Methods of treating a sleep disorder using a triple reuptake inhibitor

Abstract

Provided herein are methods of treating a sleep disorder (e.g., narcolepsy) in a subject in need thereof by administering to the subject compositions comprising a triple reuptake inhibitor.

Description

METHODS OF TREATING A SLEEP DISORDER USING A TRIPLE REUPTAKEINHIBITORBACKGROUND

[0001] Difficulties in falling asleep, remaining asleep, sleeping for adequate lengths of time, and abnormal sleep behaviors are common symptoms for those suffering with a sleep disorder. Current treatment of many sleep disorders include the use of prescription hypnotics, e.g., benzodiazapines, that may be habit-forming, lose their effectiveness after extended use, and metabolize more slowly for certain designated groups, e.g., elderly persons, resulting in persisting medicative effects. Other, milder treatments include over-the-counter antihistamines, e.g., diphenhydramine or dimenhydrinate, which are not designed to be strictly sedative in their activity. This method of treatment is also associated with a number of adverse side effects, e.g., persistence of the sedating medication after the prescribed time of treatment, or the so-called “hangover effect”.

[0002] Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, including cataplexy (sudden loss of muscle tone triggered by strong emotions), direct transition from wakefulness to REM sleep (DREMs) periods, sleep paralysis and hypnagogic hallucinations. Patients with narcolepsy experience irresistible attacks of sleep at any time during the day and may fall asleep for a period lasting from seconds to few hours. Such attacks can occur without any warning, which can cause serious problems in daily routines. There is currently no cure for narcolepsy and narcolepsy patients depend on medicines and lifestyle changes to manage their symtpoms. Therefore, there is an unmet medical need for new methods that address treating individuals suffering from narcolepsy and other sleep disorders.SUMMARY

[0003] Provided herein, in part, are method of treating or preventing a sleep disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 :or a pharmaceutically acceptable salt thereof.

[0004] In some embodiments, the sleep disorder is a disorder selected from the group consisting of insomnia, hypersomnolence, narcolepsy, cataplexy, idiopathic hypersomnia, sleep paralysis, hypnagogic hallucinations, hypnopompic hallucinations, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a non-24-hour sleep wake disorder, a non-rapid eye movement sleep arousal disorder, a nightmare disorder, a rapid eye movement sleep behavior disorder, restless leg syndrome, a medication-induced sleep disorder, a substance-induced sleep disorder, excessive daytime sleepiness, excessive need for sleep, shift work sleep disorder, and Kleine Levin syndrome.

[0005] Also provided herein is a method of treating or preventing hypersomnolence in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the hypersomnolence is a disorder selected from the group consisting of idiopathic hypersomnia, recurrent hypersomnia, narcolepsy, shift work sleeping disorder, endozepine induced-recurrent stupor and amphetamine-resistant hypersomnia.

[0007] Also provided herein is a method of treating or preventing narcolepsy in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the narcolepsy is narcolepsy type 1 or narcolepsy type 2.

[0009] In some embodiments, the treating or preventing comprises: (a) reducing one or more symptoms of narcolepsy in the subject; and / or (b) modulating an rapid eye movement REM sleep in the subject. In some embodiments, the one or more symptoms of narcolepsy isselected from the group consisting of: (a) excessive daytime sleepiness; (b) cataplexy; (c) sleep paralysis; (d) hallucinations; (e) deficiency of the hormone hypocretin; (f) changes in rapid eye movement (REM) sleep; (g) excessive need for sleep; (h) metabolic-syndrome- related disorder. In some embodiments, the modulation of REM sleep comprises decreasing the rate of eye movement, reducing the density and latency of REM sleep, disrupting REM sleep or increasing non-REM sleep, decreasing ratio of REM:non-REM sleep, or REM sleep onset latency. In some embodiments, the narcolepsy is associated with a metabolic- syndrome-related disorder. In some embodiments, the metabolic-syndrome-related disorder is selected from the group consisting of hypertension, diabetes, and dyslipidemia.

[0010] In some embodiments, the subject experienced weight gain, obesity, high body mass index, or cardiometabolic risks.

[0011] In some embodiments, the therapeutically effective amount is between about 3 mg to about 60 mg. In some embodiments, Compound 1 is administered once daily.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 depicts an exemplary X-ray powder diffraction pattern of a hydrochloride quarterhydrate of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone (Compound 1).

[0013] FIG. 2 depicts an exemplary X-ray powder diffraction pattern of a hydrochloride of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone (Compound 1).

[0014] FIG. 3 depicts latency (mean ± standard error of mean) to the first 6 continuous epochs of non-rapid eye movement sleep “NR” (top) and latency (mean ± standard error of mean) to the first 3 continuous epochs of rapid eye movement sleep “REM” (bottom) measurements for Compound 1 at three concentrations (1-10 mg / kg), RO5186582 (“6582”) at three concentrations (3-30 mg / kg), caffeine “CAF” at one concentration (10 mg / kg), and a vehicle control (purified H2O), all administered by mouth. means condition is significantly different from vehicle 1, and “+” means condition is significantly different from CAF.

[0015] FIG. 4A, FIG. 4B and FIG. 4C depict hourly percent time spent in waking “W,” NR, and REM for 3 concentrations of Compound 1 vs. CAF and vehicle, respectively. Dosing occurred during the first part of ZT7. The asterisks above the graphs represent time points with significant differences. In the legends, * = condition is significantly different from vehicle, and + = condition is significantly different from CAF (p<0.05). FIG. 4A depicts percent time in W. ANOVA is significant for treatment and for treatment by time. FIG. 4B depicts percent time in NR. ANOVA is significant for treatment and for treatment by time. FIG. 4C depicts percent time in REM. ANOVA is significant for treatment (see legend) and for treatment by time.

[0016] FIG. 5 depicts average cumulative time in W, NR, and REM over the 6 h recording period for 6582, Compound 1, CAF, and vehicle. means significantly different from vehicle (p<0.05), and “+” means significantly different from CAF (p<0.05).

[0017] FIG. 6 depicts REM:NR ratio for the entire 6 h recording period for 6582, Compound 1, CAF, and vehicle. means significantly different from vehicle, and “+” means significantly different from CAF (p<0.05).

[0018] FIG. 7A and FIG. 7B depict hourly NRD normalized to the 6 h average following treatment with vehicle control (“vehicle”), CAF, or three different doses of Compound 1 or 6582. Dosing occurred during the first part of ZT7. FIG. 7A depicts 3 concentrations of Compound 1 vs. CAF and vehicle. FIG. 7B depicts 3 concentrations of 6582 vs. CAF and vehicle.

[0019] FIGS 8A-8F depict measures of sleep-wake consolidation for 3 concentrations of Compound 1 vs. CAF and vehicle. The asterisks above the graphs represent time points with significant differences. In the legends, means treatment is significantly different overall from vehicle and “+” means treatment is significantly different overall from CAF (p<0.05). FIG. 8A and FIG. 8B depict average hourly W bout duration “WBD.” FIG. 8C and FIG. 8D depict average hourly NR bout duration “NRBD.” FIG. 8E and FIG. 8F depict average hourly REM bout duration “RBD.”

[0020] FIG. 9A and FIG. 9B depict average hourly locomotor activity (EMA) and relative core body temperature (Tb) for 3 concentrations of Compound 1 vs. CAF and vehicle.The asterisks above the graphs represent time points with significant differences. In the legends, means treatment is significantly different from vehicle and “+” means treatment is significantly different from CAF (p<0.05).

[0021] FIG. 9A depicts average hourly LMA. FIG. 9B depicts average hourly Tb.

