Sunobinop for use in method of treating alcohol use disorder

Abstract

This disclosure relates to methods for treating alcohol use disorder by administering to a human subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the compound is a compound of formula (II), (IIA), (IIB), or (IIC), or a solvate thereof, and is administered in a dose of from about 0.10 mg to about 10.0 mg. The disclosure also provides methods of preventing relapse to alcohol drinking, for reducing alcohol consumption, for decreasing alcohol craving, for maintenance of alcohol abstinence, for treating or preventing withdrawal from alcohol consumption, treating alcohol-related sleep disorder, and / or for reducing stress or anxiety level in a human subject.

Description

METHOD OF TREATING ALCOHOL USE DISORDERBACKGROUND

[0001] Alcohol use disorder (AUD) is a medical condition characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences and represent an enormous public health concern in the United States [DSM-5], Alcohol addiction is a chronic relapsing disorder described to be a repeating three-stage cycle of intoxication / binge, withdrawal / negative affect, and preoccupation / craving [NIAAH 2021], It is postulated that alcohol intoxication may disturb sleep and the consequent sleep disturbance may drive further drinking; that alcohol withdrawal may disturb sleep and may be trigger for drinking to provide relief from insomnia; and that during alcohol preoccupation, sleep disruption may contribute to relapse to drinking, particularly when paired with stress and / or alcohol -related cues [Koob 2020],

[0002] There are currently only a limited number of methods for treating AUD outside of rehabilitation therapy which can be costly and very public. Also, although there are a few FDA-approved pharmacologic treatments for AUD (such as, disulfiram, naltrexone, and acamprosate), these pharmacologic treatments, however, are associated with adverse events and thus come with precautions and limitations. For example, such precautions and limitations for naltrexone include: before using the injection formulation a patient must be opioid free for 7-10 days; monitoring of liver function is recommended; and it may produce severe opioid withdrawal symptoms if a patient is currently taking opioids; and monitoring liver function is recommended as it is associated with elevations in liver enzymes.

[0003] Further, AUD is known to cause dysfunction in motivational, mood-stress regulation and sleep systems that interact in complex ways to heighten the risk of relapse during abstinence. Emerging data suggest that excessive and chronic alcohol use disrupts sleep homeostasis and, in abstinence, subjects with AUD experience insomnia that may persist for weeks to years (Roehrs et al., Neuropsychopharmacol Rep., 2020, 40(3), 211-223). Nonetheless, there have been no agents approved by FDA to treat the insomnia symptoms in AUD sufferers.

[0004] Thus, there is still an unsatisfied need for a pharmaceutical component that is able to help combat the debilitating effects of AUD and to treat the insomnia in AUD sufferers.

[0005] Identification of the NOP (nociceptin / orphanin-FQ peptide) (also known as, ORL- 1) receptor as distinct from the three long-known major classes of opioid receptors in the central nervous system - mu, kappa, and delta - resulted from experimentation on these opioid receptor classes. The NOP receptor was identified and classified as an opioid receptor based only on amino acid sequence homology, as the NOP receptor did not exhibit overlapping pharmacology with the classic mu opioid receptor. It was initially demonstrated that non-selective ligands having a high affinity for mu, kappa, and delta receptors had low affinity for the NOP receptor. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term “orphan receptor.” See, e.g., Henderson et al., “The orphan opioid receptor and its endogenous ligand - nociceptin / orphanin FQ,” Trends Pharmacol. Sci. 18(8):293-300 (1997). Subsequent research led to the isolation and structure of the endogenous ligand of the NOP receptor, a seventeen amino acid peptide structurally similar to members of the opioid peptide family. For a general discussion of NOP receptors, see Calo’ et al., “Pharmacology of nociceptin and its receptor: a novel therapeutic target,” Br. J. Pharmacol. 129: 1261-1283 (2000).

[0006] International Patent Publication WO 2018 / 020418 Al discloses certain NOP receptor modulators useful for treating and / or preventing sleep disorders. And International Patent Publication WO 2019 / 145850 Al discloses certain NOP receptor modulators useful for treating and / or preventing an insomnia disorder associated with alcohol use.

[0007] The present disclosure provides methods for treating alcohol use disorders, reducing alcohol consumption and / or preventing relapse into alcohol consumption in a human subject in need thereof by employing certain NOP receptor modulators.SUMMARY OF THE INVENTION

[0008] In one aspect, the disclosure provides methods for treating alcohol use disorder(AUD) in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound, wherein the compound is a compound of formula (I):formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0009] In certain embodiments, the compound of formula (I) or pharmaceutically acceptable salt or solvate thereof is a compound of formula (II):formula (II), or a pharmaceutically acceptable salt or a solvate thereof.

[0010] Certain embodiments provide that the compound of formula (II) or pharmaceutically acceptable salt or solvate thereof is one or more of the compounds selected from the group of(IIB) (IIC) or a solvate thereof.

[0011] In one embodiment, the method comprises administering to the human subject a therapeutically effective amount of the compound of formula (IIC) (also known as “Sunobinop Tosyl ate”).

[0012] In certain embodiments, such compounds of formula (I), (II), (IIA), (IIB), or (IIC), or pharmaceutically acceptable salts or solvates thereof (together referred to “compounds of this disclosure”), effectively treat or prevent alcohol use disorder by reducing alcohol craving, reducing frequency of alcohol consumption, and / or reducing total volume of ingested alcohol in the human subject. In other embodiments, a compound of this disclosure effectively treats or prevents alcohol use disorder by lessening symptoms associated with alcohol withdrawal in the human subject. In some embodiments, compounds of this disclosure reduce a total volume of alcohol ingested by said human subject in a single sitting compared to a corresponding total volume of alcohol ingested by a similarly situated human subject administered a placebo. As used herein, a total volume of alcohol ingested by the human subject in a “single sitting” is considered to be a total volume of alcohol ingested in one session without stopping or within a brief period of time (e.g., 1 hour or two hours). As used herein, a human subject is considered to be“similarly situated” to another human subject when the human subject satisfies the same inclusion / exclusion criteria as the human subject who is being treated with the methods of the disclosure, and who also matches other relevant characteristics, such as, gender, age, body weight, and body mass index. In some embodiments, compounds of this disclosure reduce a total volume of alcohol ingested by said human subject during a period of 30 days compared to a corresponding total volume of alcohol ingested by a similarly situated human subject administered a placebo. In other embodiments, compounds of this disclosure are effective in treating or reducing symptoms associated with alcohol withdrawal.

[0013] In one embodiment, the method of this disclosure reduces the percentage of heavy drinking days experienced by a human subject who consumes alcohol during a certain period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to a corresponding percentage of heavy drinking days experienced by a similarly situated human subject who is not treated by the method of this disclosure (e.g., a similarly situated human subject administered a placebo instead). In another embodiment, a method of this disclosure reduces the number of standard unit drinks (14 g of pure alcohol) ingested per day by the human subject who consumes alcohol, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is not treated by the method of this disclosure. In still another embodiment, the method of this disclosure reduces the percentage of drinking days experienced by the human subject during a certain period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to a corresponding percentage of drinking days experienced by a similarly situated human subject who is not treated by the method of this disclosure. In another embodiment, the method of this disclosure increases the percentage of abstinent days experienced by the human subject during a certain period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to a corresponding percentage of abstinent days experienced by a similarly situated human subject who is not treated by the method of this disclosure. In yet another embodiment, the method of this disclosure reduces the human subject’s WHO risk drinking level, compared to the WHOrisk drinking level of a similarly situated human subject who is not treated by the method of this disclosure. See U. S. Food and Drug Administration, A Reduction in the World Health Organization (WHO) Risk Levels of Alcohol Consumption as an Efficacy Outcome in Alcohol Use Disorder (AUD) Clinical Trials (November 2018).

[0014] In one aspect, the disclosure provides methods for treating alcohol use disorder (AUD) in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein the method reduces alcohol consumption in the human subject over a period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to a similarly situated human who has not been administered a compound of this disclosure, such as, a human subject who has received a placebo over the same period of time.

[0015] In another aspect, the disclosure provides methods for treating alcohol use disorder (AUD) in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein the method reduces alcohol craving experienced by the human subject over a period of time, compared to a similarly situated human subject who has not been administered a compound of this disclosure, such as, a human subject who has received a placebo over the same period of time.

[0016] In another aspect, the present disclosure is directed to a method of reducing alcohol consumption in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein the method reduces a percentage of heavy drinking days experienced by the human subject over a certain period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to a corresponding percentage of heavy drinking days experienced by a similarly situated human subject who has not been administered a compound of this disclosure, such as, a human subject who has received a placebo. In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0017] Another aspect of the disclosure provides a method of reducing alcohol consumption in a human subject who consumes alcohol, which reduces the number of standard unit drinks ingested per day by the human subject over a certain period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who has not been administered a compound of this disclosure, such as, a human subject who has received a placebo over the same period of time.

[0018] Still another aspect of the disclosure provides a method of reducing alcohol consumption in a human subject identified in need thereof, wherein the method reduces the percentage of drinking days experienced by the human subject during a certain period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to a corresponding percentage of drinking days experienced by a similarly situated human subject who has not been administered a compound of this disclosure, such as, a human subject who has received a placebo over the same period of time.

[0019] In accordance with another aspect of the disclosure, a method of reducing alcohol consumption in a human subject in need thereof is provided, which reduces the human subject’s WHO risk drinking level during a certain period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to the WHO risk drinking level of a similarly situated human subject who is not administered a compound of the disclosure, e.g., a human subject who is administered a placebo over the same period of time.

[0020] Another aspect of the disclosure is drawn to methods of preventing a human subject from relapsing to alcohol drinking, e.g., heavy alcohol drinking. The methods comprise administering to the human subject a therapeutically effective amount of a compound of formula (I), (II), (IIA), (IIB), or (IIC), or a pharmaceutically acceptable salt or solvate thereof (also referred to as “a compound of this disclosure”).

[0021] Another aspect provides methods for maintenance of abstinence in a human subject from alcohol drinking. The methods comprise administering to a human subject in need thereof a therapeutically effective amount of a compound of this disclosure.

[0022] Another aspect of the disclosure provides a method of reducing alcohol craving in a human subject, compared to a corresponding alcohol craving in a similarly situated human subject who is not treated by the method of this disclosure (e.g., a similarly situated human subject administered a placebo instead). The method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure. In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0023] In some embodiments, the method of reducing alcohol craving in a human subject reduces the human subject’s urge to drink alcohol, compared to the urge experienced by a similarly situated human subject who is not administered a compound of this disclosure, e.g., a human subject administered a placebo over the same period of time. Such urge is evaluated by tools readily available in the field (e.g., through an Alcohol Urge Questionnaire; “AUQ”).

[0024] In other embodiments, the method of reducing alcohol craving in a human subject decreases the human subject’s desire for alcohol, compared to the desire experienced by a similarly situated human subject who has not taken a compound of this disclosure, e.g., a human subject administered a placebo over the same period of time. Such desire for alcohol is evaluated by tools readily available in the field (e.g., evaluated by a Desire for Alcohol Visual Analog Scale; “DFA-VAS”).

[0025] Yet a further embodiment provides that the method of reducing alcohol craving decreases level of anxiety (e.g., tension, anxiousness, and jittery feelings) experienced by the human subject, compared to the anxiety level experienced by a similarly situated human subject who is not administered a compound of this disclosure, e.g., a human subject who is administered a placebo over the same period of time. Such anxiety level experienced by a human subject is evaluated by tools readily available in the field (e.g., evaluated by an Anxiety Visual Analog Scale; “Anxiety-VAS”).

[0026] In another aspect, the present disclosure is directed to a method of treating alcohol use disorder (AUD) in a human subject identified in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure (e.g., Compound (IIC)), wherein the method improves the human subject’s sleep profile over a certain period of time, compared to a similarlysituated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time.

[0027] In certain embodiments, the methods of this disclosure also treat or prevent a sleep disorder (e.g., insomnia) in a human subject. In one embodiment, the sleep disorder is associated with alcohol consumption, including such as, insomnia-type alcohol-induced sleep disorder, insomnia in alcohol use disorder, or insomnia associated with alcohol cessation, or a combination thereof.

[0028] Another aspect provides a method of reducing stress or anxiety level in a human subject identified as in need thereof by administering a therapeutically effective amount of a compound of the disclosure. The human subject may also suffer from another condition, such as, AUD, sleep disorders associated with alcohol drinking (e.g., insomnia associated with alcohol cessation), or opioid use disorder. Certain embodiments provide that the administration occurs during the daytime.

[0029] In certain embodiments, the therapeutically effective amount of a compound of the disclosure can be from about 0.10 mg to about 10.0 mg, from about 0.2 mg to about 8.0 mg, or from about 0.5 mg to about 6.0 mg. In other embodiments, the therapeutically effective amount is from about 0.10 mg to about 3.0 mg, for example, 0.1 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, or 3.0 mg. The effective amount of a compound of the disclosure is expressed as the amount of the free base or free acid form of the compound.

[0030] The disclosure can be further understood by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the disclosure.BRIEF DESCRIPTION OF THE FIGURES

[0031] Figs. 1 A-B show overall study designs of a randomized, double-blind, placebo- controlled, parallel-group, phase 2 clinical studies to evaluate the safety, tolerability, and impact of compound of Formula (IIC) on alcohol consumption (Fig. 1A) and on alcohol craving (Fig. IB).

[0032] Fig. 2 shows total score in Penn alcohol craving scale with by 1 mg dose and 2 mg dose of Compound (IIC) and placebo in insomnia patients in recovery from AUD.

[0033] Fig. 3 shows duration of alcohol use disorder (AUD) in insomnia patients being administered with 1 mg dose and 2 mg dose of Compound (IIC) and placebo.

[0034] Fig. 4 is a chart showing the length of alcohol cessation in insomnia patients prior to being administered with 1 mg dose and 2 mg dose of Compound (IIC) and placebo.

[0035] Fig. 5 shows effects (by PSG) of 1 mg dose and 2 mg dose of Compound (IIC) and placebo on insomnia in patients in recovery from AUD.

[0036] Fig. 6 shows effects (by diary) of 1 mg dose and 2 mg dose of Compound (IIC) and placebo on insomnia in patients in recovery from AUD.

[0037] Fig. 7 shows sleep architecture in insomnia patients in recovery from AUD after being administered with 1 mg dose and 2 mg dose of Compound (IIC) and placebo.

[0038] Fig. 8 shows sleep REM latency in insomnia patients in recovery from AUD after being administered with 1 mg dose and 2 mg dose of Compound (IIC) and placebo.

[0039] Fig. 9 shows total PACS craving score in insomnia patients in recovery from AUD after being administered with 1 mg dose and 2 mg dose of Compound (IIC) and placebo.

[0040] Fig. 10 shows total mood disturbance score in insomnia patients in recovery from AUD after being administered with 1 mg dose and 2 mg dose of Compound (IIC) and placebo.DETAILED DESCRIPTION

[0041] The inventor(s) has noted that a compound of formula (I), (II), (IIA), (IIB), or (IIC), or a pharmaceutically acceptable salt or solvate thereof, demonstrates minimal penetration across the central nervous system (“CNS”) blood-brain barrier in an animal. Such minimally-penetrating compounds are referred to as “peripherally restricted”.Without wishing to be bound by any theory, in connection with this tissue selectivity, it is useful to define KPas the ratio of the quantity of a compound that penetrates across an animal’s blood-brain barrier into the CNS (e.g., as determined from the quantity of the compound in a whole brain homogenate) to the quantity of the compound circulating in the animal’s plasma.

[0042] A compound of this disclosure can be tested for the ability to penetrate into the CNS using in vitro and in vivo methods known in the art such as, e.g. the in vivo method disclosed in Example 11 of International Patent Publication No. WO 2018 / 020418 Al. Certain compounds of formula (I), (II), (IIA), (IIB), or (IIC), or a pharmaceutically acceptable salt or solvate thereof, exhibit a reduced propensity to blood-brain barrierpenetration as measured by the Madin Darby canine kidney (“MDCK”) cell-line transport assay disclosed in, e.g., Wang et al. (“Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier,” Int. J. Pharm. 288(2):349-359 (2005)).

[0043] A compound of this disclosure, or pharmaceutical compositions comprising the same, can be administered to a human subject identified in need thereof to treat alcohol use disorder, and / or to prevent a human subject identified in need thereof from relapsing into alcohol drinking or maintaining a human subject’s abstinence from alcohol drinking. In certain embodiments, the human subject has been diagnosed with alcohol use disorder. In other embodiments, the human subject is identified as prone to alcohol use disorder or alcohol abuse. In other embodiments, the human subject is identified for or prone to alcohol misuse. In still other embodiments, the human subject is a habitual heavy drinker of alcohol. Another embodiment provides that the human subject is a moderate drinker but aims to reduce intake of alcohol. Still another embodiment provides that the human subject is a light or occasional drinker but aims to refrain from alcohol consumption.

