Dosing of orexin type 2 receptor agonists

Abstract

The present disclosure includes compositions and methods for administering to a human subject one or more orexin type 2 receptor agonists in one or more dosage forms in an amount and frequency that provides a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the agonist for the remainder of the twenty-four-hour period. Also disclosed are compositions and methods for treating narcolepsy type 1 (NT1) or the symptoms of narcolepsy type 1, in a human in need of said treatment by maintaining a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the agonist for the remainder of the twenty-four-hour period.

Description

DOSING OF OREXIN TYPE 2 RECEPTOR AGONISTSFIELD OF THE INVENTION

[0001] The present invention relates to the methods of treating sleep-wake disorders such as Narcolepsy and its daytime and nighttime symptoms. More specifically, this invention provides methods for use of orexin receptor type 2 agonists for treatment of sleep-wake disorders such as Narcolepsy and its daytime and nighttime symptoms.BACKGROUND OF THE INVENTION

[0002] Narcolepsy is a severe neurological sleep disorder characterized by excessive daytime sleepiness (EDS). In some cases, narcolepsy may be accompanied by a sudden loss of muscle tone and mobility (cataplexy). Narcolepsy accompanied by cataplexy is known as narcolepsy type 1 (NT1); narcolepsy in the absence of cataplexy is known as narcolepsy type 2 (NT2). In addition to EDS and cataplexy, other symptoms include hypnagogic / hypnopompic hallucinations, sleep paralysis and disturbed nighttime sleep (sleep fragmentation), which together comprise the narcolepsy symptom pentad. There are few effective treatments for narcolepsy and most only address one or two symptoms of the narcolepsy pentad. For example, stimulants (e.g. modafinil) may be used to treat EDS, antidepressants (e.g. clomipramine) may be used to treat cataplexy, and sodium oxybate and pitolisant may be used to treat both EDS and cataplexy. However, these drugs are known to have side effects such as insomnia, rebound symptom, and the potential for drug abuse (Zeitzer et al. (2006) Trends in Pharmacol. Sci., 27(7y.36S-74).

[0003] Orexins (also known as hypocretins), are neuropeptides expressed in the lateral hypothalamus, and play a fundamental role in the regulation of sleep and wakefulness (de Lecea / / . (1998) TWA 95: 322-327; Sakurai et al. (1998) Cell 92(4):573-85; Tsujino & Sakurai (2009) Pharmacol Rev 61 : 162-176). Loss of orexin neurons causes narcolepsy type 1 (NT1), a sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and nighttime symptoms including fragmented sleep and sleep paralysis and hallucinations (Nishino et al. (2000) Lancet 355:39-40). Orexin signaling is mediated through orexin-1 (OX1R) and orexin-2 (OX2R) receptors (Sakurai et al. (1998) Cell92(4) : 573 -85), among which OX2R plays the central role in the maintenance of sleep / wakefulness states (Lin et al. (1999) Cell 98: 365-376; Sakurai (2007) Neurosci 8: 171-181; Willie et. al. (2001) Annu Rev Neurosci 24: 429-458

[0004] Several OX2R selective agonists have been discovered which improved both EDS and cataplexy in mouse models and humans with NT1 (Evans et al. (2022) PNAS 119(35):e2207531119; Ishikawa et al. (2022) Pharmacol Biochem Behav 220: 173464;Ishikawa et. al. (2023) J. Pharmacol Exp Ther 385: 193-204). Notably, NT1 model mice and humans with NT1 showed hypersensitivity to wake-promoting effects of OX2R agonists. For example, danavorexton significantly increased the wakefulness time in orexin / ataxin-3 mice at 3-times lower dosage than in NonTg mice. Similarly, in individuals with NT1, danavorexton displayed comparable improvements in mean sleep latency in the Maintenance of Wakefulness Test (MWT) at lower dosage than in individuals with NT2 (narcolepsy type 2 which typically has normal orexin levels) at 5 mg and 44 mg, respectively (Evans et al. (2022) PNAS 119(35):e2207531119).

[0005] A need exists for a treatment that improves both daytime and nighttime symptoms of NT1 while optimally suppressing cataplexy and improving of arousal.SUMMARY OF THE INVENTION

[0006] In one aspect, the present disclosure provides compositions, dosage forms, combinations, kits and methods for treating narcolepsy type 1 (NT1) or the symptoms of narcolepsy type 1, in a human subject in need of said treatment by maintaining a wakepromoting blood plasma concentration of an orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and by maintaining a blood plasma concentration of an orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the agonist for the remainder of the twenty-four-hour period.

[0007] In one aspect, the present disclosure provides a method of treating Narcolepsy Type 1 (NT1) in a human subject, the method comprising: administering to a human subject in need of said treatment one or more orexin type 2 receptor agonists in one or more dosage forms in an amount and frequency that provides a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the orexin type 2receptor agonist for the remainder of the twenty-four-hour period; wherein the administering is such that a blood plasma concentration of the one or more orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods.

[0008] In another aspect, the present disclosure provides a method of treating Narcolepsy Type 1 (NT1) in a human subject, the method comprising: administering to a human subject in need of said treatment a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; and administering to the human subject a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject.

[0009] In some aspects, the method further comprises administering to the human subject a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is administered one or more times during waking hours of each twenty-four- hour period of the dosing interval in an amount and frequency that provides a wakepromoting effect after administration in the human subject, and wherein the amount and frequency of administration of the second dosage form no longer provides a wakepromoting effect during waking hours of the dosing interval.

[0010] In some aspects, the method further comprises: determining whether administration of the second dosage form is providing a wake-promoting effect during waking hours of the dosing interval; and if administration of the second dosage form is not providing a wake-promoting effect, then administering to the human subject a third dosage form comprising a third orexin type 2 receptor agonist one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wakepromoting effect after administration.

[0011] In another aspect, the present disclosure provides a method of treating Narcolepsy Type 1 (NT1) in a human subject, the method comprising: administering to a human subject in need of said treatment a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; administering to the human subject a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect of the second orexin type 2 receptor agonist after administration; and administering to the human subject a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is administered one or more times during waking hours of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration.

[0012] In some aspects, the method further comprises determining whether administration of the second dosage form is providing a wake-promoting effect during waking hours of the dosing interval.

[0013] In one aspect, the present disclosure provides one or more dosage forms comprising one or more orexin type 2 receptor agonists, for use in treating Narcolepsy Type 1 (NTl) in a human subject, wherein the one or more dosage forms are to be administered in an amount and frequency that provides a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for the remainder of the twenty-four-hour period; wherein the blood plasma concentration of the orexin type 2 receptor agonist is maintained at or below amaximum non-awakening plasma concentration of the orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods.

[0014] In another aspect, the present disclosure provides a first dosage form comprising a first orexin type 2 receptor agonist, for use in treating Narcolepsy Type 1 (NT1) in a human subject, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods; wherein the subject has been or is to be administered a second dosage form comprising a second orexin type 2 receptor agonist in an amount and frequency that provides a wakepromoting blood plasma concentration of the second orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period; wherein the first dosage form and the second dosage form may be the same or different, and wherein the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist may be the same or different.

[0015] Another aspect of the present disclosure provides a second dosage form comprising a second orexin type 2 receptor agonist, for use in treating Narcolepsy Type 1 (NTl) in a human subject, wherein the second dosage form is to be administered in an amount and frequency that provides a wake-promoting blood plasma concentration of the second orexin type 2 receptor agonist during a portion of waking hours of a twenty-four- hour period; wherein the subject has been or is to be administered a first dosage form comprising a first orexin type 2 receptor agonist in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist for the remainder of the twenty-four-hour period and over a dosing interval of five or more twenty-four-hour periods; and wherein the first dosage form and the second dosage form may be the same or different, and the wherein the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist may be the same or different.

[0016] Another aspect of the present disclosure provides a combination for use in treating Narcolepsy Type 1 (NTl) in a human subject, the combination comprising: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a bloodplasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; and a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject; wherein the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist may be the same or different and wherein the first dosage form and the second dosage form may be the same or different.

[0017] Another aspect of the present disclosure includes the above combination which further comprises a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject, and wherein the amount and frequency of administration of the second dosage form no longer provides a wake-promoting effect during waking hours of the dosing interval; wherein the third orexin type 2 receptor agonist may be the same as or different than the first and / or second orexin type 2 receptor agonist and wherein the third dosage form may be the same as or different than the first and / or second dosage form.

[0018] Another aspect of the present disclosure includes a combination for use in treating Narcolepsy Type 1 (NT1) in a human subject, the combination comprising: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency thatprovides a wake-promoting effect of the second orexin type 2 receptor agonist after administration; and a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration; wherein the first, second and third orexin type 2 receptor agonists may be the same as or different than each other and wherein the first, second and third dosage forms may be the same as or different than each other.

[0019] In one aspect, the present disclosure provides a kit for treating Narcolepsy Type 1 (NT1) in a human subject, which comprises: one or more dosage forms comprising one or more orexin type 2 receptor agonists, wherein the one or more dosage forms are to be administered in an amount and frequency that provide: a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for the remainder of the twenty-four-hour period; wherein the blood plasma concentration of the orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods.

[0020] Another aspect of the present disclosure provides a kit for treating Narcolepsy Type 1 (NTl) in a human subject, which comprises: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; and a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours ofeach twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject.

[0021] Another aspect of the present disclosure includes the kit in the immediately preceding paragraph, which further comprises a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject, and wherein the amount and frequency of administration of the second dosage form no longer provides a wake-promoting effect during waking hours of the dosing interval.

[0022] Another aspect of the present disclosure provides a kit for treating Narcolepsy Type 1 (NT1) in a human subject, which comprises: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect of the second orexin type 2 receptor agonist after administration; and a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration.

[0023] Another aspect of the present disclosure includes any one of the above kits further comprising instructions, which may include storage information, dosing information and / or instructions about how to administer each dosage form.

[0024] In some aspects, a blood plasma concentration providing the wake-promoting effect of the third orexin type 2 receptor agonist is higher than a blood plasmaconcentration providing the wake-promoting effect of the second orexin type 2 receptor agonist.

[0025] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are different compounds.

[0026] In some aspects, at least two of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are the same compound.

[0027] In some aspects, the second orexin type 2 receptor agonist and third orexin type 2 receptor agonist are the same compound, and an increased dose of third orexin type 2 receptor agonist is administered to provide a wake-promoting effect.

[0028] In some aspects, the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a half-life of 8 hours or less.

[0029] In some aspects, the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a half-life of more than 8 hours.

[0030] In some aspects, the dosing interval is 2 or more consecutive 24-hour periods, 7 or more consecutive 24-hour periods, 14 or more consecutive 24-hour periods, 21 or more consecutive 24-hour periods, or 28 or more consecutive 24-hour periods.

[0031] In some aspects, the second dosage form provides a wake-promoting effect during waking hours for at least one 24-hour period, for at least two 24-hour periods, for at least three 24-hour periods, or for at least fourteen 24-hour periods.

[0032] In some aspects, the first dosage form is a sustained release dosage form.

[0033] In some aspects, the first dosage form is formulated for oral administration, intravenous administration, depot administration, or subcutaneous administration.

[0034] In some aspects, the first dosage form is formulated for subcutaneous administration.

[0035] In some aspects, the dosage form comprises an infusion system designed to provide continuous subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

[0036] In some aspects, the dosage form comprises microcapsules or microparticles designed to provide sustained subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

[0037] In some aspects, the second dosage form and the third dosage form are formulated for oral administration, intravenous administration, depot administration, subcutaneous administration, or a combination thereof.

[0038] In some aspects, at least one of the second dosage form and the third dosage form is formulated for oral administration.

[0039] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist after administration reaches and maintains between about 5 percent to about 100 percent, about 10 percent to about 100 percent, about 15 percent to about 100 percent, about 20 percent to about 100 percent, about 30 percent to about 100 percent, or about 50 percent to about 100 percent of the maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist over the dosing interval.

[0040] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist for at least two weeks, at least four weeks, at least six weeks or at least eight weeks.

[0041] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist after administration is maintained for at least two weeks, at least four weeks, at least six weeks or at least eight weeks.

[0042] In some aspects, one or more daytime symptoms of narcolepsy type 1 selected from fragmented wakefulness, excessive daytime sleepiness (EDS), cataplexy, and anxiety are improved.

[0043] In some aspects, one or more nighttime symptoms of narcolepsy type 1 selected from fragmented sleep, sleep paralysis, and hallucinations are improved.

[0044] In some aspects, one or more daytime symptoms and one or more nighttime symptoms in human subjects with narcolepsy type 1 are improved.

[0045] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (I):whereinR1is(1) a hydrogen atom,(2) a Ci-6 alkyl-carbonyl group optionally substituted by 1 to 7 substituents selected from (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) a C3-10 cycloalkyl group, (v) a C1-6 alkoxy group, (vi) a Ce-14 aryl group, (vii) a Ce-14 aryloxy group, (viii) a pyrazolyl group, a thiazolyl group, a pyrimidinyl group or a pyridazinyl group, each of which is optionally substituted by an oxo group, (ix) a pyrazolyloxy group optionally substituted by 1 to 3 C1-6 alkyl groups, (x) a C1-6 alkyl-carbonyl group, (xi) a C1-6 alkoxycarbonyl group, (xii) a C1-6 alkyl-carbonyloxy group, (xiii) a C1-6 alkylsulfonyl group, (xiv) a mono- or di-Ci-6 alkylamino group, (xv) a C1-6 alkyl-carbonylamino group and (xvi) a (C1-6 alkyl)(Ci-6 alkyl-carbonyl)amino group,(3) a C3-10 cycloalkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group, an oxo group and a C1-6 alkyl group,(4) a C1-6 alkoxy-carbonyl group optionally substituted by 1 to 6 substituents selected from deuterium, a halogen atom and a Ce-14 aryl group,(5) a C3-10 cycloalkyloxy-carbonyl group optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group,(6) a Ce-14 aryl-carbonyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ce-14 aryl group,(7) a Ce-14 aryloxy-carbonyl group,(8) a furylcarbonyl group, a thienyl carbonyl group, a pyrazolylcarbonyl group, an isoxazolylcarbonyl group or a pyridyl carbonyl group, each of which is optionally substituted by 1 to 3 substituents selected from a Ci-6 alkyl group,(9) an azetidinylcarbonyl group, an oxetanyl carbonyl group, a pyrrolidinylcarbonyl group, a tetrahydrofuranylcarbonyl group, a tetrahydropyranylcarbonyl group or a morpholinylcarbonyl group, each of which is optionally substituted by 1 to 3 substituents selected from an oxo group, a Ci-6 alkyl-carbonyl group, a Ci-6 alkoxy-carbonyl group and a Ci-6 alkyl sulfonyl group,(10) a mono- or di-Ci-6 alkyl-carbamoyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group and a Ci-6 alkoxy group,(11) a mono- or di-Cs-io cycloalkyl-carbamoyl group,(12) a mono- or di-Ce-14 aryl-carbamoyl group,(13) a Ci-6 alkylsulfonyl group,(14) a C3-10 cycloalkylsulfonyl group,(15) a Ce-14 arylsulfonyl group optionally substituted by 1 to 3 halogen atoms,(16) a thienylsulfonyl group, a pyrazolyl sulfonyl group, an imidazolylsulfonyl group, a pyridyl sulfonyl group or a dihydrochromenyl sulfonyl group, each of which is optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group,(17) a mono- or di-Ci-6 alkyl-sulfamoyl group or(18) a C1-6 alkyl-carbonyl-carbonyl group;R2is a C3-6 cycloalkyl group, a pyrrolidinyl group, a piperidinyl group or a dioxanyl group, each of which is optionally substituted by 1 to 3 substituents selected from(1) deuterium,(2) a halogen atom,(3) a hydroxy group,(4) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ce-14 aryl group,(5) a C3-10 cycloalkyl group,(6) a C1-6 alkoxy group optionally substituted by a C3-10 cycloalkyl group,(7) a Ce-14 aryl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms, a Ci-6 alkoxy group optionally substituted by 1 to 3 halogen atoms and a hydroxy group,(8) a Ce-14 aryloxy group,(9) a tri-Ci-6 alkylsilyloxy group,(10) a pyrazolyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, a quinazolinyl group, a benzothiazolyl group or an isoquinolinyl group, each of which is optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci-6 alkyl group and a Ci-6 alkoxy group, and(11) a Ce-14 aryl-carbonyl group; andR3is a Ci-6 alkyl group, or a mono- or di-Ci-6 alkylamino group, or a pharmaceutically acceptable salt thereof.

[0046] In some aspects, R1is(1) a hydrogen atom,(2) a Ci-6 alkyl-carbonyl group optionally substituted by a hydroxy group,(3) a cyclopropanecarbonyl group,(4) a Ci-6 alkoxy-carbonyl group or(5) a mono- or di-Ci-6 alkyl-carbamoyl group;R2is(A) a cyclohexyl group optionally substituted by 1 to 3 substituents selected from(1) a Ci-6 alkyl group and(2) a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms and a Ci-6 alkoxy group or(B) a piperidinyl group optionally substituted by 1 to 3 pyrimidinyl groups; andR3is a Ci-6 alkyl group or a di-Ci-6 alkylamino group, or a pharmaceutically acceptable salt thereof.

[0047] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from Methyl (2R,3S)-3-((methylsulfonyl)amino)-2- (((cis-4- phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate; N-((2R,3 S)- 1 -glycoloyl-2- (((cis-4-(2,3,6-trifluorophenyl) cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide; and (2R,3S)-N-ethyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)- 3 -((methyl sulfonyl) amino)piperidine-l -carboxamide; or a pharmaceutically acceptable salt thereof.

[0048] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt thereof.

[0049] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from N-((2S,3S)-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl- 3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide; N-((2S,3S)-2-((2,3'-difluorobiphenyl-3- yl)methyl)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide; methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'- trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide; 4-(5- cyclopropyl-l,2,4-oxadiazol-3-yl)-N-{(lR,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin- l-yl]cyclohexyl}-4-methylpiperidine-l-carboxamide; N-{(lR,6S)-2,2-difluoro-6-[4- (propan-2-yl)piperazin-l-yl]cyclohexyl}-4-{5-[(lS,2S)-2-fluorocyclopropyl]-l,2,4- oxadiazol-3-yl}-4-methylpiperidine-l -carboxamide; (2R)-2-cyclopropyl-2-{(lR,3S,5S)- 3-[(3S,4R)-l-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8- azabicyclo[3.2.1]octan-8-yl}acetamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5- fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3- methylbutaneamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5-chloropyrimidin-2-yl)-3- ethoxypiperidin-4-yl)-8-azabicyclo[3.2. l]octan-8-yl)-2-cyclopropyl acetamide; (R)-2- cyclopropyl-2-((lR,3S,5S)-3-((2S, 4S)-l-(5-fhioropyrimidin-2-yl)-2-methylpiperidin-4- yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide; and N-((21S,24S,52R,53S)-6-oxo-3,8-dioxa- l(2,3)-pyrazina-5(2,l)-piperidina-2(l,4)-cyclohexanacyclooctaphane-53- yl)methanesulfonamide; or a pharmaceutically acceptable salt thereof.

