embodiments, the flavoring agent may include natural or artificial flavors. In a particular embodiment, the flavoring agent comprises an essential oil, such as an oil derived from a plant or a fruit, peppermint oil, spearmint oil, other mint oils, clove oil, cinnamon oil, oil of wintergreen, bay, thyme, cedar leaf, nutmeg, allspice, sage, mace, and almonds. In another particular embodiment, the flavoring agent comprises a plant extract or a fruit essence such as apple, banana, watermelon, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, and mixtures thereof. In still another particular embodiment, the flavoring agent comprises a citrus flavor, such as an extract, essence, or oil of lemon, lime, orange, tangerine, grapefruit, citron, or kumquat.

[0108] In some embodiments, the oral composition may further include a coloring agent. In some embodiments, the coloring agent may be in an amount from about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or ranges including and / or spanning the aforementioned values. In some embodiments, the coloring agent may be selected from, but not limited to, natural food colorings, artificial food colorings, color additives derived from fruits and vegetables, and combinations thereof.

[0109] In some embodiments, the oral composition may further include at least one additive. In some embodiments, the additive may be in an amount from about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one additive may be an emulsifier. In some embodiments, the additive may include one or more vitamin. In some embodiments, the additive may include one or more minerals. In some embodiments, the additive may include a stabilizer.-42-

[0110] In some embodiments, the composition as described herein may include two or more compounds of Formula (I), (IA), (IB), or (II). In some embodiments, the two or more compounds described herein may be in a ratio from about 10:1 to about 1:10, or ranges including and / or spanning the aforementioned values. In some embodiments, the two or more compounds described herein may be in a ratio from about 10:1, 9.5:1, 8.5:1, 8.0:1, 7.5:1, 7:1, 6.5:1, 6:1, 5.5:1, 5:1, 4.5:1, 4:1, 3.5:1, 3.0:1, 2.5:1, 2.0:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10. In some embodiments, the two or more compounds may be selected from Table A, a salt, or isomer thereof. In some embodiments, the two or more compounds selected from Table A include Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or a combination thereof. In some embodiments, one of the two or more compounds includes Compound 1. In some embodiments, one of the two or more compounds includes Compound 2. In some embodiments, one of the two or more compounds includes Compound 3. In some embodiments, one of the two or more compounds includes Compound 4. In some embodiments, one of the two or more compounds includes Compound 5. In some embodiments, one of the two or more compounds includes Compound 6. In some embodiments, one of the two or more compounds includes Compound 7. In some embodiments, one of the two or more compounds includes Compound 8. In some embodiments, one of the two or more compounds includes Compound 9. In some embodiments, one of the two or more compounds includes Compound 10. In some embodiments, one of the two or more compounds includes Compound 11. In some embodiments, one of the two or more compounds includes Compound 12. In some embodiments, one of the two or more compounds includes Compound 13. In some embodiments, one of the two or more compounds includes Compound 14. In some embodiments, one of the two or more compounds includes Compound 15. In some embodiments, one of the two or more compounds includes Compound 16. In some embodiments, one of the two or more compounds includes Compound 17. In some embodiments, one of the two or more compounds includes Compound 18. In some embodiments, one of the two or more compounds includes Compound 19. In some embodiments, one of the two or more compounds includes Compound 20. In some embodiments, one of the two or more compounds includes Compound 21. In some embodiments, one of the two or more compounds includes Compound 22. In some embodiments, one of the two or more compounds includes Compound 23. In some embodiments, one of the two or more compounds includes Compound 24. In some-43-embodiments, one of the two or more compounds includes Compound 25. In some embodiments, one of the two or more compounds includes Compound 26. In some embodiments, the two or more compounds include at least two of Compounds 12, 14, 16, and 18. In some embodiments, the composition includes two or more compounds including Compounds 21 and 22. In some embodiments, the two or more compounds are in a ratio from about 10:1 to about 1:10. In some embodiments, the two or more compounds are in a ratio from about 5:1 to about 1:5. In some embodiments, the two or more compounds are in a ratio from about 2.5:1 to about 2:1. In some embodiments, the two or more compounds are in a ratio from about 2.5:1 to about 1:2.5. In some embodiments, the two or more compounds are in a ratio from about 5:1. In some embodiments, the two or more compounds are in a ratio from about 4:1. In some embodiments, the two or more compounds are in a ratio from about 3:1. In some embodiments, the two or more compounds are in a ratio from about 2:1. In some embodiments, the two or more compounds are in a ratio from about 1:1. In some embodiments, the two or more compounds are in a ratio from about 1:2. In some embodiments, the two or more compounds are in a ratio from about 1:3. In some embodiments, the two or more compounds are in a ratio from about 1:4. In some embodiments, the two or more compounds are in a ratio from about 1:5. In some embodiments, the oral composition includes a compound of Formula (I) but does not include a compound selected from the group of Compounds 3, 10, 12, 18, or a combination thereof. In some embodiments, the oral composition includes two or more compounds of Formula (I), (IA), (IB), or (II), but does not include a compound selected from the group of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or a combination thereof. In some embodiments, the oral composition consists essentially of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or a combination thereof, unbound to a lignocellulosic material. In some embodiments, the oral composition includes two or more compounds selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or a combination thereof, with the proviso that the two or more compound is not bound to lignin, cellulose, and / or pectin in the oral composition. In some embodiments, the oral composition includes two or more compounds selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or a combination thereof, with the proviso that the two or more compound is not from a naturally source extract or extracted from a natural source, for example, a plant.-44-

[0111] In some embodiments, the oral composition may consist essentially of one more compounds as described herein unbound to a lignocellulosic material. Lignocellulosic material refers to a composite material composed primarily of lignin, cellulose, and hemicellulose. These are naturally occurring polymers found in the cell walls of plants. Lignocellulosic materials are characterized by their rigid structure, high strength, and resistance to decomposition. This material is commonly derived from wood, grasses, and the inedible parts of plants. In some embodiments, the composition does not include lignin, cellulose, and / or pectin. In some embodiments, the composition does not include an extract from a natural source. Formulations

[0112] Aspects of the disclosure relate to formulation including one or more compounds as described herein. In some embodiments, a substantially pure compound or extract comprising one or more compounds of this disclosure can be combined with a carrier and provided in any suitable form for consumption by, provided to, or administration to a subject. In some embodiments, the one or more compounds or extract comprising one or more compounds is added as an exogenous ingredient or additive to a consumable. Suitable consumable forms include, but are not limited to, a dietary supplement, food ingredient or additive, a food product, a medical food, nutraceutical or pharmaceutical composition. In some embodiments, the one or more compounds or extract comprising one or more compounds is provided in either a liquid, granular, or powder form. In some embodiments, the formulation may be a food product.

[0113] A composition comprising a plant extract or a compound of this disclosure can be combined with a carrier and provided in any suitable form for consumption by or administration to a subject. In this respect, the plant extract or compound is added as an exogenous ingredient or additive to the consumable. Suitable consumable forms include, but are not limited to, a dietary supplement, food ingredient or additive, a medical food, nutraceutical or pharmaceutical composition. In some embodiments, the plant extract or compound is provided in either a liquid or powder form.

[0114] A food ingredient or additive is an edible substance intended to result, directly or indirectly, in becoming a component of or otherwise affecting the characteristic of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food). A food product, in particular a-45-functional food, is a food fortified or enriched during processing to include additional complementary nutrients and / or beneficial ingredients. A food product according to this disclosure can, e.g., be in the form of butter, margarine, sweet or savory spreads, condiment, biscuits, health bar, bread, cake, cereal, candy, confectionery, soup, milk, yogurt or a fermented milk product, cheese, juice-based and vegetable-based beverages, fermented beverages, shakes, flavored waters, tea, oil, or any other suitable food. In some embodiments, the food product is a whole-food product in which the concentration of the compound has been enriched through particular post-harvest and food production processing methods to levels that provide an efficacious amount of the compound. In some embodiments, the food product includes one or more compounds as described herein and a fiber source. In some embodiments, the food product includes one or more compounds as described herein. In some embodiments, the food product is a food bar. In some embodiments, the food bar comprises from about 0.01% to about 20% (w / w) of one or more compounds as described herein. In some embodiments, the food bar comprises from about 0.1% to about 10% (w / w) of one or more compounds as described herein. In some embodiments, the food product is a crisp. In some embodiments, the food crisp comprises from about 0.01% to about 20% (w / w) of one or more compounds as described herein. In some embodiments, the food crisp comprises from about 0.1% to about 10% (w / w) of one or more compounds as described herein.

[0115] The compounds, compositions and extracts of the present disclosure can be prepared as nutritional formulations such as foods, including medical or functional foods. A “medical or functional food” is defined as being consumed as part of a usual diet but which has been demonstrated to have physiological benefits and / or to reduce the risk of a disease or condition such as a chronic disease, beyond basic nutritional functions. By way of example, but not limitation, medical foods and functional foods may include one or more of the following ingredients: a compound described herein, a composition described herein, an extract described herein, vitamins, minerals, herbs, botanicals, amino acids, dietary substances intended to supplement the diet by increasing total dietary intake, concentrates, metabolites, constituents, extracts or combinations of any of the foregoing. Dietary supplements may also be incorporated into food stuffs, such as functional foods designed to promote health or to prevent disease or disorders. If administered as a medicinal preparation, the composition can be administered, either as a prophylaxis or treatment, to a patient in any of a number of methods. In some embodiments, the compositions described herein may be administered alone or in combination with other-46-additives or pharmaceutical agents and can be combined with a physiologically acceptable carrier thereof. The effective amount and method of administration and aim of the particular formulation can vary based on the individual subject, the stage of the disease or condition, and other factors evident to one skilled in the art. In the case of a pharmaceutical formulation as well as a nutraceutical formulation, during the course of the treatment, the concentration of the subject compositions may be monitored (for example, blood plasma levels may be monitored) to ensure that the desired level is maintained.

[0116] In some embodiments, food product includes a carbohydrate. A variety of carbohydrates are used in food products, such as various sugars and starches. Carbohydrates are an important source of energy for the body, including complex carbohydrates (like whole grains and vegetables) and simple carbohydrates (like sugar and refined grains). There are several common carbohydrates that are used in food products, including: starch, sugar, fructose, maltodextrin, dextrose, corn syrup, oligosaccharides, cellulose, complex carbohydrates, such as inulin that may be added as a prebiotic fiber in processed foods. According to the disclosure, the concentration of carbohydrates may vary depending on the intended use of a product. In some embodiments, carbohydrates may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, carbohydrates may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, a food product may comprise carbohydrates in a range with high and low values independently selected from about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or ranges including, between, and / or spanning the aforementioned values.

[0117] In some embodiments, the food product may include a sugar. Sugars, such as high fructose corn syrup, sucrose, glucose syrup, dextrose, and other sweeteners are often added to processed foods to make them more palatable. Additionally, sugar alcohols or maltodextrins, may be added to food products to reduce caloric content and / or to enhance nutritional profile of the product. In some embodiments, a food product may comprise one or a plurality of saccharides that are slowly or incompletely digested by humans, if not totally indigestible. These sugars can include isomaltose, panose and branched oligomers having a degree of polymerization of four or greater. Additional non-limiting examples of sugars include sucrose, HFCS, fructose, brown sugar (which can be either partially or fully refined), powdered sugar (also known as confectioner's sugar), high fructose corn syrup, honey, molasses, maple syrup, agave nectar, coconut sugar, date-47-sugar, fruit juice concentrates, maltodextrin, dextrose, glucose syrup, maple syrup, molasses, and lactose. According to the disclosure, the concentration of sugars may vary depending on the intended use of a product. In some embodiments, sugar may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, the sugar(s) component comprises from about 2% to about 10% by weight of the composition. In some embodiments, sugars may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, a food product may comprise sugars in a range with high and low values independently selected from about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or ranges including, between, and / or spanning the aforementioned values.