[0044] In certain embodiments, a compound of this disclosure or pharmaceutical compositions comprising the same, can be administered to a human subject who has one or more other addictive disorders, including addiction to sedatives or hypnotics. In one embodiment, the one or more other additive disorders are comorbid with AUD in the human subject. In other embodiments, the human subject has not been clinically identified to have AUD, but identified as having one or more other additive disorders (e.g., opioid use disorder).

[0045] In certain embodiments, a compound of this disclosure or pharmaceutical composition comprising the same, when used in accordance with the methods of this disclosure, also treats or prevents a sleep disorder (e.g., insomnia) in a human subject. The sleep disorder can be insomnia-type alcohol-induced sleep disorder, insomnia in alcohol use disorder, or insomnia associated with alcohol cessation, or a combination thereof.

[0046] It has been noted that a compound of formula (I), (II), (IIA), (IIB), or (IIC) exhibits addictive properties that are not statistically greater than placebo at a therapeutic dose level and / or are less than Drug Enforcement Administration (“DEA”) Schedule IV substances when used to treat insomnia (e.g., triazolam) at a therapeutic dose level or at a supratherapeutic dose level (e.g., a dose that is at least 5 times the therapeutic dose).

[0047] A compound of formula (I), (II), (IIA), (IIB), or (IIC) is minimally metabolized by the liver. This is advantageous, because liver damage or liver dysfunction is common in populations with alcohol use disorder. Accordingly, a compound of this disclosure or pharmaceutical composition comprising the same, addresses the need for a medicament to treat alcohol use disorder or insomnia associated with alcohol consumption without adversely impacting liver function, which thus can be used in populations with liver dysfunction without unpredictable effects on exposure.

[0048] In certain embodiments, a compound of this disclosure or pharmaceutical composition thereof can be administered to human subjects who have hepatic impairment resulting from any cause, including liver disease related to alcohol consumption. In other embodiments, a compound of this disclosure or pharmaceutical composition comprising the same, when used in accordance with the methods of this disclosure, can be administered to a human subject diagnosed as having hepatic impairment (e.g., mild or moderate impairment) at the same daily dose as to a human subject who has not been diagnosed as having hepatic impairment, e.g., a human subject who does not have hepatic impairment.

[0049] Other embodiments provide that a compound of this disclosure or pharmaceutical composition thereof can be administered to human subjects who have renal impairment resulting from any cause. In one embodiment, a compound of this disclosure or pharmaceutical composition thereof, when used in accordance with the methods of this disclosure, can be administered to a human subject diagnosed as having renal impairment (e.g., mild or moderate impairment) at the same daily dose as to a human subject who has not been diagnosed as having renal impairment, e.g., a human subject who does not have renal impairment. A compound of this disclosure or pharmaceutical composition comprising the same, can be administered to a patient who is receiving one or more concomitant therapy(ies) for treating alcohol use disorder or preventing relapse to alcohol consumption. In certain embodiments, a concomitant therapy is another therapeutic agent for treating alcohol use disorder or preventing relapse or maintaining abstinence, which is selected from disulfiram, naltrexone, acamprosate, gabapentin, topiramate, nalmefene, naloxone, fluoxetine, quetiapine, and combinations thereof.Definitions

[0050] The term “animal” includes, but is not limited to, a human or a non-human mammal, such as a companion animal or livestock, e.g., a cow, monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig. In one embodiment, an animal is a human subject.

[0051] As used herein, “alcohol withdrawal” refers to a condition when a human subject, after drinking alcohol for weeks, months or years, may experience mental and physical problems when the human subject stops or seriously cuts back on the alcohol consumption. Signs and symptoms associated with alcohol withdrawal, include conditions such as, anxiety, shaking hands, headache, nausea, vomiting, insomnia, sweating, seizure, hallucination, confusion, racing heart, high blood pressure, fever, etc. These signs and symptoms can range from mild to serious.

[0052] As used herein, “binge drinking”, as defined by National Institute on Alcohol Abuse and Alcoholism (NIAAA) in 2023, is a pattern of drinking alcohol that brings blood alcohol concentration (BAC) to 0.08 percent - or 0.08 grams of alcohol per deciliter - or higher. For a typical adult, this pattern corresponds to consuming 5 or more drinks (male), or 4 or more drinks (female), in about 2 hours. Binge drinking can increase a human subject’s risk of alcohol use disorder.

[0053] The term “concomitant therapy” is defined to include all medications (over-the- counter (OTC)) and / or prescription medications, procedures, and significant nonpharmacological therapies that are used to treat a subject during the time periods relevant to administration of a compound of this disclosure. In an embodiment, the concomitant therapy may include another agent for treating or preventing AUD.

[0054] As used herein, “heavy drinking” or “heavy alcohol use”, as defined by NIAAA in 2023, refers to consuming five or more drinks on any day or 15 or more drinks per week (for men), and consuming four or more drinks on any day or 8 or more drinks per week (for women). Heavy drinking or heavy alcohol use can increase a human subject’s risk of alcohol use disorder.

[0055] As used herein “insomnia” also includes insomnia-type alcohol-induced sleep disorder, mixed type alcohol-induced sleep disorder which includes insomnia-type alcohol-induced sleep disorder as a component, insomnia in AUD, and insomnia associated with alcohol cessation.

[0056] As used herein, the term “Time in Bed” (“TIB”) refers to the duration of time, e.g., in minutes, of an entire intended sleep episode from its beginning to its end. TIB is often of a fixed duration, e.g., 480 minutes. The beginning of the TIB is, for the purposes herein, the “intended bedtime”.

[0057] The term “Total Sleep Time” (“TST”) refers to the sum of all time epochs, e.g., in minutes, spent in either NREM (including all of Stages N 1 through N3) or REM sleep.

[0058] The term “Sleep Efficiency” (“SE”) is measured by polysomnography in insomnia subjects and refers to the fraction of the TIB that is spent asleep in REM and NREM sleep and is calculated as the following ratio: TST / TIB. Alternately, SE can be expressed as a percentage by multiplying this ratio by 100. SE is a measure of sleep maintenance throughout the night, thus, assessment of SE also includes, inter alia, assessment of prolonged LPS and / or assessment of prolonged WASO.

[0059] The term “Latency to Persistent Sleep” (“LPS”) refers to the time, e.g, in minutes, from the beginning of the TIB until the start of a period of least 10 uninterrupted minutes of sleep epochs - in any sleep stage. LPS is a measure of the “speed” of going to sleep.

[0060] The term “Wake During Sleep” (“WDS”) refers to the total time, e.g, in minutes, of epochs spent awake occurring after the onset of persistent sleep (defined as at least 10 consecutive minutes of sleep epochs of any sleep stage) and before the onset of the final epoch of sleep (of any sleep stage) during the TIB.

[0061] The term “Wake After Sleep” (“WAS”) refers to the duration, e.g., in minutes, of time spent awake after the conclusion of final sleep epoch (of any sleep stage) until the end of the TIB.

[0062] The term “Wake After Sleep Onset” (“WASO”) refers to the sum of WDS and WAS. WASO is another measure of sleep maintenance throughout the night.

[0063] The term “Number of Awakenings” (“NAW”) refers to the number of times after onset of persistent sleep in which an awakening for a period of greater than 30 seconds occurs.

[0064] The term “REM latency” refers to the time, e.g., in minutes, from the beginning of the TIB until the beginning of the first epoch of REM sleep.

[0065] As used herein, the term “pharmaceutically acceptable salt”, is any pharmaceutically acceptable salt that can be prepared from a compound including a salt formed from an acid and a basic functional group, such as a nitrogen group, of thecompound. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -toluenesulfonate, and pamoate (z.e., l,l’-methylene-bis-(2-hydroxy- 3 -naphthoate)) salts. The term “pharmaceutically acceptable salt” also includes a salt prepared from a compound having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, cesium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines, such as 7V-methyl-7V-ethylamine, diethylamine, triethylamine, tributyl amine, (tert-butylamino)methanol, and tris-(hydroxymethyl)amine; dicyclohexylamine; pyridine; picoline; mono-, bis-, or tris-(2-hydroxy-(Ci-C3)alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, and 7V,7V-di-[(Ci-C3)alkyl]-7V-(hydroxy-(Ci-C3)alkyl)- amines, such as 7V,7V-dimethyl-7V-(2-hydroxyethyl)amine; 7V-methyl-D-glucamine; an amino acid, such as arginine and lysine; an amino acid derivative, such as choline (z.e., 2- hydroxy- / f-trimethylethan- l -aminium), a derivative of the amino acid serine; and the like. In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt, a sulfate salt, a sodium salt, a potassium salt, a benzene sulfonic acid salt, a para- toluenesulfonic acid salt, or a fumaric acid salt. In another embodiment, the pharmaceutically acceptable salt is a hydrochloride salt or a sulfate salt. In another embodiment, the pharmaceutically acceptable salt is a hydrochloride salt. In another embodiment, the pharmaceutically acceptable salt is a sulfate salt. In another embodiment, the pharmaceutically acceptable salt is a sodium salt. In another embodiment, the pharmaceutically acceptable salt is a potassium salt. In another embodiment, the pharmaceutically acceptable salt is a fumaric acid salt. In another embodiment, the pharmaceutically acceptable salt is a / / ra-toluenesulfonic acid salt. In another embodiment, the pharmaceutically acceptable salt is a choline salt.

[0066] In one embodiment, a compound of formula (IIC) contains one equivalent of the free base of the compound without / / ra-toluenesulfonic acid being present, and about 1.0 equivalent of / / ra-toluenesulfonic acid, e.g., from about 0.8 to about 1.2 equivalents of / / ra-toluenesulfonic acid in one embodiment or from about 0.9 to about 1.1 equivalents, from about 0.93 to about 1.07 equivalents, from about 0.95 to about 1.05 equivalents, from about 0.98 to about 1.02 equivalents, or from about 0.99 to about 1.01 equivalents of / / ra-toluenesulfonic acid in other embodiments. In another embodiment, the compound of formula (IIC) contains 1.0 equivalent of the free base of the compound and 1.0 equivalent of / / ra-toluenesulfonic acid, z.e., is a mono-tosylate salt.

[0067] The methods of the disclosure provided herein also encompass the use of any solvate of a compound of this disclosure. “Solvates” are generally known in the art, and are considered herein to be a combination, physical association, and / or solvation of a compound of this disclosure with a solvent molecule. This physical association can involve varying degrees of ionic and covalent bonding, including hydrogen bonding. When the solvate is of the stoichiometric type, there is a fixed ratio of the solvent molecule to the compound of this disclosure, e.g., a di-solvate, mono-solvate, or hemisolvate when the [solvent molecule]: [compound of this disclosure] molar ratio is 2: 1, 1 :1, or 1 :2, respectively. In other embodiments, the solvate is of the non-stoichiometric type. For example, the compound of this disclosure crystal can contain solvent molecules in the structural voids, e.g., channels, of the crystal lattice. In certain instances, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate”, as used herein, encompasses both solution-phase and isolatable solvates.

[0068] A compound of the disclosure can be present as a solvated form with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure include both solvated and unsolvated forms of a compound of formula (I), (II), (IIA), (IIB), and (IIC). As “hydrate” relates to a particular subgroup of solvates, z.e., where the solvent molecule is water, hydrates are included within the solvates of the disclosure. In one embodiment, the compound of formula (I), (II), (IIA), (IIB), or (IIC) is present as a mono-hydrate, e.g., where the water: [compound of this disclosure] molar ratio is about 1 : 1, e.g., from 0.91 : 1 to 1.09: 1 in one embodiment or from 0.94: 1 to 1.06: 1, from 0.97: 1 to 1.03: 1, or from 0.985:1 to 1.015: 1 in otherembodiments, each said embodiment taking no account of surface water that might be present, if any.

[0069] Solvates can be made according to known techniques in view of the present disclosure. For example, Caira etal., “Preparation and Crystal Characterization of a Polymorph, a Mono-hydrate, and an Ethyl Acetate Solvate of the Antifungal Fluconazole,” J. Pharmaceut. Sci., 93(3):601-611 (2004), describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparations of solvates, hemi-solvate, hydrates, and the like are described by Van Tender et al., “Preparation and Physicochemical Characterization of 5 Niclosamide Solvates and 1 Hemisolvate,” AAPS Pharm. Sci. Tech., 5(1): Article 12 (2004), and Bingham et al., “Over one hundred solvates of sulfathiazole,” Chem. Comm., pp. 603-604 (2001). In one embodiment, a non-limiting, process involves dissolving the compound of this disclosure in a desired amount of the solvent (organic, water or mixtures thereof) at temperatures above about 20°C to about 25°C, cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques, for example, infrared spectroscopy, can be used to show the presence of the solvent in a crystal of the solvate.

[0070] A compound of formula (I), (II), (IIA), (IIB), or (IIC) or a pharmaceutically acceptable salt or solvate thereof can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Unless specifically otherwise indicated, the disclosure encompasses compounds with all such possible forms as well as their racemic and resolved forms, and all mixtures thereof. Unless specifically otherwise indicated, all “tautomers”, e.g., lactam-lactim, urea-isourea, ketone-enol, amide-imidic acid, enamine-imine, amine-imine, and enamine-enimine tautomers, are intended to be encompassed by the disclosure as well.

[0071] As used herein, the terms “stereoisomer”, “stereoisomeric form”, and related terms as used herein are general terms for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (“diastereomers”).

[0072] The term “chiral center” refers to a carbon atom to which four different groups are attached.

[0073] The term “enantiomer” or “enantiomeric” refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

[0074] The term “racemic” refers to a mixture of equal parts of enantiomers which is optically inactive.

[0075] The term “resolution” refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule. Optical isomers of a compound of formula (I), (II), (IIA), or (IIB) can be obtained by known techniques such as chiral chromatography or formation of diastereomeric salts from an optically active acid or base.

[0076] Optical purity can be stated in terms of enantiomeric excess (“% ee”) and / or diastereomeric excess (% de), each which is determined by the appropriate formula below: / oo ee =major enantiomer(mol) - minor enantiomerfmol)X^QQO / Omajor enantiomer(mol) + minor enantiomer(mol)% de = major diastereomer(mol) - minor diastereomers(mol) x 100% major diastereomer(mol) + minor diastereomers(mol)

[0077] As used herein, the term “eGFR” refers to an estimated glomerular filtration rate (eGFR) that is calculated with the formula shown below: eGFR= 142 x min (standardized Scr / k,l)a x max (standardized Scr / k,l)-1200 x0.9938Age x 1.012 [if female] where k is 0.7 for females and 0.9 for males, a is -0.241 for females and-0.302 for males, min indicates the minimum of Scr / k or 1, and max indicates the maximum of Scr / k or 1

[0078] As used herein, a human subject with “no renal insufficiency” or with “normal renal function” means that the human subject has an eGFR of 90 mL / min or more.

[0079] As used herein, a human subject with “mild renal impairment” means that the human subject has an eGFR of about 60 mL / min to about 89 mL / min.

[0080] As used herein, a human subject with “mild to moderate renal impairment” means that the human subject has an eGFR of about 45 mL / min to about 59 mL / min.

[0081] The term “effective amount”, used in connection with methods of this disclosure when administering a compound of this disclosure, refers to the amount of the unsolvated compound (in terms of the amount of its corresponding free base or free acid form) administered to a human subject that provides desired therapeutic effects.

[0082] The terms “modulate”, “modulating”, and related terms as used herein with respect to the NOP receptor mean the mediation of a pharmacodynamic response (e.g., AUD) in a disorder from (i) inhibiting or activating the receptor, or (ii) directly or indirectly affecting the normal regulation of the receptor activity. Compounds that modulate the receptor activity include agonists, partial agonists, antagonists, mixed agonists / antagonists, mixed partial agonists / antagonists, and compounds which directly or indirectly affect regulation of the receptor activity.

[0083] As used herein, a compound that binds to a receptor and mimics the regulatory effect(s) of an endogenous ligand is defined as an “agonist”. As used herein, a compound that binds to a receptor and is only partly effective as an agonist is defined as a “partial agonist”. As used herein, a compound that binds to a receptor but produces no regulatory effect, but rather blocks binding of another agent to the receptor is defined as an “antagonist”. (See Ross etal., “Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug Concentration and Effect,” in Goodman and Gilman ’s The Pharmacological Basis of Therapeutics pp. 31-43 (Goodman el al., eds., 10thEd., McGraw-Hill, New York 2001)).