[0050] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (II):whereinR1is(1) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom, and(b) a Ci-6 alkoxy group,(2) a C3-6 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, or(3) a mono- or di-Ci-6 alkylamino group;R2is a hydrogen atom;R3is(1) a C1-6 alkoxy-carbonyl group,(2) a C1-6 alkyl-carbonyl group optionally substituted by 1 to 3 hydroxy groups,(3) a mono- or di-Ci-6 alkyl-carbamoyl group,(4) a N-Ci-6 alkyl-N-Ci-6 alkoxy-carbamoyl group,(5) a C3-6 cycloalkyl-carbonyl group (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group may be a bridged ring group) optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,(c) a hydroxy group,(d) a C1-6 alkoxy group, and(e) a cyano group,(6) an oxetanylcarbonyl group,(7) an azetidinylcarbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom, and(b) a Ci-6 alkyl group, or(8) a 5-azaspiro[2.3]hexylcarbonyl group;R4and R5are both hydrogen atoms;Ring A is(1) a pyrrolidine ring, or(2) a piperidine ring; andRing B is(1) a benzene ring further substituted by one phenyl group optionally substituted by 1 to 3 substituents selected from(i) a halogen atom, and(ii) a Ci-6 alkyl group, and optionally further substituted by one halogen atom,(2) a pyridine ring further substituted by one phenyl group optionally substituted by 1 to 3 halogen atoms,(3) a thiazole ring further substituted by one phenyl group optionally substituted by 1 to 3 halogen atoms, or(4) a piperidine ring further substituted by one phenyl group; or a pharmaceutically acceptable salt thereof.

[0051] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3- yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0052] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3S)-2-( (2,3'-difluorobiphenyl-3-yl)methyl)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3- yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0053] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (III):R1is(1) a Ci-6 alkyl group,(2) a mono- or di-Ci-6 alkylamino group, or(3) a C3-6 cycloalkyl group;R2is(1) a hydrogen atom,(2) a fluorine atom, or(3) a C1-6 alkyl group;R3is(1) a C1-6 alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group, and(c) a cyano group,(2) a C1-6 alkoxy-carbonyl group,(3) a C3-10 cycloalkyl-carbonyl group (the C3-10 cycloalkyl moiety of the C3-10 cycloalkylcarbonyl group is optionally bridged) optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group,(c) a cyano group, and(d) a C1-6 alkyl group,(4) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group, and(c) a Ci-6 alkyl group,(5) a mono- or di-Ci-6 alkyl-carbamoyl group, or(6) a N-CI-6 alkyl-N-Ci-6 alkoxy-carbamoyl group; andRing A is(1) a benzene ring optionally substituted by one substituent selected from(a) a Ce-i4 aryl group optionally substituted by 1 to 3 substituents selected from(i) a halogen atom,(ii) an optionally halogenated Ci-6 alkyl group, and(iii) an optionally halogenated Ci-6 alkoxy group, and(b) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from(i) a Ci-6 alkyl group, and(ii) a Ci-6 alkoxy group, and optionally further substituted by 1 to 3 halogen atoms, or(2) a 5- or 6-membered aromatic heterocycle further substituted by one Ce-14 aryl group optionally substituted by 1 to 3 halogen atoms; or a pharmaceutically acceptable salt thereof.

[0054] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-{(2S,3R)-4.4-difhioro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3- yl)methyl]pyrrolidin-3-yl} ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0055] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3R)-4.4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluoro-[l,r-biphenyl]-3- yl)methyl)pyrrolidin-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0056] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from N'-{(2S,3R,4S)-l-(azetidine-l-carbonyl)-4-fluoro-2-[(2-fluoro-3methyl[l,l'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethyl sulfuric diamide; N- [(2S,3R)-2-[(2,3'-difluoro[l,l'-biphenyl]-3-yl)methyl]-4,4-difluoro-l-(2- methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-(2- hydroxy-2-methylpropanoyl)-2-[(2, 3 ',5 '-tri fluorofl, l'-biphenyl]-3-yl)methyl]pyrrolidin-3- yl} ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2- [(2, 3', 5 '-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl (methanesulfonamide; N- {(2S, 3R)-l-(bicyclo[l. l.l]pentane-l-carbonyl)-4,4-difluoro-2-[(2, 3 ', 5'-tri fluorofl, 1'- biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide; N-{(2S,3R)-1- (cyclopropanecarbonyl)-4,4-difluoro-2-[(2, 3 ', 5'-tri fluorofl, l'-biphenyl]-3- yl)methyl]pyrrolidin-3-yl} ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-((lS,3R)-3- fluorocyclobutane- 1 -carbonyl)-2-[(2,3 5 '-trifluorof 1 , 1 '-biphenyl]-3 -yl)methyl]pyrrolidin- 3 -yl} ethanesulfonamide; N-{(2S,3R)-4,4-difhioro-l-((lS,3R)-3-fluorocyclobutane-l- carbonyl)-2-[(2, 3 ',5 '-trifluorof l,l'-biphenyl]-3-yl)methyl]pyrrolidin-3- yl (methanesulfonamide; N'- { (2S,3R)- 1 -(azetidine- 1 -carbonyl)-4,4-difluoro-2-[(2-fluoro- 3'-methyl[l,l'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl(-N,N-dimethylsulfuric diamide; or a pharmaceutically acceptable salt thereof.

[0057] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (IV):whereinR1is a Ci-6 alkyl group, a C3-10 cycloalkyl group, or a mono-Ci-6 alkylamino group; r is 0 or 1;R2and R3are each independently a hydrogen atom, or when r is 0, then R2and R3may be taken together with each other to form a bond;R4is a hydrogen atom;R5is a phenyl group optionally substituted by 1 to 3 halogen atoms;R6and R7are each independently a hydrogen atom, or a halogen atom;X5is CH or N; andR12and R13are each independently a hydrogen atom, a Ci-6 alkyl group, or a halogen atom; or a pharmaceutically acceptable salt thereof.

[0058] In some aspects, R1is a Ci-6 alkyl group; r is 0 or 1;R2and R3are each a hydrogen atom, or when r is 0, then R2and R3may be taken together with each other to form a bond;R4is a hydrogen atom;R5is a phenyl group substituted by 1 to 3 halogen atoms;R6and R7are each a halogen atom;X5is CH; andR12and R13are each independently a hydrogen atom, or a halogen atom; or a pharmaceutically acceptable salt thereof.

[0059] In some aspects, the compound of formula IV is selected from the group consisting of: N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-l,2-benzoxazol-3-yl]-3-oxohexahydro-lH- pyrrolo[ 1 ,2-c]imidazol-6-yl } ethanesulfonamide;N-{(6R)-7, 7-difluoro-3 -oxo-2- [4-(2, 4, 6-tri fluorophenyl)- l,2-benzoxazol-3-yl]-2, 5,6,7- tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]hexahydro-lH-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide;N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-l,2-benzoxazol-3-yl]-3-oxohexahydro- lH-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide;N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]hexahydro-lH-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3-yl]-3-oxo- 2,5,6,7-tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3-yl]-3- oxohexahydro-lH-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(4aR,6R)-5,5-difluoro-l-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]octahydropyrrolo[l,2-c]pyrimidin-6-yl}methanesulfonamide;N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3-yl]-5,5-difluoro- l-oxooctahydropyrrolo[l,2-c]pyrimidin-6-yl}methanesulfonamide;N-{(4aR,6R)-2-[4-(2,6-difhiorophenyl)-5-fluoro-l,2-benzoxazol-3-yl]-5,5-difluoro-l- oxooctahydropyrrolo[l,2-c]pyrimidin-6-yl}methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-l,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo- 2,5,6,7-tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide; or a pharmaceutically acceptable salt thereof.

[0060] Additional aspects and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The aspects and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0061] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and do not restrict the scope of the claims.BRIEF DESCRIPTION OF THE DRAWINGS / FIGURES

[0062] FIG. 1 shows the effect of daytime administration of Compound A (Cpd A) on wakefulness in OX DTA mice. FIG. l is a bar graph that shows total wakefulness time in 1-h bins after oral administration of Compound A at ZT 12 in OX DTA mice and Non- transgenic mice between 32 - 37 weeks-old (OX DTA n = 6; Non-Tg n= 8).+P < 0.05, ++P < 0.01 (William’s or Shirley -Williams’s test). Data are mean ± s.e.m.

[0063] FIGS. 2A-2B show the effect of Compound A by low-flat exposure alone on NT1- like symptoms in OX DTA mice. FIGS. 2A-2B show OX DTA mice or NonTg mice (33 - 35 weeks-old) treated with low-flat exposure of vehicle or Compound A for 14 days. FIG. 2A is a line graph depicting the concentrations of low-flat exposure of Compound A in OX DTA mice at two doses [Dose 1 : around 90 ng / mL, Dose 2: around 320 ng / mL] (mean ± s.d., n = 4). Non-awakening and potent awakening plasma concentrations were determined based on FIGs. 4A and 4B. FIG. 2B shows bar graphs depicting observed sleep / wakefulness and cataplexy-like episodes of mice following administration ofCompound A. They provide the number and mean duration of wakefulness episodes and the number of cataplexy-like episodes during the active phase (12 h), and number and mean duration of NREM sleep episodes, and the number of direct-REM transitions from wakefulness (DREM) during the sleep phase (12 h) on day 14 in OX DTA mice and NonTg mice at 35 weeks-old. [NonTg (Veh; vehicle), n = 16; Tg (Veh; vehicle), n = 15; Tg (Compound A Dose 1), n = 16; Tg (Compound A Dose 2), n = 14], *P < 0.05, **P < 0.01, ***p < 0.001 (Dunnetf s multiple comparison test). Data are mean ± s.e.m.

[0064] FIGS. 3A-3D show the time-dependent change in sensitivity to wake-promoting effects of Compound A after low-flat exposure in combination with daily daytime administration in OX DTA mice. FIG. 3A shows the schematics of the experimental design for Chronic dosing study 4 (Example 3). OX DTA mice (39 - 41 weeks-old) were administered with low-flat exposure of vehicle or Compound A for 15 days in combination with daily daytime treatment of vehicle or Compound A (3 mg / kg, p.o.; minimum effective dose (MED) in OX DTA as shown in Fig. 1) at ZT 12 and ZT 15 between day 4 and 14. On day 15, the second gavage of Compound A at ZT 15 was 10 mg / kg (MED of non-tg mice shown in Fig. 1). Daytime administration commenced on day 4. FIG. 3B shows wakefulness times in 10-min or 2-h bins detected by EEGZEMG recording following administration of Compound A (3 or 10 mg / kg, p.o.) or vehicle on days 4, 14, and 15 in OX DTA mice. [Veh (low-flat: vehicle; daytime oral administration: vehicle), n = 12; Cpd A (low-flat: Cpd A; daytime oral administration: Cpd A), n = 12] FIG. 3C shows Schematics of the experimental design for Chronic dosing study 5 (Example 4). OX DTA mice (31 - 33 weeks-old) were administered with low-flat exposure of vehicle or Compound A for 14 days in combination with daily daytime treatment of vehicle or Compound A (30 mg / kg, p.o.; 3-fold higher than MED in non-tg mice shown in Fig.1) at ZT 12 and ZT 15 between day 4 and 14. Daytime administration commenced on day 4. FIG. 3D shows wakefulness times in 10-min or 2-h bins detected by EEGZEMG recording in following administration of Compound A (30 mg / kg, p.o.) or vehicle on days 4, 7, 10, and 14 in OX DTA mice. [Veh (low-flat: vehicle; daytime oral administration: vehicle), n = 12; Cpd A (low-flat: Cpd A; daytime oral administration: Cpd A), n = 12] *P < 0.05, ***p < 0.001 (Student’s t-test or Aspin-Welch's test). Data are mean ± s.e.m.

[0065] FIGS. 4A-4B. show the effect of Compound A by acute administration on sleep / wakefulness states in OX DTA mice. FIG. 4A shows wakefulness times detected by EEG / EMG recording following administration of Compound A at ZT 5 in OX DTA mice (39 - 40 weeks-old, n = 8). The dotted line indicates 75% wakefulness time.+++P < 0.001 (William’s test). Data are mean ± s.e.m. FIG. 4B shows plasma concentrations of Compound A following administration at 1 and 10 mg / kg (p.o.) in OX DTA mice (34 and 39 weeks-old, respectively; mean ± s.d., n = 3 and 5, respectively). The non-awakening concentration was estimated to be around 371.6 ng / mL (Cmax at 1 mg / kg). The potentawakening concentration (sufficient to maintain >75% wakefulness time in 10-min bins) was estimated to be around 1128.9 ng / mL (plasma concentration after 120 min after administration).

[0066] FIGS. 5A-5C show the effect of Compound A by low-flat exposure in combination with daily daytime administration (3 or 10 mg / kg) on the pharmacokinetic profile and the cataplexy-like symptoms in OX DTA mice related to Chronic Dosing Study 4. FIG. 5 A shows the total wakefulness time in 10-min or 2-h bins after administration of Compound A (3 or 10 mg / kg, p.o.) at baseline in OX DTA mice (38 weeks-old). FIG. 5B shows the plasma concentrations of Compound A following administration at 3 or 10 mg / kg (p.o.) at ZT 12 and ZT 15 in combination with low-flat exposure on day 4, 14, and 15 in OX DTA mice (39 - 41 weeks-old; mean ± s.d., n = 5). FIG. 5C shows the number of cataplexy-like episodes during 2 h after administration of Compound A (3 or 10 mg / kg, p.o.) on day 4, 14, and 15 in OX DTA mice. [Veh (low-flat: vehicle; daytime oral administration: vehicle), n = 12; Cpd A (low-flat: Cpd A; daytime oral administration: Cpd A), n = 12] *P < 0.05, **P < 0.01, ***p < 0.001 (Student’s t-test or Aspin-Welch's test). Data are mean ± s.e.m.

[0067] FIGS. 6A-6C show the effect of Compound A by low-flat exposure in combination with daily daytime administration of (30 mg / kg) on the pharmacokinetic profile and the wake-promoting effect in OX DTA mice related to Chronic Dosing Study 5. OX DTA mice (31 - 33 weeks-old) were daily administered with Compound A (30 mg / kg, p.o.) at ZT 12 and ZT 15 in combination with low-flat exposure of Compound A. FIG. 6A shows the plasma concentrations of Compound A following administration at 30 mg / kg (p.o.) on day 4 and 14 (mean ± s.d., n = 6). FIG. 6B shows the wakefulness time in 10-min or 2-h bins after administration of vehicle or Compound A (30 mg / kg, p.o.) atbaseline. FIG. 6C shows the total wakefulness time in 10-min bins after oral administration of vehicle or Compound A (30 mg / kg, p.o.) in OX DTA mice after chronic administration (day 14) or NonTg mice (35 - 36 weeks-old) after acute administration. [OX DTA; Vehicle (low-flat: vehicle; daytime oral administration: vehicle), n = 12; Compound A (low-flat: Cpd A; daytime oral administration: Cpd A), n = 12, NonTg; n = 10 (crossover design)] ***p < 0.001 (Aspin-Welch's test). Data are mean ± s.e.m.

[0068] FIG. 7 depicts the Three Brain Concept of NT1. In NT1, the neuronal pathways undergo neuroplastic change ("NT1 brain"), which can be normalized by chronic exposure of OX2R agonist ("Normalized NT1 brain" which is nearly like healthy brain). The NT1 brain is highly sensitive to wake-promoting effects of OX2R agonist (wakepromoting dose is NT1 brain « Healthy brain). A long half-life molecule with a good day / night exposure would robustly shift the NT1 brain to Normalized NT1 brain resulting in the rise in wake-promoting dose of OX2R agonist to the level in Healthy brain, but not with a short half-life molecule.DETAILED DESCRIPTION OF THE INVENTION

[0069] Generally, when a pharmacological substance is administered to a subject, the blood plasma concentration of the substance increases for a time, reaches a maximum concentration and then decays. Consequently, the medicinal effect of the substance generally follows its blood plasma concentration. In the case of an OX2R agonist administered to promote arousal in subjects having NT1, once the blood plasma concentration of the agonist exceeds the maximum non-awakening concentration, the subjects experience marginal arousal, which is followed by full arousal once the concentration exceeds a certain threshold (the arousal-promoting concentration). Certain OX2R agonists have been shown to produce potent efficacy in wakefulness when the blood plasma concentration of the OX2R agonist exceeds the arousal-promoting concentration in subjects having NT1.

[0070] The present disclosure relates to the use of one or more orexin type 2 receptor (OX2R) agonists at a wake-promoting blood plasma concentration in a subject (e.g. mammal) during daytime hours and at a non-awakening blood plasma concentration in the subject during the remaining hours of a twenty-four-hour period.

[0071] In one aspect, the present disclosure is related to the use of one or more orexin type 2 receptor agonists to provide both a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during at least as portion of waking hours of a twenty-four- hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for the remainder of the twenty-four-hour period.

[0072] In another aspect, the present disclosure provides a method of treating Narcolepsy Type 1 (NT1), in a human subject in need of treatment.

[0073] The present disclosure also relates to a method of treatment of narcolepsy type 1 (NT1) in a subject (e.g. mammal) in need of treatment by achieving a wake-promoting blood plasma concentration of an 0X2R agonist after administration during waking hours of a twenty-four-hour period and by maintaining a non-zero blood plasma concentration of an 0X2R agonist after administration that is at or below the maximum non-awakening concentration of the agonist during the remainder of the twenty-four-hour period over a dosing interval of multiple twenty-four-hour periods (i.e., chronically) in the subject.

[0074] In some aspects, the blood plasma concentration of an 0X2R agonist after administration during the remainder of the twenty-four-hour period is about 1 / 20 to about 1 / 1 of the maximum non-awakening concentration of the agonist over the dosing interval.

[0075] The present disclosure also relates to a dosing regimen for treatment of NT1 in a subject (e.g. mammal) by administering a first 0X2R agonist at a dose sufficient to provide a blood plasma concentration at or below the maximum non-awakening concentration of the agonist, and administering a second 0X2R agonist, which may be the same or different than the first 0X2R agonist, at a dose sufficient to bring the plasma blood concentration of the 0X2R agonist above the non-awakening blood plasma concentration, preferably above the arousal-promoting concentration.

[0076] The current approach for treating NT1 with 0X2R agonists aims to induce and promote arousal of NT1 subjects, and therefore the dose needs to exceed the maximum non-awakening blood plasma concentration and to reach the arousal-promoting (or wakepromoting) concentration. The present disclosure focuses on the effect of 0X2R agonists at non-awakening blood plasma concentration combined with the effects of 0X2R agonists at a wake-promoting blood plasma concentration during waking hours. Continuous or repeated administration of 0X2R agonist at non-awakening blood plasmaconcentration combined with administration of 0X2R agonist at wake-promoting blood plasma concentration unexpectedly improves both daytime and nighttime symptoms in a subject with narcolepsy type 1. The use of 0X2R agonists of the present disclosure is expected to provide a new method and strategy for treating NT1 and other sleep-related symptoms.

[0077] In another aspect, the present disclosure provides a method of treating Narcolepsy Type 1 (NT1) in a human subject, the method comprising: administering to a human subject in need of said treatment one or more orexin type 2 receptor agonists in one or more dosage forms in an amount and frequency that provides a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for the remainder of the twenty-four-hour period; wherein the administering is such that a blood plasma concentration of the one or more orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods.

[0078] In another aspect, the present disclosure provides a method of treating Narcolepsy Type 1 (NTl) in a human subject, the method comprising: administering to the human subject in need of said treatment a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; and administering to the human subject a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject.

[0079] In some aspects, the method further comprises administering to the human subject a third dosage form comprising a third orexin type 2 receptor agonist, wherein the thirddosage form is administered one or more times during waking hours of each twenty-four- hour period of the dosing interval in an amount and frequency that provides a wakepromoting effect after administration in the human subject, and wherein the amount and frequency of administration of the second dosage form no longer provides a wakepromoting effect during waking hours of the dosing interval.