[0022] FIG. 10A, FIG. 10B and FIG. 10C depict hourly percent time spent in W, NR, and REM for 3 concentrations of 6582 vs. CAF and vehicle. Dosing occurred during the first part of ZT7. The asterisks above the graphs represent time points with significant differences. In the legends, means condition is significantly different from vehicle and “+” means condition is significantly different from CAF (p<0.05).

[0023] FIGS 11A-11F depict measures of sleep-wake consolidation for 3 concentrations of 6582 vs. CAF and vehicle. The asterisks above the graphs represent time points with significant differences. In the legends, means treatment is overall significantly different from vehicle and “+” means treatment is overall significantly different from CAF (p<0.05). FIG. 11A and FIG. 11B depict average hourly WBD. FIG. 11C and FIG. 11D depict average hourly NRBD. FIG. HE and FIG. HF depict average hourly RNB.

[0024] FIG. 12A and FIG. 12B depict average hourly EMA and relative Tb for 3 concentrations of 6582 vs. CAF and vehicle. The asterisks above the graphs represent time points with significant differences. In the legends, means treatment is significantly different from vehicle and “+” means treatment is significantly different from CAF (p<0.05). FIG. 12A depicts average hourly LMA. FIG. 12B depicts average hourly Tb.DETAILED DESCRIPTION

[0025] As generally described herein, the present disclosure provides methods of treating a sleep disorder (e.g., narcolepsy) in a subject in need thereof. The methods comprise administering to a subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. In addition, the present disclosure provides methods of treating a sleep disorder (e.g., narcolepsy) with a crystalline form of either Compound 1 or a pharmaceutically acceptable salt thereof.

[0026] Provided herein, in part, are methods of treating or preventing a sleep disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the sleep disorder is a disorder selected from the group consisting of insomnia, hypersomnolence, narcolepsy, cataplexy, idiopathic hypersomnia, sleep paralysis, hypnagogic hallucinations, hypnopompic hallucinations, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a non-24-hour sleep wake disorder, a non-rapid eye movement sleep arousal disorder, a nightmare disorder, a rapid eye movement sleep behavior disorder, restless leg syndrome, a medication-induced sleep disorder, a substance-induced sleep disorder, excessive daytime sleepiness, excessive need for sleep, shift work sleep disorder, and Kleine Levin syndrome.

[0028] Also provided herein is a method of treating or preventing hypersomnolence in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the hypersomnolence is a disorder selected from the group consisting of idiopathic hypersomnia, recurrent hypersomnia, narcolepsy, shift work sleeping disorder, endozepine induced-recurrent stupor, and amphetamine-resistant hypersomnia.

[0030] Also provided herein is a method of treating or preventing narcolepsy in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the narcolepsy is narcolepsy type 1 or narcolepsy type 2.

[0032] In some embodiments, the treating or preventing comprises: a. reducing one or more symptoms of narcolepsy in the subject; and / or b. modulating an rapid eye movement REM sleep in the subject.

[0033] In some embodiments, the one or more symptoms of narcolepsy is selected from the group consisting of: a. excessive daytime sleepiness; b. cataplexy; c. sleep paralysis; d. hallucinations; e. deficiency of the hormone hypocretin; f. changes in rapid eye movement (REM) sleep; g. excessive need for sleep; and h. metabolic-syndrome-related disorder.

[0034] In some embodiments, the modulation of REM sleep comprises decreasing the rate of eye movement, reducing the density and latency of REM sleep, disrupting REM sleep or increasing non-REM sleep, decreasing ratio of REM:non-REM sleep, or REM sleep onset latency.

[0035] In some embodiments, the narcolepsy is associated with a metabolic-syndrome- related disorder.

[0036] In some embodiments, the metabolic-syndrome-related disorder is selected from the group consisting of hypertension, diabetes, and dyslipidemia.

[0037] In some embodiments, the subject experienced weight gain, obesity, high body mass index, or cardiometabolic risks.

[0038] In some embodiments, the therapeutically effective amount is between about 3 mg to about 60 mg.

[0039] In some embodiments, the therapeutically effective amount is about 3 mg, about 9 mg, or about 30 mg.

[0040] In some embodiments, Compound 1 is administered once daily.Dosage

[0041] The compounds and compositions of the disclosure are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The quantity to be administered depends on the subject to be treated, in some embodiments. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each subject. Suitable regimes for initial administration, but are typified by an initial administration followed by repeated doses at one hour intervals or longer by a subsequent administration. Alternatively, continuous administration that is sufficient to maintain concentrations in the blood are contemplated.

[0042] The amounts of the active ingredients (e.g., compound of the disclosure or a pharmaceutically acceptable salt thereof) in the compositions, the composition formulation, and the mode of administration, are among the factors that are varied to provide an amount of the active ingredient that is effective to achieve the desired therapeutic response for each subject, without being unduly toxic to the subject. The selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular composition employed, the age, sex,weight, condition, general health, diet and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0043] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is administered to a subject in various dosing amounts and over various time frames. Additionally, the dose(s) of a compound is administered, in some embodiments, twice a week, weekly, every two weeks, every three weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 12 weeks, or any combination of weeks therein. Dosing cycles are also contemplated, such as, e.g. , administering the compound once or twice a week for 4 weeks, followed by two weeks without therapy. Additional dosing cycles including, e.g., different combinations of the doses and weekly cycles described herein are also contemplated within the disclosure.

[0044] Therapeutically effective amounts of a composition, in some embodiments, vary and depend on the severity of the disease, the subject’s weight, and general state of the subject being treated. Administration is, in some embodiments, daily, on alternating days, weekly, twice a month, monthly, or more or less frequently, as necessary depending on the response of the disorder or condition and the subject’s tolerance to the therapy. In some embodiments, maintenance dosages over a longer period of time, such as 4, 5, 6, 7, 8, 10, or 12 weeks or longer, are needed until a desired suppression of disorder symptoms occurs, and dosages are adjusted as necessary. The progress of this therapy is easily monitored by conventional techniques and assays.

[0045] A physician having ordinary skill in the art, in some cases, readily determines and prescribes the effective dose (ED50) of the composition required. For example, the physician could start doses of the compounds employed in the composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Alternatively, a dose remains constant in some embodiments.

[0046] The compounds and pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dose” or “unit dosage forms” refers to physically discrete units suitable as unitary dosages for humansubjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some embodiments, the pharmaceutical dosage forms described herein can be administered as a unit dose. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

[0047] The dosage of the compound of the disclosure or compositions comprising the compound can vary depending on multiple factors, such as, e.g., the pharmacodynamic properties of the compound, the mode of administration, age, health, or weight of the recipient, the nature and extent of the symptoms, frequency of the treatment, the type of concurrent treatment, if any, and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compound of the disclosure or a pharmaceutically acceptable salt thereof may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the disclosure are administered to a human at a daily dosage of, e.g., between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 0.1-1000 mg (e.g., 0.2-950, 0.4-900, 0.6-850, 0.8-800, 1-750, 1-20, 2-16, 2-700, 4-650, 6-600, 8-550, 10-500, 15-450, 20-400, 30-350, 40-300, 50-250, 75-200, or 100-150 mg). In some embodiments, about 1, 2, 2.5, 4, 5, 8, 10, 15, or 20 mg of the compound of the disclosure or a pharmaceutically acceptable salt thereof is administered, e.g., per day. A single dose or multiple doses may be administered in a 24-hour period. For example, in some embodiments, between 0.5-8 mg (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 mg) of the compound is administered to the subject once or more than once, e.g., twice, daily.