[0084] The terms “treatment of’, “treating”, and related terms as used herein include the amelioration, reduction, slowing, or cessation of a disorder or a symptom thereof by administration of a compound of this disclosure. In some embodiments, treating includes inhibiting, for example, decreasing the overall frequency of episodes of a disorder or a symptom thereof, or reducing the severity of a disorder or a symptom thereof.

[0085] The terms “prevention of’, “preventing”, and related terms as used herein include the avoidance or delay of the onset of a disorder or a symptom thereof by administration of a compound of this disclosure.

[0086] The term “UI” means urinary incontinence. The term “IBD” means inflammatory-bowel disease. The term “IBS” means irritable-bowel syndrome. The term “ALS” means amyotrophic lateral sclerosis.

[0087] The term “SD” as used herein means standard deviation. The term “LSM” as used herein means least-squares mean. The term “STDE” as used herein means standard error.

[0088] The term “N / A” as used herein means not applicable.

[0089] The term “recovery”, when used herein in conjunction with a human subject in respect to a disease or condition, is meant to include both a situation where the human subject is in abstinence from the source / activities associated with the disease or condition for a certain period of time, e.g., a designated “recovery period”, and a situation where the human subject is just released from that disease or condition. For example, in the context of treating a human subject suffers from insomnia associated with alcohol cessation, the subject who is in recovery includes a subject in a 2-weeks or longer post- detoxication phase.

[0090] In the event of doubt as to the agreement of a depicted chemical structure and a chemical name, the chemical name governs.

[0091] It is appreciated that various features of the disclosure which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment unless otherwise specifically herein excluded. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately and / or in any suitable subcombination unless otherwise specifically herein excluded.Alcohol Use Disorder and Other Conditions

[0092] Alcohol use disorder (AUD) is a medical condition characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences. It encompasses the conditions that some people refer to as alcohol abuse, alcohol dependence, alcohol addiction. Considered a brain disorder, AUD can be mild, moderate, or severe. Lasting changes in the brain caused by alcohol misuse perpetuate AUD and make individuals vulnerable to relapse. According to the 2021 National Survey on Drug Use and Health, 28.6 million adults ages 18 and older (11.3% in this age group) had AUD in 2021 (see SAMHSA, Center for Behavioral Health Statistics and Quality. 2021 National Survey on Drug Use and Health). Among youth, an estimated 894,000 adolescents ages 12 to 17 (3.4% of this age group) had AUD during this time frame (seehttps: / / www.niaaa.nih.gov / publications / brochures-and-fact-sheets / understanding-alcohol- use-disorder).

[0093] According to the above NIH publication, a person’s risk for developing AUD depends in part on how much, how often, and how quickly he / she consumes alcohol. Alcohol misuse, which includes binge drinking and heavy alcohol use, over time increases the risk of AUD. Other factors also increase the risk of AUD, including such as, drinking at an early age; genetics and family history of alcohol problems; and mental health conditions and a history of trauma.

[0094] Health care professionals use criteria from DSM-5 to assess whether a person has AUD and to determine the severity, which is based on the number of criteria a person meets based on their symptoms: mild (2-3 criteria), moderate (4-5 criteria), or severe (6 or more criteria).

[0095] Only a few (~3) pharmacotherapeutic treatments (e.g., naltrexone, acamprosate, and disulfiram) have been approved by FDA for Alcohol Use Disorder (AUD), none of which are widely used or show a strong effect to reduce risky or dependence-based drinking in the long-term (<20% see sustained decreased drinking outcomes). Unfortunately, approximately 10% of the US population suffers from AUD and over 5% of all medical morbidities share risky ethanol consumption as an underlying issue. As a consequence, intoxication, in general, and ‘alcohol addiction’ (moderate to severe AUD), in particular, are important clinical problems. Given the limited pharmacotherapeutic options, there is a compelling need for continued development of new treatments across the AUD spectrum (mild to severe DSM-V classification).

[0096] There is certain pre-clinical evidence suggesting that nociceptin / orphanin-FQ peptide receptor (NOP) activation blocks the reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse [Jenck 2000, Varty 2005, Varty 2008, Bloms 2000, Wnendth 1999, Lufty 2003, Huang 2001], It has been proposed that nociceptin can block ethanol induced GABAergic transmission [Robero 2006] and reduce withdrawal effects in rats [Economidou 2011], Synthetic agonists reduce ethanol consumption and self-admin, ethanol seeking, reinforcement and relapse-type drinking in rats [Kuzmin 2007; Ciccocioppo 2014, de Guflielmo 2014, Aziz 2016, Zaveri 2018, Kuzmin 2003] and decrease ethanol intake in monkeys [Flynn 2019], The precursor of the native ligand andthe nociceptin receptor are downregulated in brains from humans with alcohol use disorder [Kuzmin 2009] and certain single nucleotide polymorphisms of the nociceptin receptor are associated with alcohol use disorder [Huang 2008],

[0097] The compounds of this disclosure selectively activate NOP, and thus are efficacious to treat alcohol use disorders, to reduce alcohol consumption, to reduce alcohol cravings, to reduce withdrawal symptoms associated with alcohol abstinence, to prevent a human subject from relapsing into alcohol drinking, and / or to maintain a human subject’s abstinence from alcohol drinking.

[0098] In certain embodiments, the compounds of this disclosure offer improved treatments targeting high alcohol consumption and withdrawal -related symptoms. The pharmacokinetics of the compounds of this disclosure are unaffected when coadministered with alcohol (aka, ethanol). Similarly, the pharmacokinetics of the ethanol are unaffected when co-administered with a compound of this disclosure.

[0099] It has been observed that no major metabolite of a compound of this disclosure is identified in human plasma after the administration of the compound. It is thus believed that the compounds of this disclosure are effective in resisting metabolism by the human liver. In certain embodiments, the compounds of this disclosure can be administered to treat AUD in human subjects with mild hepatic impairment. In other embodiments, the compounds of this disclosure can be administered to treat AUD in human subjects with moderate hepatic impairment.

[0100] In other embodiments, the compounds of this disclosure can be administered to treat AUD in human subjects with mild renal impairment. In another embodiment, the compounds of this disclosure can be administered to treat AUD in human subjects with moderate renal impairment.

[0101] In certain embodiments, a compound of this disclosure is used to decrease alcohol craving in any human subject, including such as, people identified through DSM-5 as having a mild, moderate, or severe AUD as well as people recovered from AUD.

[0102] In other embodiments, the compounds of this disclosure can be used to reduce the amount and / or frequency of alcohol intake (or consumption) in any human subject, including such as, people identified through DSM-5 as having a mild, moderate, or severe AUD, and people are prone to alcohol misuse.

[0103] In one embodiment, the amount of alcohol consumption by a human subject is decreased by at least 30%, compared to the amount consumed by the same human subject or a human subject similarly situated but without being treated by a compound of this disclosure. In another embodiment, the total amount of alcohol consumption by a human subject during a period of time (e.g., a month, a week, three days, one day, within 12 hours, or within 3 hours) is decreased by at least 30%, compared to the total amount consumed by the same human subject or a similarly situated human subject who is not administered a compound of this disclosure. In other embodiments, the frequency of alcohol consumption by a human subject during a period of time (e.g., three months, one month, a week, or three days) is decreased by at least 30%, compared to the frequency in the same human subject or a similarly situated human subject who is not administered a compound of this disclosure. In another embodiment, a method of this disclosure decreases the percentage of days of heavy drinking by at least 30% in a human subject identified in need thereof.

[0104] In certain embodiment, a method of this disclosure reduces symptoms of alcohol withdrawal in a human subject identified in need thereof (e.g., those who are alcohol dependent). These symptoms of alcohol withdrawal include such as, anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever.

[0105] In one embodiment, a compound of this disclosure, after being administered in one or multiple doses, achieves cessation of alcohol consumption altogether in a human subject in need thereof. In still other embodiments, a compound of this disclosure, after being administered in one or multiple doses, can prevent a human subject who has achieved cessation of alcohol consumption from relapsing back to alcohol drinking.

[0106] In another embodiment, a method of this disclosure achieves a partial or complete abstinence from alcohol consumption in any human subject, including such as, people identified with a mild, moderate, or severe AUD, people recovering from AUD, and people are prone to alcohol misuse or even abuse. In another embodiment, a method of this disclosure achieves the maintenance of abstinence from alcohol drinking in a human subject in need, including those who have achieved cessation of alcohol consumption, those who have never initiated alcohol consumption, and those who have only been occasional light drinkers previously.

[0107] In certain embodiments, a therapeutically effective amount of a compound of this disclosure is administered daily to a human subject in need thereof. One embodiment provides that a compound of this disclosure is administered to the human subject at bedtime or within one hour prior to the bedtime. Another embodiment provides that a compound of this disclosure is administered to a human subject whenever needed, such as, during the daytime.

[0108] Other embodiments provide that a compound of this disclosure is administered to the human subject at the time when needed, such as, right before the meal time or a social event where alcoholic drink is usually provided. Another embodiment provide that a compound of this disclosure is administered to the human subject in need within one hour prior to the meal time or a social event where alcoholic drink is usually provided.

[0109] In other embodiments, a therapeutically effective amount of a compound of this disclosure is administered daily, once every two days, once every three days, once every four days, or once every five days to a human subject in need thereof. In still other embodiments, a therapeutically effective amount of a compound of this disclosure is administered weekly to a human subject in need thereof.

[0110] In still other embodiments, a therapeutically effective amount of a compound of this disclosure is administered twice daily, thrice daily, or four times daily to a human subject in need thereof. Another embodiment provides that a compound of this disclosure is administered to a human subject whenever needed and / or at a frequency whatever deemed appropriate by an attending physician or therapist.[OHl] In other embodiments, a compound of this disclosure is also used in conjunction with one or more of other treatments for AUD or for other conditions / purposes as above described, including such as, counseling, behavioral therapy, and other AUD medications.

[0112] Also, it is known that human subjects, who suffer from AUD, sometimes also suffer from stress and / or anxiety. A reduction in alcohol consumption may be direct (e.g., by impacting reward system in the brain) or indirect (through sympathetic, adrenal glands) leading to impact to the reward system.

[0113] In another aspect, a compound of this disclosure can impact the stress and / or anxiety level in a human subject. In one embodiment, a compound of this disclosure is efficacious in alleviating (or reducing) anxiety or stress level in a human subject identified in need thereof. In another embodiment, a compound of this disclosure isefficacious in treating depression in a human subject identified in need thereof. Certain embodiments provide that the human subject also suffers from AUD or conditions associated with alcohol consumption. In one embodiment, the compound of this disclosure is administered during the daytime in a dose of about 0.10 mg to about 1.0 mg. Examples provide that the dose administered during the daytime is about 0.1 mg, about 0.2 mg, or about 0.5 mg. In another embodiment, the compound of this disclosure is administered before the bedtime in a dose of about 0.10 mg to about 10.0 mg.

[0114] Another aspect provides that a compound of this disclosure is efficacious in treating opioid use disorder in a human subject identified as in need. In one embodiment, the human subject concurrently suffers from AUD. In another embodiment, the human subject also has one or more conditions (as described herein) associated with alcohol consumption.

[0115] In some aspects, the present disclosure is directed to a method of treating AUD in a human subject identified in need thereof comprising administering to said human subject a therapeutically effective amount of a compound of this disclosure (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt or solvate thereof, such as, Compound (IIC)), wherein the method reduces a percentage of heavy drinking days experienced by the human subject who consumes alcohol over a certain period of time (e.g., a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study), compared to a corresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo over the same period of time. In some embodiments, the method reduces a percentage of heavy drinking days experienced by the human subject over the certain period of time by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, or by at least about 50%, compared to a corresponding percentage of heavy drinking days experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject administered a placebo over the same period of time. In some embodiments, the method reduces a percentage of heavy drinking days experienced by the human subject over the certain period of time by about 10%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, or by about 50%, compared to a corresponding percentage of heavy drinking daysexperienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time.

[0116] In another aspect, the present disclosure provides a method of treating alcohol use disorder in a human subject identified in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt or solvate thereof, such as, Compound (IIC)), wherein the method reduces the number of standard unit drinks (that is, a drink containing 14 g of pure alcohol) ingested per day by the human subject over a certain period of time compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. In some embodiments, the method reduces the number of standard unit drinks ingested per day by the human subject over a period of time, such as, a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study). In other embodiments, the method reduces the number of standard unit drinks by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 45%, or by at least about 50%, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. In other embodiments, the method reduces the number of standard unit drinks by about 10%, by about 20%, by about 25%, by about 30%, by about 35%, by about 45%, or by about 50%, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time.

[0117] In some aspects, the present disclosure is directed to a method of treating AUD in a human subject in need thereof, wherein the method comprises administering to said human subject a therapeutically effective amount of a compound of this disclosure (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt or solvate thereof, such as, Compound (IIC)), wherein the method reduces the percentage of drinking daysexperienced by the human subject during a certain period of time, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. In some embodiments, the certain period of time lasts, for example, a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study. In other embodiments, the method reduces the percentage of drinking days experienced by the human subject by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, or by at least about 50%, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject, for example, a human subject who is administered a placebo, over the same period of time. In some embodiments, the method reduces the percentage of drinking days experienced by the human subject by about 10%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, or by about 50%, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject, for example, a human subject who is administered a placebo, over the same period of time.

[0118] In some aspects, the present disclosure is directed to a method of treating alcohol use disorder in a human subject identified in need thereof comprising administering to said human subject a therapeutically effective amount of a compound of this disclosure (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt or solvate thereof, such as, Compound (IIC)), wherein the method reduces the human subject’s alcohol consumption that corresponds to WHO risk drinking level during a certain period of time, compared to a similarly situated human subject, for example, a human subject who is administered a placebo over the same period of time. In some embodiments, the certain period of time lasts a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study. In other embodiments, the reduction achieved by the present method corresponds to a one-level, two-level, or three-level reduction in the human subject’s WHO risk drinking level (based on grams of alcohol consumption per day), for example, from very high risk to high risk, from very high risk to medium risk, from very high risk to low risk, from high risk to medium risk, from high risk to low risk, or from medium risk to low risk.

[0119] In certain embodiments of the above-mentioned methods, the level of alcohol consumption by a human subject is evaluated by one or more analytical measurements including such as, Obsessive-Compulsive Drinking Scale (OCDS), Insomnia Severity Index (ISI), Alcohol Withdrawal Symptom Checklist -modified (AWSC-m), Clinical Global Impressions Improvement (CGII) scale, and Clinical Global Impressions Severity (CGIS) scale, and WHOQOL-BREF Quality of Life Assessment.

[0120] In still other aspects, the present disclosure is directed to a method of treating AUD in a human subject identified in need thereof, where the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt or solvate thereof, e.g., Compound (IIC), wherein the method reduces alcohol craving experienced by a human subject during a certain period of time, compared to the alcohol craving experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. In some embodiments, the certain period of time lasts, for example, a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study. In some embodiments, the method reduces the human subject’s desire for alcohol. In other embodiments, the method diseases the tension, anxiety, and / or jittery feelings the human subject experiences.

[0121] In some embodiments, alcohol craving experienced by a human subject is measured by an Alcohol Urge Questionnaire (AUQ) after a guided imagery induction session (e.g., an audio-tape induction session that can involve imagining a recent personal stressful situation, a personal alcohol cue-related situation, or a neutral-relaxing situation. In some embodiments, the Alcohol Urge Questionnaire (AUQ) is an 8-item questionnaire each item with a 7-item scale from 1 (strongly disagree) to 7 (strongly agree). In other embodiments, alcohol craving experienced by a human subject is determined by a Desire for Alcohol Visual Analog Scale (DFA-VAS) after a guided imagery induction session (e.g., an audio-tape induction session that can involve imagining a recent personal stressful situation, a personal alcohol cue-related situation, or a neutral-relaxing situation. In some embodiments, the DFA-VAS includes 1 item with a 10 point scale from 0 (not at all) to 10 (extremely high). In some embodiments, alcohol craving experienced by a human subject is determined by an anxiety visual analog scale (Anxiety-VAS) after aguided imagery induction session (e.g., an audio-tape induction session that can involve imagining a recent personal stressful situation, a personal alcohol cue-related situation, or a neutral-relaxing situation. In other embodiments, the Anxiety-VAS can include 1 item with a 10 point scale from 0 (not at all) to 10 (extremely high). In other embodiments, alcohol craving can also be evaluated by an Insomnia Severity Index (ISI).

[0122] Certain embodiments provide that the method reduces the alcohol craving experienced by the human subject, when numerical values are applicable, by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, or by at least about 50%, as measured by appropriate analytical methods (e.g., AUQ, DFA-VAS, Anxiety-VAS, and / or ISI), compared to the alcohol craving experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. Other embodiments provide that the method reduces the alcohol craving experienced by the human subject, when numerical values are applicable, by about 10%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, or by about 50%, as measured by appropriate analytical methods (e.g., AUQ, DFA-VAS, Anxiety-VAS, and / or ISI), compared to the alcohol craving experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time.