[0080] In some aspects, the method further comprises: determining whether administration of the second dosage form is providing a wake-promoting effect during waking hours of the dosing interval; and if administration of the second dosage form is not providing a wake-promoting effect, then administering to the human subject a third dosage form comprising a third orexin type 2 receptor agonist one or more times during waking hours of each twenty- four-hour period of the dosing interval in an amount and frequency that provides a wakepromoting effect after administration.

[0081] In another aspect, the present disclosure provides a method of treating Narcolepsy Type 1 (NT1) in a human subject, the method comprising: administering to the human subject in need of said treatment a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; administering to the human subject a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect of the second orexin type 2 receptor agonist after administration; and administering to the human subject a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is administered one or more times during waking hours of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration.

[0082] In some aspects, the method further comprises determining whether administration of the second dosage form is providing a wake-promoting effect during waking hours of the dosing interval.

[0083] In some aspects, administration of the first orexin type 2 receptor agonist to the human subject with NT1 results in normalized (or reduced) sensitivity to the wakepromoting effects of the second orexin type 2 receptor agonist. In some aspects, when the human subject with NT1 experiences normalized (or reduced) sensitivity to the wakepromoting effects of the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist is administered to the human subject in an amount and frequency that provides a wake-promoting effect after administration. In some aspects, the third orexin type 2 receptor agonist is administered to the human subject in an amount and frequency that provides a blood plasma concentration of the third agonist that is higher than the blood plasma concentration provided by administration of the second orexin type 2 receptor agonist. In some aspects, the wake-promoting blood plasma concentration of the third agonist for the human subject with NT1 is about the same as a wake-promoting blood plasma concentration of the third agonist for a human subject without NT1.

[0084] In some aspects, the human patient experiences normalized (or reduced) sensitivity to the wake-promoting effects of the second orexin type 2 receptor agonist within about 2 days, within about 4 days, within about 7 days, within about 10 days, within about 14 days, within about 21 days, or within about 2 days to about 21 days. In some aspects, the human patient experiences normalized (or reduced) sensitivity to the wake-promoting effects of the second orexin type 2 receptor agonist within about 14 days. In some aspects, the human patient experiences normalized (or reduced) sensitivity to the wake-promoting effects of the second orexin type 2 receptor agonist beyond 21 days. In some aspects, the human patient does not experience normalized (or reduced) sensitivity to the wake-promoting effects of the second orexin type 2 receptor agonist.

[0085] In some aspects, a blood plasma concentration providing the wake-promoting effect of the third orexin type 2 receptor agonist is higher than a blood plasma concentration providing the wake-promoting effect of the second orexin type 2 receptor agonist. In some aspects, a blood plasma concentration providing the wake-promoting effect of the third orexin type 2 receptor agonist is equal to or lower than a blood plasmaconcentration providing the wake-promoting effect of the second orexin type 2 receptor agonist.

[0086] In some aspects, the dose of the third orexin type 2 receptor agonist is higher than the dose of the second orexin type 2 receptor agonist. In some aspects, the dose of the third orexin type 2 receptor agonist is gradually increased from the dose of the second orexin type 2 receptor agonist. In some aspects, the second and third orexin type 2 receptor agonists are the same compound, and the dose of the third orexin type 2 receptor agonist is gradually increased from the dose of the second orexin type 2 receptor agonist. In some aspects, the second and third orexin type 2 receptor agonists are the same compound, and the dose of the third orexin type 2 receptor agonist is gradually increased from the dose of the second orexin type 2 receptor agonist until reaching the wakepromoting dose of the third agonist for a human subject without NT1 (i.e., a healthy subject).

[0087] In some aspects, the first orexin type 2 receptor agonist is administered once during each of one or more twenty-four-hour periods. In some aspects, the first orexin type 2 receptor agonist is administered twice during each of one or more twenty-four- hour periods. In some aspects, the first orexin type 2 receptor agonist is administered three times during each of one or more twenty-four-hour periods. In some aspects, the first orexin type 2 receptor agonist is administered three times or more during each of one or more twenty-four-hour periods. In some aspects, the first orexin type 2 receptor agonist is administered continuously throughout one or more twenty-four-hour periods. In some aspects, the first orexin type 2 receptor agonist is administered continuously during hours of one or more twenty-four-hour periods when the second and / or third orexin type 2 receptor agonist are not providing a wake-promoting blood plasma concentration of the second and / or third agonist.

[0088] In some aspects, the second and / or third orexin type 2 receptor agonist is administered once during each of one or more twenty-four-hour periods. In some aspects, the second and / or third orexin type 2 receptor agonist is administered twice during each of one or more twenty-four-hour periods. In some aspects, the second and / or third orexin type 2 receptor agonist is administered three times during each of one or more twenty- four-hour periods. In some aspects, the second and / or third orexin type 2 receptor agonist is administered three times or more during each of one or more twenty-four-hour periods.

[0089] In some aspects, the first orexin type 2 receptor agonist is administered by subcutaneous depot, and the second and / or third orexin type 2 receptor agonists are administered one or more times during waking hours of one or more (i.e., a plurality) of twenty-four-hour periods. In some aspects, the second and / or third orexin type 2 receptor agonists have short half-lives (i.e., less than about 8 hours).

[0090] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are the same compound.

[0091] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are different compounds.

[0092] In some aspects, at least two of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are the same compound. In some aspects, the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist are the same compound. In some aspects, the first orexin type 2 receptor agonist and the third orexin type 2 receptor agonist are the same compound. In some aspects, the second orexin type 2 receptor agonist and the third orexin type 2 receptor agonist are the same compound.

[0093] In some aspects, the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist are the same compound, and the third orexin type 2 receptor agonist is a different compound. In some aspects, the first orexin type 2 receptor agonist and the third orexin type 2 receptor agonist are the same compound, and the second orexin type 2 receptor agonist is a different compound. In some aspects, the second orexin type 2 receptor agonist and the third orexin type 2 receptor agonist are the same compound, and the first orexin type 2 receptor agonist is a different compound.

[0094] In some aspects, the second orexin type 2 receptor agonist and third orexin type 2 receptor agonist are the same compound, and an increased dose of the third orexin type 2 receptor agonist is administered to provide a wake-promoting effect.

[0095] In some aspects, the second orexin type 2 receptor agonist and third orexin type 2 receptor agonist are different compounds, and an increased dose of the third orexin type 2 receptor agonist is administered to provide a wake-promoting effect. In some aspects, the second orexin type 2 receptor agonist and third orexin type 2 receptor agonist are different compounds, and a dose of the third orexin type 2 receptor agonist equivalent to the administered dose of the second orexin type 2 receptor agonist is administered toprovide a wake-promoting effect. In some aspects, the second orexin type 2 receptor agonist and third orexin type 2 receptor agonist are different compounds, and a decreased dose of the third orexin type 2 receptor agonist is administered to provide a wakepromoting effect.

[0096] In some aspects, the first orexin type 2 receptor agonist has a short half-life (i.e., less than about 8 hours). In some aspects, the first orexin type 2 receptor agonist has a half-life of about 8 hours or less. In some aspects, the first orexin type 2 receptor agonist has a half-life of about 7 hours or less, about 6 hours or less, about 5 hours or less, about 4 hours or less, about 3 hours or less, about 2 hours or less, or about 1 hour or less.

[0097] In some aspects, the first orexin type 2 receptor agonist has a long half-life (i.e., about 8 hours or more). In some aspects, the first orexin type 2 receptor agonist has a half-life of about 8 hours or more. In some aspects, the first orexin type 2 receptor agonist has a half-life of about 9 hours or more, about 10 hours or more, about 11 hours or more, about 12 hours or more, about 13 hours or more, about 14 hours or more, about 15 hours or more, about 16 hours or more, about 18 hours or more, about 20 hours or more, or about 24 hours or more.

[0098] In some aspects, the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a short half-life (i.e., less than 8 hours). In some aspects, the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a half-life of 8 hours or less. In some aspects, the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a half-life of 7 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less.

[0099] In some aspects, the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a long half-life (i.e., 8 hours or more). In some aspects, the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a half-life of 8 hours or more. In some aspects, the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a half-life of 9 hours or more, 10 hours or more, 11 hours or more, 12 hours or more, 13 hours or more, 14 hours or more, 15 hours or more, 16 hours or more, 18 hours or more, 20 hours or more, or 24 hours or more.

[0100] In some aspects, the dosing interval is 1 twenty-four-hour period or more. In some aspects, the dosing interval is 2 or more consecutive 24-hour periods, 7 or more consecutive 24-hour periods, 14 or more consecutive 24-hour periods, 21 or more consecutive 24-hour periods, or 28 or more consecutive 24-hour periods. In some aspects, the dosing interval is 5 or more consecutive twenty-four-hour periods. In some aspects, the dosing interval is 1 24-hour period, 2 consecutive 24-hour periods, 3 consecutive 24-hour periods, 4 consecutive 24-hour periods, 5 consecutive 24-hour periods, 6 consecutive 24-hour periods, 7 consecutive 24-hour periods, 8 consecutive 24- hour periods, 9 consecutive 24-hour periods, 10 consecutive 24-hour periods, 11 consecutive 24-hour periods, 12 consecutive 24-hour periods, 13 consecutive 24-hour periods, 14 consecutive 24-hour periods, 15 consecutive 24-hour periods, 16 consecutive 24-hour periods, 17 consecutive 24-hour periods, 18 consecutive 24-hour periods, 19 consecutive 24-hour periods, 20 consecutive 24-hour periods, 21 consecutive 24-hour periods, 22 consecutive 24-hour periods, 23 consecutive 24-hour periods, 24 consecutive 24-hour periods, 25 consecutive 24-hour periods, 26 consecutive 24-hour periods, 27 consecutive 24-hour periods, 28 consecutive 24-hour periods, or any value or partial value in between any of the preceding values. In some aspects, the dosing interval is 28 or more consecutive 24-hour periods. In some aspects, the dosing interval is 42 or more consecutive 24-hour periods. In some aspects, the dosing interval is 56 or more consecutive 24-hour periods. In some aspects, the dosing interval is 112 or more consecutive 24-hour periods.

[0101] In some aspects, the dosing interval is 1 month or more. In some aspects, the dosing interval is 2 months or more, 3 months or more, 4 months or more, 6 months or more, 9 months or more, 12 months or more, or any value or partial value in between any of the preceding values.

[0102] In some aspects, the dosing interval is a plurality of consecutive twenty-four-hour periods.

[0103] In some aspects, the second dosage form provides a wake-promoting effect during waking hours for at least one 24-hour period, for at least two 24-hour periods, for at least three 24-hour periods, or for at least fourteen 24-hour periods.

[0104] In some aspects, the first dosage form provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximumnon-awakening plasma concentration of the orexin type 2 receptor agonist for at least one 24-hour period, for at least two 24-hour periods, for at least three 24-hour periods, or for at least fourteen 24-hour periods.

[0105] In some aspects, the first dosage form is a sustained release dosage form.

[0106] In some aspects, the first dosage form is formulated for oral administration, intravenous administration, depot administration, or subcutaneous administration.

[0107] In some aspects, the first dosage form is formulated for subcutaneous administration.

[0108] In some aspects, the first dosage form comprises an infusion system designed to provide continuous subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

[0109] In some aspects, the first dosage form comprises microparticles designed to provide sustained subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

[0110] In some aspects, the second dosage form and the third dosage form are formulated for oral administration, intravenous administration, depot administration, subcutaneous administration, or a combination thereof.[OHl] In some aspects, at least one of the second dosage form and the third dosage form is formulated for oral administration. In some aspects, the second dosage form is formulated for oral administration. In some aspects, the third dosage form is formulated for oral administration. In some aspects, both the second dosage form and the third dosage form are formulated for oral administration.

[0112] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist after administration reaches and maintains between about 5 percent to about 100 percent, about 10 percent to about 100 percent, about 15 percent to about 100 percent, about 20 percent to about 100 percent, about 30 percent to about 100 percent, or about 50 percent to about 100 percent of the maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist over the dosing interval. In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist after administration reaches and maintains between about 60 percent to about 100 percent, about 70 percent to about 100 percent, about 75 percent to about 100 percent, about 80 percent to about 100 percent, about 90 percent to about 100 percent, or about 95 percent to about 100 percentof the maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist over the dosing interval.

[0113] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist after administration reaches the maximum non-awakening concentration.

[0114] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist for at least two weeks, at least four weeks, at least six weeks or at least eight weeks. In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 15 weeks, 20 weeks, or any value or partial value in between any of the preceding values. In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist for more than 20 weeks.

[0115] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist after administration is maintained for at least two weeks, at least four weeks, at least six weeks or at least eight weeks. In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist after administration is maintained for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 15 weeks, 20 weeks, or any value or partial value in between any of the preceding values. In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist after administration is maintained for more than 20 weeks.

[0116] In some aspects, the method improves one or more daytime symptoms of narcolepsy type 1 selected from fragmented wakefulness, excessive daytime sleepiness (EDS), cataplexy, and anxiety.

[0117] In some aspects, the method improves one or more nighttime symptoms of narcolepsy type 1 selected from fragmented sleep, sleep paralysis, and hallucinations.

[0118] In some aspects, the method improves one or more daytime symptoms and one or more nighttime symptoms in human subjects with narcolepsy type 1. In some aspects, the method improves one or more daytime symptoms of narcolepsy type 1 selected from fragmented wakefulness, excessive daytime sleepiness (EDS), cataplexy, and anxiety andone or more nighttime symptoms of narcolepsy type 1 selected from fragmented sleep, sleep paralysis, and hallucinations in human subjects with narcolepsy type 1.

[0119] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from Methyl (2R,3 S)-3 -((methyl sulfonyl)amino)-2- (((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate; N-((2R,3S)-l-glycoloyl-2- (((cis-4-(2,3,6-trifluorophenyl) cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide; and (2R,3 S)-N-ethyl-2- (((cis-4-isopropylcyclohexyl)oxy)methyl)- 3 -((methyl sulfonyl) amino)piperidine-l- carboxamide; or a pharmaceutically acceptable salt thereof.

[0120] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt thereof.

[0121] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from N- ((2S,3S)-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3- yl)methyl)pyrrolidin-3-yl)methanesulfonamide; N-((2S,3S)-2-((2,3'-difluorobiphenyl-3- yl)methyl)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide; methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'- trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide; 4-(5- cyclopropyl-l,2,4-oxadiazol-3-yl)-N-{(lR,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin- l-yl]cyclohexyl}-4-methylpiperidine-l-carboxamide; N-{(lR,6S)-2,2-difluoro-6-[4- (propan-2-yl)piperazin-l-yl]cyclohexyl}-4-{5-[(lS,2S)-2-fluorocyclopropyl]-l,2,4- oxadiazol-3-yl}-4-methylpiperidine-l -carboxamide; (2R)-2-cyclopropyl-2-{(lR,3S,5S)- 3-[(3S,4R)-l-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8- azabicyclo[3.2.1]octan-8-yl}acetamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5- fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3- methylbutaneamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5-chloropyrimidin-2-yl)-3- ethoxypiperidin-4-yl)-8-azabicyclo[3.2. l]octan-8-yl)-2-cyclopropyl acetamide; (R)-2- cyclopropyl-2-((lR,3S,5S)-3-((2S, 4S)-l-(5-fhioropyrimidin-2-yl)-2-methylpiperidin-4- yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide; and N-((21S,24S,52R,53S)-6-oxo-3,8-dioxa-l(2,3)-pyrazina-5(2,l)-piperidina-2(l,4)-cyclohexanacyclooctaphane-53- yl)methanesulfonamide; or a pharmaceutically acceptable salt thereof.

[0122] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3- yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0123] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3S)-2-( (2,3'-difluorobiphenyl-3-yl)methyl)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3- yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0124] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-{(2S,3R)-4.4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3- yl)methyl]pyrrolidin-3-yl] ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0125] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3R)-4.4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluoro-[l,r-biphenyl]-3- yl)methyl)pyrrolidin-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0126] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from N'- {(2S,3R,4S)-l-(azetidine-l-carbonyl)-4-fhioro-2-[(2-fluoro-3 methyl[l,l'-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-N,N-dimethyl sulfuric diamide; N-[(2S,3R)-2-[(2,3'- difluoro[l,r-biphenyl]-3-yl)methyl]-4,4-difluoro-l-(2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2- [(2,3',5'-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide; N- {(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[l,r- biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide; N-{(2S,3R)-1- (bicyclo[ 1.1.1 ]pentane- 1 -carbonyl)-4,4-difluoro-2-[(2,3 ', 5 '-trifluoro[ 1 , 1 '-biphenyl]-3 - yl)methyl]pyrrolidin-3-yl}methanesulfonamide; N-{(2S,3R)-l-(cyclopropanecarbonyl)-4.4-difluoro-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl} ethanesulfonamide; N-{(2S,3R)-4,4-difhioro-l-((lS,3R)-3-fluorocyclobutane-l- carbonyl)-2-[(2, 3 ',5 '-tri fluorofl, l'-biphenyl]-3-yl)methyl]pyrrolidin-3- yl} ethanesulfonamide; N-{(2S,3R)-4,4-difhioro-l-((lS,3R)-3-fluorocyclobutane-l- carbonyl)-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3- yl (methanesulfonamide; N'- { (2S,3R)- 1 -(azetidine- 1 -carbonyl)-4,4-difluoro-2-[(2-fluoro- 3'-methyl[l,l'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric diamide; or a pharmaceutically acceptable salt thereof.

[0127] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from N- {(6S,7aS)-2-[4-(2,6-difhiorophenyl)-l,2-benzoxazol-3-yl]-3-oxohexahydro-lH- pyrrolo[l,2-c]imidazol-6-yl} ethanesulfonamide; N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6- trifluorophenyl)-l,2-benzoxazol-3-yl]-2, 5, 6, 7-tetrahy dro-3H-pyrrolo[l,2-c]imidazol-6- yl (methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1.2-benzoxazol-3 -yl]hexahydro- lH-pyrrolo[ 1 ,2-c]imidazol-6-yl ( ethanesulfonamide; N- {(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-l,2-benzoxazol-3-yl]-3-oxohexahydro-lH- pyrrolo[l,2-c]imidazol-6-yl} ethanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4- (2,4,6-trifluorophenyl)- 1 ,2-benzoxazol-3 -yl]hexahydro- lH-pyrrolo[ 1 ,2-c]imidazol-6- yl (methanesulfonamide; N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-l,2- benzoxazol-3-yl]-3 -oxo-2, 5, 6, 7-tetrahy dro-3H-pyrrolo[ l,2-c]imidazol-6- yl (methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1.2-benzoxazol-3 -y 1 ] -3 -oxohexahydro- lH-pyrrolo[ 1 ,2-c]imidazol-6- yl (methanesulfonamide; N-{(4aR,6R)-5,5-difluoro-l-oxo-2-[4-(2,4,6-trifluorophenyl)-1.2-benzoxazol-3-yl]octahydropyrrolo[l,2-c]pyrimidin-6-yl(methanesulfonamide; N- {(4aR, 6R)-2-[5,6-difluoro-4-(2, 4, 6-tri fluorophenyl)- l,2-benzoxazol-3-yl]-5,5-difluoro-l- oxooctahydropyrrolo[l,2-c]pyrimidin-6-yl (methanesulfonamide; N-{(4aR,6R)-2-[4-(2,6- difluorophenyl)-5 -fluoro- 1 ,2-benzoxazol-3 -yl]-5,5-difluoro- 1 -oxooctahydropyrrolof 1 ,2- c]pyrimidin-6-yl(methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1.2-benzoxazol-3-yl]-7, 7-difluoro-3 -oxo-2, 5, 6, 7-tetrahy dro-3H-pyrrolo[l, 2-c]imidazol-6- yl( ethanesulfonamide; or a pharmaceutically acceptable salt thereof.