[0048] Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may be 0.005-5 (0.01-4.8, 0.02-4.6, 0.04-4.4, 0.06-4.2, 0.08-4.0, 0.1-3.8, 0.2-3.6, 0.3-3.4, 0.4-3.2, 0.5-3.0, 0.6, 2.8, 0.7-2.6, 0.8-2.4, 0.9-2.2, 1-2, 1.1-1.9, 1.2-1.8, 1.3-1.7, or 1.4-1.6) mg / kg. In exemplary, non-limiting embodiments, the dose may range from 0.005-1 mg / kg e.g., 0.01-0.5, 0.01-0.2, or 0.01-0.1 mg / kg).DEFINITIONS

[0049] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0050] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0051] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from the group consisting of two or more of the recited elements or components.

[0052] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where a reference is made to a particular compound, that compound can be used in various embodiments of methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it willbe appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0053] As used herein, singular forms “a,” “and,” and “the” include plural referents unless the context clearly indicates otherwise. Thus, e.g., reference to “a compound” includes a single compound or a plurality (e.g., 2 or more) of compounds.

[0054] The use of the term “comprise,” “comprises,” “comprising,” “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0055] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, e.g., reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000 fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5 fold, etc., 2.\, 2.2, 2.3, 2.4, 2.5 fold, etc., and so forth.

[0056] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

[0057] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 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, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 isspecifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0058] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0059] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0060] As used herein, the term “administration” refers to delivery of an agent or composition disclosed herein to a subject by any acceptable route. Non-limiting examples of acceptable administration routes include oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0061] “Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate, and / or that are approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0062] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., Compound 1), which salt is compatible with pharmaceutical administration. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is Ci-4 alkyl, and the like. Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, K+, Ca2+, NH4+, and NW4+(where W can be a Ci-4 alkyl group), and the like.

[0063] For therapeutic use according to the methods disclosed herein, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0064] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and / or absorption by a subject and can beincluded in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline (PBS) solution, emulsions (e.g., such as an oil / water or water / oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. For examples of excipients, see Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0065] As used herein, the term “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

[0066] As used herein, the terms “subject” and “patient” refer to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a particular condition, or one at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. In some embodiments, the subject is a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or a non-human animal, e.g., a mammal such as a primate (e.g., cynomolgus monkey, rhesus monkey, and the like), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0067] As used herein, the term “therapeutically effective amount” of an agent or composition described herein (e.g., a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof) refer to a quantity sufficient to, when administered to a subject, including a mammal (e.g., a human), effect beneficial or desired results, including effects at the cellular level, tissue level, or clinical results, and, as such, an “therapeutically effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in the context of treating a sleep disorder, it is an amount of the agent or composition sufficient to achieve a treatment response as compared to the response obtained without administration of the agent or composition. The amount of a given agent or composition described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of condition or disorder, the identity of the subject (e.g., age, sex, and weight) or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. Also, as used herein, a “therapeutically effective amount” of agent or composition of the present disclosure is an amount that results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of an agent or composition of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.

[0068] “Treat,” “treatment,” and “treating,” as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize (i.e., not worsen), prevent or cure a disease, pathological condition, or disorder. This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy). Treatment also includes diminishment of the extent of the disease or condition; preventing spread of thedisease or condition; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable. “Ameliorating” or “palliating” a disease or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0069] As used herein, the term “sleep disorder” in general refers to any condition that would benefit from treatment with the agents of the present invention, including any sleep disease or disorder that can be treated by effective amounts of agents described herein. Sleep disorder may comprise intrinsic sleep disorders, extrinsic sleep disorders, and circadian rhythm sleep disorders. Examples of intrinsic sleep disorders include, but not limited to, psychophysiological insomnia, sleep state misperception, idiopathic insomnia, narcolepsy, recurrent hypersomnia, idiopathic hypersomnia, posttraumatic hypersomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation, periodic limb movement disorder, restless leg syndrome (RLS), etc. Examples of extrinsic sleep disorders include inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, food allergy insomnia, nocturnal eating / drinking syndrome, hypnotic-dependent sleep disorder, stimulant-dependent sleep disorder, alcoholdependent sleep disorder, toxin-induced sleep disorder, etc. Examples of circadian rhythm sleep disorders include time-zone change (jet lag) syndrome, shiftwork sleep disorder, irregular sleep / wake pattern, delayed sleep-phase syndrome, advanced sleep-phase syndrome, non-24-hour sleep / wake disorder, etc.

[0070] As used herein the term “hypersomnolence” may be understood to indicate a group of disorders characterized by excessive daytime sleepiness, which occurs despite the subject generally experiencing a normal quality and timing of nocturnal sleep. As discussedherein, excessive daytime sleepiness may be defined as the inability to stay awake and alert during major waking episodes of the day, resulting in periods of irrepressible need for sleep or unintended lapses into drowsiness or sleep. The skilled person will appreciate that hypersomnolence may be assessed and diagnosed, and treatments evaluated, according to a range of scales and / or tests as known in the art.

[0071] As used herein, the term “triple reuptake inhibitor (TRI)” refers to an agent (e.g., small molecule) capable of inhibiting: (1) reuptake of serotonin by blocking serotonin transporter (SERT) proteins at the presynaptic terminals of serotonin-releasing neurons; (2) reuptake of noradrenaline by blocking noradrenaline transporter (NAT) proteins at the presynaptic terminals of noradrenaline-releasing neurons; and (3) reuptake of dopamine by blocking dopamine transporter (DAT) proteins at the presynaptic terminals of dopamine- releasing neurons. The inhibition reuptake of each of serotonin, noradrenaline, and / or dopamine can independently be by any amount, such as at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or100%. Exemplary TRIs of the disclosure include, without limitation, Compound 1:pharmaceutically acceptable salt thereof.Narcolepsy

[0072] As used herein, “narcolepsy” refers to a chronic neurological disorder characterized by recurring episodes of sleep during the day and it also referred as a rare longterm brain disorder that causes a person to suddenly fall asleep at inappropriate times. The brain is unable to regulate sleeping and waking patterns normally, which can result in irregular sleep features, overwhelming episodes of sleep, excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, and excessive dreaming and waking in the night. In embodiments, the narcolepsy is narcolepsy type 1 or narcolepsy type 2. Type 1 narcolepsy may be referred to as “narcolepsy with cataplexy,” whereas type 2 narcolepsy may be referred to as “narcolepsy without cataplexy.” In some cases, a person may develop another type ofnarcolepsy known as secondary narcolepsy. It results from a brain injury, specifically to the hypothalamus region, which regulates sleep cycles.

[0073] As used herein, “cataplexy” refers to a sudden muscle weakness that occurs when one is awake.

[0074] As used herein, “diabetes” refers to a disease characterized by high blood sugar levels over a prolonged period. For example, the term “diabetes” and its grammatical equivalents as used herein can refer to all or any type of diabetes, including, but not limited to, type 1, type 2, cystic fibrosis-related, surgical, gestational diabetes, and mitochondrial diabetes. In some cases, diabetes can be a form of hereditary diabetes.

[0075] As used herein, “dyslipidemia,” refers to an abnormal level and / or profile of lipids and / or lipid proteins in the blood. For example, an amount of one or more lipids may be increased or decreased with respect to the levels thereof in a healthy subject. Such lipids and lipid proteins may include, for example, cholesterol, glycerides (such as triglycerides), and lipoproteins (such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL).

[0076] As used herein, the term “hypertension” is synonymous with elevated high blood pressure. In some embodiments, the term is defined as systolic blood pressure of 120 mmHg or higher.