[0118] In some embodiments, the food product includes a fiber source. In some embodiments, the food product includes from about 5% to about 30% (w / w) fiber. In some embodiments, the food product includes at least 10% fiber. In some embodiments, the food product includes at least 15% fiber. In some embodiments, the food product includes at least 20% fiber. In some embodiments, the food product includes at least 30% fiber. In some embodiments, the fiber may be selected from psyllium husk, inulin, beta-glucans, acacia fiber, pectin, wheat dextrin, cellulose, fructooligosaccharides, guar gum, fruit fiber, or a combination thereof. In some embodiments, the fiber is a soluble dietary fiber.

[0119] In some embodiments, the food product may include a protein. Proteins may be included in a range of concentrations depending on the product. Protein sources can include soy protein, soy flour, soy protein isolate, whey protein isolate, casein, gelatin, legume protein isolates, soy protein concentrate, egg albumin or egg white, wheat protein concentrate, legume protein concentrates and mixtures thereof. In some embodiments, meat products like beef jerky, sausages, or meatballs, may include proteins as a primary ingredient. Proteins may be included at concentrations ranging from about 10% to about 25% of the total ingredients. In dairy products like cheese, yogurt, or milk, proteins like casein or whey may be the primary ingredient. Proteins may be included at concentrations ranging from about 3% to about 15% of the total ingredients. In plant-based products like tofu, tempeh, or seitan, proteins from soy, peas, legumes, or wheat may be primary ingredient. Proteins may be included at concentrations ranging from about 10% to about 25% of the total ingredients. In energy bars and protein bars, proteins like whey or soy, or any protein according to the disclosure may be added to provide a source of protein. Proteins-48-may be included at concentrations ranging from about 10% to about 25% of the total ingredients. According to the disclosure, the concentration of proteins may vary depending on the intended use of a product. In some embodiments, proteins may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, proteins may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, a food product may comprise proteins in a range with high and low values independently selected from about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or ranges including, between, and / or spanning the aforementioned values.

[0120] In some embodiments, the food product may include a starch. In some embodiments, food products may additionally comprise a starch ingredient(s) in amounts sufficient to provide about 5% to 45%, or about 10%-30%, or about 15%-25 starch in the food products. Starchy components may include not only pure added cereal flours or other granulations but also any starchy fraction provided by other ingredients such as oat bran or soy protein. In some embodiments, a starch may comprise any conventionally employed starch or cereal flour ingredient, for use in a ready-to-eat cereal. Exemplary suitable starchy cereals include cereal flours from major cereal grains including wheat, rice, corn (maize), oats, barley, rye, or starch fractions isolated from the cereal flowers including, for example cornstarch, wheat starch, rice starch, and various treated starches including pre-gelatinized starches and / or modified starches.

[0121] In some embodiments, the food product may include a flour. Several types of flour may be used according to the disclosure. For example, common types of flour used in food products, include all-purpose flour (which like most other flour may include protein content), Whole wheat flour, Bread flour, Cake flour, pastry flour, self-rising flour, and gluten-free flour. According to the disclosure, the concentration of flour may vary depending on the intended use of a product. For example, in baked goods like bread, cakes, and cookies, flour is typically a main ingredient and may be included at concentrations ranging from 50% to 100% of the total dry ingredients. In soups and sauces, flour is often used as a thickener and may be included at concentrations ranging from 1% to 5% of the total ingredients. Batter and breading: In fried foods like chicken or fish, flour is often used as part of the batter or breading and may be included at concentrations ranging from 20% to 50% of the total dry ingredients. In snack foods, like crackers and chips, flour may be included at concentrations ranging from 30% to 70% of the total ingredients. In some embodiments, flour may comprise from about 1% by weight to about 95% by-49-weight of a food product. In some embodiments, flours may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, a food product may comprise flour in a range with high and low values independently selected from about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95% or ranges including, between, and / or spanning the aforementioned values.

[0122] In some embodiments, the food product may include a fat. In some embodiments, the food product may include an oil. In some embodiments, the food product may include one or more fats or oils. Several types of fats may be used according to the disclosure. For example, common types of fats include butter, margarine, vegetable oils, shortening, and lard. According to the disclosure, the concentration of fats may vary depending on the intended use of a product. In baked goods like cakes, cookies, and pastries, fats like butter, shortening, or oil are often used to provide moisture, flavor, and texture. In some embodiments, Fats may be included at concentrations ranging from 10% to 30% of the total ingredients. In some embodiments, like in sauces and dressings, fats like olive oil or mayonnaise are often used to provide flavor and texture. In some embodiments, Fats may be included at concentrations ranging from 10% to 30% of the total ingredients. In fried foods like chicken or French fries, fats like vegetable oil or lard are used for frying and may be included at concentrations ranging from 30% to 60% of the total ingredients. In snack foods like chips and crackers, fats like vegetable oil or palm oil are often used to provide flavor and texture. In some embodiments, Fats may be included at concentrations ranging from 10% to 30% of the total ingredients. In some embodiments, fats may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, fats may comprise from about 1% by weight to about 95% by weight of a food product. In some embodiments, a food product may comprise fat in a range with high and low values independently selected from about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or ranges including, between, and / or spanning the aforementioned values.

[0123] In some embodiments, the food product may include one or more additional ingredients. If desired, the disclosed food products may additionally include a variety of materials designed to improve their aesthetic or nutritional qualities. These adjuvant materials can include vitamin and / or mineral fortification, colors, flavors, sweetener(s), and mixtures thereof. The precise ingredient concentration may vary. Generally, however, such materials can each include about 0.01% to about 5%, or about 0.1% to 2% dry weight of a food product. One especially useful-50-material is common salt. In some embodiments, salt comprises about 0.1 to 5%, or about 0.5 to 4.0% of the food products.

[0124] In some embodiments, the food product is derived from a plant. In some embodiments, the food product is derived from hemp hulls. In some embodiments, the food product is a solid food. In some embodiments, the food product is a semi-solid food. In some embodiments, the food product is a puffed product, a bakery product, a pressed cake, a cooked product, a food bar, a cereal, a crisp, or a spread.

[0125] A dietary supplement is a product taken by mouth that contains a compound or extract of the disclosure and is intended to supplement the diet. A nutraceutical is a product derived from a food source that provides extra health benefits, in addition to the basic nutritional value found in the food. A pharmaceutical composition is defined as any component of a drug product intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans or other animals. Dietary supplements, nutraceuticals and pharmaceutical compositions can be found in many capsules, forms such as tablets, coated tablets, pills, capsules, pellets, granules, softgels, gelcaps, liquids, powders, emulsions, suspensions, elixirs, syrup, and any other form suitable for use. In some embodiments, the composition as described herein is provided as a dietary supplement. In some embodiments, the dietary supplement is provided as a capsule, tablet, powder, or in a liquid form. In some embodiments, the composition as described herein is provided as a nutritional supplement. In some embodiments, the nutritional supplement is provided as a capsule, tablet, powder, or in a liquid form. In some embodiments, the composition as described herein is provided as a pharmaceutical. In some embodiments, the pharmaceutical is provided as a capsule, tablet, powder, or in a liquid form.

[0126] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0127] Multiple techniques of administering a compound, salt and / or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion-51-and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound described herein, including a compound as described herein, or a pharmaceutically acceptable salt thereof, can be administered orally. In some embodiments, a compound described herein, including a compound of Formula (I), (IA), (IB), (II) or a salt thereof, can be administered orally. In some embodiments, a compound described herein, including a compound of Formula (I), (IA), (IB), (II) or a salt thereof, can be provided in a form for oral consumption.

[0128] One may also administer the compound, salt and / or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.

[0129] The oral compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and / or salt described herein formulated in a compatible pharmaceutical excipient may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0130] The compounds, salt and / or pharmaceutical composition can be provided to an administering physician or other health care professional in the form of a kit. The kit is a package which houses a container which contains the compound(s) in a suitable pharmaceutical composition, and instructions for administering the pharmaceutical composition to a subject. The kit can optionally also contain one or more additional therapeutic agents. The kit can also contain-52-separate doses of a compound(s) or pharmaceutical composition for serial or sequential administration. The kit can optionally contain one or more diagnostic tools and instructions for use. The kit can contain suitable delivery devices, for example, syringes, and the like, along with instructions for administering the compound(s) and any other therapeutic agent. The kit can optionally contain instructions for storage, reconstitution (if applicable), and administration of any or all therapeutic agents included. The kits can include a plurality of containers reflecting the number of administrations to be given to a subject.

[0131] In some embodiments, an oral composition as described herein is administered at a dose in the range of about 0.1 - 200 mg / kg body weight. In some embodiments, an oral composition as described herein dose is greater than, equal to, or about 0.1 mg, 0.3 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150mg, about 200 mg, about 300 mg. about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, an oral composition as described herein dose is about less than about 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150mg, or about 200 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the oral composition as described herein is administered as a single dose. In some embodiments, the oral composition as described herein is administered more than one dose. In some embodiments, the oral composition as described herein is administered more than one dose prior to bedtime. In some embodiments, the oral composition as described herein is administered in multiple doses throughout the night to maintain therapeutic levels.

[0132] For preparing solid compositions such as tablets or capsules, the compound or extract is mixed with a carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums) and other diluents (e.g., water) to form a solid composition. This solid composition is then subdivided into-53-unit dosage forms containing an effective amount of the compound of the present disclosure. The tablets or pills containing the compound or extract can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.

[0133] The liquid forms in which the compound or extract of the disclosure is incorporated for oral or parenteral administration include aqueous solution, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils as well as elixirs and similar vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional means with acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid); and artificial or natural colors and / or sweeteners.

[0134] Methods of preparing formulations or compositions of this disclosure include the step of bringing into association a compound or extract of the present disclosure with the carrier and, optionally, one or more accessory and / or active ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound or extract of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. As such, the disclosed formulation may consist of, or consist essentially of a compound or extract described herein in combination with a suitable carrier.

[0135] When a compound or composition of the present disclosure is administered as a dietary supplement, food ingredient or additive, a medical food, nutraceutical, food product, such as a fortified food, or pharmaceutical to humans and animals, they can be given per se or as a composition containing, for example, 0.1 to 99% active ingredient in combination with an acceptable carrier. In some embodiments, the one or more compounds or extract of the present disclosure may be administered at about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% w / w, or ranges including and / or spanning the aforementioned values.-54-

[0136] In some embodiments, the fortified food, food supplement, or medical food may further include one or more of a protein, carbohydrate and / or fat that is used in the body, preferably a human body, to sustain growth, repair, and vital processes, and to furnish energy. When provided as a fortified food, food supplement, or medical food, the compositions comprise selected compounds, compositions, or extracts of the disclosure such that they can be eaten at or about the same time as a food. In some embodiments, the fortified food, food supplement, or medical food are generally eaten within about one hour before or after the food is eaten. In some embodiments, the fortified food, food supplement, or medical food are generally eaten within about fifteen minutes before or after the food is eaten. In some embodiments, the fortified food, food supplement, or medical food are generally eaten within about five minutes before or after the food is eaten. In some embodiments, dietary supplement, or nutritional supplement also be eaten at the same time as the food, or even with fortified food, a food supplement, or medical food. Methods and Uses

[0137] In aspects, this disclosure provides methods and uses for improving, restoring, modulating, or maintaining sleep. Some embodiments include inducing sedation, inducing sleep, reducing locomotor activity, inducing somnolence, or treating insomnia in a subject. In accordance with such methods, an effective amount of the at least one compound or a composition of this disclosure is provided to a subject in need thereof. The term “subject” as used herein refers to an animal, preferably a mammal. In some embodiments, the subject is a veterinary, companion, farm, laboratory or zoological animal. In other embodiments, the subject is a human. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some-55-embodiments, the at least one compound is an extract of orange peel including compound 1 and compound 27.