[0128] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from compounds described in any of WO 2019 / 027058, WO2017 / 135306, W02020 / 158958,W02021 / 107023, W02022 / 014680, W02020 / 167701, W02020 / 167706, WO2021 / 026047, W02022 / 040070, W02022 / 094012, W02022 / 040058, W02022 / 109117, WO 2022 / 119888, WO 2022 / 132696, WO2022 / 051583, WO2022 / 051596, and WO2021 / 108628.

[0129] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from any of the orexin type 2 receptor agonists listed herein.

[0130] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist is selected by: i) determining a non-awakening plasma concentration of the first orexin type 2 receptor agonist that does not provide an arousal response in a human; and ii) determining a dose of the first orexin type 2 receptor agonist that will provide a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the agonist determined in i).

[0131] In some aspects, the blood plasma concentration of the first orexin type 2 receptor agonist is selected by: i) determining a maximum non-awakening concentration of the first orexin type 2 receptor agonist that does not provide an arousal response in a human; ii) determining the corresponding dose of the first orexin type 2 receptor agonist that provides maximum non-awakening concentration of the agonist as determined in i); and iii) selecting a dose of the first orexin type 2 receptor agonist that will provide a blood plasma concentration of the agonist that is at or below the maximum non-awakening plasma concentration of the agonist.

[0132] In some aspects, the arousal response can be determined by measuring sleep latency in one or more humans diagnosed with narcolepsy type 1.

[0133] In some aspects, the present disclosure is related to the use of an orexin type 2 receptor agonist in a human, at a blood plasma concentration that is at or below the maximum non-awakening plasma concentration of the agonist, in combination with an additional orexin type 2 receptor agonist at a blood plasma concentration that is above the maximum non-awakening blood plasma concentration of the additional orexin type 2 receptor agonist.

[0134] In another aspect, the present disclosure provides a pharmaceutical composition which comprises an orexin type 2 receptor agonist at a dose which provides a blood plasma concentration of the agonist at or below the maximum non-awakening plasmaconcentration. In some aspects, the pharmaceutical composition is used with the methods disclosed herein.

[0135] In another aspect, the present disclosure provides a pharmaceutical composition which comprises an orexin type 2 receptor agonist at a dose which provides a blood plasma concentration of the agonist above the maximum non-awakening plasma concentration. In some aspects, the present disclosure provides a pharmaceutical composition which comprises an orexin type 2 receptor agonist at a dose which provides a blood plasma concentration of the agonist that results in a wake-promoting effect after administration in a human subject. In some aspects, the pharmaceutical composition is used with the methods disclosed herein.

[0136] In another aspect, the present disclosure provides a method of administering an orexin type 2 receptor agonist (e.g., the first orexin type 2 receptor agonist) to a mammal in need thereof, wherein the method comprises maintaining the average blood plasma concentration of the agonist in the mammal which is less than about 100 ng / mL, less than about 50 ng / mL, less than about 30 ng / mL, less than about 10 ng / mL, less than about 5 ng / mL, less than about 3 ng / mL, or less than about 1 ng / mL, but greater than 0 ng / mL over a dosing interval of one or more twenty-four-hour periods. In some aspects, the average blood plasma concentration of the agonist in the mammal is maintained at less than the above values during non-waking hours of one or more twenty-four-hour periods. In some aspects, the average blood plasma concentration of the agonist in the mammal is maintained at less than the above values during the hours of one or more twenty-four- hour periods wherein the second and / or third orexin type 2 receptor agonist is not providing a blood plasma concentration of the agonist that provides a wake-promoting effect.

[0137] In another aspect, the present disclosure provides a method of administering an orexin type 2 receptor agonist (e.g., the second and / or third orexin type 2 receptor agonist) to a mammal in need thereof, wherein the method comprises maintaining the average blood plasma concentration of the agonist in the mammal which is about 30 ng / mL or more, about 40 ng / mL or more, about 50 ng / mL or more, about 60 ng / mL or more, about 80 ng / mL or more, about 100 ng / mL or more, about 120 ng / mL or more, about 140 ng / mL or more, about 160 ng / mL or more, about 180 ng / mL or more, or about 200 ng / mL or more during waking hours of one or more twenty-four-hour periods.

[0138] In some aspects, the methods, compositions, and uses disclosed herein utilize a dose of the first orexin type 2 receptor agonist that provides a blood plasma concentration which is not less than about 1 / 10 of the maximum non-awakening plasma concentration. In some aspects, the dose of the first orexin type 2 receptor agonist provides a blood plasma concentration which is not less than about 1 / 5 of the maximum non-awakening plasma concentration. In some aspects, the dose of the first orexin type 2 receptor agonist provides a blood plasma concentration which is not less than about 1 / 3 of the maximum non-awakening plasma concentration. In some aspects, the dose of the first orexin type 2 receptor agonist provides a blood plasma concentration which is not less than about 1 / 2 of the maximum non-awakening plasma concentration. In some aspects, the dose of the first orexin type 2 receptor agonist provides a blood plasma concentration which is not less than about the maximum non-awakening plasma concentration.

[0139] In another aspect, the present disclosure provides a method of producing a dosage form for treatment of NT1 in a human subject in need of said treatment, which comprises an orexin type 2 receptor agonist. In some aspects, the dosage form is a sustained release formulation for injection. In some aspects, the dosage form is an oral formulation. In some aspects, the dosage form comprises microparticles designed to provide sustained subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

[0140] In another aspect, the present disclosure provides a use of an orexin type 2 receptor agonist in manufacturing a dosage form for treatment of NT1 in a human in need of said treatment, wherein the orexin type 2 receptor agonist provides a blood plasma concentration after administration which is at or below the maximum non-awakening concentration of the agonist. In some aspects, the dosage form is a sustained release formulation for injection. In some aspects, the dosage form is an oral formulation. In some aspects, the dosage form comprises microparticles designed to provide sustained subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

[0141] In another aspect, the present disclosure provides a use of an orexin type 2 receptor agonist in manufacturing a dosage form for treatment of NT1 in a human in need of said treatment, wherein the orexin type 2 receptor agonist provides a blood plasma concentration after administration which is above the maximum non-awakening concentration of the agonist. In some aspects, the dosage form is a sustained release formulation for injection. In some aspects, the dosage form is an oral formulation. Insome aspects, the dosage form comprises microparticles designed to provide sustained subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

[0142] In one aspect, the present disclosure provides one or more dosage forms comprising one or more orexin type 2 receptor agonists, for use in treating Narcolepsy Type 1 (NT1) in a human subject, wherein the one or more dosage forms are to be administered in an amount and frequency that provides a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for the remainder of the twenty-four-hour period; wherein the blood plasma concentration of the orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods.

[0143] In another aspect, the present disclosure provides a first dosage form comprising a first orexin type 2 receptor agonist, for use in treating Narcolepsy Type 1 (NT1) in a human subject, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods; wherein the subject has been or is to be administered a second dosage form comprising a second orexin type 2 receptor agonist in an amount and frequency that provides a wakepromoting blood plasma concentration of the second orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period; wherein the first dosage form and the second dosage form may be the same or different, and wherein the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist may be the same or different.

[0144] Another aspect of the present disclosure provides a second dosage form comprising a second orexin type 2 receptor agonist, for use in treating Narcolepsy Type 1 (NTl) in a human subject, wherein the second dosage form is to be administered in an amount and frequency that provides a wake-promoting blood plasma concentration of the second orexin type 2 receptor agonist during a portion of waking hours of a twenty-four- hour period; wherein the subject has been or is to be administered a first dosage formcomprising a first orexin type 2 receptor agonist in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist for the remainder of the twenty-four-hour period and over a dosing interval of five or more twenty-four-hour periods; and wherein the first dosage form and the second dosage form may be the same or different, and the wherein the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist may be the same or different.

[0145] Another aspect of the present disclosure provides a combination for use in treating Narcolepsy Type 1 (NT1) in a human subject, the combination comprising: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; and a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject; wherein the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist may be the same or different and wherein the first dosage form and the second dosage form may be the same or different.

[0146] Another aspect of the present disclosure includes the above combination which further comprises a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject, and wherein the amount and frequency of administration of the second dosage form no longer provides a wake-promoting effect during waking hours of the dosing interval; wherein the third orexin type 2 receptor agonist may be the same as or different than the first and / or second orexin type 2 receptor agonist and wherein the third dosage form may be the same as or different than the first and / or second dosage form.

[0147] Another aspect of the present disclosure includes a combination for use in treating Narcolepsy Type 1 (NT1) in a human subject, the combination comprising: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect of the second orexin type 2 receptor agonist after administration; and a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration; wherein the first, second and third orexin type 2 receptor agonists may be the same as or different than each other and wherein the first, second and third dosage forms may be the same as or different than each other.

[0148] In one aspect, the present disclosure provides a kit for treating Narcolepsy Type 1 (NTl) in a human subject, which comprises: one or more dosage forms comprising one or more orexin type 2 receptor agonists, wherein the one or more dosage forms are to be administered in an amount and frequency that provide: a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for the remainder of the twenty-four-hour period;wherein the blood plasma concentration of the orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods.

[0149] Another aspect of the present disclosure provides a kit for treating Narcolepsy Type 1 (NT1) in a human subject, which comprises: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; and a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject.

[0150] Another aspect of the present disclosure includes the kit in the immediately preceding paragraph, which further comprises a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject, and wherein the amount and frequency of administration of the second dosage form no longer provides a wake-promoting effect during waking hours of the dosing interval.

[0151] Another aspect of the present disclosure provides a kit for treating Narcolepsy Type 1 (NTl) in a human subject, which comprises: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods;a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect of the second orexin type 2 receptor agonist after administration; and a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration.

[0152] Another aspect of the present disclosure includes any one of the above kits further comprising instructions, which may include storage information, dosing information and / or instructions about how to administer each dosage form.

[0153] In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein utilize a dose of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist for administration to a human, wherein the dose is in a range of about 1 mg to about 500 mg. In some aspects, the dose is in a range of about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 80 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, or about 1 mg to about 5 mg. In some aspects, the dose is 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 125 mg, 150 mg, 200 mg, or any or any value or partial value in between any of the preceding values.

[0154] In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein utilize a dose of the first orexin type 2 receptor agonist for administration to a human, wherein the dose is from about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, or any value or partial value in between any of the preceding values.

[0155] In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein utilize a dose of the second and / or third orexin type 2 receptoragonist for administration to a human, wherein the dose is from about 5 mg to about 500 mg, from about 5 mg to about 200 mg, from about 5 mg to about 150 mg, from about 5 mg to about 100 mg, from about 5 mg to about 50 mg, from about 5 mg to about 30 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, or any value or partial value in between any of the preceding values.

[0156] In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein utilize a dose of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist for administration to a human, wherein the dose is from about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 50 mg / kg, or any value or partial value in between any of the preceding values. In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein utilize a dose of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist for administration to a human, wherein the dose is less than 1 mg / kg.

[0157] In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein utilize a dose of the first orexin type 2 receptor agonist for administration to a human, wherein the dose is in a range of about 1 mg to about 5 mg.

[0158] In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein utilize a dose of the second and / or third orexin type 2 receptor agonist for administration to a human, wherein the dose is in a range of about 5 mg to about 150 mg.

[0159] In another aspect, the present disclosure provides a method of treating narcolepsy type 1 in a human in need of said treatment by administering a first and second orexin type 2 receptor agonist, which method comprises i) obtaining the maximum nonawakening plasma concentration of the first agonist in the human; ii) selecting a dose of the first agonist that provides blood plasma concentration at or below the maximum nonawakening plasma concentration in the human; iii) administering the dose of the agonist selected in ii) repeatedly or continuously to the human subject; iv) obtaining the minimum wake-promoting plasma concentration of the second agonist in the humansubject; v) selecting a dose of the second agonist that provides wake-promoting blood plasma concentration in the human; and vi) administering the dose of the second agonist selected in v) to the human subject.

[0160] In another aspect, the present disclosure provides a method of producing a pharmaceutical composition for treatment of narcolepsy type 1 (NT1) in a human in need of treatment comprising a first orexin type 2 receptor agonist, wherein the method comprises: i) determining the maximum non-awakening concentration of the first orexin type 2 receptor agonist in a human with NT1; ii) selecting a dose of the first agonist that provides blood plasma concentration at or below the maximum non-awakening plasma concentration in the human with NT1; iii) combining the dose of the agonist and pharmaceutically acceptable carriers to formulate the pharmaceutical composition.

[0161] In another aspect, the present disclosure provides a method of producing a pharmaceutical composition for treatment of narcolepsy type 1 (NT1) in a human in need of treatment comprising a second and / or third orexin type 2 receptor agonist, wherein the method comprises: i) determining the wake-promoting concentration of the second and / or third orexin type 2 receptor agonist in a human with NT1; ii) selecting a dose of the second and / or third agonist that provides a wake-promoting blood plasma concentration in the human with NT1; iii) combining the dose of the second and / or third agonist and pharmaceutically acceptable carriers to formulate the pharmaceutical composition.

[0162] In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein reduce sleep fragmentation during the dark phase in an NT1 patient by about 10% to about 20%.

[0163] In some aspects, the methods, compositions, dosage forms, combinations, kits and uses disclosed herein reduce cataplexy -like symptoms during light phase in an NT1 patient by about 15% to about 50%.METHODS AND USES

[0164] The methods and uses disclosed herein may treat narcolepsy type 1 in a subject in need of said treatment. The methods and uses disclosed herein may also treat symptoms such as excessive daytime sleepiness (EDS), cataplexy, hypnagogic / hypnopompic hallucinations, sleep paralysis, disturbed nighttime sleep (sleep fragmentation or fragmented sleep), fragmented wakefulness, and anxiety. In some embodiments, treating narcolepsy type 1 may comprise reducing or alleviating one or more symptoms ofnarcolepsy type 1. The one or more symptoms of narcolepsy type 1 may be selected from excessive daytime sleepiness (EDS), cataplexy, hypnagogic / hypnopompic hallucinations, sleep paralysis, disturbed nighttime sleep (sleep fragmentation or fragmented sleep), fragmented wakefulness, and anxiety. In some aspects, the one or more symptoms of narcolepsy type 1 is selected from excessive daytime sleepiness (EDS), cataplexy (including cataplexy-like symptom) in active phase, and sleep fragmentation during sleep phase.

[0165] The methods and uses disclosed herein may also treat comorbidities of narcolepsy type 1, such as obesity, type 2 diabetes, cardiovascular diseases, apnea during sleep, mood disorders, anxiety, attention-deficit hyperactivity disorder (ADHD), restless leg syndrome, sleep parasomnias and the like. Narcolepsy may be diagnosed by diagnostic criteria generally used in the field, e.g., the third edition of the International Classification of Sleep Disorders (ICSD-3) and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (Current Medical Research and Opinion, 32: 10, 1611- 1622, (2016)). Additionally, nighttime sleep will be improved, for example, by reducing the number of waking incidents during the sleep cycle.

[0166] The methods and uses disclosed herein may increase wakefulness, and / or decrease and / or treat excessive sleepiness, and / or decrease occurrence of cataplexy episodes in a subject in need thereof during active phase. In some embodiments, excessive sleepiness as used herein is also known as excessive daytime sleepiness (EDS) or excessive need for sleep (ENS). The methods and uses disclosed herein may also decrease sleep fragmentation, and / or decrease occurrence of sleep paralysis / hallucinations during the sleep phase. In some embodiments, wakefulness, excessive sleepiness, cataplexy symptom, sleep fragmentation, and / or sleep paralysis / hallucinations is determined by known method such as using any one or more of electroencephalogram (EEG), electromyogram (EMG), Maintenance Wakefulness Test (MWT), polysomnography, and the like (Sleep, Vol. 45, Issue 8, zsac091, (2022)). MWT is a validated objective measure of the time taken for a subject to fall asleep under soporific conditions (Electroencephalogr. Clin. Neurophysiol. 53(6): 658-661, (1982). MWT is quantified by EEG optionally combined with EMG. An electroencephalogram (EEG) is a test that detects electrical activity in the brain using small, metal discs or electrodes attached to the scalp. In some embodiments, wakefulness and / or decrease of sleepiness is determined byusing the multiple sleep latency test (MSLT) or the Oxford Sleep Resistance (OSLER) test. In some embodiments, the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS) or the Stanford Sleepiness Scale. MSLT and polysomnography have been used to assess the sleep in patients with potential narcolepsy, and some electrophysiological features appears in NT1 patients were reported previously (Nat Rev Dis Primers 3, 16100 (2017)). In some embodiments, treating excessive sleepiness may comprise reducing or alleviating one or more symptoms of excessive sleepiness. The one or more symptoms of excessive daytime sleepiness may be selected from drowsiness, languor, inertness, fatigue, sluggishness.

[0167] In some aspects, the subject suffers from the diseases or disorders or symptoms associated with excessive sleepiness. In some embodiments, the subject is a sleep- deprived subject, a subject with excessive sleepiness, a subject with disruptive regular sleep cycle, or a subject with a need to decrease sleepiness.DEFINITIONS

[0168] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0169] As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0170] Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B,and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). In addition, "or" is used mean an open list of the components in the list. For example, "wherein X comprises A or B" means X comprises A, X comprises B, X comprises A and B, or X comprises A or B and any other components.

[0171] As used herein, the term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.

[0172] As used herein, the term "administration" of an agent to a subject includes any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable non-oral route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self-administration and the administration by another. Administration of an 0X2R agonist for treatment purpose in this invention is generally long-term, continuous, chronic, and / or repetitive. "After administration" of an 0X2R agonist in the present invention means a certain time period elapses from the administration of the 0X2R agonist to a subject. Generally, this means from about 24 to about 48 hours after the initial administration.

[0173] As used herein, the term "dosage form" or "pharmaceutical composition" means a composition containing a drug molecules. Examples of the dosage form include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal tablet), capsule (including soft capsule, microcapsule), pill, granule, powder, troche, syrup, liquid, emulsion, suspension, aerosol, films (e.g., orally disintegrable films, oral mucosa-adhesive film) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (e.g., transdermal absorption type preparation, ointment, lotion, adhesive preparation), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation,pulmonary preparation (inhalant), eye drop, microparticles, depot, and the like. The compound and medicament of the present invention can be respectively safely administered orally or parenterally (e.g., intrarectal, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intravaginal, intraperitoneal, intratumoral, proximal tumor administrations, and administration to the lesion). These preparations may be a release control preparation (e.g., sustained-release microcapsule) such as an immediate-release preparation, a sustained-release preparation and the like.

[0174] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a quantity of a compound sufficient to achieve a desired effect or a desired therapeutic effect. In the context of therapeutic applications, the amount of the compound administered to the subject may depend on the type and severity of the disease or symptom and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.

[0175] As used herein, the term "modulate" refers positively or negatively alter.Exemplary modulations include an about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100% change.

[0176] As used herein, the term "increase" refers to alter positively by at least about 5%, including, but not limited to, alter positively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.

[0177] As used herein, the term "reduce" refers to alter negatively by at least about 5% including, but not limited to, alter negatively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.