[0077] As used herein, “hypocretin” or “orexin” refers to a neurotransmitter that regulates arousal, wakefulness, and appetite. Narcolepsy may be caused by a lack of orexin in the brain due to the destruction of the cells that produce it.

[0078] As used herein, “hallucinations” refers to vivid images or other sensory experiences that may occur when a subject is falling asleep or waking up.

[0079] As used herein, “insomnia” refers to difficulty in falling or staying asleep at night.

[0080] As used herein, “rapid eye movement (REM) sleep” refers to a stage of sleep that is often associated with very vivid dreams due to the increase in brain activity. The REM sleep may be characterized by relaxed muscles, quick eye movement, irregular breathing, elevated heart rate, and increased brain activity.

[0081] As used herein, “sleep paralysis” refers to a temporary inability to speak or move that may occur when a subject is falling asleep or waking up.

[0082] In some embodiments, narcolepsy is associated with a metabolic-syndrome- related disorder. In fact, people with narcolepsy have a higher risk for developing metabolic disorders, which relate to energy, weight, and sexual development. Overweight and obesity are common in people with narcolepsy, with adults weighing on average 15 percent to 20 percent more than those without narcolepsy. Children who develop narcolepsy often gain significant weight in the months following the emergence of symptoms. Obesity was nearly twice as likely in children with narcolepsy — 74 percent compared with 36 percent in the general population. A 2007 study including 13 people with narcolepsy found that those with type 1 narcolepsy (narcolepsy with cataplexy) had a lower metabolism and tended to eat less than people without narcolepsy. The researchers theorized that the changes in metabolism may be connected to low levels of hypocretin (also referred to as orexin), a brain chemical connected with the cause of narcolepsy.

[0083] In some embodiments, narcolepsy is associated with cardiometabolic risks. Specifically, a subject with narcolepsy may experience weight gain, obesity, high body mass index, or cardiometabolic risks. Disrupted nighttime sleep and excessive daytime sleepiness, which are characteristic of narcolepsy, may increase cardiovascular risk. Patients with narcolepsy also often present with other comorbidities (e.g., obesity, diabetes, depression, other sleep disorders) that may contribute to increased cardiovascular risk. Often these disorders are overlooked, but they have important implications in the management of this condition. Some medications used to treat symptoms of narcolepsy may have potential negative effects on cardiovascular health, including in patients that are sensitive to sodium, such as those with hypertension, heart failure, or impaired renal function.COMPOUNDCompound 1

[0084] Compound 1 , as depicted below, is a triple reuptake inhibitor, also known as (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone.

[0085] The chemical structure of Compound 1 is:(Compound 1).

[0086] A method of chemically synthesizing Compound 1 is described in U.S. Patent No. 8,084,623 and U.S. Patent No. 9,527,810 which are incorporated by reference in their entirety.

[0087] In various embodiments, methods described herein comprise administering Compound 1 or a pharmaceutically acceptable salt thereof. In various embodiments, the pharmaceutically acceptable salt of Compound 1 can be a salt of Compound 1 with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p- toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

[0088] In certain embodiments, the pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt, being in a hydrate or an anhydrate form (e.g., anhydrate, hemihydrate, monohydrate, or quarterhydrate). In certain embodiments, the pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt, being in a quarterhydrate form.

[0089] In various embodiments, the pharmaceutically acceptable salt of Compound 1 is, or a hydrate thereof.

[0090] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in an amorphous form. In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in a crystalline form. In certain embodiments, the crystalline form is a crystalline polymorph or a hydrate thereof. In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanonehydrochloride quarterhydrate (Form 1). In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (Form 2).Form 1

[0091] In some embodiments, the compound is in a crystalline quarterhydrate form (Form 1) of a hydrochloride salt of Compound 1, wherein Form 1 has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 1. In some embodiments, Form 1 is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cu^aradiation at 20 (2 Theta): 5.5+0.20°, 9.4+0.20°, 10.6+0.20°, 12.5+0.20°, 14.6+0.20°, 16.2+0.20°, 16.6+0.20°, 17.3+0.20°, 18.6+0.20°, 19.6+0.20°, 22.2+0.20°, 22.7+0.20°, 23.1+0.20°, 23.7+0.20°, and 25.3+0.20°.Form 2

[0092] In some embodiments, the compound is in a crystalline form (Form 2) of a hydrochloride salt of Compound 1 , wherein Form 2 has an X-ray powder diffraction (XRPD) pattern as substantially shown in FIG. 2. In some embodiments, Form 2 is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cu^a radiation at 26 (2 Theta): 5.2+0.20°, 10.5+0.20°, 12.3+0.20°, 15.3+0.20°, 15.6+0.20°, 16.0+0.20°, 17.1+0.20°, 18.8+0.20°, 23.0+0.20°, 23.9+0.20°, 27.2+0.20°, 28.2+0.20°, and 30.5+0.20°.

[0093] In one aspect, the present disclosure relates to a composition, such as a pharmaceutical composition comprising Compound 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of a sleep disorder in a subject in need thereof. In certain embodiments, the sleep disorder is narcolepsy. In another aspect, the present disclosure relates to a composition such as a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for the treatment of a medical condition associated with a sleep disorder in a subject in need thereof. In certain embodiments, the sleep disorder is narcolepsy. In various embodiments, the composition is a solid pharmaceutical composition.

[0094] In various embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 1 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 1 mg to about 60 mg. In some embodiments, the composition comprises from about 1 mg to about 45 mg. In some embodiments, the composition comprises from about 1 mg to about 30 mg. In some embodiments, the composition comprises from about 1 mg to about 15 mg. In some embodiments, the composition comprises from about 1 mg to about 5 mg. In some embodiments, the composition comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, or about 70 mg.

[0095] In various embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 3 mg to about 70 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In various embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be from about 3 mg to about60 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 3 mg to about 50 mg. In some embodiments, the composition comprises from about 3 mg to about 40 mg. In some embodiments, the composition comprises from about 3 mg to about 30 mg. In some embodiments, the composition comprises from about 3 mg to about 20 mg. In some embodiments, the composition comprises from about 3 mg to about 10 mg. In some embodiments, the composition comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 13 mg, about 16 mg, about 19 mg, about 22 mg, about 25 mg, about 28 mg, about 31 mg, about 34 mg, about 37 mg, about 40 mg, about 43 mg, about 46 mg, about 49 mg, about 52 mg, about 55 mg, or about 58 mg.

[0096] In various embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can beadministered at a dose of from about 1 mg / kg to about 70 mg / kg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition can be administered at a dose of from about 1 mg / kg to about 60 mg / kg. In some embodiments, the composition can be administered at a dose of from about 1 mg / kg to about 45 mg / kg. In some embodiments, the composition can be administered at a dose of from about 1 mg / kg to about 30 mg / kg. In some embodiments, the composition can be administered at a dose of from about 1 mg / kg to about 15 mg / kg. In some embodiments, the composition can be administered at a dose of from about 1 mg / kg to about 5 mg / kg. In some embodiments, the composition can be administered at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, or about 70 mg / kg.