[0138] Several signaling molecules that play a role in sleep have been identified. Various neurotransmitters, including noradrenaline, acetylcholine, histamine, dopamine, serotonin, and the neuropeptides orexin A and B (also referred to as hypocretins), promote wakefulness. Orexins are neuropeptides involved in the regulation of the sleep-wake cycle, feeding pattern, energy balance, and stress in mammals. Dysregulation or loss of orexin signaling has been linked to narcolepsy. In some embodiments, the plant extract or compound as described herein are orexin receptor antagonists. In some embodiments, the plant extract or compound as described herein include an orexin receptor 2 (OX2) antagonist. In some embodiments, the plant extract or compound as described herein include an orexin receptor 1 (OX1) antagonist. In some embodiments, the plant extract or compound as described herein are capable of being an antagonist for both orexin receptor 1 and orexin receptor 2. In some embodiments, the compounds or compositions described herein may be useful in a method of antagonizing orexin receptor activity in a subject in need of such inhibition comprising the administration of an effective amount of the compound. The utility of the compounds in accordance with the present disclosure as OX1 and / or OX2 antagonists may be readily determined without undue experimentation by methodology known in the art, including the “FLIPR Ca2+Flux Assay” (Okumura et al., Biochem. Biophys. Res. Comm.280:976-981, 2001).

[0139] Some embodiments relate to a method to treat, reduce, modulate, or ameliorate insomnia in a subject. In some embodiments, the method includes providing to the subject at least one compound, composition, or formulation as described herein. In some embodiments, treating, reducing, modulating, or ameliorating insomnia in the subject may treat, reduce, modulate, or ameliorate one or more conditions associated with insomnia. In some embodiments, the one or more conditions associated with insomnia include, but are not limited to, difficulty falling asleep at the beginning of the night, difficulty staying asleep, waking up frequently during the night, waking up too early in the morning, being unable to fall back asleep, or a combination thereof. In some embodiments, the at least one compound, composition, or formulation is provided in an effective amount to treat, reduce, modulate, or ameliorate insomnia or one or more conditions associated with insomnia. In some embodiments, the insomnia is sleep onset insomnia. In some embodiments, the insomnia is sleep maintenance insomnia. In some embodiments, the insomnia-56-is early morning awakening insomnia. In some embodiments, the method includes administering a timed-release capsule that releases the active compound gradually throughout the night to maintain consistent therapeutic levels and improve sleep maintenance. In some embodiments, the method includes a dosage form configured for immediate release to provide rapid onset of action of the one or more compounds. In some embodiments, the compound, composition, or formulation is administered sublingually to ensure rapid absorption and quick onset of action, beneficial for treating sleep onset insomnia. In some embodiments, treating insomnia reduces the frequency of nocturnal awakenings in the subject. In some embodiments, treating insomnia enhances the subject’s sleep efficiency, calculated as the ratio of total sleep time to time spent in bed. In some embodiments, treating insomnia reduces the subject’s sleep disturbances caused by external factors such as noise or light. In some embodiments, the method involves a combination of the compound, composition, or formulation with cognitive behavioral therapy (CBT) techniques to enhance the overall efficacy of insomnia treatment. In some embodiments, the method includes the use of light therapy in conjunction with the compound, composition, or formulation to regulate circadian rhythms and improve sleep patterns, particularly in cases of early morning awakening insomnia. In some embodiments, the method includes a tapering strategy for the compound, composition, or formulation to reduce the risk of rebound insomnia upon discontinuation of the treatment. In some embodiments, the method includes providing age-specific formulations of the compound, composition, or formulation, tailored to meet the unique physiological needs of different age groups, such as children or the elderly. In some embodiments, the compound, composition, or formulation is designed to minimize side effects such as daytime drowsiness or cognitive impairment, enhancing the safety profile of the treatment for insomnia. Some embodiments relate to methods for treating one or more conditions or symptoms of a subject suffering from a sleep disorder, such as insomnia. In some embodiments, the subject may be provided the one or more compounds, the composition, or the formulation as described herein. In some embodiments, the individual may suffer from chronic insomnia (e.g., lasting more than 3-4 weeks) or non-chronic insomnia. For chronic or non-chronic insomnia, a subject may experience difficulties in sleep onset, sleep maintenance (interruption of sleep during the night by periods of wakefulness), sleep duration, sleep efficiency, premature early-morning awakening, or a combination thereof. Insomnia may also be attributable to the concurrent use of other medication. Non-chronic insomnia can be, for example, short-term or transient insomnia. Both chronic and non-chronic insomnia can-57-be primary (not attributable to another condition) or secondary (attributable to another condition, such as a disease like depression or chronic fatigue syndrome). In some embodiments, the subject can be one who is not suffering from insomnia as a component of a disease or a patient who is otherwise healthy. Primary insomnia refers to insomnia that is not attributable to another mental disorder, a general medical condition, or substance use. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is an extract of orange peel including compound 1 and compound 27.

[0140] Some embodiments relate to a method to induce sedation in a subject. In some embodiments, the method includes providing one or more compounds, a composition, or formulation as described herein in an amount sufficient to induce sedation in a subject. In some embodiments, the one or more compounds include compounds 1, 19, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35 or a combination thereof. In some embodiments, the one or more compounds is formulated to synergistically support the body's natural ability to relax. In some embodiments, the method supports achieving a state of calmness that is also associated with fostering a positive mood or general emotional well-being. In some embodiments, the method aids in achieving a restful state conducive to normal sleep patterns, allowing the individual to wake feeling refreshed and without undue daytime grogginess. In some embodiments, the recommended serving of the one or more compounds is intended for general adult consumption to support relaxation or as an aid in preparing for a normal sleep cycle. In some embodiments, the method helps an individual achieve a state of relaxation from which they can readily transition back to normal alertness as their daily activities require. In some embodiments, the method involves consuming an amount of Compound 1, Compound 19, Compound 22, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or a combination thereof, which is recognized for supporting the body's inherent relaxation responses.-58-In some embodiments, the one or more compounds are selected due to their natural origin or a biochemical profile that aligns with supporting the body’s normal physiological pathways involved in achieving rest and recovery. In some embodiments, the method is intended for use in non- clinical settings, such as at home, to assist individuals in unwinding after daily stressors or to support preparation for a more restful night's sleep. In some embodiments, guidance is provided with the one or more compounds encouraging consumers to consider their individual dietary plans or consult with a healthcare practitioner, particularly if they have pre-existing health considerations or are taking other supplements or medications. In some embodiments, the method is used to complement established lifestyle practices aimed at stress management and supporting healthy sleep hygiene, such as mindfulness exercises or maintaining a consistent pre-sleep routine. In some embodiments, the promotion of relaxation or readiness for sleep is achieved in a way that supports the body's natural rhythms without leading to concerns of habituation with regular use as directed. In some embodiments, the method aids an individual in experiencing a quicker transition into a relaxed state or a sense of readiness for sleep compared to typical unassisted efforts to unwind. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is an extract of orange peel including compound 1 and compound 27.

[0141] Some embodiments relate to a method to reduce locomotor activity in a subject. In some embodiments, the method includes providing one or more compounds, a composition, or formulation as described herein in an amount sufficient to reduce locomotor activity in a subject. In some embodiments, the one or more compounds include compounds 1, 19, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35 or a combination thereof. In some embodiments, the reduction in locomotor activity is experienced by the subject as a welcome state of physical calm and a noticeable decrease in restlessness. In some embodiments, the method aids in achieving a level of reduced physical activity that is conducive to effective relaxation, meditation, or settling down before sleep. In some embodiments, the one or more compounds, or a composition thereof, are consumed approximately 30 to 60 minutes prior to an intended period of rest, quiet reflection, or bedtime to support a gentle transition to stillness. In some embodiments, the support for reduced locomotor activity and-59-physical quietude is maintained for a duration that helps an individual unwind or comfortably remain in a restful state. In some embodiments, the experienced reduction in locomotor activity is characterized by a feeling of bodily ease and tranquility, rather than a sense of sluggishness or heaviness. In some embodiments, the method helps to foster both physical stillness and a corresponding sense of mental quiet, thereby supporting overall repose and serenity. In some embodiments, individuals consuming the one or more compounds, including compounds 1, 19, 22, 27, 29, 30, 31, 32, 33, 34, 35 or a combination thereof, report feeling less physically fidgety or agitated during times of normal daily stress or while trying to relax. In some embodiments, the method is particularly suited for encouraging a physically quiet state in the evening, facilitating a smoother transition from the activities of the day to a restful night. In some embodiments, compounds 1, 19, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35 or combinations thereof, are selected for their recognized properties in supporting the body’s natural pathways that lead to physical calmness and reduced agitation. In some embodiments, the supported reduction in locomotor activity is achieved without substantially interfering with the ability to perform light, voluntary movements or maintain comfortable, relaxed postures. In some embodiments, the method assists in quieting physical restlessness to better enable an individual to focus on mindful activities, reading, or other calming practices. In some embodiments, the amount of the one or more compounds provided is sufficient to encourage a noticeable decrease in restless movements while still allowing for comfortable and intentional light activity as desired by the subject. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is an extract of orange peel including compound 1 and compound 27.

[0142] Some embodiments relate to a method to induce somnolence in a subject. In some embodiments, the method includes providing one or more compounds, a composition, or formulation as described herein in an amount sufficient to induce somnolence in a subject. In some embodiments, the one or more compounds include compounds 1, 19, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35 or a combination thereof. In some embodiments, the method supports the onset of drowsiness typically within 30 to 60 minutes after consumption of the one or more compounds,-60-aligning with a natural bedtime routine. In some embodiments, the encouraged somnolence facilitates falling asleep and contributes to a night perceived by the subject as more restful or sound. In some embodiments, the method is intended to aid individuals in achieving a state of readiness for sleep, particularly during periods of occasional sleeplessness related to everyday stress or minor disruptions in their normal routine. In some embodiments, the one or more compounds, including compounds 1, 19, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35 or a combination thereof, are used to complement established good sleep hygiene practices, thereby further supporting the body's natural sleep-wake cycle. In some embodiments, the induced somnolence is characterized by a calm and peaceful transition into a sleep state, without feelings of being overly sedated. In some embodiments, the method not only aids in encouraging the initial phase of sleepiness but also supports maintaining a tranquil state conducive to uninterrupted rest throughout the night. In some embodiments, the amount of the one or more compounds provided is sufficient to gently encourage drowsiness and ease the process of falling asleep without resulting in significant grogginess or impairment to normal functioning the following morning. In some embodiments, the method is suitable for regular or as-needed use as a dietary supplement to help support consistent and healthy sleep patterns, without fostering concerns of habituation. In some embodiments, a specific combination of compounds, such as Compound 1 and Compound 22, is chosen for its synergistic qualities in promoting a state of peaceful drowsiness and readiness for sleep. In some embodiments, the subject reports a subjective improvement in the ease of falling asleep or the overall quality of their sleep experience when using the one or more compounds as part of their evening routine. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is an extract of orange peel including compound 1 and compound 27.

[0143] Some embodiments relate to a method to induce sedation in a subject. In some embodiments, the method includes providing one or more compounds, a composition, or formulation as described herein in an amount sufficient to induce sedation in a subject. In some embodiments, the one or more compounds includes compounds 1, 19, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35 or a combination thereof. In some embodiments, the sedation is induced within, for-61-example, 5-30 minutes, less than 15 minutes, of administration. In some embodiments, the induced sedation is characterized by a specific level on a recognized sedation scale (e.g., a score of 3 to 4 on the Ramsay Sedation Scale, a score of -2 to -4 on the Richmond Agitation-Sedation Scale). In some embodiments, the induced sedation is maintained for a duration of at least, for example, 1 hour, 2-4 hours. In some embodiments, sedation is induced to manage agitation or anxiety in the subject. In some embodiments, the subject is a human. In some embodiments, the subject is a non- human animal. In some embodiments, inducing sedation comprises achieving a reduction in locomotor activity of the subject by at least, for example, 50% or 75%. In some embodiments, the amount sufficient to induce sedation is administered as a single dose. In some embodiments, recovery from induced sedation occurs within, for example, 30 minutes or an 1 hour, after cessation of administration or peak effect. In some embodiments, providing the amount sufficient comprises titrating the dose of the one or more compounds, composition, or formulation to achieve a target level of sedation. In some embodiments, the subject is selected from a group consisting of subjects with anxiety disorders, subjects undergoing uncomfortable procedures, or subjects in an intensive care setting. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is an extract of orange peel including compound 1 and compound 27.