[0178] As used herein, the term "orexin receptor 2 agonist" or "0X2R agonist" refers to a drug or substance, such as a small molecule, that activates 0X2R. 0X2R is a G-protein coupled receptor (GPCR) which interacts with Gq class of heterotrimeric G proteins and P-arrestins. Orexin-A and Orexin-B peptides are known to increase calcium mobilization (Cell, Vol. 92, 573-585, (1998)) and promote recruitment of P-arrestins (J. Biol. Chem. Vol. 286, No. 19, 16726-16733, (2011)) in OX2R-expressed recombinant cells. 0X2R agonists such as Danavorexton and YNT-185 have also been shown to increase calcium mobilization and promote recruitment of P-arrestins (Pharmacol. Biochem. Behav.,187(2019), 172794; Proc. Natl Acad. Sci. USA., 114(22), 5731-5736, (2017)). Therefore, 0X2R agonistic activity of drug candidates may be evaluated by calcium mobilization assays or P-arrestin recruitment assays using OX2R-expressed cells.

[0179] As used herein, the term "arousal" (including "arousal" in "arousal-promoting concentration") and "wake-promoting" (including in "wake-promoting effect" and "wakepromoting concentration") may be used interchangeably and mean the status of a subject is near complete wakefulness which is examined by known measures such as Maintenance of Wakefulness Test (MWT) and EEG / EMG recordings.

[0180] As used herein, "blood plasma concentration" (sometimes simplified as "plasma concentration") refers to a concentration of a pharmaceutical substance in blood plasma derived from a subject blood collected at certain time point. "Blood plasma concentration after administration" in the present invention means the blood plasma concentration of the pharmaceutical substance at the time point during the period that a subject intends to either be awake or during a period that the subject does not intend to be awake. The particular time from administration to concentration measurement will depend upon the PK / PD properties for a particular 0X2R agonist. The time between administration and concentration measurement can be for a particular 0X2R agonist, between about 30 minutes to about 12 hours or later, for example, about 30 minutes, or about 1 hour, or about 2 hours, or about 4 hours, or about 6 hours, or about 8 hours, or about 12 hours or later, or any number of hours in between the preceding values, following administration of the substance. "Average blood plasma concentration" means average of blood plasma concentrations of different time points 30 minutes or later following the administration of a pharmaceutical substance in a subject.

[0181] As used herein, the terms "non-awakening plasma concentration" and "nonawakening concentration" may be used interchangeably and refer to a plasma concentration of an orexin type 2 receptor agonist that will not induce arousal in a subject. Non-awakening plasma concentration can be identified by conducting a multiple-dose study. Such study may be conducted as part of preclinical and clinical PK / PD studies during drug development. Among non-awakening plasma concentrations, the "maximum non-awakening plasma concentration" is the highest concentration above which marginal arousal effect occurs. The phrase "at or below the maximum non-awakening plasma concentration" of an 0X2R agonist means the plasma concentration of the 0X2R agonistin a subject is larger than 0 (zero) and the same or less than the maximum non-awakening plasma concentration. In some embodiments, the plasma concentration of the 0X2R agonist in a subject over a dosing interval is at or below the maximum non-awakening plasmatic concentration, but not less than about 1 / 20, about 1 / 12, about 1 / 10, about 1 / 8, about 1 / 5, or about 1 / 3 of the maximum non-awakening concentration of the agonist. The average plasma concentration of an OX2R agonist can be about 1 / 20, about 1 / 10, about 1 / 8, about 1 / 5, about 1 / 4, about 1 / 3, about 1 / 2, or 1 / 1 of the maximum non-awakening concentration of the agonist, + 5%. In some embodiments, the average plasma concentration of the OX2R agonist, at or below the maximum non-awakening plasma concentration, is about 1 / 60, 1 / 40 1 / 36, 1 / 30, 1 / 20 / or 1 / 10 of the arousal-promoting plasma concentration. The non-awakening plasma concentration of an OX2R agonist can be measured during non-waking hours or intended non-waking hours. In some aspects, the non-awakening plasma concentration of an OX2R agonist is measured while a subject is asleep or not awake and at a time point of about 30 minutes, or about 1 hour, or about 2 hours, or about 4 hours, or about 6 hours, or about 8 hours, or any number of hours in between the preceding values, following administration of the OX2R agonist.

[0182] As used herein, the term "arousal-promoting concentration," "wake-promoting concentration," and "wake-promoting effect" of an OX2R agonist may be used interchangeably and refer to a threshold blood plasma concentration of the agonist which provides nearly complete wakefulness effect (i.e. maintenance of wakefulness for more than 75% in 10 min-bins.) in a subject. Certain OX2R agonists have been shown to produce potent efficacy in wakefulness when the blood plasma concentration of the 0X2R agonist exceeded its arousal-promoting or wake-promoting concentration in NT1 subjects. The arousal -promoting or wake-promoting concentration of an OX2R agonist is significantly higher than the maximum non-awakening concentration of the OX2R agonist. The wake-promoting concentration can be measured during waking hours or intended waking hours. In some aspects, the wake-promoting concentration of an OX2R agonist is measured while a subject is awake and at a time point of about 30 minutes, or about 1 hour, or about 2 hours, or about 4 hours, or about 6 hours, or about 8 hours, or about 12 hours or later, or any number of hours in between the preceding values, following administration of the OX2R agonist.

[0183] The determination of blood plasma concentration can be performed with measures known to the skilled person in the art, including high-performance liquid chromatography-tandem mass spectrometry. The level is typically expressed as ng of analyte / mL. A maximum non-awakening concentration and an arousal-promoting concentration of an OX2R agonist in a subject can be determined by combining timeseries measurement of blood plasma concentration with recording of nighttime and / or daytime sleep and awake patterns in the subject by known methods including EEGZEMG recording and actigraphy. When detecting the maximum non-awakening concentration or arousal-promoting concentration of an OX2R agonist in a non-NTl subject, the measurement is performed during night time when autogenic orexin-A level of the subject is generally low.

[0184] As used herein, the term "actigraphy" refers to methods using miniaturized computerized wristwatch-like devices to monitor and collect data generated by movements. Most actigraphs contain an analogue system to detect movements. In some devices, a piezo-electric beam detects movement.

[0185] As used herein, the term "treatment", "treating", or "treat" includes improvement, reduction, alleviation, or amelioration of one or more symptoms associated with a disease. In one embodiment of the methods and uses disclosed herein may improve one or more nighttime symptoms selected from fragmented sleep, sleep paralysis and hallucinations; and / or improves one or more daytime symptoms selected from fragmented wakefulness and cataplexy. Such improvements can be assessed using any one or more of MWT, MALT, EEG, or EMG, by comparing the conditions before and after administration of an OX2R agonist to the subject, or by comparing the conditions between subjects administered placebo and administered an OX2R agonist. In one embodiment, an OX2R agonist of the present invention improves night time sleep fragmentation of NT1 patients as indicated by reducing the number of episodes of wakefulness during sleep phase (dark phase) by about 10% to about 20%, and / or increasing NREM sleep duration during the light phase by 10% to about 30%.

[0186] As used herein, the term "dosing interval" refers to one or more twenty-four-hour periods during which a human subject is administered at least a first dosage form and a second dosage form according to the methods and uses disclosed herein.

[0187] As used herein, the term "subject" refers to a mammal including human, bovine, horse, dog, cat, monkey, mouse, and rat, and preferably refers to a human.

[0188] As used herein, the term "pharmaceutically acceptable" substances refer to those substances which are suitable for administration to subjects.

[0189] As used herein, the term "light phase" refers to the active phase or daytime for human and monkey, and sleep phase or nighttime for mice.

[0190] As used herein, the term "dark phase" refers to the sleep phase or nighttime for human and monkey, and active phase or daytime for mice.

[0191] As used herein, the term "short half-life" refers to a half-life of the relevant compound in the subject’s body of less than 8 hours.

[0192] As used herein, the term "long half-life" refers to a half-life of the relevant compound in the subject’s body of 8 hours or more.

[0193] The methods, compositions, and uses in this disclosure are characterized in that the blood plasma concentration of the first orexin type 2 receptor (0X2R) agonist in a subject is at or below the maximum non-awakening plasma concentration of the first agonist. In one aspect, when the first 0X2R agonist is administered to a subject in need thereof, the blood plasma concentration of the first 0X2R agonist in the subject is at or below the maximum non-awakening plasma concentration of the agonist when measured after administration during hours in which the administration of a second and / or third 0X2R agonist are not providing a wake-promoting blood plasma concentration of the second and / or third 0X2R agonist. By using certain formulations, such as infusion and sustained-release formulations, an initial release of the first 0X2R agonist may continue for one or more hours following administration, and the plasma concentration of the first 0X2R agonist may rise above the maximum non-awakening concentration, but does not reach the wake-promoting concentration. When the blood plasma concentration of the first 0X2R agonist is at or below the maximum non-awakening concentration, it is larger than 0 (zero) and is the same as, or less than, the maximum non-awakening plasma concentration. In some aspects, the plasma concentration of the 0X2R agonist in a subject is about 1 / 20 to 1 / 1, about 1 / 12 to 1 / 1, about 1 / 10 to 1 / 1, about 1 / 8 to 1 / 1, about 1 / 5 to 1 / 1, or about 1 / 3 to 1 / 1 of the maximum non-awakening concentration of the agonist.

[0194] In one aspect, the first OX2R agonist is administered over multiple twenty-four- hour periods in a subject for the treatment of NT1 and / or sleep-related symptoms, and throughout each twenty-four-hour period, the plasma concentration of the first 0X2R agonist is at or below the maximum non-awakening plasma concentration of the first agonist. As used in this disclosure in connection with the administration of an 0X2R agonist, the terms “repeated,” “repetitive,” “repeatedly,” “continued,” “continuously,” “chronic,” “chronically,” or “long-term” means the 0X2R agonist is administered over multiple twenty-four-hour periods.

[0195] In some aspects, the first OX2R agonist is administered to a subject by repeated oral administration or by infusion administration, or by using a slow-release formulation or a sustained-release formulation of the first OX2R agonist. The suitable formulation may be selected based on the characteristics of the first OX2R agonist. A sustained- release or slow-release formulation may be particularly useful for administering the first OX2R agonist having a short half-life (i.e., less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, or less than 4 hours).

[0196] In some aspects, the second and / or third OX2R agonist is administered to a subject by repeated oral administration or by infusion administration, or by using a slow- release formulation or a sustained-release formulation. The suitable formulation may be selected based on the characteristics of the second and / or third OX2R agonist.

[0197] The dose of the first OX2R agonist may be determined by i) identifying the maximum non-awakening concentration of the first OX2R agonist in a subject (e.g. by using EEG), and then ii) identifying the dose of the first OX2R agonist that achieves the maximum non-awakening concentration after administration. The person skilled in the art in the pharmaceutical industry can select a dose that is lower than the dose determined in the step ii). In some aspects, the blood plasma concentration of the first OX2R agonist that is at or below the maximum non-awakening plasma concentration of the agonist in a human is about 0.01 ng / mL to about 1 mg / mL, about 0.03 ng / mL to about 300 ng / mL, about 0.05 ng / mL to about 100 ng / mL, about 0.08 ng / mL to about 50 ng / mL, or about 1 ng / mL to about 30 ng / mL. In some aspects, the dose of the first 0X2R agonist that provides a blood plasma concentration which is at or below the maximum non-awakening plasma concentration of the first 0X2R agonist in a human is about 0.1 mg to about 50 mg, about 0.5 mg to about 30 mg, or about 1 mg to about 20 mg.

[0198] The dose of the second and / or third 0X2R agonist may be determined by i) identifying the wake-promoting concentration of the second and / or third 0X2R agonist in a subject (e.g. by using EEG), and then ii) identifying the dose of the second and / or third 0X2R agonist that achieves the wake-promoting concentration after administration. The person skilled in the art in the pharmaceutical industry can select a dose that is higher than the dose determined in the step ii). In some aspects, the blood plasma concentration of the second and / or third 0X2R agonist that is at or above the wake-promoting plasma concentration of the agonist in a human is about 300 ng / mL or more, about 300 ng / mL to about 3 mg / mL, about 300 ng / mL to about 2 mg / mL, or about 300 ng / mL to about 1 mg / mL. In some aspects, the dose of the second and / or third 0X2R agonist that provides a blood plasma concentration which is above the wake-promoting plasma concentration of the second and / or third 0X2R agonist in a human is about 5 mg to about 500 mg, about 10 mg to about 300 mg, or about 10 mg to about 150 mg.TESTS FOR INCREASED WAKEFULNESS AND / OR DECREASED EXCESSIVE SLEEPINESS

[0199] The methods and uses disclosed herein may treat narcolepsy type 1 in a subject in need of treatment. In some embodiments, treating narcolepsy type 1 may comprise reducing or alleviating one or more symptoms of narcolepsy type 1. The one or more symptoms of narcolepsy type 1 may be selected from fragmented wakefulness, excessive daytime sleepiness (EDS), cataplexy, anxiety, fragmented sleep, sleep paralysis, and hallucinations. Narcolepsy may be diagnosed by diagnostic criteria generally used in the field, e.g., the third edition of the International Classification of Sleep Disorders (ICSD-3) and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM- 5). Additionally, nighttime sleep is expected to be improved, for example, by reducing the number of waking incidents during the sleep cycle.

[0200] The methods and uses disclosed herein may increase wakefulness and / or decrease excessive sleepiness in a subject in need thereof. In some aspects, wakefulness and / or decrease of excessive sleepiness is determined by electroencephalogram (EEG) and / or electromyogram (EMG). These tests can also be employed to determine a threshold concentration for potent arousal and a non-awakening concentration for a particular 0X2R agonist. In some aspects, wakefulness and / or decrease of sleepiness is determined by using the Maintenance Wakefulness Test (MWT) with EEG, optionally combined withEMG. An electroencephalogram (EEG) is a test that detects electrical activity in the brain, for example, by using small, metal discs or electrodes attached to the scalp. In some embodiments, wakefulness and / or decrease of sleepiness is determined by using the multiple sleep latency test (MSLT) or the Oxford Sleep Resistance (OSLER) test. In some aspects, the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS) or the Stanford Sleepiness Scale.

[0201] In some aspects, actigraphy can be employed to study the effects of an OX2R agonist on sleep and wake patterns. The term actigraphy refers to methods using miniaturized computerized wristwatch-like devices to monitor and collect data generated by movements. Most actigraphs contain an analogue system to detect movements. In some devices, a piezo-electric beam detects movement. See, Sadeh et al., Sleep Medicine Reviews 6(2); 113-124 (2002).

[0202] The methods and uses disclosed herein may decrease excessive sleepiness or improve Karolinska Sleepiness Scale (KSS) rating in a subject in need thereof. In some embodiments, the KSS rating is improved 1, 2, 3, 4, or 5 or more ratings. In some embodiments, the subject has a KSS rating of 1, 2, 3, 4, or 5 after treatment.

[0203] The methods and uses disclosed herein may comprise performing one or more tests to quantify a subject's sleepiness. In some embodiments, the test is selected from the multiple sleep latency test (MSLT), maintenance of wakefulness test (MWT), and the Oxford Sleep Resistance (OSLER) test. In some embodiments, the test is MWT. In some embodiments, the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale, Ullanlinna Narcolepsy Scale (UNS), Work Limitations Questionnaire (WLQ), SF-8 (subset of SF-36 questionnaire) or a combination of these tests.MODES OF ADMINISTRATION

[0204] The methods and uses disclosed herein comprise administering one or more OX2R agonists to a subject in need thereof. In some aspects, the OX2R agonist is administered orally. In some aspects, the OX2R agonist is administered non-orally. In some aspects, the non-oral administration is intravenous administration, subcutaneous administration, transdermal administration, intradermal administration or transmucosal administration. In some aspects, the non-oral administration is intravenous administration. In some aspects, the non-oral administration is subcutaneous administration. In someaspects, the subcutaneous administration is subcutaneous depot administration. In some aspects, the 0X2R agonist is administered using microparticles designed to provide sustained subcutaneous delivery of the 0X2R agonist to the human subject.

[0205] Dosage forms and delivery devices for particular routes are more fully described below.

[0206] In some aspects, the plasma concentration for an 0X2R agonist represents an average plasma concentration for a group of treated subjects and the time period of 1 hour or more begins at any time point following administration. As long as the average plasma concentration for a group of treated subjects meets the condition, "about XX ng / mL or more for a period of about 1 hour or more," the plasma concentration for an individually treated subject may deviate from the condition.FREQUENCY OF ADMINISTRATION

[0207] OX2R agonists of the present disclosure are used and administered over multiple twenty-four-hour periods. In some aspects, the first OX2R agonist of the present disclosure may be administered once daily, twice daily, three times daily, every other day, once a week, twice a week, bi-weekly, monthly, or bi-monthly. In some aspects, the second and / or third OX2R agonist of the present disclosure may be administered once daily, twice daily, three times daily, or more than three times daily.COMBINATION THERAPY

[0208] The methods of treating NT1 of the present disclosure may further comprise combining the administration of a first OX2R agonist at or below the maximum nonawakening blood plasma concentration and a second and / or third OX2R agonist at a wake-promoting blood plasma concentration with administration of an additional active agents, including additional OX2R agonists.OX2R AGONISTS

[0209] Useful OX2R agonists for the methods, uses, or compositions of the present disclosure are chemical molecules (compounds) having OX2R agonist activity. Such compounds may be selected from among known compounds or from newly designed / synthesized compounds. A compound having shorter half-life (i.e. less than 8hours, less than 7 hours, less than 6 hours, less than 5 hours, or less than 4 hours) is particularly useful when formulating it in a slow-release dosage form.

[0210] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (I):whereinR1is(1) a hydrogen atom,(2) a Ci-6 alkyl-carbonyl group optionally substituted by 1 to 7 substituents selected from (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) a C3-10 cycloalkyl group, (v) a C1-6 alkoxy group, (vi) a Ce-14 aryl group, (vii) a Ce-14 aryloxy group, (viii) a pyrazolyl group, a thiazolyl group, a pyrimidinyl group or a pyridazinyl group, each of which is optionally substituted by an oxo group, (ix) a pyrazolyloxy group optionally substituted by 1 to 3 C1-6 alkyl groups, (x) a C1-6 alkyl-carbonyl group, (xi) a C1-6 alkoxycarbonyl group, (xii) a C1-6 alkyl-carbonyloxy group, (xiii) a C1-6 alkylsulfonyl group, (xiv) a mono- or di-Ci-6 alkylamino group, (xv) a C1-6 alkyl-carbonylamino group and (xvi) a (C1-6 alkyl)(Ci-6 alkyl-carbonyl)amino group,(3) a C3-10 cycloalkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group, an oxo group and a C1-6 alkyl group,(4) a C1-6 alkoxy-carbonyl group optionally substituted by 1 to 6 substituents selected from deuterium, a halogen atom and a Ce-14 aryl group,(5) a C3-10 cycloalkyloxy-carbonyl group optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group,(6) a Ce-14 aryl-carbonyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ce-14 aryl group,(7) a Ce-14 aryloxy-carbonyl group,(8) a furylcarbonyl group, a thienyl carbonyl group, a pyrazolylcarbonyl group, an isoxazolylcarbonyl group or a pyridylcarbonyl group, each of which is optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group,(9) an azetidinylcarbonyl group, an oxetanyl carbonyl group, a pyrrolidinylcarbonyl group, a tetrahydrofuranylcarbonyl group, a tetrahydropyranylcarbonyl group or a morpholinylcarbonyl group, each of which is optionally substituted by 1 to 3 substituents selected from an oxo group, a C1-6 alkyl-carbonyl group, a C1-6 alkoxy-carbonyl group and a C1-6 alkyl sulfonyl group,(10) a mono- or di-Ci-6 alkyl-carbamoyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group,(11) a mono- or di-Cs-io cycloalkyl-carbamoyl group,(12) a mono- or di-Ce-14 aryl-carbamoyl group,(13) a C1-6 alkylsulfonyl group,(14) a C3-10 cycloalkylsulfonyl group,(15) a Ce-14 arylsulfonyl group optionally substituted by 1 to 3 halogen atoms,(16) a thienylsulfonyl group, a pyrazolyl sulfonyl group, an imidazolylsulfonyl group, a pyridyl sulfonyl group or a dihydrochromenyl sulfonyl group, each of which is optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group,(17) a mono- or di-Ci-6 alkyl-sulfamoyl group or(18) a C1-6 alkyl-carbonyl-carbonyl group;R2is a C3-6 cycloalkyl group, a pyrrolidinyl group, a piperidinyl group or a dioxanyl group, each of which is optionally substituted by 1 to 3 substituents selected from(1) deuterium,(2) a halogen atom,(3) a hydroxy group,(4) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ce-14 aryl group,(5) a C3-10 cycloalkyl group,(6) a C1-6 alkoxy group optionally substituted by a C3-10 cycloalkyl group,(7) a Ce-14 aryl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms and a hydroxy group,(8) a Ce-14 aryloxy group,(9) a tri-Ci-6 alkylsilyloxy group,(10) a pyrazolyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, a quinazolinyl group, a benzothiazolyl group or an isoquinolinyl group, each of which is optionally substituted by 1 to 3 substituents selected from a halogen atom, a C1-6 alkyl group and a C1-6 alkoxy group, and(11) a Ce-14 aryl-carbonyl group; andR3is a C1-6 alkyl group, or a mono- or di-Ci-6 alkylamino group, or a pharmaceutically acceptable salt thereof.