[0097] In various embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be administered at a dose of from about 3 mg / kg to about 70 mg / kg of Compound 1, or a pharmaceutically acceptable salt thereof. In various embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical compositions described herein can be administered at a dose of from about 3 mg / kg to about 60 mg / kg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition can be administered at a dose of from about 3 mg / kg to about 50 mg / kg. In some embodiments, the composition can be administered at a dose of from about 3 mg / kg to about 40 mg / kg. In some embodiments, the composition can be administered at a dose of from about 3 mg / kg to about 30 mg / kg. In some embodiments, the composition can be administered at a dose of from about 3 mg / kg to about 20 mg / kg. In some embodiments, the composition can be administered at a dose of from about 3 mg / kg to about 10 mg / kg. In some embodiments, the composition can be administered at a dose of about 1 mg / kg, about 2 mg / kg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 13 mg / kg, about 16 mg / kg, about 19 mg / kg, about 22 mg / kg, about 25 mg / kg, about 28 mg / kg, about 31 mg / kg, about 34 mg / kg,about 37 mg / kg, about 40 mg / kg, about 43 mg / kg, about 46 mg / kg, about 49 mg / kg, about 52 mg / kg, about 55 mg / kg, or about 58 mg / kg.

[0098] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the free base form of Compound 1.