[0123] In certain embodiments, a compound of this disclosure (e.g., Compound (IIC)), according to the present methods for treating alcohol use disorder, impacts multiple domains synergistically to reduce alcohol consumption by the human subject in need thereof. For example, a therapeutically effective amount of a compound of this disclosure (e.g., Compound (IIC)) achieves in the human subject one or more effects, including but not limited to, reduction in alcohol consumption, decreased alcohol craving, and improved sleep profile experienced by the human subject. In other embodiments, the present methods for treating alcohol use disorder lessen or reduce the human subject’s alcohol withdrawal signs and / or symptoms, such as, lessening level of such signs and symptoms from serious to mild.

[0124] Another aspect of the present disclosure provides a method of reducing alcohol consumption in a human subject in need thereof, wherein the method comprisesadministering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein the method reduces a percentage of heavy drinking days experienced by the human subject over a period of time, compared to a corresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo over the same period of time. In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0125] Still another aspect provides a method of reducing alcohol consumption in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein the method reduces the number of standard unit drinks ingested per day by the human subject over a period of time, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is not administered a compound of this disclosure, such as, a subject who is administered a placebo over the same period of time. In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0126] Yet a further aspect of this disclosure provides a method of reducing alcohol consumption in a human subject identified in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein the method reduces the percentage of drinking days experienced by the human subject during a certain period of time, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0127] Another further aspect is directed to a method of reducing alcohol consumption in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure,wherein the method reduces the human subject’s WHO risk drinking level during a certain period of time, compared to the WHO risk drinking level of a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0128] In other aspects, the present disclosure is directed to a method of reducing alcohol craving in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein the method reduces the human subject’s urge to drink alcohol, compared to the urge experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. Such urge is evaluated by tools readily available in the field (e.g., through Alcohol Urge Questionnaire; “AUQ”). In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0129] Yet another aspect provides a method of reducing alcohol craving in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein the method decreases the human subject’s desire for alcohol, compared to the desire experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. Such desire for alcohol is evaluated by tools readily available in the field (e.g., evaluated by Desire for Alcohol Visual Analog Scale; “DFA-VAS”). In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0130] Yet a further aspect provides a method of reducing alcohol craving in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure, wherein themethod decreases level of anxiety (e.g., tension, anxiousness, and jittery feelings) experienced by the human subject, compared to the anxiety level experienced by a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. Such anxiety level experienced by a human subject is evaluated by tools readily available in the field (e.g., evaluated by Anxiety Visual Analog Scale; “Anxiety-VAS”). In one embodiment, the human subject has been identified (e.g., medically diagnosed) as having alcohol use disorder. In another embodiment, the human subject has not yet been identified as having alcohol use disorder.

[0131] In some embodiments of the methods as above described, the period of time to measure the reduction in alcohol consumption or craving in the human subject lasts, for example, a year, three months, one month, 10 weeks, 8 weeks, two weeks, one week, 3 days, or a certain fixed period time for observational study. Certain embodiments provide that the reduction achieved by the methods of this disclosure the human subject is, when numerical value is applicable, by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, or by at least about 50%, as measured by appropriate analytical methods, compared to a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. Certain embodiments provide that the reduction achieved by the methods of this disclosure the human subject is, when numerical value is applicable, by about 10%, by about 20%, by about 25%, by about 30%, by about 35%, by about 40%, by about 45%, or by about 50%, as measured by appropriate analytical methods, compared to a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time.

[0132] In certain embodiments of all the methods of this disclosure, the therapeutically effective amount of the compound of this disclosure (for example, Compound (IIC)) administered to a human subject as a daily dose is from about 0.1 mg to about 10 mg, from about 0.2 mg to about 8 mg, or about 0.5 mg to about 6 mg. In some embodiments, the therapeutically effective amount of the compound of this disclosure is orally administered to a human subject at a daily dose of about 0.5 mg, about 1 mg, or about 2 mg at bedtime. In certain embodiments, the therapeutically effective amount of thecompound of this disclosure is about 0.5 mg, about 1 mg, 1.5 mg, or about 2 mg. One example provides that the therapeutically effective amount of the compound of this disclosure is about 1 mg. Another example provides that the therapeutically effective amount of the compound of this disclosure is about 0.5 mg. In a further example, the therapeutically effective amount of the compound of this disclosure is about 2 mg.Sleep Disorders Associated with Alcohol Consumption

[0133] Alcohol use disorder (AUD) is known to cause dysfunction in motivational, mood-stress regulation and sleep systems that interact in complex ways to heighten the risk of relapse during abstinence. Emerging data suggest that excessive and chronic alcohol use disrupts the sleep homeostat.

[0134] In one aspect, the present disclosure is directed to a method of treating alcohol use disorder (AUD) in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt or solvate thereof, such as, Compound (IIC)), wherein the method improves the human subject’s sleep profile, compared to a similarly situated human subject who is not administered a compound of this disclosure, such as, a human subject who is administered a placebo over the same period of time. The sleep profile of a human subject can be evaluated by one or more assessments such as, Polysomnography (PSG), Consensus sleep diary (CSD), Penn Alcohol Craving Scale (PACS), Hospital Anxiety and Depression Scale (HADS), and Profile of Mood States (POMS). Such assessments can be standard in the field or have been modified according to the need of a study in the manner readily ascertainable to an ordinarily skilled artisan (e.g., a clinician).

[0135] In another aspect, the present disclosure provides a method for improving sleep profile in a human subject (who consumes alcohol) in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of a compound of this disclosure (e.g., Compound (IIC)), and wherein the method improves the human subject’s sleep, compared to a similarly situated human subject who is not administered with a compound of this disclosure, such as, a human subject, who is administered a placebo over the same period of time. In one embodiment, the human subject has been identified as having AUD. In another embodiment, the human subject has not been identified as having AUD.

[0136] In certain embodiments, this disclosure provides methods of treating sleep disorders associated with alcohol use, including such as, alcohol-induced sleep disorder and any / all of its subcategories: insomnia-type alcohol-induced sleep disorder, insomnia in AUD, daytime sleepiness type alcohol-induced sleep disorder, parasomnia type alcohol-induced sleep disorder, sleep disturbances associated with alcohol cessation, and / or insomnia associated with alcohol cessation. In alcohol-induced sleep disorder, there is evidence of intoxication or withdrawal from the alcohol and the sleep disorder is associated with intoxication, discontinuation, or withdrawal therefrom.

[0137] This disclosure provides methods for treating, alleviating, or preventing in a human subject identified in need an alcohol-related sleep disorder, including such as, insomnia-type alcohol-induced sleep disorder, mixed type alcohol-induced sleep disorder which includes insomnia-type alcohol-induced sleep disorder as a component, insomnia in AUD, and insomnia associated with alcohol cessation.

[0138] Additionally, in abstinence, human subjects with AUD are known to experience insomnia that may persist for weeks to years, referred to as insomnia associated with alcohol cessation (“IAAC”).

[0139] DSM-5 sets out alcohol-induced sleep disorder as a principal diagnosis and subdivides the sleep disorder into four types: insomnia, daytime sleepiness, parasomnia, and mixed type. It discloses that alcohol-induced sleep disorder typically occurs as “insomnia type”, that is, sleep disorder characterized by “difficulty falling asleep or maintaining sleep, frequent nocturnal awakenings, or nonrestorative sleep.” Specifically, Conroy 2006 discloses alcohol consumption has a “biphasic” effect on sleep within a night. That is, in the earlier portion of the night an alcohol dose can provide an immediate sedative effect with shorter LPS and an increased duration of Stage N3 sleep. However, in the later portion of the night sleep quality deteriorates and there is a greater NAW. Yet another reference concludes that virtually every type of sleep problem occurs in alcoholdependent patients, typically, a long LPS, low SE, short TST, reduced duration of Stage N3 sleep, fragmented sleep patterns, and severely disrupted sleep architecture (Landolt et ai, “Sleep Abnormalities During Abstinence in Alcohol -Dependent Patients: Aetiology and Management,” CNS Drugs 15 5 :413-425 (2001)).

[0140] Insomnia associated with alcohol cessation can be characterized as insomnia or the worsening of insomnia that occurs after a person with AUD abstains from alcoholconsumption. For example, a subject may not experience insomnia prior to alcohol abuse, then the subject engages in alcohol abuse that leads to AUD, and then after abstaining from alcohol the subject experiences insomnia associated with alcohol cessation. In another example, a subject may not experience insomnia prior to alcohol abuse, then the subject engages in alcohol abuse that leads to AUD and the subject begins to experience insomnia-type alcohol-induced sleep disorder, and then after abstaining from alcohol the subject experiences insomnia associated with alcohol cessation.

[0141] In another example, a subject may experience insomnia prior to alcohol abuse, then the subject engages in alcohol abuse that leads to AUD, and after abstaining from alcohol the subject experiences insomnia associated with alcohol cessation that is more severe than the insomnia the subject experienced prior to experiencing AUD.

[0142] In another example, a subject may experience insomnia prior to alcohol abuse, then the subject engages in alcohol abuse that leads to AUD such that the subject begins to experience insomnia-type alcohol-induced sleep disorder that includes worsening of insomnia, and after abstaining from alcohol the subject experiences insomnia associated with alcohol cessation that is more severe than the insomnia the subject experienced prior to experiencing AUD.

[0143] Under one classification scheme six broad categories of sleep disorders have been identified: (i) insomnia, (ii) hypersomnia, (iii) parasomnia, (iv) circadian rhythm sleepwake disorders, (v) sleep-related breathing disorders, and (vi) sleep movement disorders. Multiple subcategories are recognized within each of these broad categories. Each category and subcategory is defined as a disorder.

[0144] Under another classification scheme ten broad primary categories of sleep disorders have been identified: (1) insomnia disorder, (2) hypersomnolence disorder, (3) narcolepsy, (4) breathing-related sleep disorders, (5) circadian rhythm sleep-wake disorders, (6) non-REM sleep arousal disorders, (7) nightmare disorder, (8) REM sleep behavior disorder, (9) restless leg syndrome, and (10) substance / medication-induced sleep disorder. Multiple subcategories are recognized within each of these broad categories. Each category and subcategory is also defined as a disorder. For example, the disorder substance / medication-induced sleep disorder involves a prominent sleep disturbance that is sufficiently severe to warrant independent clinical attention and that is judged to be primarily associated with the pharmacological effects of a substance, e.g., alcohol (z.e.,ethyl alcohol). The substance / medication-induced sleep disorder includes insomnia-type substance / medication-induced sleep disorder, daytime sleepiness type substance / medication-induced sleep disorder, parasomnia type substance / medication- induced sleep disorder, and mixed type substance / medication-induced sleep disorder.The mixed type relates to more than one type of these sleep disturbance-related symptoms being present but none predominating.

[0145] Insomnia in recently detoxified patients with AUD is common and distinct from generalized insomnia. Symptoms are often sufficiently severe and prolonged, and may contribute to relapses in affected individuals. Although sleep improves with continued abstinence, relatively permanent alterations to the sleep centers of the brain from chronic alcohol exposure may produce persistent abnormalities that, in many cases, require medical treatment.

[0146] Sleep disturbances following alcohol detoxification are likely mediated by adenosine, and the effects may occur as early as the first week and may persist for months or longer. These adverse events include more frequent awakenings and worsening quality of sleep. Data from polysomnography studies demonstrates multiple disturbances in sleep continuity, architecture, and other parameters, associated with alcohol cessation, including the following:• shortened sleep cycles including alterations in both REM and non-REM sleep• increased sleep onset latency• increased stage 1 sleep (light sleep)• decreased total sleep time• decreased percentage of slow-wave sleep (the deepest stage of non-REM sleep)

[0147] Insomnia associated with alcohol cessation commonly occurs in the acute withdrawal phase (1 to 2 weeks), early recovery (2 to 8 weeks after detoxification), and in sustained recovery (3 or more months after the detoxification phase). In the acute withdrawal phase, sleep disturbances are variable and can improve over the detoxification period. During the early recovery phase, sleep-related disturbances may be accompanied by mild withdrawal symptoms, such as mood changes and alcohol craving, and can persist up to 5 weeks. During sustained recovery, sleep-related disturbances can persist up to 3 years or more. (See, e.g., Chakravorty, S., Chaudhary, N.S., Brower, K.J., 2016.“Alcohol Dependence and Its Relationship With Insomnia and Other Sleep Disorders.” Alcohol Clin Exp Res. 40(11), 2271-2282.)

[0148] Even alcoholics who have been abstinent, either for short periods of time (several weeks) or extended periods of time (several years), can experience persistent sleep abnormalities such as increased LPS, frequent MOTN awakening, and poor sleep quality. In summarizing the results of multiple studies, Brower 2001 concludes that alcoholics who had been abstinent for 2-8 weeks exhibited worse sleep than did non-alcoholics, that is, TST, SE, and the amount of time spent in Stage N3 sleep generally decreased significantly whereas Stage N1 sleep time usually increased and LPS increased significantly. Moreover, sleep abnormalities can persist for 1-3 years after alcohol consumption ends. For example, Brower 2001 concludes that sleep fragmentation, expressed as increases in sleep-stage changes, brief arousals, and REM sleep disruptions, can persist for 1-3 years after establishing sobriety. Diminished REM sleep time is understood to be associated with negative cognitive consequences, e.g., poor procedural learning.

[0149] Moreover, it is recognized that the consumption of alcohol can damage the human liver, a vital organ that filters harmful substances from the blood and manufactures various substances, such as hormones, proteins, and enzymes, that the body requires. Alcohol -related liver disease (“ALD”) is caused by excessive consumption of alcohol. Its mildest form, steatosis or fatty liver, is characterized by an excessive accumulation of fat inside liver cells, making liver functioning more difficult. A more severe form of ALD that can develop from steatosis is alcoholic hepatitis, either chronic or acute. It manifests as the inflammation or swelling of the liver accompanied by the destruction of liver cells and makes liver functioning even more difficult. The most severe form of ALD that can develop from excess alcohol consumption is alcoholic cirrhosis. It is characterized by the replacement of normal liver tissue with nonliving scar tissue. Alcoholic cirrhosis can be a life-threatening disease because of the associated severe impairment of liver functioning.

[0150] Many researchers have concluded that untreated sleep disturbances can contribute to the risk of alcohol relapse after a period of abstinence and that disturbed sleep is an important predictor of relapse (See, e.g., Arnedt, J.T., Conroy, D.A., Brower, K.J., 2007. “Treatment options for sleep disturbances during alcohol recovery.” J Addict Dis. 26(4), 41-54; Miller, M.B., Donahue, M.L., Carey, K.B., Scott-Sheldon, L.A.J., 2017. “Insomniatreatment in the context of alcohol use disorder: A systematic review and meta-analysis.” Drug and alcohol dependence. 181, 200-207; Roehrs, T., Roth, T., 2008 “Sleep and quality of life in medical illnesses,” in: Verster, J.C., Pandi-Perumal, S.R., Streiner, D.L. (Eds.), Sleep, alcohol, and quality of life. Humana Press, Totowa, NJ, pp. 333-339.). Subjective and objective indicators of sleep disturbances that have been evaluated in alcohol-dependent patients after the acute abstinence period, such as difficulty in falling asleep, decreased total sleep time, and decreased sleep efficiency, predict the likelihood of relapse during longer periods of abstinence. (Arnedt et al., 2007; Koob, G.F., 2008. “A role for brain stress systems in addiction.” Neuron. 59(1), 11-34.; Roehrs, T., Roth, T., 2017. “Principles and practice of sleep medicine,” in: Kryger, M.H., Roth, T., Dement, W.C. (Eds.), Medication and substance abuse. Elsevier, Philadelphia, PA, pp. 1380-1389; Roehrs and Roth, 2015).

[0151] In an early polysomnography study, Drummond et al. (1998) showed that persistently abnormal recordings of eye-movement density in REM sleep and REM latency in primary alcohol-dependent inpatients at 14 months were associated with alcohol relapse. Other relapse predictors in this study were an increase in sleep-onset latency, a reduction in the percentage of SWS, and a reduction in sleep efficiency. These researchers determined that persistent insomnia and sleep fragmentation after 5 months of abstinence predicted relapse over 14 months of sustained abstinence. (Drummond, S.P., Gillin, J.C., Smith, T.L., DeModena, A., 1998. “The sleep of abstinent pure primary alcoholic patients: natural course and relationship to relapse.” Alcohol Clin Exp Res.22(8), 1796-1802; Kolla, B.P., Bostwick, J.M., 2011. Insomnia: The neglected component of alcohol recovery.” J Addict Res Ther. 2(0e2).).