[0144] Some embodiments relate to a method to improve sleep maintenance in a subject. In some embodiments, the method includes providing one or more compounds, a composition, or formulation as described herein in an amount sufficient to improve sleep maintenance in a subject. In some embodiments, the one or more compounds includes compounds 1, 19, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35 or a combination thereof. In some embodiments, improving sleep maintenance comprises reducing the number of nocturnal awakenings experienced by the subject. In some embodiments, improving sleep maintenance comprises reducing the total time spent awake after sleep onset (WASO). In some embodiments, improving sleep maintenance comprises increasing the duration of consolidated sleep periods. In some embodiments, improving sleep maintenance comprises reducing the frequency of transitions from deeper sleep stages to lighter sleep stages or wakefulness. In some embodiments, the improved-62-sleep maintenance is characterized by an increase in sleep efficiency, calculated as the ratio of total sleep time to time in bed. In some embodiments, improving sleep maintenance comprises sustaining sleep for at least a predetermined minimum duration following sleep onset without significant interruption. In some embodiments, the improved sleep maintenance results in the subject reporting a more continuous and less fragmented night's sleep. In some embodiments, improving sleep maintenance comprises reducing premature awakening in the latter part of the sleep period. In some embodiments, the subject has a pre-existing condition characterized by fragmented sleep, and improving sleep maintenance comprises reducing said fragmentation. In some embodiments, improving sleep maintenance specifically targets the reduction of awakenings during the second half of the subject's typical sleep period. In some embodiments, improving sleep maintenance comprises maintaining an established sleep state with fewer arousals triggered by external stimuli. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is an extract of orange peel including compound 1 and compound 27.

[0145] Some embodiments relate to treating sleep maintenance in a subject in need thereof. In some embodiments, the method includes providing at least one compound, a composition, or formulation as described herein in an amount sufficient to treat sleep maintenance in the subject. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, Compound 27, Compound 28, Compound 29, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, sleep maintenance may include chronic insomnia. In some embodiments, the subject suffers from depression. In some embodiments, the subject suffers from one or more psychiatric conditions, such as Parkinson’s Disease. In some embodiments, providing the one or more compounds, the composition, or the formulation treats early termination of sleep or-63-premature final awakening. For example, many individuals may wake prematurely and not fall back asleep, thereby failing to achieve a full night of sleep. Many drugs that are effective in inducing or expediting sleep initiation do not provide much effect in maintaining sleep, particularly through the eighth and final hour of sleep period. In some embodiments, the one or more compounds, the composition, or formulation as described herein does not include a hangover effect. For example, the patient has difficulty awakening and / or feels sedated, sleepy, or disoriented and may demonstrate impairment of psychomotor function.

[0146] Some embodiments relate to methods for reducing or preventing premature awakening in a patient in need thereof. The methods can include the steps of identifying a patient with a sleep disorder characterized by premature termination of a sleep period within a desired duration, such as an 8-hour sleep period. Specifically, the patient experiences a sleep period that terminates prior to or during the final 60 minutes of the period. In some embodiments, the method includes providing to the subject at least one or more compounds, composition, or formulation as described herein that is effective in lengthening the sleep period. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the subject can experience a sleep period that terminates within the final 60, 45, 30, or 15 minutes. In other embodiments, the sleep period can terminate even earlier, such as during the final 90 minutes, the final 120 minutes, or longer. In some embodiments, the sleep period may be lengthened by administering a low dose of the one or more compounds, the composition, or formulation as described herein to extend the sleep period to terminate during or after the 7th hour (e.g., hour 7.5) of an 8-hour sleep period. Additionally, subjects can be identified as needing reduced wake time during or after the sleep period.

[0147] Some embodiments relate to methods for improving fragmented sleep in the final hours of a sleep period for a subject. In some embodiments, the method includes providing-64-at least one compound, a composition, or a formulation as described herein in an amount sufficient to improve fragmented sleep. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the fragmented sleep is improved during the final hour or the 8th hour of sleep. The methods may include, for example, identifying a patient suffering from or experiencing fragmented sleep during the last hour or hours of a sleep period and administering to the patient one or more compounds, compositions, or formulations as described herein. In some embodiments, the methods can be used to reduce or improve fragmented sleep during the 8th hour of a sleep period. In some embodiments, the at least one compound is an extract of orange peel including compound 1 and compound 27.

[0148] Some embodiments relate to methods of providing one or more compounds, compositions, or formulations as described herein to decrease wake time after sleep onset (WTAS) in individuals prone to early awakenings. In some embodiments, the subject may be provided the at least one compounds, the composition, or the formulation as described herein prior to the sleep period. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values.

[0149] Many cases of chronic insomnia are associated with conditions like diagnosable DSM-IV disorders, anxiety, depression, or disturbances in the physiological sleep-wake system. Non-chronic insomnia is often of short duration (e.g., less than 3-4 weeks) and may be caused by extrinsic or intrinsic factors, including environmental sleep disorders as defined by the-65-International Classification of Sleep Disorders (ICSD), such as inadequate sleep hygiene, altitude insomnia, or adjustment sleep disorder (e.g., bereavement). Short-term insomnia may also result from disturbances such as shift-work sleep disorder.

[0150] Some embodiments relate to methods and uses for modulating the activity of Orexin 1 receptor and Orexin 2 receptor. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject a compound of Formula (I), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the method and uses include providing at least compound 1 or a composition including compound 1. In some embodiments, the method and uses include providing two or more compounds include at least Compounds 23 and 24. In some embodiments, the orexin receptor modulator is administered to treat insomnia in the subject. In some embodiments, the orexin receptor modulator is administered to treat narcolepsy in the subject. In some embodiments, the orexin receptor modulator is administered to alleviate symptoms of anxiety in the subject. In some embodiments, the orexin receptor modulator is administered to reduce symptoms of depression. In some embodiments, the orexin receptor modulator is administered to enhance wakefulness in subjects with excessive daytime sleepiness. In some embodiments, the orexin receptor modulator is provided to treat a neurodegenerative condition associated with dysregulated sleep patterns. In some embodiments, the orexin receptor modulator specifically targets the orexin-1 receptor (OX1R) to treat addiction. In some embodiments, the orexin receptor modulator specifically targets the orexin-2 receptor (OX2R) to improve sleep initiation. In some embodiments, the orexin receptor modulator is administered in a controlled-release form to maintain therapeutic levels for at least 8 hours. In some embodiments, the orexin receptor modulator is administered to enhance cognitive performance in subjects with cognitive impairments associated with sleep disorders. In some embodiments, the orexin receptor modulator is suvorexant and is provided to a subject diagnosed with chronic insomnia. In some embodiments, the orexin receptor modulator is administered to mitigate jet lag in a subject traveling across time zones. In some embodiments, the orexin receptor modulator is administered to reduce sleep disturbances in a subject with post-traumatic stress disorder (PTSD). In some-66-embodiments, the orexin receptor modulator is administered to regulate circadian rhythm in a subject with shift work sleep disorder. In some embodiments, the oral composition further comprises a flavoring agent to increase patient compliance. In some embodiments, the orexin receptor modulator is co-administered with a sedative or hypnotic agent to enhance therapeutic efficacy. In some embodiments, the orexin receptor modulator is administered to improve the quality of sleep in elderly subjects with age-related sleep disturbances. In some embodiments, the orexin receptor modulator is administered to treat sleep-related adverse effects in subjects undergoing chemotherapy. In some embodiments, the orexin receptor modulator is administered to reduce nocturnal awakenings in subjects with obstructive sleep apnea undergoing continuous positive airway pressure (CPAP) therapy.

[0151] Some embodiments relate to a methods and uses for regulating wakefulness in a subject. Some embodiments relate to a method of improving wakefulness in a subject. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject a compound of Formula (I), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values.

[0152] Some embodiments relate to a methods and uses for suppressing arousal signals. Some embodiments relate to a method of inhibiting arousal signals in a subject’s brain. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. Some embodiments relate to a method of regulating arousal signals in a subject’s brain. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject a compound of Formula (I), or a salt thereof. In some embodiments,-67-the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the suppression of arousal signals results in the promotion of sleep onset. In some embodiments, the suppression of arousal signals reduces nighttime awakenings in the subject. In some embodiments, the suppression of arousal signals alleviates symptoms of hyperarousal in subjects with insomnia. In some embodiments, the suppression of arousal signals reduces physiological markers of arousal, including elevated heart rate and cortisol levels. In some embodiments, the suppression of arousal signals enables the subject to maintain a consolidated sleep duration of at least seven hours.

[0153] Some embodiments relate to methods and uses for regulating appetite. Some embodiments relate to a method for improving appetite in a subject. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject a compound of Formula (I), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values.-68-

[0154] Some embodiments relate to methods and uses for regulating energy homeostasis in a subject. Some embodiments relate to a method of improving energy homeostasis in a subject. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject a compound of Formula (I), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the method promotes weight loss by reducing excessive caloric intake in the subject. In some embodiments, the method reduces energy expenditure associated with hyperactivity or restlessness in the subject. In some embodiments, the regulation of energy homeostasis decreases symptoms of fatigue in the subject. In some embodiments, the regulation of energy homeostasis improves thermoregulation in the subject under varying environmental conditions.

[0155] Some embodiments relate to methods and uses for reducing wake-promoting effects of orexins in a subject. Some embodiments relate to a method of improving wake- promoting effects of orexins in a subject. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject a compound of Formula (I), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one-69-compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values.

[0156] Some embodiments relate to methods and uses for regulating energy balance in a subject. Some embodiments relate to a method for improving energy balance in a subject. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject a compound of Formula (I), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, improving energy balance includes increasing energy expenditure through enhanced physical activity levels in the subject. In some embodiments, the improvement in energy balance reduces excessive weight gain in the subject. In some embodiments, the improvement in energy balance promotes a reduction in abdominal fat accumulation in the subject. In some embodiments, the method reduces fatigue and increases daytime alertness to support an active lifestyle in the subject. In some embodiments, the improvement in energy balance restores circadian rhythm alignment, optimizing the subject’s sleep-wake cycle.

[0157] Some embodiments relate to methods and uses for regulating a mood disorder in a subject. Some embodiments relate to a method for improving a mood disorder in a subject. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject-70-a compound of Formula (I), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values.

[0158] Some embodiments relate to methods and uses for regulating a stress response in a subject. Some embodiments relate to a method for improving a stress response in a subject. In some embodiments, the method includes providing to a subject at least one compound or composition as described herein. In some embodiments, the method includes providing a subject a compound of Formula (I), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IA), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (IB), or a salt thereof. In some embodiments, the method includes providing a subject a compound of Formula (II), or a salt thereof. In some embodiments, the at least one compound is selected from a compound of Table A. In some embodiments, the at least one compound is Compound 1, Compound 19, Compound 22, or a combination thereof. In some embodiments, the at least one compound is provided at a dose of about 15 mg, 30 mg, 60 mg, 100 mg, 200 mg, 315 mg, 500 mg, or ranges including and / or spanning the aforementioned values. In some embodiments, the at least one compound is provided at a dose of about 30 mg / kg, 100 mg / kg, 315 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, regulating the stress response reduces the subject’s heart rate variability associated with stress. In some embodiments, regulating the stress response alleviates symptoms of anxiety in the subject. In some embodiments, the method decreases pro- inflammatory cytokine levels associated with chronic stress in the subject. In some embodiments, the regulation of the stress response improves cognitive performance in the subject under stressful-71-conditions. In some embodiments, regulating the stress response enhances resilience to future stressors by promoting adaptive physiological and behavioral responses in the subject.

[0159] In some embodiments, treating insomnia decreases sleep latency in the subject. In some embodiments, treating insomnia decreases sleep latency in the subject by at least 50%, by at least 60%, by at least 70%, by at least 80%, by at least 90%, by at least 95%, by at least 99%, or ranges including and / or spanning the aforementioned values.