[0099] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutically acceptable salt of Compound 1 can be a salt of Compound 1 with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.[000100] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.[000101] The pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.[000102] The pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dose” or “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In various embodiments, the pharmaceutical dosage forms described herein can be administered as a unit dose. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.[000103] The pharmaceutical compositions provided herein may be presented in sustained release form. A sustained release form is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time. A sustained release form can be formulated to sustain, for example, the compound's action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.[000104] In various embodiments, the pharmaceutical compositions provided herein are administered to the patient as a solid dosage form. In certain embodiments, the solid dosage form is a capsule. In certain embodiments, the solid dosage form is a tablet.[000105] In various embodiments, the pharmaceutical compositions provided herein comprise Compound 1 as the sole active agent, or in combination with other active agents.[000106] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21sted., Lippincott Williams & Wilkins, 2005.EXAMPLES[000107] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.[000108] In the Examples provided below, the following abbreviations are used: “Cmpd 1” refers to Compound 1; “ANOVA” refers to analysis of variance test; “AP” refers to anteroposterior; “EEG” refers to electroencephalograph; “EMG” refers to electromyograph; “LMA” refers to locomotor activity; “ML” refers to medial-lateral; “CAF” refers to caffeine; “NR” refers to non-rapid eye movement sleep; “NRBD” refers to NR bout duration; “NRD” refers to EEG delta power (1-4 Hz) within NR; “NRNB” refers to number of NR bouts; “RBD” refers to REM bout duration; “REM” refers to rapid eye movement sleep; “RNB” refers to number of REM bouts; “SEM” refers to standard error of mean; “Tb” refers to core body temperature; “W” refers to waking; “WBD” refers to W bout duration; “WNB” refers to number of W bouts; “ZT” refers to zeitgeber hour; “VEH” refers to vehicle; “po,” “p.o.” or "per os” refers to by mouth; “DAT” refers to dopamine transporters; “SERT” refers to serotonin transporters; “TRI” refers to triple reuptake inhibitor; and “RO5186582” or “6582”refers to BASMISANIL, which has the structure:Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)- methanone (Compound 1) hydrochloride (15) quarterhydrate [See U.S. Patent No.9,527,810][000109] (S)-(l-benzyl-3-propylpyrrolidin-3-yl)(3,4-dichlorophenyl)methanone (IX-1) (5 g, 13.3 mmol, Eq: 1.00, see U.S. Patent No. 9,527,810 for synthesis) was dissolved in dichloromethane (30 mL). The light yellow solution was cooled to 0-5 °C and N- ethyldiisopropylamine (172 mg, 226 pL, 1.33 mmol, Eq: 0.1) was added. 1 -Chloroethyl chloroformate (2.28 g, 1.74 mL, 15.9 mmol, Eq: 1.2) was added dropwise while the temperature was maintained in between 0-5 °C. The reaction was warmed to room temperature over 30 min and was stirred 1 h at room temperature. Methanol (25 mL) was added and the light yellow solution was heated to 40°C for 40 min. The reaction mixture was concentrated under reduced pressure (40°C, 600-15 mbar) to give 5.48 g of crude product. Ethyl acetate (30.0 mL) was added and the suspension was heated to 50°C. A solution of water (239 mg, 239 pL, 13.3 mmol, Eq: 1.0) in ethyl acetate (35 mL) was added over 10 min. The white suspension was stirred for 1 h at 50°C and cooled to room temperature over 1.5 h. The suspension was filtered, and the filter cake was washed twice with ethyl acetate (10 mL) and dried under reduced pressure (40° C, 15 mbar) to give 4.02 g of (15) as quarterhydrate (93% yield).Example 2. Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)- methanone (Compound 1) hydrochloride (15) quarterhydrate [See U.S. Patent No. 9,527,810]1. Grignard formation (A ’)[000110] 6.8 g of Magnesium (279 mmol, 1.3 equiv.) was suspended in 60 mL tetrahydrofuran. The suspension was heated to 40°C, and 2% of a solution of 70.5 g 3,4- dichlorobromobenzene (A) in 200 mL tetrahydrofuran was added (the Grignard started within a few minutes). After the exotherm ceased, the remaining aryl bromide solution was added over 2 h. The reaction mixture was stirred for 1 h at 40°C, and then the mixture was cooled to room temperature.2. Grignard addition[000111] A solution of the acid chloride (13) (see U.S. Patent No. 9,527,810 for synthesis) was degassed 3 times and 55.8 g of N,N,N',N',N"-pentamethyldiethylenetriamine (PMDTA) (322 mmol, 1.5 equiv.) was added. The light suspension was heated to 40-45°C, and the Grignard solution (A') was added dropwise over 1.5 h. After 1 h of additional reaction time, the reaction mixture was cooled to room temperature. 500 mL of 2 M HC1 (aq), 300 mL saturated NaCl (aq) and 300 mL ethanol were added. The organic phase was separated and washed with a mixture consisting of 500 mL 2 M HC1 (aq), 300 mL saturated NaCl (aq) and 300 mL ethanol. The organic phase was washed with 400 mL of IM NaOH (aq) and twice with 150 mL 10% NaCl (aq). The organic phase was concentrated under reduced pressure to an oil, taken up in 100 mL toluene and concentrated again to give 87 g of crude (14) with 80% purity.3. (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) as quarterhydrate[000112] The crude (14) was dissolved in 130 mL of toluene and the solution was added dropwise to a mixture of 140 mL toluene and 70 mL 37% HO (aq) at 60-70°C. After 1 h, the reaction mixture was azeotroped with toluene (Tr max=70°C, Tj max=120°C, reduced pressure) and adjusted to a volume of 350-400 mL. A mixture consisting of 700 mL ethyl acetate and 3.6 mL water was added at 65 °C. The solution was cooled to room temperature over 1 h, during which crystallization started (around 45°C). After stirring overnight, the suspension was cooled to 0-5 °C for 2 h, filtered and washed twice with 200 mL ethyl acetate. The crystals were re-suspended in 250 mL of ethyl acetate, digested at 55 °C for 2 h, and then cooled to room temperature. The suspension was filtered, and the filter cake was washed with 200 mL ethyl acetate. The crystals were dried at 50°C under reduced pressure to give 54.4 g of the (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarterhydrate as a powder with 99% purity.An alternative route for (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) as quarterhydrate[000113] The crude (14) was dissolved in 63 mL toluene and deprotected at 60°C with 24 mL 37% HC1 (aq). After completion of the reaction, the reaction mixture was dried azeotropically with toluene at 50-60°C. The solution was cooled to room temperature, and 100 mL water was added. The aqueous phase was separated and washed with 50 mL toluene. The aqueous phase was dried azeotropically with toluene and concentrated to dryness to give 22.5 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarterhydrate (90% yield). (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)- methanone hydrochloride quarterhydrate can be obtained by digestion or recrystallization, for example, by processes described below.Transformation of ( 3 ,4-dichloro-phenyl )-( ( S)-3-propyl-pyrrolidin-3-yl fmethanone hydrochloride anhydrate to the quarterhydrate form:[000114] (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride anhydrate (40 g, 124 mmol, Eq: 1.00, see Example 3 or U.S. Patent No. 9,527,810 for synthesis) was suspended in a mixture of ethyl acetate (340 mL), ethanol (36 mL) and water (0.6 mL) at room temperature. The suspension was heated to 40°C and a mixture consisting of ethyl acetate (20 mL), ethanol (0.5 mL) and water (0.6 mL) was added over 1 h. The suspension was cooled to room temperature over 1 h. After stirring overnight at room temperature, the suspension was cooled over 2-3 h at 0-5°C, filtered and washed with a cold (0-5 °C) mixture of ethyl acetate (55 mL), ethanol (5 mL) and water (0.5 mL). The filter cake was dried at 50°C under reduced pressure to give 38 g of (3,4-dichloro-phenyl)-((S)-3- propyl-pyrrolidin-3-yl)-methanone hydrochloride quarterhydrate (1.5% water).Recrystallization of ( 3,4-dichloro-phenyl )-( ( S )-3-propyl-pyrrolidin-3-yl fmethanone hydrochloride quarterhydrate:[000115] 54.4 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarterhydrate was dissolved at room temperature in 550 mL ethanol. The solution was filtered and concentrated under reduce pressure at 60°C to a volume of 140 mL. The volume was adjusted to 550 mL by the addition of ethyl acetate. The remaining ethanol was solvent exchanged to ethyl acetate (60°C, reduced pressure), and 55 mL ethanol was added to the resulting suspension at 60 °C. 1.5 mL water was then added and the solution was slowly cooled to room temperature, during which the crystallization occurred. After stirring at room temperature overnight, the suspension was cooled to 0-5 °C for 1 h and was filtered. The filter cake was washed with a mixture of 50 mL ethyl acetate and 5 mL ethanol, followed by two more washes with 50 mL ethyl acetate. The crystals were dried at 50°C overnight under reduced pressure to give 48.9 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3- yl)-methanone hydrochloride quarterhydrate as a powder with 99% purity.Example 3. Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)- methanone (Compound 1) hydrochloride (15) anhydrate [See U.S. Patent No. 9,527,810][000116] 50 g of sodium salt was transformed into the corresponding acid chloride (13) (see U.S. Patent No. 9,527,810 for synthesis). The acid chloride (13) was reacted with 3,4- dichlorophenyl-MgBr (A'), and then deprotected. After azeotrope drying, an orange turbid toluene solution (300 g, water content <0.1%) was obtained by Karl Fischer titration of the crude (15).[000117] (i) 1 / 5 of the crude (15) solution (max theoretical content: 11.3 g of (15)) was cooled to room temperature. After storing for overnight at room temperature, the resulting suspension was filtered. The filter cake was washed with ethyl acetate (Karl Fischer titration of wet filter cake 0.2%) and dried at 50-60°C under reduced pressure to give 5.9 g of (15) crystals.[000118] (ii) 1 / 5 of the crude (15) solution (max theoretical content: 11.3 g of (15)) was cooled to room temperature. After storing for 4 days at room temperature, the resulting suspension was stirred at 0-2°C for 4 h. The resulting suspenction was filtered, the filter cake was washed with ethylacetate (Karl Fischer titration of wet filter cake 0.2%) and dried at 50- 60°C under reduced pressure to give 8.8 g of (15) crystals.Example 4. Crystalline Forms of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)- methanone hydrochloride and (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)- methanone hydrochloride quarterhydrate [See U.S. Patent No. 9,527,810][000119] Characterization methods and data of crystalline forms of Compound 1 are described in U.S. Patent No. 9,527,810, which is incorporated by reference in its entirety.X-ray Powder Diffraction (XRPD)[000120] X-ray diffraction powder patterns were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu^aradiation, primary monochromator, position sensitive detector, angular range 3° to 42° (2 Theta), approximately60 minutes total measurement time). The samples were prepared and analyzed without further processing (e.g., grinding or sieving) of the substance.XRPD Pattern of (3,4-dichloro-phemT)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarterhydrate ( Form 1 )[000121] The hydrochloride quarterhydrate of (3,4-dichloro-phenyl)-((S)-3-propyl- pyrrolidin-3-yl)-methanone solid (Form 1) can be identified by as few as one characteristic peak in its powder X-ray diffraction patterns as shown in FIG. 1. Exemplary X-ray powder diffraction patterns of hydrochloride quarterhydrate of (3,4-dichloro-phenyl)-((S)-3-propyl- pyrrolidin-3-yl)-methanone (Form 1) in terms of 20 (2 Theta) are: 5.5+0.20°, 9.4+0.20°, 10.6+0.20°, 12.5+0.20°, 14.6+0.20°, 16.2+0.20°, 16.6+0.20°, 17.3+0.20°, 18.6+0.20°, 19.6+0.20°, 22.2+0.20°, 22.7+0.20°, 23.1+0.20°, 23.7+0.20° and 25.3+0.20°; in particular characteristic peaks are 9.4+0.20°, 14.6+0.20°, 16.6+0.20°, 19.6+0.20° and 22.2+0.20°.XRPD Pattern of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride ( Form 2 )[000122] The hydrochloride of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)- methanone solid (Form 2) can be identified by as few as one characteristic peak in its powder X-ray diffraction patterns as shown in FIG. 2. Exemplary X-ray powder diffraction patterns of hydrochloride of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone solid (Form 2) in terms of 20 (2 Theta) are: 5.2+0.20°, 10.5+0.20°, 12.3+0.20°, 15.3+0.20°, 15.6+0.20°, 16.0+0.20°, 17.1+0.20°, 18.8+0.20°, 23.0+0.20°, 23.9+0.20°, 27.2+0.20°, 28.2+0.20°, and 30.5+0.20°.Crystal Structure Analysis[000123] For single crystal structure analysis, a single crystal was mounted in a loop on a goniometer and measured at ambient conditions. Data were collected on a GEMINI R Ultra diffractometer from Oxford Diffraction (Oxford). Cu-radiation of 1.54 A wavelength was used for data collection. Data was processed with the software CRYSAEIS. The crystalstructure was solved and refined with standard crystallographic software. In this case, the program ShelXTL from Bruker AXS (Karlsruhe) was used.Preparation of single crystals of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)- methanone monohydrochloride quarterhydrate[000124] 10 mg of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride were dissolved in 0.226 mL of nitromethane at 60°C. The solution was allowed to reach the ambient temperature without agitation. After 24 h, single crystals were harvested and subjected to X-ray crystal structure analysis.