[0211] In some aspects, R1is(1) a hydrogen atom,(2) a C1-6 alkyl-carbonyl group optionally substituted by a hydroxy group,(3) a cyclopropanecarbonyl group,(4) a C1-6 alkoxy-carbonyl group or(5) a mono- or di-Ci-6 alkyl-carbamoyl group;R2is(A) a cyclohexyl group optionally substituted by 1 to 3 substituents selected from(1) a C1-6 alkyl group and(2) a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms and a C1-6 alkoxy group or(B) a piperidinyl group optionally substituted by 1 to 3 pyrimidinyl groups; andR3is a C1-6 alkyl group or a di-Ci-6 alkylamino group, or a pharmaceutically acceptable salt thereof.

[0212] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are each independently selected from Methyl (2R,3S)-3-((methylsulfonyl)amino)-2- (((cis-4- phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate; N-((2R,3 S)- 1 -glycoloyl-2- (((cis-4-(2,3,6-trifluorophenyl) cyclohexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide; and (2R,3S)-N-ethyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)- 3 -((methyl sulfonyl) amino)piperidine-l -carboxamide; or a pharmaceutically acceptable salt thereof.

[0213] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are selected from methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt thereof.

[0214] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are each independently selected from N-((2S,3S)-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl- 3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide; N-((2S,3S)-2-((2,3'-difluorobiphenyl-3- yl)methyl)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide; methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine- 1 -carboxylate; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'- trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide; 4-(5- cyclopropyl-l,2,4-oxadiazol-3-yl)-N-{(lR,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin- l-yl]cyclohexyl}-4-methylpiperidine-l-carboxamide; N-{(lR,6S)-2,2-difluoro-6-[4- (propan-2-yl)piperazin-l-yl]cyclohexyl}-4-{5-[(lS,2S)-2-fluorocyclopropyl]-l,2,4- oxadiazol-3-yl}-4-methylpiperidine-l -carboxamide; (2R)-2-cyclopropyl-2-{(lR,3S,5S)- 3-[(3S,4R)-l-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8- azabicyclo[3.2.1]octan-8-yl}acetamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5- fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-3- methylbutaneamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5-chloropyrimidin-2-yl)-3- ethoxypiperidin-4-yl)-8-azabicyclo[3.2. l]octan-8-yl)-2-cyclopropyl acetamide; (R)-2- cyclopropyl-2-((lR,3S,5S)-3-((2S, 4S)-l-(5-fluoropyrimidin-2-yl)-2-methylpiperidin-4- yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide; and N-((21S,24S,52R,53S)-6-oxo-3,8-dioxa-l(2,3)-pyrazina-5(2,l)-piperidina-2(l,4)-cyclohexanacyclooctaphane-53- yl)methanesulfonamide; or a pharmaceutically acceptable salt thereof.

[0215] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (II):whereinR1is(1) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom, and(b) a Ci-6 alkoxy group,(2) a C3-6 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, or(3) a mono- or di-Ci-6 alkylamino group;R2is a hydrogen atom;R3is(1) a C1-6 alkoxy-carbonyl group,(2) a C1-6 alkyl-carbonyl group optionally substituted by 1 to 3 hydroxy groups,(3) a mono- or di-Ci-6 alkyl-carbamoyl group,(4) a N-Ci-6 alkyl-N-Ci-6 alkoxy-carbamoyl group,(5) a C3-6 cycloalkyl-carbonyl group (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group may be a bridged ring group) optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms,(c) a hydroxy group,(d) a Ci-6 alkoxy group, and(e) a cyano group,(6) an oxetanylcarbonyl group,(7) an azetidinylcarbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom, and(b) a Ci-6 alkyl group, or(8) a 5-azaspiro[2.3]hexylcarbonyl group;R4and R5are both hydrogen atoms;Ring A is(1) a pyrrolidine ring, or(2) a piperidine ring; andRing B is(1) a benzene ring further substituted by one phenyl group optionally substituted by 1 to 3 substituents selected from(i) a halogen atom, and(ii) a Ci-6 alkyl group, and optionally further substituted by one halogen atom,(2) a pyridine ring further substituted by one phenyl group optionally substituted by 1 to 3 halogen atoms,(3) a thiazole ring further substituted by one phenyl group optionally substituted by 1 to 3 halogen atoms, or(4) a piperidine ring further substituted by one phenyl group; or a pharmaceutically acceptable salt thereof.

[0216] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist is N- ((2S,3S)-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3- yl)methyl)pyrrolidin-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0217] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist is N- ((2S,3S)-2-( (2,3'-difluorobiphenyl-3-yl)methyl)-l-(2-hydroxy-2- methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0218] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (III):R1is(1) a Ci-6 alkyl group,(2) a mono- or di-Ci-6 alkylamino group, or(3) a C3-6 cycloalkyl group;R2is(1) a hydrogen atom,(2) a fluorine atom, or(3) a C1-6 alkyl group;R3is(1) a C1-6 alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group, and(c) a cyano group,(2) a C1-6 alkoxy-carbonyl group,(3) a C3-10 cycloalkyl-carbonyl group (the C3-10 cycloalkyl moiety of the C3-10 cycloalkylcarbonyl group is optionally bridged) optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group,(c) a cyano group, and(d) a C1-6 alkyl group,(4) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group, and(c) a C1-6 alkyl group,(5) a mono- or di-Ci-6 alkyl-carbamoyl group, or(6) a N-C1-6 alkyl-N-Ci-6 alkoxy-carbamoyl group; andRing A is(1) a benzene ring optionally substituted by one substituent selected from(a) a Ce-14 aryl group optionally substituted by 1 to 3 substituents selected from(i) a halogen atom,(ii) an optionally halogenated C1-6 alkyl group, and(iii) an optionally halogenated C1-6 alkoxy group, and(b) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from(i) a C1-6 alkyl group, and(ii) a C1-6 alkoxy group, and optionally further substituted by 1 to 3 halogen atoms, or(2) a 5- or 6-membered aromatic heterocycle further substituted by one Ce-14 aryl group optionally substituted by 1 to 3 halogen atoms; or a pharmaceutically acceptable salt thereof.

[0219] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist is N- {(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0220] In some aspects, at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist is N- ((2S,3R)-4,4-difhioro-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluoro-[l,r- biphenyl]-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0221] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are each independently selected from N'-{(2S,3R,4S)-l-(azetidine-l-carbonyl)-4-fluoro-2-[(2-fluoro-3 methyl[l,l'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethyl sulfuric diamide; N- [(2S,3R)-2-[(2,3'-difhioro[l,l'-biphenyl]-3-yl)methyl]-4,4-difhioro-l-(2- methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-(2- hydroxy-2-methylpropanoyl)-2-[(2, 3 ',5 '-tri fluorofl, l'-biphenyl]-3-yl)methyl]pyrrolidin-3- yl] ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2- [(2, 3', 5 '-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl (methanesulfonamide; N- {(2S, 3R)-l-(bicyclo[l. l.l]pentane-l-carbonyl)-4,4-difluoro-2-[(2, 3 ', 5'-tri fluorofl, 1'- biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide; N-{(2S,3R)-1- (cyclopropanecarbonyl)-4,4-difhioro-2-[(2, 3 ', 5'-tri fluorofl, l'-biphenyl]-3- yl)methyl]pyrrolidin-3-yl} ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-((lS,3R)-3- fluorocyclobutane- 1 -carbonyl)-2-[(2,3 ', 5 '-trifluorof 1 , 1 '-biphenyl]-3 -yl)methyl]pyrrolidin- 3 -yl] ethanesulfonamide; N-{(2S,3R)-4,4-difhioro-l-((lS,3R)-3-fluorocyclobutane-l- carbonyl)-2-[(2, 3 ',5 '-tri fluorofl, l'-biphenyl]-3-yl)methyl]pyrrolidin-3- yl (methanesulfonamide; N'- { (2S,3R)- 1 -(azetidine- 1 -carbonyl)-4,4-difluoro-2-[(2-fluoro- 3'-methyl[l,l'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl(-N,N-dimethylsulfuric diamide; or a pharmaceutically acceptable salt thereof.

[0222] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (IV):whereinR1is a Ci-6 alkyl group, a C3-10 cycloalkyl group, or a mono-Ci-6 alkylamino group; r is 0 or 1;R2and R3are each independently a hydrogen atom, or when r is 0, then R2and R3may be taken together with each other to form a bond;R4is a hydrogen atom;R5is a phenyl group optionally substituted by 1 to 3 halogen atoms;R6and R7are each independently a hydrogen atom, or a halogen atom;X5is CH or N; andR12and R13are each independently a hydrogen atom, a C1-6 alkyl group, or a halogen atom; or a pharmaceutically acceptable salt thereof.

[0223] In some aspects, R1is a C1-6 alkyl group; r is 0 or 1;R2and R3are each a hydrogen atom, or when r is 0, then R2and R3may be taken together with each other to form a bond;R4is a hydrogen atom;R5is a phenyl group substituted by 1 to 3 halogen atoms;R6and R7are each a halogen atom;X5is CH; andR12and R13are each independently a hydrogen atom, or a halogen atom; or a pharmaceutically acceptable salt thereof.

[0224] In some aspects, the compound of formula IV is selected from the group consisting of: N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-l,2-benzoxazol-3-yl]-3-oxohexahydro-lH- pyrrolo[ 1 ,2-c]imidazol-6-yl } ethanesulfonamide;N-{(6R)-7, 7-difluoro-3-oxo-2-[4-(2, 4, 6-tri fluorophenyl)- l,2-benzoxazol-3-yl]-2, 5,6,7- tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]hexahydro-lH-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide;N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-l,2-benzoxazol-3-yl]-3-oxohexahydro- lH-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide;N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]hexahydro-lH-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3-yl]-3-oxo-2.5.6.7-tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3-yl]-3- oxohexahydro-lH-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(4aR,6R)-5,5-difluoro-l-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]octahydropyrrolo[l,2-c]pyrimidin-6-yl}methanesulfonamide;N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3-yl]-5,5-difluoro- l-oxooctahydropyrrolo[l,2-c]pyrimidin-6-yl}methanesulfonamide;N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-l,2-benzoxazol-3-yl]-5,5-difluoro-l- oxooctahydropyrrolo[l,2-c]pyrimidin-6-yl}methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-l,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2.5.6.7-tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide; or a pharmaceutically acceptable salt thereof.

[0225] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist is N-((2S,3S)-l-(2- hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3- yl)methanesulfonamide and pharmaceutically acceptable salts and hydrates thereof (also referred to as Compound A herein). Compound A is described in WO 2019 / 027058.

[0226] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist is methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylate and pharmaceutically acceptable salts and hydrates thereof (also referred to as Compound B or danavorexton herein). Compound B is described in WO2017 / 135306.

[0227] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist is N-((2S,3S)-2-((2,3'- difluorobiphenyl-3-yl)methyl)-l-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3- yl)ethanesulfonamide and pharmaceutically acceptable salts and hydrates thereof (also referred to as Compound C herein). Compound C is described in WO 2019 / 027058.

[0228] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist is N-{(2S,3R)-4,4- difluoro- 1 -(2-hydroxy-2-methylpropanoyl)-2-[(2,3 ', 5'-trifluoro[ 1 , 1 '-biphenyl]-3 - yl)methyl]pyrrolidin-3-yl}methanesulfonamide and pharmaceutically acceptable salts and hydrates thereof (also referred to as Compound D herein). Compound D is described in W02020 / 158958

[0229] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist are selected from JZP441 / DSP-0187, ALKS2680, and E2086.

[0230] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist include compounds disclosed in PCT Published Appl. No. W02021 / 107023, which is fully incorporated by reference herein, and include the following compounds and their pharmaceutically acceptable salts and hydrates: 4-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-N-{(lR,6S)-2,2- difluoro-6-[4-(propan-2-yl)piperazin- 1 -yl]cyclohexyl } -4-m ethylpiperidine- 1 - carboxamide represented by the following formula (I):N-{(lR,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-l-yl]cyclohexyl}-4-{5-[(lS,2S)-2- fluorocy cl opropyl]-l, 2, 4-oxadiazol-3-yl}-4-methylpiperi dine- 1 -carboxamide represented by the following formula (II):

[0231] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist include compounds disclosed in PCT Published Appl. No. W02022 / 014680, which is fully incorporated by reference herein, and include the following compounds and their pharmaceutically acceptable salts and hydrates: (R)-2-cyclopropyl-2-((lR,3S,5S)-3-((3S,4R)-l-(5- fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide represented by the following formula (III):(III),(also referred to as Compound F herein);(R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl)-8- azabicyclo[3.2.1]octan-8-yl)-3-methylbutaneamide represented by the following formula (IV):(IV);(R)-2-((lR,3R,5S)-3-((3S,4R)-l-(5-chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8- azabicyclo[3.2.1]octan-8-yl)-2-cyclopropylacetamide represented by the following formula (V):(R)-2-cyclopropyl-2-((lR,3S,5S)-3-((2S, 4S)-l-(5-fluoropyrimidin-2-yl)-2- methylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)acetamide represented by the following formula (VI):

[0232] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist include compounds disclosed in PCT Published Appl. Nos. W02020 / 167701, W02020 / 167706, WO2021 / 026047, W02022 / 040070, W02022 / 040058, W02022 / 109117, WO 2022119888, WO 2022 / 132696 and WO 2022094012, which are fully incorporated by reference herein.

[0233] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist include compounds disclosed in PCT Published Appl. No. WO2022 / 051583 and No. WO2022 / 051596, which are fully incorporated by reference herein.

[0234] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist include compounds disclosed in PCT Published Appl. No. WO2021 / 108628, which is fully incorporated by reference herein, and include the following compounds and their pharmaceutically acceptable salts and hydrates thereof represented by Formula I-A:wherein: ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; n is 1, 2, or 3;T is CR1R2 or O;W is CR4R5 or O;U is CR6R7;X is CR8R9;V is CR3or N;Y is NR10, O or absent;Z is (CRi2Ri3)m;R is halogen or deuterium; p is 0, 1, 2, 3, or 4; and m is 1, 2, 3, or 4;Ri, R2, R4, and Rs are each, independently, selected from the group consisting of H, halogen, and deuterium; or, alternatively, R2 and Rs together with the carbon atoms to which they are attached, form a single bond;R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano; or, alternatively, R3 and Ri, together with the carbon atoms to which they are attached, form a Cs-Cscycloalkyl; or, alternatively, R3 and R4, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;Re, R7, Rs, R9, and R11 are each, independently, selected from the group consisting of H, halogen, and deuterium;Rio is selected from the group consisting of H, unsubstituted Ci-Csalkyl, and Ci- Csalkyl substituted with one or more halogen atoms; and each R12 and R13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted Ci-C3alkyl, and Cl-C3alkyl substituted with one or more halogen atoms; andR12 and R13 are, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted Ci-C3alkyl, and Ci-C3alkyl substituted with one or more halogen atoms.

[0235] In some aspects, the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and / or the third orexin type 2 receptor agonist include compounds disclosed in W02019 / 027058 including N-((21S,24S,52R,53S)-6-oxo-3,8-dioxa-l(2,3)- pyrazina-5(2,l)-piperidina-2(l,4)-cyclohexanacyclooctaphane-53-yl)methanesulfonamide represented by the following formula (VII):or a pharmaceutically acceptable salt thereof (also referred to as Compound E herein); and N-((21S,24S,52R,53S)-6-oxo-3,8-dioxa-5(2,l)-piperidina-l(l,2)-benzena-2(l,4)- cyclohexanacyclooctaphane-53-yl)methanesulfonamide represented by the following formula (VIII):or a pharmaceutically acceptable salt or hydrate thereof.

[0236] The 0X2R agonists may exist as a pharmaceutically acceptable salt. Examples of such salts include a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid and the like. Examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, ammonium salt and the like. Examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], tertbutylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N- dibenzylethylenediamine and the like. Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like. Examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. Examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

[0237] The OX2R agonists may exist as a hydrate or a non-hydrate, or a non-solvate (e.g., anhydride), or a solvate (e.g., hydrate).

[0238] Furthermore, the OX2R agonists may exist as a pharmaceutically acceptable cocrystal or cocrystal salt. The cocrystal or cocrystal salt means a crystalline substance constituted with two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability). The cocrystal or cocrystal salt may be produced by known methods.PHARMACEUTICAL COMPOSITIONS, DOSAGE FORMS AND DELIVERY DEVICES

[0239] The pharmaceutical compositions disclosed herein comprise pharmaceutically acceptable carriers. As pharmaceutically acceptable carriers, various organic or inorganic carrier substances conventionally used as preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations; and the like; and preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary.

[0240] Examples of the dosage forms of the aforementioned pharmaceutical compositions include tablet (including sugar-coated tablet, film-coated tablet, orally disintegrating tablet), capsule (including soft capsule, microcapsule), granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films), injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), microparticles for subcutaneous injection, external preparation (e.g., dermal preparation, ointment), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like, which can be respectively safely administered orally or non-orally (e.g., topical, rectal, intravenous administration). These preparations may be a release control preparation such as an immediate-release preparation, a sustained-release preparation and the like.

[0241] In some aspects, the pharmaceutical composition is formulated for oral administration. In some aspects, the pharmaceutical composition is formulated for nonoral administration. In some aspects, the pharmaceutical composition is formulated for intravenous administration, subcutaneous administration, transdermal administration, intradermal administration or transmucosal administration. In some aspects, the pharmaceutical composition is formulated for intravenous administration. In some aspects, the pharmaceutical composition is formulated for subcutaneous administration. In some aspects, the pharmaceutical composition is formulated for transdermal administration.SUSTAINED RELEASE FORMULATION

[0242] In one aspect, a pharmaceutical composition comprises (a) a first orexin type 2 receptor (OX2R) agonist; and (b) one or more pharmaceutically acceptable carriers that are capable of providing a sustained release of the OX2R agonist at or below the maximum non-awakening plasma concentration.