[0160] In some embodiments, a method as described herein includes speedily inducing sleep in a subject by administering composition as described herein. In some embodiments, the subject falls asleep more quickly from about 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, 20%, 25,0%, 50.0%, 75.0%, or ranges including and / or spanning the aforementioned values.

[0161] In some embodiments, a method as described herein includes promoting good quality sleep in a subject by administering a composition as described herein. In some embodiments, the subject quality of sleep improves from about 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, 20%, 25,0%, 50.0%, 75.0%, or ranges including and / or spanning the aforementioned values.

[0162] In some embodiments, a method as described herein includes providing resultful sleep in a subject by administering a composition as described herein. In some embodiments, the subjects resultful sleep improves from about 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, 20%, 25,0%, 50.0%, 75.0%, or ranges including and / or spanning the aforementioned values.

[0163] In some embodiments, a method includes providing a full night’s sleep in a subject by administering a composition as described herein. In some embodiments, the subject sleeps longer on average by an additional about 15 min, 30 min, 45 min, 60 min, 75 min, 90 min, 105 min, 120 min, 135 min, 150 min, 165 min, 180 min, or ranges including and / or spanning the aforementioned values. In some embodiments, a method includes decreasing the time to sleep onset in a subject by administering a composition as described herein. In some embodiments, the subject decreases the time to sleep onset on average from about 15 min, 30 min, 45 min, 60 min, 75 min, 90 min, 105 min, 120 min, 135 min, 150 min, 165 min, 180 min, or ranges including and / or spanning the aforementioned values.-72-

[0164] In some embodiments, a method includes increasing Slow-Wave-Sleep 1-4 in a subject by administering a composition as described herein. In some embodiments, a method includes increasing REM sleep in a subject by administering a composition as described herein. In some embodiments, a method includes increasing deep sleep in a subject by administering a composition as described herein. There are many different periods of sleep a person goes through. These include Slow-Wave-Sleep 1 (SWS1), Slow-Wave-Sleep 2 (SWS 2), Slow-Wave-Sleep 3 (SWS 3) Slow-Wave-Sleep 4 (SWS 4) and Rapid Eye Movement (REM). SWS 1 and SWS 2 are both periods of light sleep where it is relatively easy to wake someone up. Light sleep is usually more frequent in the second half of sleep. SWS 3 and SWS 4 are both periods of deep sleep, where it is difficult to wake the sleeper. Deep sleep is more frequent in the first half of sleep and each period will get shorter each time afterward. REM is a period of sleep in which people have their most vivid dreams. The wave patterns are similar to the patterns in which a person is awake. For healthy people, SWS1 will occupy about 5% of sleep, SWS2 will occupy about 50% of sleep, SWS3 will occupy about 10% of sleep, SWS4 will occupy about 10% of sleep and REM will occupy about 25% of sleep. In some embodiments, the method may increase the Slow-Wave-Sleep 1 by about 1% to about 5% of the subject’s sleep. In some embodiments, the method may increase the Slow-Wave-Sleep 2 by about 10% to about 50% of the subject’s sleep. In some embodiments, the method may increase the Slow-Wave-Sleep 3 by about 2% to about 10% of the subject’s sleep. In some embodiments, the method may increase the Slow-Wave-Sleep 4 by about 2% to about 10% of the subject’s sleep. In some embodiments, the method may increase the REM by about 10% to about 25% of the subject’s sleep.

[0165] In some embodiments, a method improves a sleep disorder in a subject by administering to the subject a composition as described herein. Sleep disorders are described in the International Classification of Sleep Disorders (ICDS). ICDS-3 was published in 2014 and characterizes sleep disorders as belonging to one of the following classes: (1) Insomnias; (2) Sleep Related Breathing Disorders; (3) Central Disorders of Hypersomnolence; (3) Circadian Rhythm Sleep-Wake Disorders; (4) Parasomnias; (5) Sleep Related Movement Disorders. Accordingly, the sleep disorders to be treated by the oral composition described herein may include any sleep disorders from the classes (1) Insomnias; (2) Sleep Related Breathing Disorders; (3) Central Disorders of Hypersomnolence; (3) Circadian Rhythm Sleep-Wake Disorders; (4) Parasomnias; (5) Sleep Related Movement Disorders. In particular, the oral compositions may be effective in-73-the treatment of a sleep disorder selected from: insomnia, narcolepsy, hypersomnia, sleep apnea, periodic limb movement disorder, restless legs syndrome, nocturnal eating (drinking) syndrome, jet lag, shift work sleep disorder, irregular sleep-wake pattern, confusional arousals, sleepwalking, sleep terrors, sleep talking, nightmares, sleep paralysis, REM sleep behavior disorder, snoring, sleeping sickness, a sleep disorder associated with another disease or condition, or any other sleep disorder.

[0166] In some embodiments, the method to treat insomnia in a subject includes administering one or more compounds as described herein. In some embodiments, the method to treat insomnia in a subject includes administering an oral composition as described herein. Symptoms and severity of insomnia may be measured by the Insomnia Severity Index (ISI) questionnaire. Typically, the ISI is administered by a clinician, nurse or researcher or may be self- administered by the patient. The ISI assesses both night-time and daytime components of insomnia and is available in several languages. The ISI asks seven questions each to be scored on a scale of 0-4 relating to (1) the difficulty in falling asleep, (2) difficulty staying asleep, (3) problems waking too early, (4) satisfaction relating to current sleep patterns, (5) perception as to how noticeable the sleep problem may be to others, (6) degree of concern regarding the sleep problem, and (7) the extent to which the sleep problem interferes with daily functioning. The methods may provide an improvement in one or more of these seven aspects of insomnia. In some embodiments of the methods of treatment, the subject to be treated may have an initial ISI score of 7 or more, in some cases, the initial ISI score may be 10 or more. In some embodiments, a method of treating insomnia may provide a reduction of the ISI score of the patient relative to an initial ISI score. This reduction in ISI score may be by 1, 2, 3, 4, 5, 6 or more units on the ISI scale, and preferably results in the patient having an ISI score of 7 or less after treatment.

[0167] The ISI may be used alone to assess the severity of the subject’s insomnia or it may be used together with one or more other questionnaires, such as quality of life enjoyment and satisfaction questionnaire (Q-les-Q), work and social adjustment scale (WSAS), depression anxiety stress scale (DASS) questionnaire, dysfunctional beliefs about sleep (DBAS) questionnaire, multidimensional fatigue inventory questionnaire, and any other recognized questionnaire known in the field.

[0168] Typically the patient is assessed by one or more questionnaires prior to receiving treatment and then at regular intervals (e.g., an interval of 1, 2, 3, 4, 5, 6, 7 or 8 weeks)-74-during the course of treatment. The assessment during treatment may begin 2 weeks after commencement of treatment.

[0169] In some embodiments, the treatment may be maintained for up to 14 days, for example, the treatment may be maintained for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days. In some embodiments, the treatment is maintained for longer than 14 days, for example, for 3 weeks, 1, 2, 3, 4, 5, 6, 12, 18, 24, 36 months or longer.

[0170] Typically, the oral composition is administered once daily preferably a short time before the patient attempts to sleep. In some embodiments, the oral composition is administered within about 2 hours of the patient attempting to sleep, for example, within about 1 .5 hours, within about 1 hour or within about 30 minutes prior to sleep.

[0171] In some embodiments, the insomnia may be assessed by measuring one or more objective measures of sleep. Objective measures of sleep may be measured by polysomnography (PSG) and / or actigraphy. The objective measures of sleep may include measuring: Sleep Onset Latency (SO); Wake After Sleep Onset (WASO); Total Sleep Time (TST); Sleep Efficiency (SE); REM versus NREM sleep patterns including slow-wave sleep patterns and percentage of time in all sleep stages; sleep apnea; periodic limb movements; and combinations thereof. In some embodiments, a method of treating insomnia may provide an improvement in one or more objective measures of sleep, for example, 2, 3, 4, 5, 6 or more of the objective measures of sleep.

[0172] In some embodiments, the compounds or compositions of the present disclosure may be administered in combination with other compounds to improve sleep quality. In some embodiments, the compounds or compositions of the present disclosure may be administered in combination with other compounds to treat or prevent sleep disorders and sleep disturbances. In some embodiments, the other compounds may include, but are not limited to, sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT- 2A / 2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride,-75-carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and salts thereof, and combinations thereof, and the like, or the compound of the present invention may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

[0173] Accordingly, some aspects described herein relate to the following numbered alternatives:

[0174] 1. An oral composition, the oral composition comprising at least one carrier; and at least one compound selected from the group consisting of: , ,-76-, , , ,-77-,-78-, ,-79-.compound is f.native 1, wherein the one or more compound is is-80-

[0178] 5. The oral composition of alternative 1, wherein the one or more compound is of. e 1, wherein the one or more compound isf.ative 1, wherein the one or more compound is , or a salt thereof.. p sition of any one of alternatives 1 to 7, wherein the oral composition is formulated as a dietary supplement, food ingredient or additive, a medical food or functional food, nutraceutical or pharmaceutical composition.

[0182] 9. The oral composition of any one of alternatives 1 to 8, wherein the oral composition is in a dosage form configured as one of a soft-gel capsule, a hard capsule, liquid, powder, granule, and a tablet.

[0183] 10. The oral composition of alternative 8, wherein the oral composition is formulated as a functional food.-81-

[0184] 11. The oral composition of any one of alternatives 1 to 9, wherein the oral composition comprises 0.01% to 99% w / w of the one or more compounds.

[0185] 12. The oral composition of any one of alternatives 1 to 11, wherein the one or more compounds is derived from a plant extract.

[0186] 13. The oral composition of alternative 12, wherein the oral composition comprises 0.01% to 99% w / w of the plant extract.

[0187] 14. The oral composition of any one of alternatives 1 to 13, wherein the oral composition further comprises a preservative.

[0188] 15. The oral composition of alternative 14, wherein the preservative is from about 0.01% to about 5% by weight of the oral composition.

[0189] 16. The oral composition of any one of alternatives 1 to 15, wherein the oral composition further comprises a sweetener.

[0190] 17. The oral composition of any one of alternatives 1 to 16, wherein the oral composition further comprises a coloring agent.

[0191] 18. The oral composition of any one of alternatives 1 to 17, wherein the oral composition further comprises an additive.

[0192] 19. The oral composition of any one of alternatives 1 to 18, wherein the oral composition further comprises a flavoring agent.

[0193] 20. The oral composition of any one of alternatives 1 to 19, wherein the one or more compounds is unbound to a lignocellulosic material.

[0194] 21. The oral composition of any one of alternatives 1 to 20, with a proviso that the oral composition does not comprise lignin, cellulose, or pectin.

[0195] 22. The oral composition of any one of alternatives 1 to 21, with a proviso that the one or more compounds is not an extract from a natural source.

[0196] 23. The oral composition of any one of alternatives 1 to 22, wherein the oral composition comprises an orexin receptor 2 antagonist.

[0197] 24. The oral composition of any one of alternatives 1 to 23, wherein the oral composition an orexin receptor 1 antagonist.

[0198] 25. A method for treating insomnia or reducing, modulating, or ameliorating one or more conditions of insomnia in a subject in need thereof, the method comprising: administering an oral composition of any one of alternatives 1 to 24, wherein the oral composition-82-is administered in an amount sufficient to treat insomnia or reduce, modulate, or ameliorate one or more conditions of insomnia in the subject in need thereof.

[0199] 26. The method of alternative 25, wherein the one or more conditions associated with insomnia is selected from the group consisting of difficulty falling asleep at the beginning of the night, difficulty staying asleep, waking up frequently during the night, waking up too early in the morning, being unable to fall back asleep, or a combination thereof.

[0200] 27. The method of alternative 25 or 26, the insomnia is sleep onset insomnia.

[0201] 28. The method of alternative 25 or 26, the insomnia is sleep maintenance insomnia.

[0202] 29. The method of alternative 25 or 26, the insomnia is early morning awakening insomnia.

[0203] 30. The method of any one of alternatives 25 to 29, wherein the subject is suffering from depression.