[000125] Structural data derived from (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3- yl)-methanone hydrochloride quarterhydrate single crystal X-ray analysis are the following unit cell parameters:wherein a, b and c are each a representative length of the crystal lattice, and alpha, beta and gamma are unit cell angles. The salt crystallizes in the space group Pl, affording a cell volume of 1623.82 A3.Differential Scanning Calorimetry (DSC)[000126] Differential Scanning Calorimetry curves were recorded using a Mettler- Toledo™ differential scanning calorimeter DSC820, DSC821, or DSC1 with a FRS05 sensor. System suitability tests were performed with Indium as reference substance and calibrations were carried out using Indium, Benzoic acid, Biphenyl and Zinc as reference substances.[000127] For the measurements, approximately 2-6 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the lids were automatically pierced resulting in approximately 1.5 mm pin holes. The samples were then heated under a flow of nitrogen of about 100 mL / min using heating rates of usually 10 K / min.Thermal Gravimetric Analysis (TGA)[000128] Thermal Gravimetric Analysis was performed on a Mettler-Toledo™ thermogravimetric analyzer (TGA850 or TGA851). System suitability tests were performed with Hydranal as reference substance and calibrations using Aluminum and Indium as reference substances.[000129] For the thermogravimetric analyses, approximately 5-10 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to the measurement, the lids were automatically pierced resulting in approximately 1.5 mm pin holes. The samples were then heated under a flow of nitrogen of about 50 mL / min using a heating rate of 5 K / min.Example 5. Effect of Compound 1 on sleep and wake profile in Sprague Dawley rats[000130] Using a counter-balanced, repeated measures design, three doses of Compound 1 (1-10 mg / kg, po) and RO5186582 (3-30 mg / kg, po) were tested for their effects on sleep / wake parameters, core body temperature (Tb), and locomotor activity (LMA) in adult male Sprague-Dawley rats; the results were compared with the effects of caffeine (CAF; 10 mg / kg).[000131] Latency to sleep, hourly sleep / wake amounts, sleep intensity, and sleep consolidation measures (bout duration and number of bouts per hour) were assessed for 6 h after injections that occurred during the middle of the light period, at the start of Zeitgeber hour 7 (ZT7).MATERIALS AND METHODS[000132] Animal Recording and Surgical Procedures. Animals were housed in a temperature-controlled recording room under a 12 hour / 12 hour light / dark cycle (lights on at 5:00 AM), with food and water available ad libitum. Room temperature (24±2°C), humidity (50+20% relative humidity), and lighting conditions were monitored continuously via computer. Animals were inspected daily in accordance with AAALAC and SRI guidelines. All experimental procedures involving animals were approved by SRI’s Institutional Animal Care and Use Committee and were in accordance with U.S. National Institute of Health guidelines.[000133] Eight male Sprague-Dawley rats (300+25 g; Charles River, Wilmington, MA) were implanted with chronic recording devices for continuous recordings of electroencephalograph (EEG), electromyograph (EMG), core body temperature (Tb), and locomotor activity (LMA) via telemetry. Under isofluorane anesthesia (1-4%), the fur was shaved from the top of the head and from the midabdominal region. After the skin was disinfected with Betadine and alcohol, a dorsal midline incision on top of the head and a midventral incision along the linea alba through the peritoneum were made. Sterile miniature transmitters (F40-EET, Data Sciences Inc., St Paul, MN) were inserted through this incision and sewn to the musculature with a single stitch of silk suture (4-0). Four biopotential leads from the transmitters were inserted sc into the neck and head region. The abdominal musculature was then closed with absorbable suture (Vicryl 3-0), and the peritoneum was closed with silk suture (4-0). Furacin ointment was applied to the sutured incision. The temporalis muscle was then retracted, and the skull was cauterized and thoroughly cleaned with a 2% hydrogen peroxide solution. Holes were drilled through the skull bilaterally at - 5.0 mm AP from bregma and 2.0 mm ML. The two biopotential leads used as EEG electrodes were inserted into the holes and affixed to the skull with dental acrylic. The two biopotential leads used as EMG electrodes were sutured into the neck musculature. The incision was closed with suture (silk 4-0), and antibiotics were administered topically. Pain was relieved by a long-lasting analgesic (Buprenorphine) administered im postoperatively. After surgery, animals were placed in a clean cage and observed until they recovered.[000134] EEG, EMG, Tb, and LMA were recorded via telemetry using DQ ART 4.1 software (Data Sciences Inc., St Paul, MN). Animals were acclimated to the handling procedures and were given two separate 1 mL doses of vehicle, one 7 days and the other 3 days before the first experimental day. Following completion of the data collection, expert scorers determined states of sleep and wakefulness in 10 s epochs by examining the recordings visually using NeuroScore software (Data Sciences Inc., St Paul, MN). The EEG and EMG data were scored for waking (W), rapid eye movement sleep (REM), and non-rapid eye movement sleep (NR). Tb and LMA (counts per minute) were analyzed as mean counts per hour.[000135] Experimental Design. A repeated measures design was employed in which each rat received eight separate dosings. The dosing conditions included Compound 1 at three concentrations (1-10 mg / kg), 6582 at three concentrations (3-30 mg / kg), CAF at one concentration (10 mg / kg), and a vehicle control (purified H2O), all administered po. A minimum of 3 days elapsed between doses. Because the test compounds were hypothesized to promote W, dosing occurred during the middle of the rats’ normal inactive period. The dosing procedure began approximately 6 h after lights on during the start of Zeitgeber hour 7 (ZT7) and was typically completed within 10 min. After each dose, animals were continuously recorded for 30 h until lights out the following day (ZT12). However, only the first 6 h of the recording were scored and analyzed for this study.[000136] Data Analysis. EEG and EMG data were scored visually in 10 s epochs for W, REM, and NR. Scored data were analyzed and expressed as time spent in each state per hour. Latency to NR onset for each rat was calculated from the time of drug injection to the first six continuous 10 s epochs scored as NR. Latency to REM onset for each rat was calculated from the time of drug injection to the first three continuous 10 s epochs scored as REM. Cumulative time spent in W, NR, and REM, as well as the REM:NR ratios, were calculated for the 6 h recording period. To determine whether any of the pharmacological treatments affected the consolidation of behavioral states, the duration and number of bouts for each state were calculated in hourly bins. A “bout” consisted of a minimum of two consecutive 10 s epochs of a given state and ended with any single state change epoch. The EEG spectraduring NR sleep were analyzed offline with a fast Fourier transform algorithm (NeuroScore software, Data Sciences Inc., St Paul, MN) on all epochs without a visually detectable artifact. EEG delta power (1-4 Hz) within NR (NRD) was then calculated in hourly bins. Tb and LMA (counts per minute) were analyzed as mean values per hour (hourly means).[000137] Latency to NR and REM, REM:NR ratios, and cumulative state data were analyzed using one-way repeated-measures analysis of variance (ANOVA); all other data were analyzed using two-way repeated-measures ANOVA. When one-way repeated- measures ANOVA indicated statistical significance, t-tests were performed for post hoc analysis. For two-way repeated- measures ANOVA, both a treatment effect and an effect that changed over time were predicted.[000138] Therefore, both a treatment effect (factor A) and a time (factor B) by treatment effect were analyzed for each rat. When ANOVA indicated statistical significance in a time by treatment interaction, Fisher’s LSD t-tests were performed to determine which groups differed. When ANOVA indicated statistical significance for overall condition effects (factor A), t-tests were performed to determine which conditions differed across the recording period.RESULTS[000139] Throughout the Results section and the Summary section, when values are written as “increased” or “decreased,” the meaning is an increase or decrease relative to the vehicle control. When the term “small effect” is used, it refers to at most small differences between values for vehicle control and values for the test articles.Compound 1[000140] Administration of Compound 1 was strongly wake-promoting but only at 10 mg / kg. The latency to both NR and REM onset was significantly increased following administration of Compound 1 at 10 mg / kg compared to vehicle and CAF (FIG. 3). Rats were in W for almost the entire recording period following Compound 1 at 10 mg / kg (FIG. 4A, FIG. 4B, FIG. 4C). While NR began to occur near the end of the recording period,REM was completely suppressed throughout the entire 6 h following Compound 1 at 10 mg / kg.[000141] Administration of Compound 1 at 3 mg / kg was followed by increased W during ZT7 and ZT11 and decreased REM during ZT8-ZT11. Cumulative W was increased, cumulative NR decreased and REM was absent following Compound 1 at 10 mg / kg (FIG. 5). Cumulative W was increased and cumulative REM decreased following Compound 1 at 3 mg / kg. The relatively stronger REM-suppressive versus NR-suppressive effects of Compound 1 are evident from the significant decrease in the REM: NR ratio following Compound 1 at 3 and 10 mg / kg (FIG. 6). Only small effects on NRD were found following administration of Compound 1 (FIG. 7A, FIG. 7B).[000142] Compound 1 at 10 mg / kg produced highly consolidated W (FIG. 8A, FIG. 8B, FIG. 8C, FIG. 8D, FIG. 8E, FIG. 8F). W bout duration (WBD) was increased while the number of W bouts (WNB), the number of NR bouts (NRNB) and the number of REM bouts (RNB) were all decreased for the entire recording period. Since there was little or no NR or REM following Compound 1 at 10 mg / kg, neither the NR bout duration (NRBD) nor the REM bout duration (RBD) following this condition could be analyzed. Following Compound 1 at 3 mg / kg, WBD was increased, and NRNB and RBD were decreased during ZT7. Compound 1 at 3 mg / kg was also followed by decreased RNB during ZT8-ZT9 and ZT12.[000143] LMA was increased across the entire recording period following Compound 1 at 10 mg / kg and during ZT7 following Compound 1 at 3 mg / kg (FIG. 9). Interestingly, even though both W and LMA were increased, Tb was not elevated following Compound 1 at 10 mg / kg. Tb was decreased during ZT9- ZT10 and overall following administration of Compound 1 at 1 and 3 mg / kg.RO5186582[000144] Administration of RO5186582 (“6582”) at all tested concentrations produced remarkably little effect on the parameters measured in this study. Compared to vehicle, no effect was found on the latency to NR or REM onset (FIG. 3), W, NR and REM (FIG. 10A, FIG. 10B, FIG. 10C), cumulative W, NR and REM (FIG. 5) or REM:NR ratios (FIG. 6)following 6582 at any concentration. NRD was increased during ZT7 following 6582 at 10 mg / kg and during ZT10 following 6582 at 30 mg / kg (FIG. 7A, FIG. 7B). Almost no effects in measures of sleep / wake consolidation were found (FIG. 11A, FIG. 11B, FIG. 11C, FIG. 11D, FIG. HE, FIG. HF).[000145] WBD was increased during ZT7 and RBD increased during ZT12 following 6582 at 10 mg / kg while RBD was increased during ZT7 following 6582 at 30 mg / kg. No effect on LMA or Tb were found following any concentration of 6582 (FIG. 12A, FIG. 12B).Caffeine[000146] CAF produced the expected effects on sleep / wake parameters, LMA, and Tb.SUMMARY[000147] Administration of Compound 1 at 10 mg / kg was strongly wake-promoting. The latency to non-rapid eye movement sleep (NR) and rapid eye movement sleep (REM) onset were both significantly increased compared to vehicle and CAF. Rats were awake (W) for almost the entire recording period following Compound 1 at 10 mg / kg. While NR began to occur near the end of the recording period, REM was completely suppressed throughout following Compound 1 at 10 mg / kg.[000148] Administration of Compound 1 at 3 mg / kg was followed by increased W during ZT7 and ZT11 and decreased REM during ZT8-ZT10 compared to vehicle. Cumulative W was increased, cumulative NR decreased and REM was eliminated following Compound 1 at 10 mg / kg compared to vehicle. Cumulative W was increased and cumulative REM decreased following Compound 1 at 3 mg / kg compared to vehicle. REM: NR ratios were decreased following Compound 1 at 3 and 10 mg / kg compared to vehicle and CAF. Only small effects on NR delta power (NRD) were found following administration of Compound 1. W following Compound 1 administration was highly consolidated. W bout duration was increased while the number of W bouts, the number of NR bouts and the number of REM bouts were all decreased for the entire recording period following Compound 1 at 10 mg / kg compared to vehicle. LMA was increased across the entire recording period followingCompound 1 at 10 mg / kg compared to vehicle. Tb was decreased during ZT9-ZT10 following administration of Compound 1 at 1 and 3 mg / kg compared to vehicle.[000149] Administration of 6582 at all concentrations tested produced remarkably little effect on the parameters measured in this study. Compared to vehicle, no effect was found on the latency to NR or REM onset, W, NR and REM, cumulative W, NR and REM orREM:NR ratios following 6582 at any concentration. Only very small effects on NRD and in measures of sleep / wake consolidation were found compared to vehicle. No effects on LMA or Tb were found following any concentration of 6582.[000150] CAF produced the expected effects on sleep / wake parameters, LMA, and Tb. EQUIVALENTS AND SCOPE[000151] Various modifications and variations of the described disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure that are obvious to those skilled in the art are intended to be within the scope of the disclosure. Other embodiments are in the claims.