[0152] In certain embodiments, a method of this disclosure also treats or prevents a sleep disorder (e.g., insomnia) in the human subject. In certain embodiments, the therapeutically effective amount in treating or preventing the sleep disorder is the same dose used to treat AUD in the human subject. In other embodiments, the therapeutically effective amount in treating or preventing the sleep disorder is the same dose used to achieve and / or maintain alcohol abstinence in the human subject. In still other embodiments, the therapeutically effective amount in treating or preventing the sleep disorder is the same dose used to prevent relapse to alcohol drinking in the human subject.

[0153] The sleep disorder that can be treated or prevented includes alcohol-induced sleep disorder and any / all of its subcategories: insomnia-type alcohol-induced sleep disorder, daytime sleepiness type alcohol-induced sleep disorder, parasomnia type alcohol-induced sleep disorder, and mixed type alcohol-induced sleep disorder. In alcohol-induced sleep disorder, there is evidence of intoxication or withdrawal from the alcohol and the sleep disorder is associated with intoxication, discontinuation, or withdrawal therefrom. Other allied Disorders that can be treated and / or prevented include insomnia in AUD, sleep disturbances associated with alcohol cessation, and / or insomnia associated with alcohol cessation.

[0154] According to certain embodiments of this disclosure, the average sleep efficiency of the human subject administered daily with the therapeutically effective amount of the compound on two consecutive days is at least about 1.04 times of the average sleep efficiency of a human subject administered a placebo.

[0155] Other embodiments provide that average total sleep time of said human subject administered daily with the therapeutically effective amount of the compound on two consecutive days is at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 30 minutes, or at least one hour more than the average total sleep time of a human subject administered a placebo.

[0156] Still other embodiments provide that average wake after sleep onset (WASO) of said human subject administered daily with the therapeutically effective amount of the compound on two consecutive days is at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 30 minutes, or at least one hour less than the average WASO of a human subject administered a placebo.Compositions, Doses, Administration, and Kits

[0157] When administered to a human subject, a compound of this disclosure can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient.

[0158] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, oral, transmucosal, buccal, gingival, sublingual, intraocular, intracerebral, intravaginal, transdermal (e.g., via a patch), rectal, by inhalation, or topical, particularly to the ears,nose, eyes, or skin. In another embodiment, the method of administration is oral, parenteral, intravenous, intramuscular, intraocular, transdermal, or transmucosal.

[0159] In one embodiment, the method of administration is oral. In another embodiment, the method of administration is buccal, gingival, sublingual, or by a swallowed-intact oral dosage form. In a certain embodiment, the method of administration is by a swallowed- intact oral dosage form.

[0160] In another embodiment, the method of administration is intravenous. In another embodiment, the method of administration is by inhalation. The method of administration is left to the discretion of the practitioner. In some instances, administration will result in the release of a compound of this disclosure into the bloodstream. In other instances, administration will result in only local release of a compound of this disclosure thereof.

[0161] In certain embodiments, it can be desirable to introduce a compound of this disclosure into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, or epidural injection, or enema. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.

[0162] Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, a compound of this disclosure can be formulated as a suppository, with traditional binders and excipients such as triglycerides.

[0163] When a compound of the disclosure is incorporated for parenteral administration by injection (e.g., continuous infusion or bolus injection), the formulation for parenteral administration can be in the form of a suspension, solution, emulsion in an oily or aqueous vehicle. Such formulations can further comprise pharmaceutically necessary additives such as one or more stabilizing agents, suspending agents, dispersing agents, buffers, and the like. A compound of the disclosure can also be in the form of a powder for reconstitution as an injectable formulation.

[0164] In another embodiment, a compound of this disclosure can be delivered in a vesicle, in particular a liposome (see Langer, “New Methods of Drug Delivery,” Science 249: 1527-1533 (1990); and Treat etal., “Liposome Encapsulated DoxorubicinPreliminary Results of Phase I and Phase II Trials,” pp. 317-327 and 353-365 in Liposomes in the Therapy of Infectious Disease and Cancer (1989)).

[0165] In yet another embodiment, a compound of this disclosure can be delivered in a controlled-release system or sustained-release system. Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained-release counterparts.

[0166] In one embodiment, a controlled- or sustained-release composition comprises a minimal amount of a compound of this disclosure to treat AUD and / or to treat or prevent one or more other conditions afore-mentioned. In one embodiment, a controlled- or sustained-release composition comprises a therapeutically effective amount of a compound of this disclosure to treat AUD or a symptom associated with withdrawal from alcohol consumption in an extended amount of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosing frequency, and increased compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the compound of this disclosure and can thus reduce the occurrence of adverse side effects.

[0167] Controlled- or sustained-release compositions can initially, e.g., substantially immediately, release an amount of a compound of this disclosure that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the compound of this disclosure to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the compound of this disclosure, in the body, the compound of this disclosure can be released from the dosage form at a rate that will replace the amount of the compound of this disclosure being metabolized and excreted from the body. Controlled- or sustained- release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds. In yet another embodiment, a controlled- or sustained-release system can be placed in proximity of a target of a compound of this disclosure, e.g., the spinal column or brain, thus requiring only a fraction of the systemic dose.

[0168] Administration of a compound of this disclosure can be by controlled-release or sustained-release means or by delivery devices that are known to those in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Numerous other controlled-release or sustained-release delivery devices that are known to those in the art (see, e.g., Goodson, “Dental Applications,” in Medical Applications of Controlled Release, Vol. 2, Applications and Evaluation, Langer and Wise, eds., CRC Press, Chapter 6, pp. 115-138 (1984), hereafter “Goodson”). Other controlled- or sustained-release systems discussed in the review by Langer, Science 249: 1527-1533 (1990) can be used. In one embodiment, a pump can be used (Langer, Science 249: 1527-1533 (1990); Sefton, “Implantable Pumps,” in CRC Crit. Rev. Biomed. Eng. 14(3):201-240 (1987); Buchwald et al., “Long-term, Continuous Intravenous Heparin Administration by an Implantable Infusion Pump in Ambulatory Patients with Recurrent Venous Thrombosis,” Surgery 88:507-516 (1980); and Saudek et al., “A Preliminary Trial of the Programmable Implantable Medication System for Insulin Delivery,” New Engl. J. Med. 321 :574-579 (1989)).

[0169] In another embodiment, polymeric materials can be used (see Goodson; Smolen et al., “Drug Product Design and Performance,” Controlled Drug Bioavailability Vol. 1, John Wiley and Sons, New York (1984); Langer et al., “Chemical and Physical Structure of Polymers as Carriers for Controlled Release of Bioactive Agents: A Review,” J. Macromol. Sci. Rev. Macromol. Chem. C23(l): 61-126 (1983); Levy et al., “Inhibition of Calcification of Bioprosthetic Heart Valves by Local Controlled-Release Diphosphonate,” Science 228: 190-192 (1985); During et al., “Controlled Release of Dopamine from a Polymeric Brain Implant: In Vivo Characterization,” Ann. Neurol. 25:351-356 (1989); and Howard et al., “Intracerebral drug delivery in rats with lesion- induced memory deficits,” J. Neurosurg. 71 : 105-112 (1989)). International Patent Publication WO2020 / 157691 discloses various polymorphic forms of a compound of this disclosure, and thus is incorporated herein by its entirety.

[0170] Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, ethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, multiparticulates, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those in the art, including those described herein, can be readily selected for use with the active ingredients of the disclosure. The disclosure thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.

[0171] The compositions can optionally, but preferably, further comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal. Such a pharmaceutical excipient can be a diluent, suspending agent, solubilizer, binder, disintegrant, preservative, coloring agent, lubricant, and the like. The pharmaceutical excipient can be a liquid, such as water or an oil, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. The pharmaceutical excipient can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to an animal. Water is a particularly useful excipient when a compound of this disclosure is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, (Amer. Pharmaceutical Ass’n, Washington, DC, 1986), incorporated herein by reference. Other examples of suitable pharmaceutical excipients are described by Radebough et al., “Preformulation,” pp. 1447-1676 in Remington ’s Pharmaceutical Sciences Vol. 2 (Gennaro, ed., 19thEd., Mack Publishing, Easton, PA, 1995), incorporated herein by reference.

[0172] The compositions can take the form of solutions, suspensions, emulsions, tablets such as an orally disintegrating tablet (ODT), a sublingual tablet, or a swallowed-intact tablet, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, microparticles, multiparticulates, rapidly dissolving films or other forms for oral or mucosal administration, or any other form suitable for use. In one embodiment, the composition is in the form of an ODT (see, e.g., U.S. Pat. Nos. 7,749,533 and 9,241,910). In another embodiment, the composition is in the form of a sublingual tablet (see, e.g., U.S. Pat.Nos. 6,572,891 and 9,308,175). In another embodiment, the composition is in the form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). In another embodiment, the composition is in a form suitable for buccal administration, e.g., as a tablet, lozenge, gel, patch, or film, formulated in a conventional manner (see, e.g., Pather et al., “Current status and the future of buccal drug delivery systems,” Expert Opin. Drug Deliv. 5(5): 531-542 (2008)). In another embodiment, the composition is in a form suitable for gingival administration, e.g., as a polymeric film comprising polyvinyl alcohol, chitosan, polycarbophil, hydroxypropylcellulose, or Eudragit S-100, as disclosed by Padula et al., "In Vitro Evaluation of Mucoadhesive Films for Gingival Administration of Lidocaine,” AAPS PharmSciTech 14(4): 1279-1283 (2013). In another embodiment, the composition is in a form of a swallowed-intact oral dosage form. In another embodiment, the composition is in a form suitable for intraocular administration.

[0173] In one embodiment, the compounds of this disclosure are formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. A compound of this disclosure to be orally delivered can be in the form of tablets, capsules, gelcaps, caplets, lozenges, aqueous or oily solutions, suspensions, granules, microparticles, multiparticulates, powders, emulsions, syrups, or elixirs, for example. The oral dosage form can be a swallowed-intact oral dosage form, such as a tablet, capsule, or gelcap. When a compound of this disclosure is incorporated into oral tablets, such tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, multiply compressed, or multiply layered. Techniques and compositions for making solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman et al., eds., 2ndEd., Marcel Dekker, Inc., 1989 and 1990). Techniques and compositions for making tablets (compressed and molded), capsules (hard and softgelatin) and pills are also described by King, “Tablets, Capsules, and Pills,” pp. 1553- 1593 in Remington ’s Pharmaceutical Sciences (Osol, ed., 16thEd., Mack Publishing, Easton, PA, 1980).

[0174] Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, and solutions and / or suspensions reconstituted from non-effervescent granules, optionally containing one or more suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, flavoring agents, and the like. Techniques and composition for making liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman el al., eds., 2ndEd., Marcel Dekker, Inc., 1996 and 1998).

[0175] An orally administered compound of this disclosure can contain one or more agents, for example, sweetening agents such as fructose, aspartame, or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol mono-stearate or glycerol stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0176] When a compound of this disclosure is to be injected parenterally, it can be, e.g., in the form of an isotonic sterile solution. Alternatively, when a compound of this disclosure is to be inhaled, it can be formulated into a dry aerosol or can be formulated into an aqueous or partially aqueous solution.

[0177] In another embodiment, the compounds of this disclosure can be formulated for intravenous administration. In certain embodiments, compositions for intravenousadministration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. A compound of this disclosure, for intravenous administration can optionally include a local anesthetic such as benzocaine or prilocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where a compound of this disclosure is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where a compound of this disclosure is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0178] The effective amount of the compound of this disclosure that is effective for achieving the desired therapeutic effects (e.g., treating AUD) can be determined by standard clinical techniques. In addition, in vitro and / or in vivo assays can optionally be employed to help identify optimal dose ranges. The precise dose to be employed will also depend on, e.g., the route of administration and the seriousness of the disorder, and can be decided according to the judgment of a clinician or a physician. In other examples thereof, variations will necessarily occur depending upon the weight and physical condition (e.g., hepatic and renal function) of the animal (e.g., human subject) being treated, the disorder to be treated, the severity of the symptoms, the frequency of the dosing interval, the presence of any deleterious side-effects, and the particular compound utilized, among other things.

[0179] In one embodiment, a therapeutically effective amount of the compound of this disclosure administered to a human subject as a daily dose is from about 0.10 mg to about 10.0 mg, from about 0.2 mg to about 8.0 mg, or about 0.5 mg to about 6.0 mg. In other embodiments, the therapeutically effective amount of the compound of this disclosure, administered to a human subject as a daily dose is from about 0.2 mg to about 8.0 mg, from about 0.2 mg to about 7.0 mg, from about 0.2 mg to about 6.0 mg, from about 0.2 mg to about 5.5 mg, from about 0.2 mg to about 5.0 mg, from about 0.2 mg to about 4.5 mg, from about 0.2 mg to about 4.0 mg, from about 0.2 mg to about 3.5 mg, from about 0.2 mg to about 3.0 mg, from about 0.2 mg to about 2.5 mg, about 1.0 mg, 0.25 mg toabout 8.0 mg, from about 0.25 mg to about 7.0 mg, from about 0.25 mg to about 6.0 mg, from about 0.5 mg to about 6.0 mg, from about 0.5 mg to about 5.5 mg, from about 0.5 mg to about 5.0 mg, from about 0.5 mg to about 4.5 mg, from about 0.5 mg to about 4.0 mg, from about 0.5 mg to about 3.5 mg, from about 0.5 mg to about 3.0 mg, from about 0.5 mg to about 2.5 mg, from about 0.5 mg to about 2.0 mg, from about 0.5 mg to about 1.8 mg, from about 0.5 mg to about 1.6 mg, from about 0.5 mg to about 1.5 mg, from about 0.5 mg to about 1.4 mg, from about 0.5 mg to about 1.3 mg, from about 0.5 mg to about 1.2 mg, from about 0.5 mg to about 1.1 mg, from about 0.5 mg to about 1.0 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, or about 3.0 mg. In any of these embodiments, the daily dose is optionally a single daily dose. In any of these embodiments, the daily dose is optionally a divided daily dose, e.g., 67%, 60% 50%, 40%, or 33% of any of the above doses is administered before the intended bedtime and the remaining 33%, 40%, 50%, 60%, or 67%, respectively, is administered either earlier or later during the daily period.

[0180] It is to be understood that the term “daily” means a 24 hour cycle beginning at the time of administration of a compound of this disclosure. For example, for an ordinary overnight sleep cycle, if a compound of this disclosure is administered at 9:30 PM, then that “day” ends at 9:29 PM on the following calendar day. In another example, for a shift- worker’ s sleep cycle if a compound of this disclosure is administered at 8: 15 AM, then that “day” ends at 8: 14 AM on the following calendar day.

[0181] As known to those in the art, for a human a daily dose (in mg) can be converted to a mg / kg / day dosage amount by dividing the mg dose by 60 kg, an art-recognized average mass of a human. For example, a daily human dose of 1.25 mg is so-converted to a dosage amount of about 0.021 mg / kg / day.

[0182] The effective amount described herein refer to total amounts (in terms of free acid or free base form) administered; that is, if more than one compound of this disclosure is administered, the effective dosing amount corresponds to the total amount administered.

[0183] Administration can be as a single dose or as a divided dose. In one embodiment, an effective amount is administered only as needed (pro re nata). In another embodiment, an effective amount is administered about every 24 hours, for example, before the intended bedtime. In other embodiments, an effective amount is administered before the intended bedtime on 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12, up to 14,14, at least 14, up to 21, 21, at least 21, up to 28, 28, at least 28, up to 34, 34 at least 34, up to 40, 40, at least 40, up to 50, 50, at least 50, up to 60, 60, at least 60, up to 75, 75, at least 75, up to 90, 90, at least 90, up to 120, 120, at least 120, up to 150, 150, at least 150, up to 180, 180, at least 180, up to 270, 270, at least 270, up to 360, 360, or on at least 360 consecutive days to treat AUD, or to prevent relapse to alcohol consumption, or to reduce alcohol consumption, or to decrease alcohol craving, or to abate a sleep disorder associated with alcohol use, or for another method of this disclosure. In other embodiments, an effective amount is administered before the intended bedtime daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12, up to 16, 16, at least 16, up to 26, 26, at least 26, up to 52, 52, at least 52 weeks. In other embodiments, an effective amount is administered before the intended bedtime daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12 months. In any of these embodiments, the daily dose is optionally a single daily dose.