[0204] 31. The method of any one of alternatives 25 to 30, wherein the subject is suffering from psychosis.

[0205] 32. The method of any one of alternatives 25 to 31, wherein the subject is suffering from Parkinson’s disease.

[0206] 33. The method of any one of alternatives 25 to 31, wherein administering the composition to the subject provides total sleep time and restores normal sleep architecture in the subject’s with insomnia by increasing slow wave sleep early in the night.

[0207] 34. The method of any one of alternatives 25 to 31, wherein administering the composition increases stage 2 sleep late in the night in the subject.

[0208] 35. The method of any one of alternatives 25 to 31, wherein administering the composition does not suppress REM sleep.

[0209] 36. The method of any one of alternatives 25 to 31, wherein administering the composition does not increase rebound insomnia.

[0210] 37. The method of any one of alternatives 25 to 32, wherein the oral composition is administered as a timed-release capsule that releases the oral composition gradually throughout the night to maintain consistent therapeutic levels thereby treating insomnia.-83-

[0211] 38. The method of any one of alternatives 25 to 37, the oral composition is administered sublingually to ensure rapid absorption and quick onset of action thereby treating insomnia.

[0212] 39. The method of any one of alternatives 25 to 38, further comprising providing the subject cognitive behavioral therapy (CBT) techniques to enhance the overall efficacy of the oral composition.

[0213] 40. The method of any one of alternatives 25 to 39, further comprising administering light therapy.

[0214] 41. The method of any one of alternatives 25 to 40, wherein treating insomnia provides the subject a full night’s sleep.

[0215] 42. The method of any one of alternatives 25 to 41, wherein treating insomnia provides the subject a restful night’s sleep.

[0216] 43. The method of any one of alternatives 25 to 42, wherein treating insomnia provides the subject an increase in Slow-Wave-Sleep 1-4.

[0217] 44. The method of any one of alternatives 25 to 43, wherein treating insomnia provides the subject an increase in REM sleep.

[0218] 45. The method of any one of alternatives 25 to 44, wherein treating insomnia decreases the time to sleep onset in the subject.

[0219] 46. The method of alternative 45, wherein the time to sleep onset is from about 15 minutes to about 180 minutes.

[0220] 47. The method of any one of alternatives 25 to 46, wherein treating insomnia increases the average sleep length in the subject.

[0221] 48. The method of alternative 47, wherein the average sleep length is increased from about 15 minutes to about 180 minutes.

[0222] 49. The method of any one of alternatives 25 to 48, wherein the oral composition is administered to the subject prior to sleep.

[0223] 50. A method for providing improved sleep maintenance in a subject in need thereof, the method comprising: administering an oral composition of any one of alternatives 1 to 24, wherein the oral composition is administered in an amount sufficient to improve sleep maintenance in the subject in need thereof.-84-

[0224] 51. The method of alternative 50, wherein the oral composition is administered as a timed-release capsule that releases the oral composition gradually throughout the night to maintain consistent therapeutic levels thereby providing improved sleep maintenance

[0225] 52. The method of alternative 50 or 51, the oral composition is administered sublingually to ensure rapid absorption and quick onset of action thereby providing improved sleep maintenance.

[0226] 53. The method of any one of alternatives 50 to 52, further comprising providing the subject cognitive behavioral therapy (CBT) techniques to enhance the overall efficacy of the oral composition.

[0227] 54. The method of any one of alternatives 50 to 53, further comprising administering light therapy.

[0228] 55. The method of any one of alternatives 50 to 54, wherein improving sleep maintenance provides the subject a full night’s sleep.

[0229] 56. The method of any one of alternatives 50 to 55, wherein improving sleep maintenance provides the subject with a restful night’s sleep.

[0230] 57. The method of any one of alternatives 50 to 56, wherein improving sleep maintenance provides the subject an increase in Slow-Wave-Sleep 1-4.

[0231] 58. The method of any one of alternatives 50 to 57, wherein improving sleep maintenance provides the subject an increase in REM sleep.

[0232] 59. The method of any one of alternatives 50 to 58, wherein improving sleep maintenance decreases the time to sleep onset in the subject.

[0233] 60. The method of alternative 59, wherein the time to sleep onset is from about 15 minutes to about 180 minutes.

[0234] 61. The method of any one of alternatives 50 to 60, wherein improving sleep maintenance increases the average sleep length in the subject.

[0235] 62. The method of alternative 61, wherein the average sleep length is increased from about 15 minutes to about 180 minutes.

[0236] 63. The method of any one of alternatives 50 to 62, wherein the oral composition is administered to the subject prior to sleep.

[0237] 64. A method for modulating the activity of an orexin receptor in a subject in need thereof, the method comprising: providing an oral composition of any one of alternatives 1-85-to 24, wherein the oral composition is administered in an amount sufficient to modulate an orexin receptor in the subject in need thereof.

[0238] 65. The method of alternative 64, wherein the orexin receptor modulator is administered to treat insomnia in the subject.

[0239] 66. The method of alternative 64 or 65, wherein the orexin receptor modulator is administered to treat narcolepsy in the subject.

[0240] 67. The method of any one of alternatives 64 to 66, wherein the orexin receptor modulator is administered to alleviate symptoms of anxiety in the subject.

[0241] 68. The method of any one of alternatives 64 to 67, wherein the orexin receptor modulator is administered to reduce symptoms of depression.

[0242] 69. The method of any one of alternatives 64 to 68, wherein the orexin receptor modulator is administered to enhance wakefulness in subjects with excessive daytime sleepiness.

[0243] 70. The method of any one of alternatives 64 to 69, wherein the orexin receptor modulator is administered to treat a neurodegenerative condition associated with dysregulated sleep patterns.

[0244] 71. The method of any one of alternatives 64 to 70, wherein the orexin receptor modulator specifically targets the orexin-1 receptor (OX1R) to treat addiction.

[0245] 72. The method of any one of alternatives 64 to 71, wherein the orexin receptor modulator specifically targets the orexin-2 receptor (OX2R) to improve sleep initiation.

[0246] 73. The method of any one of alternatives 64 to 72, wherein the orexin receptor modulator is administered in a controlled-release form to maintain therapeutic levels for at least 8 hours.

[0247] 74. The method of any one of alternatives 64 to 73, wherein the orexin receptor modulator is administered to enhance cognitive performance in subjects with cognitive impairments associated with sleep disorders.

[0248] 75. The method of any one of alternatives 64 to 74, wherein the orexin receptor modulator is suvorexant and is administered to a subject diagnosed with chronic insomnia.

[0249] 76. The method of any one of alternatives 64 to 75, wherein the orexin receptor modulator is administered to mitigate jet lag in a subject traveling across time zones.-86-

[0250] 77. The method of any one of alternatives 64 to 76, wherein the orexin receptor modulator is administered to reduce sleep disturbances in a subject with post-traumatic stress disorder (PTSD).

[0251] 78. The method of any one of alternatives 64 to 77, wherein the orexin receptor modulator is administered to regulate circadian rhythm in a subject with shift work sleep disorder.

[0252] 79. The method of any one of alternatives 64 to 78, wherein the oral composition further comprises a flavoring agent to increase patient compliance.

[0253] 80. The method of any one of alternatives 64 to 79, wherein the orexin receptor modulator is co-administered with a sedative or hypnotic agent to enhance therapeutic efficacy.

[0254] 81. The method of any one of alternatives 64 to 80, wherein the orexin receptor modulator is administered to improve the quality of sleep in elderly subjects with age-related sleep disturbances.

[0255] 82. The method of any one of alternatives 64 to 81, wherein the orexin receptor modulator is administered to treat adverse sleep-related effects in subjects undergoing chemotherapy.

[0256] 83. The method of any one of alternatives 64 to 82, wherein the orexin receptor modulator is administered to reduce nocturnal awakenings in subjects with obstructive sleep apnea undergoing continuous positive airway pressure (CPAP) therapy.

[0257] 84. A method for regulating wakefulness in a subject in need thereof, the method comprising: providing an oral composition of any one of alternatives 1 to 24, wherein the oral composition is administered in an amount sufficient to regulate wakefulness in the subject in need thereof.

[0258] 85. The method of alternative 84, wherein the composition is provided to treat a condition associated with excessive daytime sleepiness.

[0259] 86. The method of alternative 84 or 85, wherein the composition is provided to improve alertness in subjects with shift work disorder.

[0260] 87. The method of any one of alternatives 84 to 86, wherein the orexin receptor modulator is provided as part of a therapeutic regimen to counteract the effects of sleep deprivation.

[0261] 88. A method for suppressing arousal signals in a subject in need thereof, the method comprising: providing an oral composition of any one of alternatives 1 to 24, wherein the-87-oral composition is administered in an amount sufficient to suppress arousal signals in the subject in need thereof.

[0262] 89. The method of alternative 88, wherein the suppression of arousal signals results in the promotion of sleep onset.

[0263] 90. The method of any one of alternatives 88 or 89, wherein the suppression of arousal signals reduces nighttime awakenings in the subject.

[0264] 91. The method of any one of alternatives 88 to 90, wherein the suppression of arousal signals alleviates symptoms of hyperarousal in subjects with insomnia.

[0265] 92. The method of any one of alternatives 88 to 91, wherein the suppression of arousal signals reduces physiological markers of arousal, including elevated heart rate and cortisol levels.

[0266] 93. The method of any one of alternatives 88 to 92, wherein the suppression of arousal signals enables the subject to maintain a consolidated sleep duration of at least seven hours.

[0267] 94. A method for regulating energy homeostasis in a subject in need thereof, the method comprising: providing an oral composition of any one of alternatives 1 to 24, wherein the oral composition is administered in an amount sufficient to regulate energy homeostasis in the subject in need thereof.

[0268] 95. The method of alternative 94, wherein the method promotes weight loss by reducing excessive caloric intake in the subject.

[0269] 96. The method of alternative 94 or 95, wherein the method reduces energy expenditure associated with hyperactivity or restlessness in the subject.

[0270] 97. The method of any one of alternatives 94 or 96, wherein the regulation of energy homeostasis decreases symptoms of fatigue in the subject.

[0271] 98. The method of any one of alternatives 94 or 98, wherein the regulation of energy homeostasis improves thermoregulation in the subject under varying environmental conditions.

[0272] 99. A method for improving energy balance in a subject in need thereof, the method comprising: providing an oral composition of any one of alternatives 1 to 24, wherein the oral composition is administered in an amount sufficient to improve energy balance in the subject in need thereof.-88-

[0273] 100. The method of alternative 99, wherein improving energy balance includes increasing energy expenditure through enhanced physical activity levels in the subject.

[0274] 101. The method of alternative 99 or 100, wherein the improvement in energy balance reduces excessive weight gain in the subject.

[0275] 102. The method of any one of alternatives 99 to 101, wherein the improvement in energy balance promotes a reduction in abdominal fat accumulation in the subject.

[0276] 103. The method of any one of alternatives 99 to 102, wherein the method reduces fatigue and increases daytime alertness to support an active lifestyle in the subject.

[0277] 104. The method of any one of alternatives 99 to 103, wherein the improvement in energy balance restores circadian rhythm alignment, optimizing the subject’s sleep-wake cycle.

[0278] 105. A method for regulating a stress response in a subject in need thereof, the method comprising: providing an oral composition of any one of alternatives 1 to 24, wherein the oral composition is administered in an amount sufficient to regulate a stress response in the subject in need thereof.

[0279] 106. The method of alternative 105, wherein regulating the stress response reduces the subject’s heart rate variability associated with stress.

[0280] 107. The method of alternative 105 or 106, wherein regulating the stress response alleviates symptoms of anxiety in the subject.

[0281] 108. The method of any one of alternatives 105 to 107, wherein the method decreases pro-inflammatory cytokine levels associated with chronic stress in the subject.

[0282] 109. The method of any one of alternatives 105 to 108, wherein the regulation of the stress response improves cognitive performance in the subject under stressful conditions.