Claims

CLAIMS1. A method of treating or preventing a sleep disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the sleep disorder is a disorder selected from the group consisting of insomnia, hypersomnolence, narcolepsy, cataplexy, idiopathic hypersomnia, sleep paralysis, hypnagogic hallucinations, hypnopompic hallucinations, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a non-24- hour sleep wake disorder, a non-rapid eye movement sleep arousal disorder, a nightmare disorder, a rapid eye movement sleep behavior disorder, restless leg syndrome, a medication-induced sleep disorder, a substance-induced sleep disorder, excessive daytime sleepiness, excessive need for sleep, shift work sleep disorder, and Kleine Levin syndrome.

3. A method of treating or preventing hypersomnolence in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof.

4. The method of claim 3, wherein the hypersomnolence is a disorder selected from the group consisting of idiopathic hypersomnia, recurrent hypersomnia, narcolepsy, shift work sleeping disorder, endozepine induced-recurrent stupor and amphetamine- resistant hypersomnia.

5. A method of treating or preventing narcolepsy in a subject in need thereof, the method comprising administering to the subject in need thereof a composition comprising a therapeutically effective amount of Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof.

6. The method of claim 5, wherein the narcolepsy is narcolepsy type 1 or narcolepsy type 2.

7. The method of claim 5 or 6, wherein the treating or preventing comprises: a. reducing one or more symptoms of narcolepsy in the subject; and / or b. modulating an rapid eye movement REM sleep in the subject.

8. The method of any one of claims 5-7, wherein the one or more symptoms of narcolepsy is selected from the group consisting of: a. excessive daytime sleepiness; b. cataplexy; c. sleep paralysis; d. hallucinations; e. deficiency of the hormone hypocretin; f. changes in rapid eye movement (REM) sleep;g. excessive need for sleep; and h. metabolic-syndrome-related disorder.

9. The method of claim 8, wherein the modulation of REM sleep comprises decreasing the rate of eye movement, reducing the density and latency of REM sleep, disrupting REM sleep or increasing non-REM sleep, decreasing ratio of REM:non-REM sleep, or REM sleep onset latency.

10. The method of claim 5, wherein the narcolepsy is associated with a metabolic- syndrome-related disorder.

11. The method of claim 10, wherein the metabolic-syndrome-related disorder is selected from the group consisting of hypertension, diabetes, and dyslipidemia.

12. The method of claim 5, wherein the subject experienced weight gain, obesity, high body mass index, or cardiometabolic risks.

13. The method of any one of claims 1-12, wherein the therapeutically effective amount is between about 3 mg to about 60 mg.

14. The method of any one of claims 1-13, wherein the therapeutically effective amount is about 3 mg, about 9 mg, or about 30 mg.

15. The method of any one of claims 1-14, wherein Compound 1 is administered once daily.

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