[0184] In another embodiment, an effective amount is administered in advance of a drinking or social event, which can be, e.g., about 90 minutes, about 75 minutes before, about 60 minutes before, about 45 minutes before, about 30 minutes before, about 20 minutes before, about 20 minutes or less before, about 15 minutes before, about 15 minutes or less before, about 10 minutes before, about 10 minutes or less before, about 5 minutes before, about 5 minutes or less before, about 2 minutes before, about 2 minutes or less before, or about 1 minute before the intended time or event.

[0185] In another embodiment, an effective amount is administered in preparation for sleep, which can be, e.g., from about 90 minutes before to about 30 minutes, from about 60 minutes before to about 30 minutes before, from about 45 minutes before to about 30 minutes before, from about 90 minutes before to about 20 minutes before, from about 60 minutes before to about 20 minutes before, from about 45 minutes before to about 20 minutes before, from about 30 minutes before to about 20 minutes before, from about 90 minutes before to about 15 minutes before, from about 90 minutes before to about 10 minutes before, from about 60 minutes before to about 10 minutes before, from about 45 minutes before to about 10 minutes before, from about 30 minutes before to about 10 minutes before, from about 20 minutes before to about 10 minutes before, from about 15 minutes before to about 10 minutes before, from about 90 minutes before to about 5 minutes before, from about 60 minutes before to about 5 minutes before, from about 45minutes before to about 5 minutes before, from about 30 minutes before to about 5 minutes before, from about 20 minutes before to about 5 minutes before, from about 15 minutes before to about 5 minutes before, from about 10 minutes before to about 5 minutes before the intended bedtime, or from about 90, 75, 60, 45, 30, 20, 15, or 10 minutes before the intended bedtime to about the intended bedtime.

[0186] In one embodiment, an effective amount is administered daily to prevent relapse to alcohol drinking in a human subject after alcohol cessation. In one embodiment, the effective amount is administered before the bedtime also treats or prevents insomnia associated with alcohol cessation. In another embodiment, an effective amount is administered starting after alcohol consumption is ceased (e.g., after a subject with AUD begins abstaining from alcohol consumption). In other embodiments, an effective amount is administered starting at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12, up to 14, 14, at least 14, up to 21, 21, at least 21, up to 28, 28, at least 28, up to 34, 34 at least 34, up to 40, 40, at least 40, up to 50, 50, at least 50, up to 60, 60, at least 60, up to 75, 75, at least 75, up to 90, 90, at least 90, up to 120, 120, at least 120, up to 150, 150, at least 150, up to 180, 180, at least 180, up to 270, 270, at least 270, up to 360, 360, or at least 360 days after alcohol consumption ceases. In other embodiments, an effective amount is administered starting at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12, up to 16, 16, at least 16, up to 26, 26, at least 26, up to 52, 52, at least 52 weeks after alcohol consumption ceases. In other embodiments, an effective amount is administered starting at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12 months after alcohol consumption ceases. In any of these embodiments, the daily dose is optionally a single daily dose.

[0187] In another embodiment, an effective amount that is administered starting after alcohol consumption is ceased can continue to be administered after alcohol is consumed (e.g., a subject who has abstained from alcohol consumes alcohol). In another embodiment, an effective amount is administered before alcohol consumption is ceased (e.g., while subject with AUD continues to consume). In these embodiments, the methods of this disclosure reduce the amount and / or frequency of the alcohol consumption by the human subject.

[0188] A compound of this disclosure can be administered to a human subject who has ingested alcohol or a human subject may ingest alcohol following administration of thecompound. In an embodiment, the amount of ethanol ingested is about 0.05 g / kg to about 5.0 g / kg; about 0.05 g / kg to about 2.0 g / kg; about 0.05 g / kg to about 1.0 g / kg; about 0.05 g / kg to about 0.5 g / kg; about 0.05 g / kg to about 0.2 g / kg; about 0.2 g / kg to about 5.0 g / kg; about 0.2 g / kg to about 2.0 g / kg; about 0.2 g / kg to about 1.0 g / kg; about 0.2 g / kg to about 0.8 g / kg; about 0.2 g / kg to about 0.5 g / kg; about 0.5 g / kg to about 5.0 g / kg; about 0.5 g / kg to about 2.0 g / kg; about 0.5 g / kg to about 1.0 g / kg; or about 0.5 g / kg to about 0.8 g / kg-

[0189] In one embodiment, a composition comprising a compound of this disclosure in accordance with the disclosure is used as a medicament. In another embodiment, compositions comprising a compound of this disclosure, are disclosed which can be used for preparing a medicament containing said compositions.

[0190] For any of these uses, the composition comprising a compound of this disclosure can further comprise a second therapeutic agent in the medicament.

[0191] The methods in accordance with this disclosure can further comprise coadministering to the human subject being administered a compound of this disclosure (z.e., a first therapeutic agent), a second therapeutic agent. In one embodiment, the second therapeutic agent is administered in an effective amount.

[0192] An effective amount of the second therapeutic agent will be known to those skilled the art depending on the agent. However, it is well within the skilled artisan’s purview to determine the second therapeutic agent’s optimal effective-amount range in view of this disclosure. A compound of this disclosure and the second therapeutic agent combined can act either additively or synergistically to treat a disorder or a symptom afore-mentioned, or they may act independently of each other such that the compound of this disclosure treats or prevents a first disorder, and the second therapeutic agent treats or prevents another disorder, which can be the same as or different from the first disorder. In one embodiment of the disclosure, where a second therapeutic agent is co-administered to a human subject for treatment of a disorder (e.g., AUD), the minimal effective amount of the compound of this disclosure can be less than its minimal effective amount would be where the second therapeutic agent is not administered. In this embodiment, the compound of this disclosure and the second therapeutic agent can act synergistically to treat or prevent the disorder described herein.

[0193] In one embodiment, a compound of this disclosure is administered concurrently with a second therapeutic agent as a single composition comprising an effective amount of a c compound of this disclosure an effective amount of the second therapeutic agent. Alternatively, a composition comprising an effective amount of a compound of this disclosure and a second composition comprising an effective amount of the second therapeutic agent are concurrently administered. In another embodiment, an effective amount of a compound of this disclosure is administered prior or subsequent to administration of an effective amount of the second therapeutic agent. In this embodiment, the compound of this disclosure is administered while the second therapeutic agent exerts its therapeutic effect, or the second therapeutic agent is administered while the compound of this disclosure exerts its therapeutic effect for treating or preventing a disorder described herein.

[0194] The second therapeutic agent can be, but is not limited to, an agent to treat AUD, an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraine agent, a second sedative or hypnotic, an anti-cancer agent, an agent for treating or preventing UI, an agent for treating or preventing anxiety, an agent for treating or preventing a memory disorder, an agent for treating or preventing obesity, an agent for treating or preventing constipation, an agent for treating or preventing cough, an agent for treating or preventing diarrhea, an agent for treating or preventing high blood pressure, an agent for treating or preventing epilepsy, an agent for treating or preventing anorexia / cachexia, an agent for treating or preventing drug abuse, an agent for treating or preventing an ulcer, an agent for treating or preventing IBD, an agent for treating or preventing IBS, an agent for treating or preventing addictive disorder, an agent for treating or preventing Parkinson’s disease and parkinsonism, an agent for treating or preventing a stroke, an agent for treating or preventing a seizure, an agent for treating or preventing a pruritic condition, an agent for treating or preventing psychosis, an agent for treating or preventing Huntington’ s chorea, an agent for treating or preventing a cognitive disorder, an agent for treating or preventing a migraine, an agent for inhibiting vomiting, an agent for treating or preventing depression, an agent for treating or preventing alcohol use disorder, or any mixture thereof.

[0195] Examples of useful therapeutic agents for treating or preventing alcohol use disorder, include, but are not limited to disulfiram, naltrexone, acamprosate, gabapentin, topiramate, nalmefenem, naloxone, fluoxetine, and quetiapine.

[0196] Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts or solvates thereof, or any mixture thereof.

[0197] In certain embodiments, the opioid agonist is codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts or solvates thereof, or any mixture thereof.

[0198] Examples of useful non-opioid analgesics include, but are not limited to, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, a pharmaceutically acceptable salt thereof, or any mixture thereof. Other suitable non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs; salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesiumtrisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); alkanones, including nabumetone; a pharmaceutically acceptable salt thereof; or any mixture thereof. For a more detailed description of the NSAIDs, see Insel, “Analgesic- Antipyretic and Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout,” pp. 617-657 in Goodman and Gilman ’s The Pharmacological Basis of Therapeutics (Goodman el al.. eds., 9thEd., McGraw-Hill, New York 1996), and Hanson, “Analgesic, Antipyretic and Anti-Inflammatory Drugs,” pp. 1196-1221 in Remington: The Science and Practice of Pharmacy Vol. / / (Gennaro, ed., 19thEd., Mack Publishing, Easton, PA, 1995), which are hereby incorporated by reference in their entireties.

[0199] Examples of useful second sedatives or hypnotics include, but are not limited to, benzodiazepines, including lorazepam, temazepam, and triazolam; barbiturates, including phenobarbital, pentobarbital, and secobarbital; so-called “z-drugs,” including zaleplon, zolpidem, and zopiclone; ramelteon; suvorexant; a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0200] Examples of useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0201] Examples of useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin, aloxidone, aminoglutethimide, 4-amino-3 -hydroxybutyric acid, atrolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, 5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide, sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, zonisamide, a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0202] Examples of useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, dicyclomine, a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0203] Examples of useful therapeutic agents for treating or preventing anxiety include, but are not limited to, benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non-benzodiazepine agents, such as buspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, and thiopental; propanediol carbamates, such as meprobamate and tybamate; a pharmaceutically acceptable salt thereof; or any mixture thereof.

[0204] Examples of useful therapeutic agents for treating or preventing diarrhea include, but are not limited to, diphenoxylate, loperamide, a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0205] Examples of useful therapeutic agents for treating or preventing epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, y vinyl GABA, acetazolamide, felbamate, a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0206] Examples of useful therapeutic agents for treating or preventing drug abuse include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist, 3 -phenoxypyridine, levomethadyl acetatehydrochloride, serotonin antagonists, a pharmaceutically acceptable salt thereof, or any mixture thereof.

[0207] Examples of non-steroidal anti-inflammatory agents, 5 -lipoxygenase inhibitors, anti-emetics, P-adrenergic blockers, antidepressants, and anti -cancer agents are known in the art and can be selected by those skilled in the art. Examples of useful therapeutic agents for treating or preventing memory disorder, obesity, constipation, cough, high blood pressure, anorexia / cachexia, an ulcer, IBD, IBS, addictive disorder, Parkinson’s disease and parkinsonism, a stroke, a seizure, a pruritic condition, psychosis, Huntington’s chorea, a cognitive disorder, a migraine, depression, and / or treating, preventing or inhibiting vomiting include those that are known in the art and can be selected by those skilled in the art.

[0208] A composition of the disclosure is prepared by a method comprising admixing a compound of this disclosure, with a pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods known for admixing a compound (or derivative) and a pharmaceutically acceptable carrier or excipient. In one embodiment, the compound of this disclosure is present in the composition in an effective amount.

[0209] The disclosure further provides kits that can simplify the handling and administration of a compound of this disclosure to a human subject.

[0210] A typical kit of the disclosure comprises a unit dosage form of a compound of this disclosure. In one embodiment, the unit dosage form is suitable for oral administration such as, but not limited to, a capsule, a gelcap, a caplet, or a tablet, such as an ODT or a swallowed-intact tablet. In another embodiment, the unit dosage form comprises a first container, which can be sterile, containing an effective amount of a compound of this disclosure, and a pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed specific instructions for the use of the compound of this disclosure to treat or prevent one or more disorders or conditions as above described, including such as, AUD. The kit can further comprise a unit dosage form of a second therapeutic agent, for example, a second container containing an effective amount of the second therapeutic agent and a pharmaceutically acceptable carrier or excipient. In another embodiment, the kit comprises a container containing an effective amount of a compound of this disclosure an effective amount of a second therapeutic agent and apharmaceutically acceptable carrier or excipient. Examples of second therapeutic agents include, but are not limited to, those listed above.

[0211] Kits of the disclosure can further comprise a device useful for administering the unit dosage form. Examples of such a device include, but are not limited to, a syringe, a drip bag, a patch, an inhaler, an injection device (e.g., autoinjector), and an enema bag.

[0212] The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, that would be within the purview of those skilled in the art, and changes in formulation or changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.EXAMPLES

[0213] Certain examples below relate to methods for treating or preventing a condition (e.g., AUD) as afore-mentioned by administering a compound of this disclosure to a human in need of such treatment.Example 1: Study to assess the safety / tolerability and pharmacokinetics (PK) of Compound (IIC)

[0214] Following single-dose oral administration, Compound of formula (IIC) (abbreviated as “Cpd (IIC)” or “Compound (IIC)”) showed approximately doseproportional exposure up to 10 mg as defined by area under the concentration-time curve (AUC) and up to 2 mg as defined by maximum observed plasma concentration (Cmax). No increase in exposure at dose levels equal or higher than 10 mg was apparent after a single oral dose. Once daily dosing of Compound (IIC) for 14 days showed approximately doseproportional exposure, as defined by both AUC and Cmax, up to 10 mg with no apparent accumulation observed.

[0215] The most common treatment emergent adverse events reported in human studies have been somnolence and headache. No death or serious adverse event has been reported.

[0216] In nondependent, recreational, polydrug users with history of central nervous system depressant use, 1 mg of Compound (IIC) and placebo were associated withstatistically significant lower potential for abuse and reduced cognitive / motor impairment compared with the two supratherapeutic doses of Compound (IIC) (6 mg, 10 mg), and triazolam (0.5 mg, 1 mg). Compound (IIC) 1 mg met the FDA statistical criterion for similarity to placebo.

[0217] In a study conducted to assess the safety / tolerability and pharmacokinetics (PK) of Compound (IIC) (2 mg and 6 mg dose) with co-administered alcohol, a dose-effect relationship in the magnitude and duration of impairment was observed for most psychomotor / cognitive performance parameters evaluated. Additive or greater than additive effects of Compound (IIC) with alcohol treatments were observed for most psychomotor / cognitive performance parameters up to 6 hours post-dose. There was no notable PK interaction between Compound (IIC) and alcohol. Single oral doses of Compound (IIC) were otherwise safe and tolerated when administered alone or in combination with alcohol in healthy subjects.

[0218] In healthy volunteers evaluated for next day residual drug effects, a dose dependent impairment of cognitive and motor function was observed after evening administration of Compound (IIC) at doses of 0.2 mg, 0.6 mg, 2 mg and 6 mg. The greatest decreases from baseline were generally observed from 8 to 16 hours after administration of 2 mg and 6 mg Compound (IIC).

[0219] Single-dose exposures range from 1 mg to 30 mg of Compound (IIC) and highest multiple-dose exposures include 14-day treatment with 10 mg in healthy volunteers and 28-day treatment with 2 mg in subjects with alcohol use disorder. Compound (IIC) exhibited fast absorption and rapid elimination with a mean time to reach the maximum observed plasma concentration (Tmax) of about 1.5 hours and a mean apparent terminal half-life (ti / 2) between 2 to 3 hours. Renal elimination is the major elimination pathway for Compound (IIC) with nearly 100% of unchanged drug recovered in urine within 48 hours. No major metabolite has been identified in human plasma.Example 2: Study to assess the safety / tolerability and pharmacokinetics (PK) of Compound (IIC) in insomnia patients and in subjects who are with DSM-5 alcohol use disorder and sleep disorders

[0220] In subjects with DSM-5 insomnia disorder, Compound (IIC) doses of 0.5 mg, 1 mg, 3 mg, 6 mg and 10 mg administered as single doses improved sleep efficiency, decreased latency to persistent sleep, decreased wakefulness after sleep onset, increasedtotal sleep time, and reduced numbers of awakenings as measured by polysomnography (PSG).

[0221] In subjects with DSM-5 alcohol use disorder self-reporting alcohol abstinence for proceeding 3 weeks to 6 months, doses of 1 mg and 2 mg Compound (IIC) administered daily at bedtime improved several sleep endpoints as measured by polysomnography. Somnolence was the most frequently reported event in subjects treated with 1 mg (2 of 38 subjects; 5%) and 2 mg (10 of 38 subjects; 26%) of Compound (IIC).Example 3: A Two-part, Randomized, Double-blind, Placebo-controlled, Parallel- group Phase 2 Study to Evaluate Impact of Compound (IIC) on Alcohol Consumption (Part A) and Alcohol Craving (Part B) in Subjects Diagnosed with Moderate to Severe Alcohol Use Disorder and Seeking Treatment.

[0222] Part A is a randomized, double-blind, parallel group, placebo-controlled phase 2 study to evaluate the impact of Compound (IIC) on alcohol consumption in subjects diagnosed with moderate to severe alcohol use disorder and seeking treatment.