[0283] 110. The method of any one of alternatives 105 to 109, wherein regulating the stress response enhances resilience to future stressors by promoting adaptive physiological and behavioral responses in the subject. EXAMPLES

[0284] The following non-limiting examples are provided to further illustrate the present disclosure. Example 1 – Assay overview for Orexin 1 & Orexin 2 receptor antagonism-89-

[0285] The Orexin 1 & Orexin 2 receptor antagonism assay for compounds of the disclosure was performed using the following protocol.

[0286] Cell Culture Preparation: DiscoverX CHO-K1 cells were thawed and cultured in appropriate growth medium, specifically DiscoverX Cell Culture Reagent 107 supplemented with Hygromycin B and G418. The cells were incubated at 37°C in a humidified atmosphere with 5% CO2 until they reached 80-90% confluence.

[0287] Cell Seeding: Once the cells reached the desired confluence, they were passaged as necessary and seeded into 384-well plates at a density of 1,250 cells per well. The cells were then allowed to adhere and grow overnight at 37°C.

[0288] Compound Treatment: For the compound treatment, a stock solution of the test compound(s) was prepared in DMSO at a concentration of 20 µM. This stock solution was then diluted in assay buffer to achieve a final concentration of 100 µM. The compound(s) were added to the appropriate wells containing the Caco-2 cells, and appropriate controls such as vehicle control and positive control were included. The cells were incubated with the compound(s) for 30 minutes at 37°C.

[0289] Stimulation of Receptor for Beta-Arrestin Signaling: Following the compound treatment, beta-arrestin recruitment was induced by stimulating the cells with an appropriate agonist. Specifically, Orexin A was used for the Orexin 1 receptor and Orexin B for the Orexin 2 receptor, each at a predetermined concentration. The cells were incubated for 1.5 hours to allow for the accumulation of beta-arrestin.

[0290] Beta-Arrestin Detection: After the stimulation with the agonist, detection reagents were added to induce a luminescence reaction. The luminescent signal was then read on a plate reader according to the product specifications and manufacturer protocols.

[0291] Data Analysis: Finally, the raw data, represented as relative luminescence units, were normalized to the vehicle control to provide biological context of the sample performance. This normalization allowed for accurate assessment of the sample's biological activity compared to the control.

[0292] FIGs. 1-14 illustrate the results from these studies. FIG. 1 illustrates a graph depicting in vitro bioactivity of compounds as orexin2 receptor antagonists of the disclosure. FIG. 2 illustrates a graph depicting in vitro bioactivity of compound 1 against orexin receptor 2 and orexin receptor 1. FIG.3 illustrates a graph depicting in vitro bioactivity of compound 5 against-90-orexin receptor 2 and orexin receptor 1. FIG.4 illustrates a graph depicting in vitro bioactivity of compound 6 against orexin receptor 2 and orexin receptor 1. FIG.5 illustrates data demonstrating that Compound 1 can effectively inhibit the activity of Orexin 1 and Orexin 2 receptors while maintaining high cell viability. These findings confirm that the observed inhibition is a genuine biological effect. Compound 1 exhibits biological activity as a dual orexin receptor antagonist (DORA). DORAs function by blocking the action of orexin, a neurotransmitter responsible for promoting wakefulness. By inhibiting arousal signals in the brain, these compounds promote sleep onset and maintenance, effectively counteracting the wake-promoting effects of orexin. FIG. 6 illustrates a graph depicting in vitro bioactivity of compound 19 against orexin receptor 2 and orexin receptor 1. FIG.7 illustrates a graph depicting in vitro bioactivity of compound 20 against orexin receptor 2 and orexin receptor 1. FIG.8 illustrates a graph depicting in vitro bioactivity of compound 21 against orexin receptor 2 and orexin receptor 1. FIG.9 illustrates a graph depicting in vitro bioactivity of compound 22 against orexin receptor 2 and orexin receptor 1. FIG. 10 illustrates a graph depicting in vitro bioactivity of compound 23 against orexin receptor 2 and orexin receptor 1. FIG.11 illustrates graphs depicting in vitro bioactivity of compound 24 against orexin receptor 2 and orexin receptor 1. FIG.12 illustrates graphs depicting in vitro bioactivity of compound 25 against orexin receptor 2 and orexin receptor 1. FIG.13 illustrates graphs depicting in vitro bioactivity of compound 26 against orexin receptor 2 and orexin receptor 1. Table 1 Cmpd ID IC50 of Orexin 2 (μM) IC50 of Orexin 1 (μM)

[0293] The data demonstrate that Compounds 1-26 inhibit the activity of Orexin 1 and Orexin 2 receptors. The inhibitory activity is presented as IC50 values in Table 1. Corresponding-91-IC50 curves are described in detail above and illustrated in the FIGs. 6-13. Accordingly, compounds 1-26 as described herein have been shown to exhibit biological activity as DORAs. Example 2 – Tolerability Study

[0294] A tolerability test was conducted to determine the highest dose of a compound of the disclosure that induced fewer than three undesired effects in each of three treated animals within a 1-hour observation period post-administration. The doses of the compound administered were selected based on the decision-making tree detailed (see FIG.14). A maximum of four dose levels were evaluated.

[0295] Study Design

[0296] A tolerability test was conducted to determine the highest dose of a test compound that induced fewer than three (i.e., zero, one, or two) undesired effects in each of three treated animals within a 1-hour observation period post-administration. For Compound 1 and Compound 19, administered dose levels were selected using an up-and-down methodology. Specifically, the subsequent dose was increased if animals in the preceding treatment group met this defined tolerability criterion (fewer than three undesired effects per animal), and the subsequent dose was decreased if this criterion was not met by the animals in the preceding treatment group. A maximum of four distinct dose levels were evaluated for each compound.

[0297] Animals were allocated to several distinct treatment groups for the study. One group of animals received a vehicle administration and served as a control. Compound 1 was administered to separate groups of animals at doses of 30 mg / kg (designated as a starting dose), 100 mg / kg, 315 mg / kg, and 500 mg / kg. Similarly, Compound 19 was administered to other separate animal groups at doses of 30 mg / kg (also a designated starting dose), 100 mg / kg, 315 mg / kg, and 500 mg / kg. The actual administered doses of 100 mg / kg, 315 mg / kg, and 500 mg / kg for both Compound 1 and Compound 19 were selected from a potential dosing range of 15 mg / kg to 500 mg / kg. Table 2 provides the scaled-up dosing amounts. Table 2 Doses in mg / kg-92-Dose 2 60 60 Dose 3 100 100

[0298] Dosing foprepared as follows. A stock formulation of Compound 1 (100 mg / mL) was prepared by first forming a paste by mixing 1200 mg of Compound 1 with 1.2 mL of polyethylene glycol 400 (PEG400). This paste was then dispersed in 10.8 mL of phosphate-buffered saline (PBS), and the resulting mixture was stirred overnight at room temperature. From this 100 mg / mL stock formulation, serial dilutions were made using a vehicle composed of 10% PEG400 in PBS to achieve the following concentrations: a 63 mg / mL formulation was prepared by combining 6.46 mL of the 100 mg / mL stock with 3.81 mL of vehicle; a 40 mg / mL formulation was prepared by combining 5.77 mL of the 63 mg / mL formulation with 3.34 mL of vehicle; a 20 mg / mL formulation was prepared by combining 4.61 mL of the 40 mg / mL formulation with 4.61 mL of vehicle; a 12 mg / mL formulation was prepared by combining 4.72 mL of the 20 mg / mL formulation with 4.72 mL of vehicle; a 6 mg / mL formulation was prepared by combining 3.38 mL of the 12 mg / mL formulation with 3.38 mL of vehicle; and a 3 mg / mL formulation was prepared by combining 2.25 mL of the 6 mg / mL formulation with 2.25 mL of vehicle.

[0299] Dosing formulations of Compound 19 were prepared in a similar manner. To create a 100 mg / mL stock formulation, 1200 mg of Compound 19 was first mixed with 0.6 mL of propylene glycol (PG) to form a paste. This paste was subsequently dispersed in a mixture consisting of an additional 5.4 mL of PG and 6.0 mL of PBS (resulting in a final vehicle composition of 50% PG in PBS). The complete formulation was stirred for 1 hour at room temperature prior to administration. Serial dilutions of this 100 mg / mL Compound 19 stock formulation were then prepared using its corresponding vehicle (50% PG in PBS) to achieve the following lower concentrations: a 63 mg / mL formulation was prepared by combining 6.46 mL of the 100 mg / mL stock with 3.81 mL of vehicle; a 40 mg / mL formulation was prepared by combining 5.77 mL of the 63 mg / mL formulation with 3.34 mL of vehicle; a 20 mg / mL formulation was prepared by combining 4.61 mL of the 40 mg / mL formulation with 4.61 mL of vehicle; a 12 mg / mL formulation was prepared by combining 4.72 mL of the 20 mg / mL formulation with 4.72 mL of vehicle; a 6 mg / mL formulation was prepared by combining 3.38 mL-93-of the 12 mg / mL formulation with 3.38 mL of vehicle; and a 3 mg / mL formulation was prepared by combining 2.25 mL of the 6 mg / mL formulation with 2.25 mL of vehicle.

[0300] The prepared formulations of Compound 1 and Compound 19 were administered orally (p.o.) at a volume of 5 mL / kg body weight. These test articles were administered on Day 0 of the tolerability study, immediately before the commencement of observations.

[0301] An in vivo tolerability study was conducted using twenty-four male Sprague- Dawley rats, weighing 200-220g upon arrival (sourced from Charles River, Margate, Kent, UK). Animals were individually identified by tail marking and allowed a 7-day acclimatization period before the commencement of the study. All experimental procedures were performed at Transpharmation Ltd., adhering to the Animals (Scientific Procedures) Act 1986 and European Directive 2010 / 63 / EU, with prior approval from the Discovery Park Animal Welfare and Ethics Review Body. The animals were group-housed (up to three per cage) in standard individually ventilated cages under controlled environmental conditions, including a 12h / 12h light / dark cycle, regulated temperature (20-24°C) and humidity (45-65%), and appropriate ventilation. They had ad libitum access to a certified rodent diet (5CR4, LabDiet) and pathogen-free water, and environmental enrichment was provided. No concurrent medications were administered during the study.

[0302] The primary objective of the study was to determine the highest tolerated oral (p.o.) dose of the test articles (Compound 1, Compound 19 [and morphine, if it was indeed a test article in this specific tolerability assessment]) based on a pre-defined tolerability criterion. This criterion defined a dose as "tolerated" if it induced fewer than three undesired effects per animal within a 1-hour observation period immediately following its administration on Day 0 of the study. An up-and-down dosing methodology was employed: if a tested dose was tolerated, a higher dose was administered in the subsequent session; conversely, if a dose was deemed "not tolerated" (i.e., induced three or more undesired effects), a lower dose was administered in the next session. Dose selection was guided by a decision-making tree (FIG.14). A maximum of four dose levels, selected from a potential range (e.g., 15 mg / kg to 500 mg / kg for Compound 1 and Compound 19), were evaluated for each test article. All animals were weighed prior to dosing. Formulations were vortexed before filling gavage cannulas and administered at a volume of 5 mL / kg. A protocol was in place for early culling if an animal displayed more than three undesired effects in a single-94-session; however, this intervention was not required for any animal during the study, and no animals were otherwise removed.

[0303] The study was conducted without any amendments to, or deviations from, the agreed-upon protocol. Upon conclusion of the observation periods and study, all animals were humanely culled using an approved Schedule 1 method (concussion followed by cervical dislocation). No biological samples were collected from the animals as part of this study. The determination of tolerated dose levels was based on the direct observational criteria outlined, and no further formal statistical data analysis was performed for this specific example. The remainder of the test articles were retained at the test facility, and raw data were archived.

[0304] During the experimental procedures, three animals from the same home cage were tested at a time. Furthermore, the study was conducted in a blinded manner, whereby the operators performing the procedures and recording observations were unaware of the specific treatment administered to each group of animals.