[0243] In some embodiments, the pharmaceutical composition provides an average plasma concentration of the first OX2R agonist after administration of about 0.01 ng / mL to about 1 mg / mL, about 0.03 ng / mL to about 300 ng / mL, about 0.05 ng / mL to about 100 ng / mL, about 0.08 ng / mL to about 50 ng / mL, or about 1 ng / mL to about 30 ng / mL.

[0244] In one aspect, a pharmaceutical composition comprises (a) a second or third orexin type 2 receptor (OX2R) agonist; and (b) one or more pharmaceutically acceptable carriers that are capable of providing a release of the OX2R agonist at or above a wakepromoting plasma concentration.

[0245] In some embodiments, the pharmaceutical composition provides an average plasma concentration of the second and / or third OX2R agonist after administration of about 300 ng / mL to about 3 mg / mL, about 300 ng / mL to about 2 mg / mL, or about 300 ng / mL to about 1 mg / mL.EXAMPLES

[0246] The following non-limiting examples provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the compositions, and assay, screening, and therapeutic methods of the invention, and are not intended to limit the scope of what the inventors regard as their invention.Materials and Methods

[0247] Animals: Orexin-tTA mice with a C57BL / 6J genetic background were obtained from Nagoya University. Orexin-tTA mice were crossed with TetO diphtheria toxin A (DTA) mice (B6.Cg-Tg(tetO-DTA)lGfi / J, The Jackson Laboratory, Bar Harbor, ME, USA) to generate orexin-tTA; TetO DTA (OX DTA) mice (Tabuchi, et al., J. Neurosci 34: 6495-6509 (2014)). In OX DTA mice, degeneration of orexin neurons by DTA expression occurs in the absence of doxycycline (DOX). OX DTA mice and NonTg micewere fed DOX-containing chow (5TP7, Japan SLC, Inc., Shizuoka, Japan) until 6 weeks of age, and then DOX was removed from the chow (CE-2, CLEA Japan Inc.). Male mice were used. All mice were housed under laboratory conditions (12 h light / dark cycles) with food and water available ad libitum. The care and the use of the animals and the experimental protocols were approved by the Institutional Animal Care and Use Committee of Takeda Pharmaceutical Company, Ltd. (Japan).

[0248] Compounds: Compound A was synthesized by Takeda Pharmaceutical Company, Ltd. Compounds were suspended in 0.5% (w / v) methylcellulose (MC) in distilled water (Fujifilm Wako Pure Chemical Co., Osaka, Japan) for oral administration (p.o.) at a volume of 10 mL / kg of body weight for mice. For subcutaneous administration by mini- osmotic pump (Alzet model 2002, Muromachi), Compound A was dissolved in 40% Captisol / 0.1% Polysorbate 80 in distilled water. Compound A is N-((2S,3S)-l-(2- hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3- yl)methanesulfonamide.

[0249] Electroencephalogram / electromyogram (EEG / EMG) surgery, data acquisition, and vigilance state determination in mice: Surgeries were performed under anesthesia (pentobarbital sodium (50 mg / kg, i.p., Somnopentyl®, Kyoritsu Seiyaku, Tokyo, Japan) or 0.3 mg / kg medetomidine, 4 mg / kg midazolam, 5 mg / kg butorphanol in saline) using stereotaxic apparatus (Kopf Instruments, Tujunga, CA, USA). Implantation of electroencephalogram / electromyogram (EEG / EMG) electrodes and EEGZEMG recordings were performed as described previously (Yukitake, et al., Pharmacol Biochem Behav 187: 172794 (2019)). Briefly, to record EEG, two stainless steel screw electrodes (Biotex, Kyoto, Japan) were implanted epidurally into the cortex (1.0 mm anterior to the bregma and 1.5 mm lateral to the midline, 1.0 mm anterior to the lambda and 1.5 mm lateral to the midline) using coordinates from the atlas of Paxinos and Franklin (Franklin K.B.J., P. G. The Mouse Brain in Stereotaxic Coordinates. Academic Press Third Edition. U.S.A (2007)). To record EMG, stainless steel wire electrodes (Biotex, Kyoto, Japan) were implanted bilaterally into the dorsal neck muscle. Atipamezole (3 mg / kg in saline) was administered after surgery to induce rapid recovery from the anesthesia. After at least a 1-week recovery period in home cages, mice were placed in the EEG / EMG recording chambers and were connected with recording cables. EEG / EMG signals were amplified, filtered (EEG, 0.5-100 Hz; EMG, 16-200 Hz), digitized at a sampling rate of 128 - 200Hz, and recorded using VitalRecorder (Kissei Comtec Co, Ltd, Nagano, Japan). Locomotor activity was measured by an infrared activity sensor (Biotex, Kyoto, Japan). SleepSign (Kissei Comtec, Nagano, Japan) was used to classify sleep / wakefulness states in 4-sec epochs as wakefulness, non-rapid eye movement (NREM) sleep, or REM sleep according to the standard criteria, and to calculate the total time, episode number or duration under each state. Each stage was characterized as follows: (1) wakefulness, low- amplitude EEG and high-voltage EMG activities or locomotion score; (2) NREM sleep, high-amplitude slow EEG and low-voltage EMG activities; and (3) REM sleep, theta- dominated EEG and EMG atonia. Wakefulness or sleep fragmentations were determined by total number and mean duration of wakefulness / sleep episodes.

[0250] Evaluation of sleep / wakefulness states: Evaluation of drug efficacy by acute oral administration on sleep / wakefulness states in mice was conducted with a cross-over design. Compounds were administered to mice at zeitgeber time (ZT) 5 (start of the lights-on period is ZT 0) for sleep phase study, and at ZT 12 for active phase study, and then EEG / EMG were recorded. Effect of subcutaneous administration of drugs by mini- osmotic pump on sleep / wakefulness states in mice was evaluated by 24 h recording without disturbance by the experimenter.

[0251] Evaluation of cataplexy-like episodes in mice: Transitions from wakefulness to REM sleep is regarded as a murine analog of human cataplexy (thereafter called cataplexy-like episodes) (Scammell, T.E., et al., Sleep 32: 111-116 (2009)). Cataplexylike episodes were analyzed as described previously (Scammell, T.E., etal., Sleep 32: 111-116 (2009)). Episodes were defined according to the following criteria: an abrupt episode of EMG atonia lasting for more than 20 s, lack of locomotor activity, predominance of theta EEG activity, and wakefulness lasting for more than 40 s before the episode.

[0252] Chronic dosing studies in mice: The baseline sleep / wakefulness states were recorded 1 - 3 days before the chronic dosing commenced. Mice were orally administered with vehicle or Compound A twice a day at 3 h intervals. Drug administration during the active phase was conducted under red light. The first day of administration was assigned day 1 in all studies. For low-flat exposure studies, mini-osmotic pumps (Model: 2002) were filled with vehicle (40% modified beta cyclodextrin (Formula C) / 0.1% Polysorbate 80 in distilled water) or Compound A solubilized in vehicle at 7.5 and 17.5 mg / mL toachieve plasma concentration of around 90 and 320 ng / mL, respectively. Pumps were primed in sterile 0.9% saline at 37 degrees for around 40 h before implantation. Pumps were subcutaneously implanted from a small incision made in the skin behind the neck of mice under anesthesia by isoflurane. Plasma samples for pharmacokinetic analysis were obtained from a different cohort of littermate mice from the study cohort for EEGZEMG recordings after the chronic treatment under the same conditions.

[0253] Measurement of plasma concentration of compounds: Compounds were orally administered to mice. Blood samples from the tail vein were collected at indicated timepoints with a heparinized Pasteur pipette. Plasma was separated from the blood samples by centrifugation. The concentrations of Compound A in the plasma were determined using liquid chromatography / tandem mass spectrometry (LC-MS / MS).

[0254] Statistical analysis: Statistical analysis was performed using EXSUS (EP Croit Company Limited, Tokyo, Japan). The pairwise differences between groups were identified using a two-tailed Student’s t-test or Aspin-Welch’s test. In experiments with multiple doses of test compounds, the statistical differences were analyzed using a two- tailed Williams test or a two-tailed Shirley-Williams test. Dunnett’s multiple comparison test was used for comparison between three groups. All data were presented as the mean ± standard deviation (S.D.) or mean ± standard error of the mean (S.E.M.).EXAMPLE 1 : NT1 model mice show elevated sensitivity to wake-promoting effects of Compound A compared with Non-Tg mice

[0255] Compound A is an orally available OX2R selective agonist with >700-fold selectivity for OX2R over OX1R (Ishikawa et. al. (2023) J. Pharmacol Exp Ther 385: 193-204). In an NT1 mouse model, OX-tTA / TetO-DTA (OX DTA) mice, oral administration of Compound A at 3 mg / kg and above induced significant wakepromoting effects during the active phase for 2 h after administration at zeitgeber time (ZT) 12 (FIG. 1). The duration of analysis was determined based on the plasma mean residence time of around 2 h at the lowest dose tested (1 mg / kg) in OX DTA mice (Ishikawa et. al. (2023) J. Pharmacol Exp Ther 385: 193-204). Compound A at 3 mg / kg and above also suppressed the number of cataplexy-like episodes in OX DTA. In NonTg mice, the wake-promoting effect emerged from 10 mg / kg (FIG. 1), suggesting that OXDTA mice has around 3 -fold higher sensitivity to the wake-promoting effects of Compound A compared with NonTg mice.EXAMPLE 2: Analysis of chronic exposure with Compound A on NT1 symptoms in OX DTA mice (Chronic Dosing Study 2)

[0256] Next, chronic exposure with Compound A was looked at to see whether it can normalize the NT1 symptoms in OX DTA mice (Chronic Dosing Study 2). Low-flat exposure of Compound A was designed at non-awakening exposures during the sleep phase. Oral administration of Compound A to OX DTA mice at ZT 5 during the sleep phase did not significantly increase the wakefulness time below 1 mg / kg, when the maximum plasma concentration reached 371.6 ng / mL (FIG. 4A and 4B). Thus, low-flat exposure was designed to maintain plasma concentrations at around 90 ng / mL or 320 ng / mL (one-fourth or near threshold non-awakening plasma concentrations, respectively) for 14 days (FIG. 2A). These doses were equivalent to around 10 and 30% of the potent wake-promoting plasma exposure to maintain over 75% wakefulness in 10-min bins (FIGs. 4A and 4B). Treatment of OX DTA mice with low-flat exposure of Compound A under these conditions for 14 days significantly ameliorated wakefulness fragmentation, as assessed by decreased episode number and increased episode duration of wakefulness and by decreased cataplexy-like symptoms during the active phase, and ameliorated NREM sleep fragmentation, as assessed by decreased episode number and increased episode duration of NREM sleep, and by the decrease in the number of direct-REM transitions from wakefulness (DREM) episodes during the sleep phase relative to the vehicle-treated OX DTA mice (FIG. 2B). These effects emerged time-dependently with comparable efficacy at one-fourth and threshold non-awakening exposure levels. These data suggest that the effect of low-flat exposure of Compound A emerges through normalization of possible neuroplastic changes associated with orexin neuron loss.EXAMPLE 3 : Chronic exposure to Compound A can alter the sensitivity of OX DTA mice to wake-promoting effect of Compound A

[0257] Experiments were performed to test the effects of low-flat exposure of Compound A in normalizing (i.e. reduce) the sensitivity to its wake-promoting effects within the same time window of 2 weeks. OX DTA mice were administered with low-flat exposureof Compound A at plasma exposure of around 320 ng / mL in combination with oral administration of Compound A (3 mg / kg, at ZT 12 and 15) for 14 days (Chronic Dosing Study 4) (FIG. 3 A). Daytime administration commenced on day 4 after the start of low- flat exposure. On day 15, the dose at ZT 15 was increased to 10 mg / kg, which is the minimum awakening dose during the active phase in NonTg mice (FIG. 1), to examine the wake-promoting effect of Compound A at the wake-promoting dosage of NonTg mice after chronic exposure. At baseline before drug treatment and on day 4, Compound A at 3 mg / kg significantly increased the wakefulness time for 2 h after administration after the first and second dosages (FIGs. 3B and 5 A). The wake-promoting effect of Compound A after the first and second administrations at baseline and on day 4 were comparable, suggesting no change in the sensitivity to the wake-promoting effect of Compound A up to day 4. However, by day 14, the wake-promoting effects of Compound A were abolished after the first and second administrations (FIG. 3B), although the plasma exposures of Compound A were comparable between day 4 and 14 (FIG. 5B). On day 15, Compound A at 3 mg / kg during the first administration did not increase the wakefulness time, however, Compound A at 10 mg / kg during the second administration significantly increased the wakefulness time (FIG. 3B). These results suggest that chronic exposure of Compound A can reduce the sensitivity to wake-promoting effects of Compound A in OX DTA mice, possibly to a similar level as in NonTg mice. Importantly, Compound A at 3 mg / kg significantly suppressed the number of cataplexy-like episodes on both days 4 and 14 (FIG. 5C), suggesting that the diminished wake-promoting effect of Compound A after chronic administration is not likely due to desensitization of the OX2R.EXAMPLE 4: The wake-promoting effect of Compound A in OX DTA mice is comparable to that in NonTg mice after chronic exposure

[0258] To study in detail the wake-promoting potential of Compound A after chronic low-flat exposure in OX DTA mice, OX DTA mice were treated with low-flat exposure of Compound A at plasma exposure of around 320 ng / mL in combination with Compound A (30 mg / kg) at ZT 12 and 15 for 14 days (Chronic Dosing Study 5) (FIG. 3C). Daytime administration commenced on day 4 after the start of low-flat exposure. The plasma exposure of Compound A were comparable between day 4 and 14 (FIG. 6A). At baseline before drug treatment and on day 4, Compound A at 30 mg / kg significantlyincreased the wakefulness time for 2 h after administration after the first and second dosages with comparable efficacy (FIGs. 3D and 6B). The wakefulness time for 2 h after the first and second administration of Compound A (30 mg / kg) declined from day 4 to day 10; however, it was comparable on day 10 and 14 (FIG. 3D). The wake-promoting effect of Compound A on day 14 in OX DTA mice was comparable to that in NonTg mice after acute administration of Compound A (30 mg / kg), with maintenance of >75% wakefulness time in 10-min bins after administration up to 120 and 130 min after the first administration and 90 and 100 min after the second administration in NonTg and OX DTA mice, respectively (FIG. 6C). These results suggest that the reduction in the sensitivity to the wake-promoting effects of Compound A in OX DTA mice reaches a plateau after 10 days of chronic administration, and become comparable to that in NonTg mice after chronic administration.EXAMPLE 5: Formulation of a sustained release formulation of an OX2R agonist

[0259] Microcapsule1) OX2R Agonist 90 mg2) Poly lactic acid- glycolic acid copolymer (PLGA) 210 mg3) Mannitol 52.94 mgTotal 352. 94 mg

[0260] DiluentCarboxymethyl cellulose 5 mg;Polysorbate80 0.3 mg; andMannitol 15 mg; in distilled water 1 mL

[0261] Microcapsule powders comprising of 1), 2), and 3) are formulated using in-water drying method (O / W) as described in W003 / 002092. The total amount of 1) and 2) are dissolved in di chloromethane, then added to an aqueous phase to make an emulsion. Microcapsules are obtained during emulsification and are collected after evaporating dichloromethane. Collected microcapsules are washed and lyophilized with the whole amount of 3) to give rise to microcapsule powders. The obtained microcapsule powders are dispersed in diluent and are administered to rats by subcutaneous administration.EXAMPLE 6: Formulation - Production of Tablet

[0262] 1) OX2R Agonist (e.g., Compound A) 30 g2) lactose 50 g3) cornstarch 15 g4) calcium carboxymethylcellulose 44 g5) magnesium stearate 1 g 1000 tablets 140 g in total

[0263] The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is punched by a tableting machine. In this way, 1000 tablets containing 30 mg of the 0X2R per tablet are obtained.

[0264] All the publications, patents, and the patent applications cited herein are incorporated herein by reference in their entireties.

[0265] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the disclosure. All the various embodiments of the present disclosure will not be described herein. Any modifications and variations of the disclosure can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0266] It is to be understood that the present disclosure is not limited to particular uses, methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0267] 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 therebydescribed in terms of any individual member or subgroup of members of the Markush group.

[0268] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges 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 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 subranges 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 to 3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.

Claims

WHAT IS CLAIMED IS:

1. One or more dosage forms comprising one or more orexin type 2 receptor agonists, for use in treating Narcolepsy Type 1 (NT1) in a human subject, wherein the one or more dosage forms are to be administered in an amount and frequency that provides:1) a wake-promoting blood plasma concentration of orexin type 2 receptor agonist during a portion of waking hours of a twenty-four-hour period, and2) a blood plasma concentration of orexin type 2 receptor agonist at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for the remainder of the twenty-four-hour period; wherein the blood plasma concentration of the orexin type 2 receptor agonist is maintained at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist for a dosing interval of five or more twenty-four-hour periods.

2. A combination for use in treating Narcolepsy Type 1 (NT1) in a human subject, the combination comprising: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the first orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; and a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is administered one or more times during waking hours of each twenty-four- hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject; wherein the first orexin type 2 receptor agonist and the second orexin type 2 receptor agonist may be the same or different and wherein the first dosage form and the second dosage form may be the same or different.

3. The combination for use of claim 2, further comprising a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is administered one or moretimes during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration in the human subject, and wherein the amount and frequency of administration of the second dosage form no longer provides a wake-promoting effect during waking hours of the dosing interval; wherein the third orexin type 2 receptor agonist may be the same as or different than the first and / or second orexin type 2 receptor agonist and wherein the third dosage form may be the same as or different than the first and / or second dosage form.

4. The combination of claim 2, further comprising: determining whether administration of the second dosage form is providing a wakepromoting effect during waking hours of the dosing interval; and if administration of the second dosage form is not providing a wake-promoting effect, then a third dosage form comprising a third orexin type 2 receptor agonist is to be administered one or more times during waking hours of each twenty-four-hour period of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration.

5. A combination for use in treating Narcolepsy Type 1 (NT1), in a human subject, the combination comprising: a first dosage form comprising a first orexin type 2 receptor agonist, wherein the first dosage form is to be administered in an amount and frequency that provides a blood plasma concentration of the first orexin type 2 receptor agonist after administration that is at or below a maximum non-awakening plasma concentration of the orexin type 2 receptor agonist over a dosing interval of a plurality of consecutive twenty-four-hour periods; a second dosage form comprising a second orexin type 2 receptor agonist, wherein the second dosage form is to be administered one or more times during waking hours of each twenty- four-hour period of the dosing interval in an amount and frequency that provides a wakepromoting effect of the second orexin type 2 receptor agonist after administration; and a third dosage form comprising a third orexin type 2 receptor agonist, wherein the third dosage form is to be administered one or more times during waking hours of the dosing interval in an amount and frequency that provides a wake-promoting effect after administration; wherein the first, second and third orexin type 2 receptor agonists may be the same as or different than each other and wherein the first, second and third dosage forms may be the same as or different than each other.

6. The combination of claim 5, further comprising determining whether administration of the second dosage form is providing a wake-promoting effect during waking hours of the dosing interval.

7. The combination of any one of claims 2-6, wherein a blood plasma concentration providing the wake-promoting effect of the third orexin type 2 receptor agonist is higher than a blood plasma concentration providing the wake-promoting effect of the second orexin type 2 receptor agonist.