[0223] Part B is a randomized, double-blind, parallel group, placebo-controlled phase 2 study to evaluate the impact of Compound (IIC) on alcohol craving in subjects diagnosed with moderate to severe alcohol use disorder and seeking treatment.

[0224] The overall study designs are presented in Fig. 1A and Fig. IB.PART A: Alcohol ConsumptionStudy Design and Methodology:

[0225] The study has the following periods:

[0226] 1. Screening Period: up to 1-week and includes, after providing written informed consent, assessing inclusion / exclusion criteria. All protocol-specific activity which is not part of the normal clinical practice of the site must be performed only after obtaining the subject’s consent. The screening period may be extended by 30 days to allow for washout of prohibited medications, if applicable, though subjects who are taking prohibited medications should not discontinue medically indicated treatments to meet criteria for study participation. However, there are no minimum number of days for screening, and subjects may be randomized as soon as eligibility is confirmed.

[0227] 2. Baseline Visit (Dav 0): Eligible subjects are randomized to double-blind treatment (Compound (IIC) 0.5 mg, Compound (IIC) 1.0 mg, Compound (IIC) 2.0 mg, or placebo) maintaining a 1 : 1 : 1 : 1 ratio allocation.

[0228] 3 Double-blind Treatment Period: 8-week double blind treatment period during which subjects ingest study medication every day at bedtime starting at bedtime on the day of the Baseline visit and continue up to the End of Study visit. Each day of the double treatment period, subjects complete the daily dosing eDiary. At the protocol- specified clinic and telephone visits additional procedures including questionnaires and lab assessments are completed.

[0229] 4. End of study (EOS): Study procedures are performed for all subjects who complete study.

[0230] 5. Early termination (ET): End of Study procedures are performed for all subjects who early terminate from study. Additionally, these subjects are asked to return to the clinical site to complete the Timeline Followback interview at week 8 of the study regardless of when they discontinued the study.

[0231] 6. Follow-up Period: 7-day safety follow up visit after the last dose of study medication to evaluate discontinuation-emergent adverse events.Number of Subjects and Study Population:

[0232] The sample size is designed to provide sufficient data to assess the potential efficacy, safety and tolerability of the investigational treatment. Approximately 200 subjects (~50 per treatment group) are screened to randomize to give at least 45 subjects per group to complete the 8-week double-blind period.

[0233] Subjects must meet all inclusion criteria and none of the exclusion criteria (below) before they participate in the study, and also only those who have completed all prerandomization assessments (in SoA) are eligible for randomization.Inclusion Criteria:

[0234] 1. Male and females age > 18 years.

[0235] 2. Current diagnosis of moderate or severe alcohol use disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders 5thedition Text Revision (DSM-V-TR) and confirmed by Structured Clinical Interview for DSM Disorders Research Version (SCID-5).

[0236] 3. Currently seeking treatment for alcohol use disorder.

[0237] 4. Has > 4 heavy drinking days (HDD) in each of the 4 weeks prior to baseline visit defined as >4 standard drinks per day for females and >5 standard drinks per day for males as assessed by Timeline Followback interview. A standard drink is defined as 12 ounces (-355 mL) of 5% beer, 5 ounces (150 mL) of 12% wine, or 1.5 ounces (44 mL) of 80-proof (40%) distilled spirits.

[0238] 5. Males and females:- A male subject with a heterosexual partner who is a woman of childbearing potential must either be vasectomized or agree to use condoms during the trial and for 30 days following the treatment period.- A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:• Not a woman of childbearing potential (WOCBP). Females who are postmenopausal must have been postmenopausal > 1 year and have elevated serum FSH.• Female subjects of childbearing potential must agree to use a reliable method of contraception with a failure rate of less than 1 % per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intra uterine devices [IUDs], heterosexual abstinence or vasectomized partner during the trial and for 30 days following the treatment period. A female is considered to be of childbearing potential unless she has had a hysterectomy, has undergone tubal ligation or is at least one year post-menopausal with elevated serum FSH.

[0239] 6. Willing to be compliant with the protocol (including dosing instructions, daily electronic diary completion and clinic visit attendance) and are able to read and understand questionnaires.Exclusion Criteria:

[0240] 1. Subjects that meet current DSM-5 criteria for moderate or severe substance use disorder other than alcohol and nicotine.

[0241] 2. Subjects with clinically unstable medical, neurologic or psychiatric conditions, or any other medical condition that, in the investigator’s opinion, is inadequately treated and precludes entry into the study. Minor or well-controlled medical conditions that in the opinion of the investigator would not affect the subject’s safety or interfere with study assessments may be allowed.

[0242] 3. Subjects at significant risk of acute withdrawal syndrome in the opinion of the investigator; or, score > 8 on the Clinical Institute Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar) at screening; or had prior seizures (other than febrile seizure) or other conditions that would place the patient at increased risk of seizure, or are taking anticonvulsants.

[0243] 4. Subjects who are prescribed prohibited medications for medical or psychiatric indications (see Table 1).

[0244] 5. Subjects with clinically significant kidney disease or abnormal kidney function or screening estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0245] 6. Subjects with clinically significant liver disease or abnormal liver function or screening value >3 times the upper limit of normal for aspartate transaminase (AST / SGOT) or alanine transaminase (ALT / SGPT) or a screening bilirubin value >1.5 mg / dL.

[0246] 7. Subjects with a screening electrocardiogram showing a QTcF value (QT data corrected for heart rate using the Fridericia formula) of > 470 msec for females or > 450 msec for males, or other ECG findings that, in the investigator’s opinion, would preclude participation in the study.

[0247] 8. Subjects with suicidal ideation associated with actual intent and a method or plan in the past 1 year (“Yes” answer on items 4 or 5 of the C-SSRS); subjects with active suicidal ideation (“Yes” answer on items 2 or 3 of the C-SSRS); a previous history of suicidal behaviors in the past 2 years (“Yes” answer to any of the suicidal behavior items of the C-SSRS), or any lifetime history of serious or recurrent suicidal behavior.

[0248] 9. Subjects that have used of an investigational drug within 30 days (90 days for biologies) or participation in an investigational study within 30 days prior to screening.

[0249] 10. Females who are pregnant or lactating or planning to become pregnant during the study.

[0250] 11. Subjects who have ongoing legal issues that require abstinence from alcohol or have legal charges that have the risk of incarceration during the study period.

[0251] 12. Subjects that do not have a stable living situation or plan to move during the study period.

[0252] 13. Subjects who, in the opinion of the investigator, are unsuitable to participate in this study for any other reason.Treatment, Dose, and Mode of Administration:

[0253] Take 1 tablet daily at bedtime (time at which the subject goes to bed). Swallow the tablet whole with a drink of water. Take tablet immediately prior to going to bed; allow a period of at least 10 hours after taking this medication before engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle. The study medication should not be taken with alcohol.• Compound (IIC) 0.5 mg, tablet, oral administration at bedtime• Compound (IIC)) 1.0 mg, tablet, oral administration at bedtime• Compound (IIC) 2.0 mg, tablet, oral administration at bedtime• Placebo, tablet, oral administration at bedtimeConcomitant Medication:

[0254] Medications for chronic conditions may be allowed on a case-by-case basis if the subject is on a stable dose / regimen throughout study participation and are expected to continue this dose / regimen during study and require consensus of investigator and Medical Monitor. Stable, prescribed antidepressants and anti-anxiety medication to treat co-occurring psychiatric disorders is allowed on a case-by-case basis and require consensus of investigator and Medical Monitor.Prohibited Medications / Therapy:

[0255] Eligible subjects who are currently taking a prohibited medication / therapy may begin a washout prior to randomization. The washout period for AUD medications / therapies is 30 days and all other prohibited medications is the longer of 7 days or 5 half-lives. Exceptions are made on a case-by-case basis and require consensus of investigator and Medical Monitor. If a medication / therapy is not listed but does fit intoa class of medications noted, the Medical Monitor must be consulted to determine whether it is permitted or not.

[0256] The following medications in the table are prohibited during the study:Table 1Duration of Treatment and Study Duration:

[0257] Total study duration is approximately 10 weeks (consisting of 1-week screening, 8-week double-blind treatment period, and 1-week safety follow-up period). Screening may be up to 4 weeks (e.g., washout).Efficacy Assessments:

[0258] Daily alcohol consumption as reported by subject in Timeline Followback (TLFB) interview from which the following metrics are calculated:- percent heavy drinking days (HDD)- number of standard unit drinks ingested per day- percent of days drinking (PDD) / percent days abstinent (PDA)- WHO risk level of alcohol consumption

[0259] Evaluation of global impressions by investigator, quality of life by subject, cognitive aspects of alcohol craving by subject, alcohol withdrawal symptoms by subject, and sleep by subject.- Obsessive-Compulsive Drinking Scale (OCDS)- Insomnia Severity Index (ISI)- Alcohol Withdrawal Symptom Checklist, modified (AWCS-m)- Clinical Global Impressions-Improvement (CGI-I) scale- Clinical Global Impressions-Severity (CGI-S) scale- Montgomery- Asberg Depression Rating Scale (MADRS)- WHOQOL-BREF Quality of Life AssessmentSafety Assessments:- AEs, Labs, ECGs, Vital signs, Columbia Suicide Severity Rating Scale (C- SSRS), Discontinuation Emergent Signs and Symptoms (DESS).Efficacy Analyses:

[0260] Listings, tables, and figures of efficacy variables are based on the full analysis population.Primary Efficacy Analyses:

[0261] Use Timeline Followback interview to assess percent heavy drinking days (HDD). The baseline, postbaseline, and change from baseline of the response variable is summarized by treatment group using descriptive statistics and presented graphically.

[0262] The analysis comparing Compound (IIC) to placebo is conducted utilizing a mixed effects model with repeated measures (MMRM). The MMRM model includestreatment, time, treatment*time, baseline and site as fixed effects, with subjects fitted as random effects. Baseline covariates may include but not limited to disease severity, time since last drink, sleep disturbance. Details are pre-specified in statistical analysis plan (SAP) prior to locking study database. Unstructured covariance matrix is used for the model. 90% confidence intervals (Cis) and p-values comparing the active treatments and placebo are presented. Figures of the LS mean change from baseline along with 90% Cis, are presented by treatment group and visit.

[0263] Key Secondary Analyses undergo analysis in a manner consistent with the primary efficacy endpoint.Other Secondary Efficacy Analyses:

[0264] Secondary efficacy endpoints percent days abstinent (PDA), number of standard unit drinks undergo analysis in a manner consistent with the primary efficacy endpoint, if it’s a continuous variable.

[0265] For categorical endpoints (such as CGI-S and CGI-I), when dichotomized as responders and non-responders, Chi-Square Test or Logistic regression model can be used to compare active arms vs placebo. The 90% Cis for the mean in the above summaries are displayed based on binomial proportions.

[0266] More details are pre-specified in the Statistical Analysis Plan.Safety Analyses

[0267] All safety data are listed for safety population.

[0268] AEs are categorized into preferred terms and associated system organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs (TEAEs) are defined as AEs that start or increase in intensity after the first dose of study drug. TEAEs are summarized by presenting the incidence of AEs for each treatment group by the MedDRA preferred term, nested within System Organ Class for the randomized safety population.

[0269] Concomitant and prior medications are coded using the latest version of the WHO-DD and presented in tables and listings.

[0270] Medical history is coded to MedDRA terms. Coded medical history terms are summarized for all subjects in the randomized safety population.

[0271] Laboratory evaluations, vital signs are summarized by treatment and time point for the randomized safety population.PART B: Alcohol CravingStudy Design and Methodology:

[0272] The part of the study has the following periods:

[0273] 1. Screening Period: up to 1-week and includes, after providing written informed consent, assessing inclusion / exclusion criteria. All protocol-specific activity which is not part of the normal clinical practice of the site must be performed only after obtaining the subject’s consent. The screening period may be extended by 30 days to allow for washout of prohibited medications, if applicable, though subjects who are taking prohibited medications should not discontinue medically indicated treatments to meet criteria for study participation. However, there are no minimum number of days for screening, and subjects may be randomized as soon as eligibility is confirmed.

[0274] Craving Lab Session A (Narrative Script Development): Completed with the subject in screening, prior to randomization. Imagery scripts are developed using a Scene Construction Questionnaire for alcohol cue-, stress-, and neutral-relaxing situations with final scripts audio-taped. To ensure specificity of script content, each set of scripts will be rated for content using a Script Independent Rating Scale (Script-IRS).

[0275] 2. Baseline Visit (Dav 0): after subject randomization eligibility is confirmed and Lab Session A has been completed, eligible subjects are randomized to double-blind treatment (Compound (IIC) 0.5 mg, Compound (IIC) 1.0 mg, Compound (IIC) 2.0 mg, or placebo) maintaining a 1 : 1 : 1 : 1 ratio allocation.

[0276] 3. Double-blind Treatment Period: 2-week double-blind treatment period during which subjects ingest study medication every day at bedtime starting at bedtime on the day of the Baseline visit and continue up to the End of Study visit. Each day of the double-blind treatment period, subjects complete the daily dosing eDiary. At protocol- specified clinic and telephone visits, additional procedures including questionnaires and lab assessments are completed.

[0277] Craving Lab Session B (-Day 7, Imagery Response and Relaxation Training): Relaxation training involves a progressive muscle relaxation procedure that allows the subject to achieve a relaxed state and focus on the imagery training that follows. Imagerytraining involves the subject visualizing commonplace scenes as they are presented to them. After the image period the subject make a rating on the Image Vividness Visual Analog Scale (Image-VAS).

[0278] Craving Lab Session C (-Day 14, Experimental Craving Session): A one-day laboratory experiment that involves subjects participating in 3 separate experimental testing sessions (alcohol cue-, stress-, and neutral-relaxing situations). Data is collected following each of the assigned periods. Research staff remain blinded to order of the audio-taped imagery condition presented and subjects remain blinded until imagery presentation. The order and content of each audio-tape imagery condition are randomized and counterbalanced across subjects. Subjects complete the Alcohol Urge Questionnaire (AUQ), Desire for Alcohol Visual Analog Scale (DFA-VAS), and Anxiety Visual Analog Scale (Anxiety-VAS) immediately following each audio-tape induction session. The session takes -3 hours.

[0279] 4. End of study (EOS): Study procedures are performed for all subjects who complete study.

[0280] 5. Early termination (ET): End of Study procedures are performed for all subjects who early terminate from study.

[0281] 6. Follow-up Period: 7-day safety follow up visit after the last dose of study medication to evaluate discontinuation-emergent adverse events.Number of Subjects and Study Population:

[0282] The sample size is designed to provide sufficient data to assess the potential efficacy, safety and tolerability of the investigational treatment. Approximately 40 subjects (-10 per treatment group) are screened to randomize to give at least 8 subjects per group to complete the 2-week double-blind period. Subjects must meet all inclusion criteria and none of the exclusion criteria (below) before they participate in the study, and also those who have completed all pre-randomization assessments (in SoA) are eligible for randomization.Inclusion Criteria:

[0283] 1. Male and female age > 18 years.

[0284] 2. Current diagnosis of moderate or severe alcohol use disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders 5th edition Text Revision(DSM-V-TR) and confirmed by Structured Clinical Interview for DSM Disorders Research Version (SCID-5).

[0285] 3. Currently seeking treatment for alcohol use disorder.

[0286] 4. Has > 4 heavy drinking days (HDD) in each of the 4 weeks prior to baseline visit defined as >4 standard drinks per day for females and >5 standard drinks per day for males as assessed by Timeline Followback interview. A standard drink is defined as 12 ounces (-355 mL) of 5% beer, 5 ounces (150 mL) of 12% wine, or 1.5 ounces (44 mL) of 80-proof (40%) distilled spirits.

[0287] 5. Males and females:- A male subject with a heterosexual partner who is a woman of childbearing potential must either be vasectomized or agree to use condoms during the trial and for 30 days following the treatment period.- A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP). Females who are postmenopausal must have been postmenopausal > 1 year and have elevated serum FSH. b. Female subjects of childbearing potential must agree to use a reliable method of contraception with a failure rate of less than 1 % per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intra uterine devices [IUDs], heterosexual abstinence or vasectomized partner during the trial and for 30 days following the treatment period. A female is considered to be of childbearing potential unless she has had a hysterectomy, has undergone tubal ligation or is at least one year post-menopausal with elevated serum FSH.

[0288] 6. Willing to be compliant with the protocol (including dosing instructions, daily electronic diary completion and clinic visit attendance) and able to read and understand questionnaires.Exclusion Criteria:

[0289] 1. Subjects that meet current DSM-5 criteria for moderate or severe substance use disorder other than alcohol and nicotine.