[0305] Results

[0306] Compound 1 was tolerated up to 500 mg / kg in the male Sprague-Dawley rate. Compound 19 was tolerated up to 500 mg / kg in the male Sprague-Dawley rate. Table 3 summarizes the tolerability of Compound 1. Table 3 Compound Dose Effects Effects Effects Tolerated?-95-500 mg / kg was C d 1 500 / / / hat induced less than three undesired effects in three animals within a 1h observation window. The doses of Compound 1 were decided in an up-and-down manner, depending on whether undesired effects were observed or not in the previous session. Table 4 summarizes the tolerability of Compound 19. Table 4 Compound Dose Effects Effects Effects Tolerated?at induced less than three undesired effects in three animals within a 1h observation window. The doses of Compound 19 were decided in an up-and-down manner, depending on whether undesired effects were observed or not in the previous session.-96-

[0309] After determining the tolerability of the two compounds, this study further evaluated the tolerability and efficacy of Compound 1 in animal models, with desired outcomes including a reduction in locomotor activity (e.g., sleepiness), the initiation of sleep (e.g., hypnotic effects), and a reduction in food intake (e.g., anorectic effects). It was hypothesized that Compound 1 administration would induce a rapid onset of reduced locomotion, indicative of sleepiness, within 0-15 minutes post-administration. Following an initial tolerability assessment, animal subjects receiving Compound 1 were monitored for behavioral changes. Consistent with initial expectations, one animal subject exhibited a noticeable reduction in locomotor activity within the 0-15 minute timeframe. Subsequently, between 15-30 minutes post-administration, additional animal subjects began to demonstrate signs of reduced locomotion and the initiation of sleep, with these effects observed in animals receiving lower doses as well as in additional animals at higher doses. By the 30-60 minute observation period, three out of four (3 / 4) animal subjects displayed clear signs of reduced locomotor activity. All animal subjects appeared to be in a stable condition by the two-hour mark, indicating good acute tolerability. However, at the 4-6 hour observation point, all animal subjects were observed to be sleepy, suggesting a sustained or delayed sedative / hypnotic effect. Minor, dose-dependent adverse effects were noted at higher doses after 24 and 48 hours, consisting of red-colored feces (firm but wet in consistency) and bright orange urine, which resolved without intervention. Overall, the tolerability of Compound 1 was established, and the compound demonstrated efficacy in reducing locomotor activity and initiating sleep; detailed summaries of these results for Compound 1, including quantitative data on locomotor activity, sleep induction, and food intake, are provided in Tables 5. Table 5 Time CMPD Dose DV 4H / f 015 i 1530 i 3060 i 2H 24H ll K ll K-97-EXPECTED: EXPECTED: EXPECTED: n / a initiation of reduction in sleep locomotion ll K ll K

[0310] Following the initial behavioral assessments, a study was conducted to further evaluate the effects of Compound 1 at various dosages on animal subjects. Compound 1 was administered to four groups of animal subjects (n=3 per group, for a total of 12 animals) at doses of 30 mg / kg, 100 mg / kg, 315 mg / kg, and 500 mg / kg. Over a three-day observation period, a slight overall increase in body weight was noted across the treated animals.

[0311] Specifically, at the lowest dose of 30 mg / kg, the animal subjects exhibited an average body weight increase of approximately 6%. Animals in the 100 mg / kg dosing group showed an average body weight increase of approximately 1%. For the higher doses of 315 mg / kg and 500 mg / kg, the animal subjects demonstrated an average body weight increase of approximately 4%. It was observed that, unlike the lowest dose group, animals in the 100 mg / kg, 315 mg / kg, and 500 mg / kg dose groups experienced a modest decrease in body weight after the first day of administration. This transient decrease in body weight is attributed, at least in part, to an initial reduction in food intake observed in these groups. Notably, this initial reduction in food intake and the associated modest, temporary decrease in body weight were not considered to be adverse effects of Compound 1 administration. The results of these body weight and food intake-98-observations were further observed over three days and is described in Tables 6 and 7, and FIG. 15. Table 6 CMPD Dose DV Weight Weight Weight Weight Time of ID (mg / kg) (5 mL / kg) 0H 24H 48H 72H dosingTable 7 % change BW % change BW % change BW % change BW-99-0 1 5 7 0 3 3 6c ange c ange c ange c ange W 0H 24H 48H 72H

[0312] The observational tolerability study was successfully conducted to determine the Maximum Tolerated Dose (MTD) of compounds of the disclosure, providing data for guiding subsequent investigations. The primary objective of this study was to identify the highest dose of a compound of the disclosure could be administered without inducing unacceptable adverse effects in a preclinical model. The study was performed in rats, wherein subjects were administered the-100-test compound and meticulously monitored for a range of clinical signs indicative of potential toxicity. This comprehensive observational assessment included, but was not limited to, monitoring for behavioral changes such as the onset of hyperactivity or sedation; neurological signs including tremors, ataxia, or seizures; autonomic responses by monitoring for changes in salivation or respiration; and alterations in general appearance, such as posture or grooming habits.

[0313] Findings were systematically documented at predetermined intervals (e.g., 0– 15 minutes, 15–30 minutes, and 30–60 minutes post-administration). In this instance, the observation period was extended beyond typical durations at the investigators' request to ensure a more thorough and rigorous assessment of acute tolerability, further enhancing the reliability of the MTD determination. Standardized checklists were employed throughout the observation period to ensure consistency and accuracy in data collection. An important outcome metric, "ALL OK," (see Table 5) was utilized to denote observation epochs during which no noteworthy changes in the subject's behavior or general condition were observed. This "ALL OK" status (see Table 5) at a given dose level was indicative of good tolerability. While minor, transient observations, such as temporary sleepiness or a slight reduction in locomotion, were carefully noted as part of the complete dataset, these were considered within the context of a study specifically designed to assess tolerability rather than to provide a detailed mechanistic interpretation of such effects. The focused design of this observational study allowed for the clear and effective determination of the MTD. The results successfully established a well-tolerated dose range, paving the way for further development and testing of the compound.

[0314] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (for example, bodies of the appended claims) are generally intended as “open” terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim-101-recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (for example, “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of

[0315] A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example,“ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0316] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0317] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will-102-also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0318] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.-103-

Claims

WHAT IS CLAIMED IS:

1. A method for inducing sedation, inducing sleep, reducing locomotor activity, inducing somnolence, or treating insomnia in a mammal, the method comprising: providing an oral composition comprising at least one carrier and at least one compound selected from the group consisting of: , , , ,-104-, , ,-105-, ,-106-,2. The method of claim 1, wherein the at least one compound is selected from ,-107-3. The method of claim 2, wherein the at least one compound is is5. The method of claim 1, wherein the at least one compound is selected from the , ,-108-, , ,-109-,6. The method of claim 5, wherein the at least one compound is , or a salt thereof.

7. The method of claim 1, wherein the at least one compound is of.-110-8. The method of claim 1, wherein the at least one compound is f. erein the at least one compound isof.

10. The method of any one of claims 1 to 9, wherein the oral composition is formulated as a dietary supplement, a food ingredient or an additive, a medical food, a functional food, a nutraceutical or a pharmaceutical composition.

11. The method of any one of claims 1 to 10, wherein the oral composition is in a dosage form configured as one of a soft-gel capsule, a hard capsule, liquid, powder, granule, and a tablet.

12. The oral composition of any one of claims 1 to 11, wherein the oral composition comprises 0.01% to 99% w / w of the at least one compound.

13. The oral composition of any one of claims 1 to 12, wherein the at least one compound is derived from a plant extract.-111-14. The method of claim 13, wherein the oral composition comprises 0.01% to 99% w / w of the plant extract.

15. The method of claim 13 or 14, wherein the plant extract is Capparis spinosa or Citrus Aurantium Dulcis.

16. The method of claim 15, wherein the plant extract is Citrus Aurantium Dulcis and ral alt17. The method of any one of claims 1 to 16, wherein the oral composition further comprises a preservative, a sweetener, a coloring agent, an additive, a flavoring agent, or a combination thereof.

18. The method of claim 17, wherein the preservative is from about 0.01% to about 5% by weight of the oral composition.

19. The method of any one of claims 1 to 12, with a proviso that the at least one compound is not an extract from a natural source.

20. The method of any one of claims 1 to 19, wherein the at least one compound is an orexin receptor 2 antagonist.-112-21. The method of any one of claims 1 to 20, wherein the oral composition an orexin receptor 1 antagonist.

22. The method of any one of claims 1 to 21, wherein the oral composition comprises between 1 mg to about 5000 mg of the at least one compound.

23. The method of any one of claims 1 to 22, wherein one or more conditions associated with insomnia is selected from the group consisting of difficulty falling asleep at the beginning of the night, difficulty staying asleep, waking up frequently during the night, waking up too early in the morning, being unable to fall back asleep, or a combination thereof.

24. The method of any one of claims 1 to 23, wherein providing the oral composition to the mammal provides total sleep time and restores normal sleep architecture in the mammal with insomnia by increasing slow wave sleep early in the night.

25. The method of any one of claims 1 to 24, wherein administering the oral composition increases stage 2 sleep late in the night in the mammal.

26. The method of any one of claims 1 to 25, wherein administering the oral composition does not suppress REM sleep.

27. The method of any one of claims 1 to 26, wherein administering the oral composition does not increase rebound insomnia.

28. The method of any one of claims 1 to 27 wherein the oral composition is administered as a timed-release capsule that releases the oral composition gradually throughout the night to maintain consistent therapeutic levels thereby treating insomnia.

29. The method of any one of claims 1 to 27, the oral composition is administered sublingually to ensure rapid absorption and quick onset of action thereby treating insomnia.-113-30. The method of any one of claims 1 to 28, further comprising providing the subject cognitive behavioral therapy (CBT) techniques to enhance the overall efficacy of the oral composition.

31. The method of any one of claims 1 to 30, further comprising administering light therapy.

32. The method of any one of claims 1 to 31, wherein treating insomnia provides the mammal a full night’s sleep.

33. The method of any one of claims 1 to 32, wherein treating insomnia provides the mammal a restful night’s sleep.

34. The method of any one of claims 1 to 33, wherein treating insomnia provides the mammal an increase in Slow-Wave-Sleep 1-4.

35. The method of any one of claims 1 to 34, wherein treating insomnia provides the subject an increase in REM sleep.

36. A method for providing improved sleep maintenance in a subject in need thereof, the method comprising: providing at least one compound selected from the group consisting of: , ,-114-, , , ,-115-,-116-, ,-117-.

37. The method of claim 36, wherein the at least one compound is selected from the group consisting ,is-118-39. The method of claim 37, wherein the at least one compound is , or a salt thereof.

40. The method of claim 36, wherein the at least one compound is selected from the , , ,-119-, ,-120-,41. The method of claim 40, wherein the at least one compound is , or a salt thereof.

42. The method of claim 36, wherein the at least one compound is of.-121-43. The method of claim 36, wherein the at least one compound is a salt thereof.. e met o o c aim 36, wherein the at least one compound is f.

45. The method of any one of claims 36 to 44, wherein the at least one compound is in a composition formulated as a dietary supplement, a food ingredient or an additive, a medical food, a functional food, a nutraceutical or a pharmaceutical composition.

46. The method of any one of claims 36 to 45, wherein the at least one compound is in a composition in a dosage form configured as one of a soft-gel capsule, a hard capsule, liquid, powder, granule, and a tablet.

47. The method of any one of claims 36 to 46, wherein the at least one compound is administered in a timed-release capsule that releases the at least one compound gradually throughout the night to maintain consistent therapeutic levels thereby providing improved sleep maintenance.-122-48. The method of any one of claims 36 to 47, wherein improving sleep maintenance comprises sustaining sleep for at least a predetermined minimum duration following sleep onset without significant interruption.

49. The method of any one of claims 36 to 48, wherein improving sleep maintenance comprises reducing the number of nocturnal awakenings experienced by the subject.

50. The method of any one of claims 36 to 49, wherein improving sleep maintenance comprises reducing the frequency of transitions from deeper sleep stages to lighter sleep stages or wakefulness.-123-

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