8. The one or more dosage forms or combination of any one of claims 1-7, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are different compounds.

9. The one or more dosage forms or combination of any one of claims 1-7 wherein at least two of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are the same compound.

10. The combination of any one of claims 2-6, wherein the second orexin type 2 receptor agonist and third orexin type 2 receptor agonist are the same compound, and an increased dose of third orexin type 2 receptor agonist is to be administered to provide a wake-promoting effect.

11. The one or more dosage forms or combination of any one of claims 1-10, wherein the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a half-life of less than 8 hours.

12. The one or more dosage forms or combination of any one of claims 1-10, wherein the second orexin type 2 receptor agonist, the third orexin type 2 receptor agonist, or both, have a half-life of 8 hours or more.

13. The one or more dosage forms or combination of any one of claims 2-12, wherein the dosing interval is 2 or more consecutive 24-hour periods, 7 or more consecutive 24-hour periods, 14 or more consecutive 24-hour periods, 21 or more consecutive 24-hour periods, or 28 or more consecutive 24-hour periods.

14. The one or more dosage forms or combination of any one of claims 1-12, wherein the second dosage form provides a wake-promoting effect during waking hours for at least one 24-hour period, for at least two 24-hour periods, for at least three 24-hour periods, or for at least fourteen 24-hour periods.

15. The one or more dosage forms or combination of any one of claims 1-14, wherein the first dosage form is a sustained release dosage form.

16. The one or more dosage forms or combination of any one of claims 1-15, wherein the first dosage form is formulated for oral administration, intravenous administration, depot administration, or subcutaneous administration.

17. The one or more dosage forms or combination of claim 16, wherein the first dosage form is formulated for subcutaneous administration.

18. The one or more dosage forms or combination of claim 17, wherein the first dosage form comprises an infusion system designed to provide continuous subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

19. The one or more dosage forms or combination of claim 17, wherein the first dosage form comprises microparticles designed to provide sustained subcutaneous delivery of the first orexin type 2 receptor agonist to the human subject.

20. The one or more dosage forms or combination of any one of claims 1-19, wherein the second dosage form and the third dosage form are formulated for oral administration, intravenous administration, depot administration, subcutaneous administration, or a combination thereof.

21. The one or more dosage forms or combination of claim 20, wherein at least one of the second dosage form and the third dosage form is formulated for oral administration.

22. The one or more dosage forms or combination of any one of claims 2-21, wherein the blood plasma concentration of the first orexin type 2 receptor agonist after administration reaches and maintains between about 5 percent to about 100 percent, about 10 percent to about 100 percent, about 15 percent to about 100 percent, about 20 percent to about 100 percent, about 30 percent to about 100 percent, or about 50 percent to about 100 percent of the maximum nonawakening plasma concentration of the first orexin type 2 receptor agonist over the dosing interval.

23. The one or more dosage forms or combination of any one of claims 2-22, wherein the blood plasma concentration of the first orexin type 2 receptor agonist after administration is maintained for at least two weeks, at least four weeks, at least six weeks or at least eight weeks.

24. The one or more dosage forms or combination of any one of claims 1-23, wherein the one or more dosage forms or combination improves one or more daytime symptoms of narcolepsy type 1 selected from fragmented wakefulness, excessive daytime sleepiness (EDS), cataplexy, and anxiety.

25. The one or more dosage forms or combination of any one of claims 1-23, wherein the one or more dosage forms or combination improves one or more nighttime symptoms of narcolepsy type 1 selected from fragmented sleep, sleep paralysis, and hallucinations.

26. The one or more dosage forms or combination of any one of claims 1-23, wherein the one or more dosage forms or combination improves one or more daytime symptoms and one or more nighttime symptoms in human subjects with narcolepsy type 1.

27. The one or more dosage forms or combination of any of claims 1-26, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (I):whereinR1is(1) a hydrogen atom,(2) a Ci-6 alkyl-carbonyl group optionally substituted by 1 to 7 substituents selected from (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) a C3-10 cycloalkyl group, (v) a C1-6 alkoxy group, (vi) a Ce-14 aryl group, (vii) a Ce-14 aryloxy group, (viii) a pyrazolyl group, a thiazolyl group, a pyrimidinyl group or a pyridazinyl group, each of which is optionally substituted by an oxo group, (ix) a pyrazolyloxy group optionally substituted by 1 to 3 C1-6 alkyl groups, (x) a C1-6 alkyl-carbonyl group, (xi) a C1-6 alkoxycarbonyl group, (xii) a C1-6 alkyl-carbonyloxy group, (xiii) a C1-6 alkylsulfonyl group, (xiv) a mono- or di-Ci-6 alkylamino group, (xv) a C1-6 alkyl-carbonylamino group and (xvi) a (C1-6 alkyl)(Ci-6 alkyl-carbonyl)amino group,(3) a C3-10 cycloalkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group, an oxo group and a C1-6 alkyl group,(4) a C1-6 alkoxy-carbonyl group optionally substituted by 1 to 6 substituents selected from deuterium, a halogen atom and a Ce-14 aryl group,(5) a C3-10 cycloalkyloxy-carbonyl group optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group,(6) a Ce-14 aryl-carbonyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ce-14 aryl group,(7) a Ce-14 aryloxy-carbonyl group,(8) a furylcarbonyl group, a thienyl carbonyl group, a pyrazolylcarbonyl group, an isoxazolylcarbonyl group or a pyridylcarbonyl group, each of which is optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group,(9) an azetidinylcarbonyl group, an oxetanyl carbonyl group, a pyrrolidinylcarbonyl group, a tetrahydrofuranylcarbonyl group, a tetrahydropyranylcarbonyl group or a morpholinylcarbonyl group, each of which is optionally substituted by 1 to 3 substituents selected from an oxo group, a C1-6 alkyl-carbonyl group, a C1-6 alkoxy-carbonyl group and a C1-6 alkyl sulfonyl group,(10) a mono- or di-Ci-6 alkyl-carbamoyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group,(11) a mono- or di-C3-io cycloalkyl-carbamoyl group,(12) a mono- or di-Ce-14 aryl-carbamoyl group,(13) a Ci-6 alkylsulfonyl group,(14) a C3-10 cycloalkylsulfonyl group,(15) a Ce-14 arylsulfonyl group optionally substituted by 1 to 3 halogen atoms,(16) a thienylsulfonyl group, a pyrazolyl sulfonyl group, an imidazolylsulfonyl group, a pyridyl sulfonyl group or a dihydrochromenyl sulfonyl group, each of which is optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group,(17) a mono- or di-Ci-6 alkyl-sulfamoyl group or(18) a C1-6 alkyl-carbonyl-carbonyl group;R2is a C3-6 cycloalkyl group, a pyrrolidinyl group, a piperidinyl group or a dioxanyl group, each of which is optionally substituted by 1 to 3 substituents selected from(1) deuterium,(2) a halogen atom,(3) a hydroxy group,(4) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a Ce-14 aryl group,(5) a C3-10 cycloalkyl group,(6) a C1-6 alkoxy group optionally substituted by a C3-10 cycloalkyl group,(7) a Ce-14 aryl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a cyano group, a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms and a hydroxy group,(8) a Ce-14 aryloxy group,(9) a tri-Ci-6 alkylsilyloxy group,(10) a pyrazolyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, a quinazolinyl group, a benzothiazolyl group or an isoquinolinyl group, each of which is optionally substituted by 1 to 3 substituents selected from a halogen atom, a C1-6 alkyl group and a C1-6 alkoxy group, and(11) a Ce-14 aryl-carbonyl group; andR3is a C1-6 alkyl group, or a mono- or di-Ci-6 alkylamino group, or a pharmaceutically acceptable salt thereof.

28. The one or more dosage forms or combination of claim 27, wherein in formula (I):R1is(1) a hydrogen atom,(2) a Ci-6 alkyl-carbonyl group optionally substituted by a hydroxy group,(3) a cyclopropanecarbonyl group,(4) a Ci-6 alkoxy-carbonyl group or(5) a mono- or di-Ci-6 alkyl-carbamoyl group;R2is(A) a cyclohexyl group optionally substituted by 1 to 3 substituents selected from(1) a Ci-6 alkyl group and(2) a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci-6 alkyl group optionally substituted by 1 to 3 halogen atoms and a Ci-6 alkoxy group or(B) a piperidinyl group optionally substituted by 1 to 3 pyrimidinyl groups; andR3is a Ci-6 alkyl group or a di-Ci-6 alkylamino group, or a pharmaceutically acceptable salt thereof.

29. The one or more dosage forms or combination of claim 27, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from Methyl (2R, 3 S)-3 -((methyl sulfony l)amino)-2- (((cis-4-phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate; N-((2R,3 S)-l -glycol oyl-2- (((cis-4-(2,3,6-trifluorophenyl) cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide; and (2R,3S)-N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- 3 -((methyl sulfonyl) amino)piperidine-l -carboxamide; or a pharmaceutically acceptable salt thereof.

30. The one or more dosage forms or combination of claim 29, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl) piperidine- 1 -carboxylate, or a pharmaceutically acceptable salt thereof.

31. The one or more dosage forms or combination of any one of claims 1-27, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from N-((2S,3S)-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide; N-((2S, 3 S)-2-((2,3'-difluorobiphenyl-3-yl)methyl)-l-(2 -hydroxy -2-methylpropanoyl)pyrrolidin- 3-yl)ethanesulfonamide; methyl (2R,3 S)-3 -((methyl sulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-l -carboxylate; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy- 2-methylpropanoyl)-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3- yljmethanesulfonamide; 4-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-N-{(lR,6S)-2,2-difluoro-6-[4- (propan-2-yl)piperazin- 1 -yl]cyclohexyl } -4-methylpiperidine- 1 -carboxamide; N-{(lR,6S)-2,2- difhioro-6-[4-(propan-2-yl)piperazin-l-yl]cyclohexyl}-4-{5-[(lS,2S)-2-fluorocyclopropyl]-l,2,4- oxadiazol-3-yl}-4-methylpiperidine-l-carboxamide; (2R)-2-cyclopropyl-2-{(lR,3S,5S)-3- [(3S,4R)-l-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4-yl]-8-azabicyclo[3.2.1]octan-8- yljacetamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5-fluoropyrimidin-2-yl)-3-methoxypiperidin-4- yl)-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbutaneamide; (R)-2-((lR,3S,5S)-3-((3S,4R)-l-(5- chloropyrimidin-2-yl)-3-ethoxypiperidin-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-cyclopropyl acetamide; (R)-2-cyclopropyl-2-((lR,3S,5S)-3-((2S, 4S)-l-(5-fluoropyrimidin-2-yl)-2- methylpiperidin-4-yl)-8-azabicyclo[3.

2. l]octan-8-yl)acetamide; and N-((21S,24S,52R,53S)-6-oxo- 3,8-dioxa-l(2,3)-pyrazina-5(2,l)-piperidina-2(l,4)-cyclohexanacyclooctaphane-53- yl)methanesulfonamide; or a pharmaceutically acceptable salt thereof.

32. The one or more dosage forms or combination of any one of claims 1-27, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (II):whereinR1is(1) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom, and(b) a Ci-6 alkoxy group,(2) a C3-6 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, or(3) a mono- or di-Ci-6 alkylamino group;R2is a hydrogen atom;R3is(1) a C1-6 alkoxy-carbonyl group,(2) a C1-6 alkyl-carbonyl group optionally substituted by 1 to 3 hydroxy groups,(3) a mono- or di-Ci-6 alkyl-carbamoyl group,(4) a N-Ci-6 alkyl-N-Ci-6 alkoxy-carbamoyl group,(5) a C3-6 cycloalkyl-carbonyl group (the C3-6 cycloalkyl in the C3-6 cycloalkyl-carbonyl group may be a bridged ring group) optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,(c) a hydroxy group,(d) a C1-6 alkoxy group, and(e) a cyano group,(6) an oxetanylcarbonyl group,(7) an azetidinylcarbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom, and(b) a C1-6 alkyl group, or(8) a 5-azaspiro[2.3]hexylcarbonyl group;R4and R5are both hydrogen atoms;Ring A is(1) a pyrrolidine ring, or(2) a piperidine ring; andRing B is(1) a benzene ringfurther substituted by one phenyl group optionally substituted by 1 to 3 substituents selected from(i) a halogen atom, and(ii) a Ci-6 alkyl group, and optionally further substituted by one halogen atom,(2) a pyridine ring further substituted by one phenyl group optionally substituted by 1 to 3 halogen atoms,(3) a thiazole ring further substituted by one phenyl group optionally substituted by 1 to 3 halogen atoms, or(4) a piperidine ring further substituted by one phenyl group; or a pharmaceutically acceptable salt thereof.

33. The one or more dosage forms or combination of claim 32, wherein at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3S)-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'- trifluorobiphenyl-3-yl)methyl)pyrrolidin-3-yl)m ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

34. The one or more dosage forms or combination of claim 32, wherein at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3S)-2-( (2,3'-difluorobiphenyl-3-yl)methyl)-l-(2-hydroxy-2- methylpropanoyl)pyrrolidin-3-yl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

35. The one or more dosage forms or combination of any one of claims 1-27, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (III):R1is(1) a Ci-6 alkyl group,(2) a mono- or di-Ci-6 alkylamino group, or(3) a C3-6 cycloalkyl group;R2is(1) a hydrogen atom,(2) a fluorine atom, or(3) a C1-6 alkyl group;R3is(1) a C1-6 alkyl-carbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group, and(c) a cyano group,(2) a C1-6 alkoxy-carbonyl group,(3) a C3-10 cycloalkyl-carbonyl group (the C3-10 cycloalkyl moiety of the C3-10 cycloalkylcarbonyl group is optionally bridged) optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group,(c) a cyano group, and(d) a C1-6 alkyl group,(4) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group optionally substituted by 1 to 3 substituents selected from(a) a halogen atom,(b) a hydroxy group, and(c) a Ci-6 alkyl group,(5) a mono- or di-Ci-6 alkyl-carbamoyl group, or(6) a N-CI-6 alkyl-N-Ci-6 alkoxy-carbamoyl group; andRing A is(1) a benzene ring optionally substituted by one substituent selected from(a) a Ce-i4 aryl group optionally substituted by 1 to 3 substituents selected from(i) a halogen atom,(ii) an optionally halogenated Ci-6 alkyl group, and(iii) an optionally halogenated Ci-6 alkoxy group, and(b) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from(i) a Ci-6 alkyl group, and(ii) a Ci-6 alkoxy group, and optionally further substituted by 1 to 3 halogen atoms, or(2) a 5- or 6-membered aromatic heterocycle further substituted by one Ce-14 aryl group optionally substituted by 1 to 3 halogen atoms; or a pharmaceutically acceptable salt thereof.

36. The one or more dosage forms or combination of claim 35, wherein at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-{(2S,3R)-4,4-difhioro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'- trifluoro[l,T-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

37. The one or more dosage forms or combination of claim 35, wherein at least one of the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist is N-((2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-((2,3',5'-trifluoro-[l,r-biphenyl]-3-yl)methyl)pyrrolidin-3-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

38. The one or more dosage forms or combination of claim 35, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from N'-{(2S,3R,4S)-l-(azetidine-l-carbonyl)-4-fluoro-2-[(2-fluoro-3 methylfl, 1 '-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethyl sulfuric diamide; N-[(2S,3R)-2-[(2,3'-difhioro[l,l'-biphenyl]-3-yl)methyl]-4,4-difhioro-l-(2- methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2- methylpropanoyl)-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3- yl} ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'- trifhioro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide; N-{(2S,3R)-1- (bicyclofl .

1. l]pentane-l-carbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[l, 1 '-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}methanesulfonamide; N-{(2S,3R)-l-(cyclopropanecarbonyl)-4,4- difluoro-2-[(2,3',5'-trifluoro[l,r-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide; N- {(2S,3R)-4,4-difluoro-l-((lS,3R)-3-fluorocyclobutane-l-carbonyl)-2-[(2,3',5'-trifluoro[l,r- biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide; N-{(2S,3R)-4,4-difluoro-l-((lS,3R)-3-fhiorocyclobutane-l-carbonyl)-2-[(2,3(5'-trifhioro[l,T-biphenyl]-3-yl)methyl]pyrrolidin-3- yljmethanesulfonamide; N'-{(2S,3R)-l-(azetidine-l-carbonyl)-4,4-difluoro-2-[(2-fluoro-3'- methyl[l,l'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric diamide; or a pharmaceutically acceptable salt thereof.

39. The one or more dosage forms or combination of any one of claims 1-27, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are each independently selected from compounds represented by the formula (IV):whereinR1is a Ci-6 alkyl group, a C3-10 cycloalkyl group, or a mono-Ci-6 alkylamino group; r is 0 or 1;R2and R3are each independently a hydrogen atom, or when r is 0, then R2and R3may be taken together with each other to form a bond;R4is a hydrogen atom;R5is a phenyl group optionally substituted by 1 to 3 halogen atoms;R6and R7are each independently a hydrogen atom, or a halogen atom;X5is CH or N; andR12and R13are each independently a hydrogen atom, a C1-6 alkyl group, or a halogen atom; or a pharmaceutically acceptable salt thereof.

40. The one or more dosage forms or combination of claim 39, whereinR1is a C1-6 alkyl group; r is 0 or 1;R2and R3are each a hydrogen atom, or when r is 0, then R2and R3may be taken together with each other to form a bond;R4is a hydrogen atom;R5is a phenyl group substituted by 1 to 3 halogen atoms;R6and R7are each a halogen atom;X5is CH; andR12and R13are each independently a hydrogen atom, or a halogen atom; or a pharmaceutically acceptable salt thereof.

41. The one or more dosage forms or combination of claim 39, wherein the first orexin type 2 receptor agonist, the second orexin type 2 receptor agonist, and the third orexin type 2 receptor agonist are selected from:N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-l,2-benzoxazol-3-yl]-3-oxohexahydro-lH- pyrrolof 1 ,2-c]imidazol-6-yl } ethanesulfonamide;N-{(6R)-7, 7-difluoro-3 -oxo-2- [4-(2, 4, 6-tri fluorophenyl)- l,2-benzoxazol-3-yl]-2, 5,6,7- tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]hexahydro-lH-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide;N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-l,2-benzoxazol-3-yl]-3-oxohexahydro- lH-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide;N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]hexahydro-lH-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3-yl]-3-oxo-2.5.6.7-tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}methanesulfonamide;N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3-yl]-3- oxohexahydro- lH-pyrrolo[ 1 ,2-c]imidazol-6-yl Jmethanesulfonamide;N-{(4aR,6R)-5,5-difluoro-l-oxo-2-[4-(2,4,6-trifluorophenyl)-l,2-benzoxazol-3- yl]octahydropyrrolo[l,2-c]pyrimidin-6-yl}methanesulfonamide;N-{(4aR, 6R)-2-[5,6-difluoro-4-(2, 4, 6-tri fluorophenyl)- 1, 2-benzoxazol-3-yl]-5, 5-difluoro- 1 -oxooctahydropyrrolof 1 ,2-c]pyrimidin-6-yl } methanesulfonamide;N-{(4aR,6R)-2-[4-(2,6-difhiorophenyl)-5-fluoro-l,2-benzoxazol-3-yl]-5,5-difluoro-l- oxooctahydropyrrolof 1 ,2-c]pyrimidin-6-yl } methanesulfonamide; andN-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-l,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2.5.6.7-tetrahydro-3H-pyrrolo[l,2-c]imidazol-6-yl}ethanesulfonamide; or a pharmaceutically acceptable salt thereof.

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