[0290] 2. Subjects with clinically unstable medical, neurologic or psychiatric conditions, or any other medical condition that, in the investigator’s opinion, is inadequately treated and precludes entry into the study. Minor or well-controlled medical conditions that in the opinion of the investigator would not affect the subject’s safety or interfere with study assessments may be allowed.

[0291] 3. Subjects at significant risk of acute withdrawal syndrome in the opinion of the investigator; or, score > 8 on the Clinical Institute Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar) at screening; or had prior seizures (other than febrile seizure) or other conditions that would place the patient at increased risk of seizure, or are taking anticonvulsants.

[0292] 4. Subjects who are prescribed prohibited medications for medical or psychiatric indications (see Table 2 below).

[0293] 5. Subjects with clinically significant kidney disease or abnormal kidney function or screening estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2.

[0294] 6. Subjects with clinically significant liver disease or abnormal liver function or screening value >3 times the upper limit of normal for aspartate transaminase (AST / SGOT) or alanine transaminase (ALT / SGPT) or a screening bilirubin value >1.5 mg / dL.

[0295] 7. Subjects with a screening electrocardiogram showing a QTcF value (QT data corrected for heart rate using the Fridericia formula) of > 470 msec for females or > 450 msec for males, or other ECG findings that, in the investigator’s opinion, would preclude participation in the study.

[0296] 8. Subjects with suicidal ideation associated with actual intent and a method or plan in the past 1 year (“Yes” answer on items 4 or 5 of the C-SSRS); subjects with active suicidal ideation (“Yes” answer on items 2 or 3 of the C-SSRS); a previous history of suicidal behaviors in the past 2 years (“Yes” answer to any of the suicidal behavior items of the C-SSRS), or any lifetime history of serious or recurrent suicidal behavior.

[0297] 9. Subjects that have used an investigational drug within 30 days (90 days for biologies) or participation in an investigational study within 30 days prior to screening.

[0298] 10. Females who are pregnant or lactating or planning to become pregnant during the study.

[0299] 11. Subjects who have ongoing legal issues that require abstinence from alcohol or have legal charges that have the risk of incarceration during the study period.

[0300] 12. Subjects that do not have a stable living situation or plan to move during the study period.

[0301] 13. Subjects who, in the opinion of the investigator, are unsuitable to participate in this study for any other reason.Treatment, Dose, and Mode of Administration:

[0302] Take 1 tablet daily at bedtime (time at which the subject goes to bed). Swallow the tablet whole with a drink of water.

[0303] Take tablet immediately prior to going to bed; make sure that you have a period of at least 10 hours after taking this medication before engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle. The study medication should not be taken with alcohol.• Compound (IIC) 0.5 mg, tablet, oral administration at bedtime• Compound (IIC) 1.0 mg, tablet, oral administration at bedtime• Compound (IIC) 2.0 mg, tablet, oral administration at bedtime• Placebo, tablet, oral administration at bedtimeConcomitant Medication:

[0304] Same consideration as Part A.Prohibited Medications / Therapy:

[0305] Eligible subjects who are currently taking a prohibited medication / therapy begin a washout prior to randomization. Exceptions are made on a case-by-case basis and require consensus of investigator and Medical Monitor. The washout period for AUD medications / therapies is 30 days and all other prohibited medications is the longer of 7 days or 5 half-lives. If a medication / therapy is not listed but does fit into a class of medications noted, the Medical Monitor must be consulted to determine whether it is permitted or not.

[0306] The following medications in Table 2 are prohibited during the study:Table 2Duration of Treatment and Study Duration:

[0307] Total study duration is approximately 4 weeks (consisting of 1-week screening, 2- week double-blind treatment period, and 1-week safety follow-up period). Screening may be up to 4 weeks (e.g., washout).Efficacy Assessments:

[0308] Craving Laboratory Session primary and secondary endpoint evaluations:Alcohol Urge Questionnaire (AUQ)Desire for Alcohol Visual Analog Scale (DFA-VAS)- Anxiety Visual Analog Scale (Anxiety-VAS)

[0309] Additional Craving Laboratory Session evaluations:- Script Independent Rating Scale (Script-IRS)- Image Vividness Visual Analog Scale (Image-VAS)- Desire for cigarette scale (DFCS)- Revised Differential Emotion Scale (RDES)- Insomnia Severity Index (ISI)Safety Assessments:AEs, Labs, ECGs, Vital signs, Columbia Suicide Severity Rating Scale (C- SSRS), Discontinuation Emergent Signs and Symptoms (DESS).Efficacy Analyses:

[0310] Listings, tables, and figures of efficacy variables are based on the full analysis population.Primary Efficacy Analyses

[0311] Alcohol Urge Questionnaire (AUQ). The analysis comparing active treatments to placebo is conducted utilizing an analysis of covariance (ANCOVA). The ANCOVA model includes treatment and baseline as fixed effects. The 90% confidence intervals (Cis) and p-values comparing the active treatments and placebo are presented. Figures of the LS mean change from baseline along with 90% Cis, are presented by treatment group and visit.Secondary Analyses

[0312] The Desire for Alcohol Visual Analog Scale (DFA-VAS) and Anxiety Visual Analog Scale (Anxiety-VAS) undergoes analysis in a manner consistent with the primary efficacy endpoint.Exploratory Analyses

[0313] Insomnia Severity Index (ISI) undergoes analysis in a manner consistent with the primary efficacy endpoint, if it’s a continuous variable.Safety Analyses:

[0314] All safety data is listed for safety population.

[0315] AEs are categorized into preferred terms and associated system organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs (TEAEs) are defined as AEs that start after or increase in intensity after the first dose of study drug. TEAEs are summarized by presenting the incidence of AEs for each treatment group by the MedDRA preferred term, nested within System Organ Class for the randomized safety population.

[0316] Concomitant and prior medications are coded using the latest version of the WHO-DD and presented in tables and listings.

[0317] Medical history is coded to MedDRA terms. Coded medical history terms are summarized for all subjects in the randomized safety population.

[0318] Laboratory evaluations, vital signs are summarized by treatment and time point for the randomized safety population.Example 4: A Phase 2, Randomized, Double-Blind, Multi-Center, Placebo- Controlled, Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of Compound (IIC) in Subjects with an Alcohol Use Disorder who are Experiencing Insomnia Associated with Alcohol Cessation

[0319] This is a phase 2, randomized, double-blind, multi-center, placebo-controlled, parallel-group study in subjects with an alcohol use disorder (AUD), who are experiencing insomnia associated with alcohol cessation (IAAC). The total duration of the study for a given subject is up to 59 days inclusive of a 21 -day screening period, 21- day treatment period, 3-day washout period, and follow-up period of up to 14 days.

[0320] During the screening period subjects were assessed to determine eligibility for enrollment in the study. Subjects complete the Consensus Sleep Diary -Morning (CSD-M) at home and if at least 3 nights of any 7-night period indicate insomnia, they enter a sleep lab for 2 consecutive nights of polysomnography (PSG) evaluation.

[0321] During the treatment period, eligible subjects are randomly assigned to Compound (IIC) 1 mg QHS, Compound (IIC) 2 mg QHS or placebo QHS (approximately 50 per arm, in a 1 : 1 : 1 ratio). Eligible subjects are required to attend clinic visits (days 1, 3, 8, 15 and 20) and overnight sleep lab visits (days 1, 2, 20 and 21). On every day of the treatment period, the subject completes the CSD-M. At sleep lab visits,the subject undergoes PSG and completes the Digit Symbol Substitution Test (DSST), Karolinska Sleepiness Scale (KSS), and Profile of Mood States-Brief Form (POMS™- Brief). At clinic visits, subjects complete: the Columbia-Suicide Severity Rating Scale (C-SSRS), Hospital Anxiety and Depression Scale (HADS); undergo clinical laboratory testing, drug / alcohol screening, vital sign measurements, 12-lead electrocardiogram and a neurological exam. Adverse events and concomitant medications are assessed. Blood samples for sparse pharmacokinetic (PK) analysis are collected during clinic visits.

[0322] During the washout period, (days 22 and 23) subjects receive placebo treatment in a single-blind manner and undergo PSG testing. An end of treatment (EOT) clinic visit is conducted on day 24.

[0323] The subject will return home and continue to complete the CSD-M and PACS and return for a clinic visit approximately 1 week after the last double-blind treatment dose to perform end of study (EOS) evaluations. A follow-up phone contact to assess safety is done approximately 1 week after EOS visit.Inclusion Criteria:

[0324] Participants are eligible if they meet all the following criteria:

[0325] 1. Male or female, 18-64 years of age with a body weight of 50-100 kg (110-220 lbs) and a body mass index (BMI) of 18-32 kg / m2.

[0326] 2. Otherwise healthy as determined by medical evaluation that includes: medical history, physical examination, neurological exam, laboratory tests, vital signs, and cardiac monitoring.

[0327] 3. History of moderate or severe alcohol use disorder (AUD) categorized based on DSM-5 criteria, as follows:• Moderate as defined by presence of 4-5 of the 11 criteria• Severe as defined by the presence of > 6 of the 11 criteria.

[0328] 4. At least 3 weeks and not more than 6 months since last alcoholic beverage intake at the time of study screening. Any subject who completed an alcohol detoxification program must be at least 7 days from completion of the program at the time of screening.

[0329] 5. Persistent insomnia that emerged or worsened during AUD period, or during or after alcohol cessation characterized by:Screening period patient diary data indicating that in at least 3 nights of any 7-day period: a. subjective total sleep time (sTST) is <6.5 hours; and, b. subjective sleep onset latency (sSOL) is >30 minutes; and, c. subjective wakefulness after sleep onset (sWASO) is >1 hour; and, d. subjective time in bed (sTIB) sleeping or trying to sleep is between 7 and 9 hours in duration and the [regular] sleep time is between 21 :00 and 24:00 and the [regular] wake time is between 05:00 and 09:00.Screening period sleep lab polysomnography (PSG) data indicating: e. latency to persistent sleep (LPS) is >20 min as averaged on 2 consecutive night PSGs with neither night <15 min; and, f. wakefulness after sleep onset (WASO) is >30 min as averaged on 2 consecutive night PSGs with neither night <20 min; and, g. sleep efficiency (SE) is < 85% as averaged on 2 consecutive night PSGs with neither night >87.5%.

[0330] 6. A female participant is eligible to participate if she is not pregnant and not breastfeeding. Both females of childbearing potential (i.e., not medically or surgically sterilized or not postmenopausal more than 1 year with confirmatory FSH) and nonsurgically sterilized males with a sexual partner of childbearing potential must be willing to use adequate and reliable contraception throughout the study (e.g., heterosexual abstinence or barrier with additional spermicidal foam or jelly, or the use of intrauterine device or hormonal contraception by female subjects and partners of male subjects)

[0331] 7. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

[0332] 8. Willing to refrain from a behavioral or other treatment program for insomnia during participation in the study.Exclusion Criteria:

[0333] Participants are excluded from the study if they meet any of the following criteria:Medical Conditions

[0334] 1. Current diagnosis of a sleep-related breathing disorder including obstructive sleep apnea (with or without continuous positive airway pressure (CPAP) treatment), periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder, narcolepsy, or an exclusionary score on any of the following: a. STOPBang: score > 5 b. International Restless Legs Scale: score > 16 c. Epworth Sleepiness Scale: Score > 10.

[0335] 2. An apnea-hypopnea index (AHI) score of >10 or a periodic limb movement arousal index (PLMAI) score of > 15 recorded during the screening period PSG.

[0336] 3. Documented history of insomnia prior to onset of the alcohol use disorder(AUD), which did not worsen during the AUD period or during or after alcohol cessation.

[0337] 4. Comorbid nocturia or other conditions (e.g., benign prostatic hyperplasia) resulting in frequent need to get out of bed to use the bathroom during the night (>3 times per night average).

[0338] 5. Any lifetime history of suicidal ideation with intent, with or without a plan at the time of or within 6 months before screening (i.e., answering “Yes” to questions 4 or5 on the Suicidal Ideation section of the C-SSRS).

[0339] 6. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).

[0340] 7. Diagnosis of premenstrual dysphoric disorder (females).

[0341] 8. History of or any current conditions that might interfere with drug absorption, distribution, metabolism, or excretion (including any surgical interventions for weight loss).

[0342] 9. Any history of seizures (except related to alcohol withdrawal) or head trauma with sequelae.

[0343] 10. Known human immunodeficiency virus (HIV) positive.

[0344] 11. HBsAg or anti-HCV positive (tested at screening).

[0345] 12. History of diagnosed, active liver disease or elevated liver enzymes / bilirubin:a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times upper limit of normal (ULN) b. Total bilirubin > 1.5 times ULN (except due to confirmed Gilbert’s Syndrome).

[0346] 13. History of kidney stones or renal insufficiency or abnormal kidney function at screening as evidenced by abnormal blood urea nitrogen (BUN) and creatinine values and an estimated glomerular filtration rate (eGFR) < 90 mL / min / 1.73 m2.

[0347] 14. Abnormal cardiac conditions including uncontrolled hypertension. (> 140 mm Hg systolic / 90 mm Hg diastolic). Subjects with QTcF > 450 msec (male) and QTcF > 470 msec (female) confirmed on repeat ECG.

[0348] 15. Any history and / or current evidence of other medical (e.g., cardiac, respiratory, gastrointestinal, renal, malignancy other than basal cell carcinoma), neurological, or psychiatric conditions that, in the opinion of the investigator, could affect the subject’s safety or interfere with the study assessments.Prior / Concomitant Therapy

[0349] 16. Use of any medication that affects sleep and / or wake function during the week before starting the Consensus Sleep Diary-Morning (CSD-M).

[0350] 17. Subjects currently undergoing treatment of other addictions in addition to alcohol (e.g. nicotine, cocaine, opioids, methamphetamine, etc. or other substances)

[0351] 18. Excessive caffeine consumption >300 mg / day (e.g., approximately three 6 oz. cups of caffeinated coffee, or three 12 oz. caffeinated sodas, or three 8 oz. caffeinated tea beverages).Prior / Concurrent Clinical Study Experience

[0352] 19. Dosing in a clinical drug study during the 30 days (or 5 half-lives of investigational drug treatment, whichever is longer) preceding the initial dose of study drug dispensed in this study.

[0353] 20. Subjects previously exposed to Compound (IIC).

[0354] 21. Subjects with hypersensitivity to Compound (IIC) or any of its ingredients.Diagnostic assessments

[0355] 22. Positive urine drug screen or alcohol screen at any time during the study, except for cannabis on a case-by-case basis.

[0356] 23. History of drug use disorder over the past year, other than alcohol / nicotine / caffeine / cannabi s .Test Treatment, Dose, and Mode of Administration

[0357] All doses are administered with water in the evening at bedtime, at least 1 hour after the last meal of the day, for up to 21 consecutive nights during the double-blind treatment period (for placebo, 21 nights during the double-blind treatment period and for 2 nights during the wash-out period to all subjects):• Compound (IIC) 1 mg, tablet, oral administration (subjects take 2 tablets, each containing 0.5 mg of the compound)• Compound (IIC) 2 mg, tablet, oral administration (subjects take 2 tablets, each containing 1 mg of the compound)• Placebo tablet (subjects take 2 placebo tablets)Concomitant Medication• Medications for chronic conditions, e.g., antihypertensives, lipid lowering agents, acetaminophen, NSAIDs and vitamins, are allowed as long as the subject is on a stable regimen throughout their study participation.Criteria and Methods for EvaluationPrimary Efficacy Variable:

[0358] The primary efficacy variable is derived using 2 consecutive nights of data from polysomnography (PSG): Change from baseline of wakefulness after sleep onset (WASO) is measured by PSG.Secondary Efficacy Variables:

[0359] The secondary efficacy variables are derived from PSG recordings as well as CSD-M (sleep diary) data: SE (Sleep efficiency); LPS (Latency to persistent sleep); TST (Total sleep time); NAW (Number of awakenings)

[0360] The secondary efficacy variables derived from the CSD-M (sleep diary) include the following: sSleep (subject estimated sleep quality); sTST (subject estimated amount of time spent asleep); sWASO (subject estimated minutes of wakefulness during the night after initial sleep onset); sSOL(subject estimated minutes from lights off to sleep onset); sSE (subject estimated proportion of time spent asleep per time spent in bed derived from sTST divided by sTIB): sNAW (subject estimated number of awakenings); and subject estimated morning sleepiness on awakening.Additional secondary efficacy variables:• Proportion of responders derived from PSG and CSD-M (sleep diary)• Rebound insomnia end points as assessed from the CSD-M (sleep diary) during the washout / follow-up periodPharmacodynamic variables:

[0361] The pharmacodynamic variables assessing next-day residual effects: DSST (Digit Symbol Substitution Test); KSS (Karolinska Sleepiness Scale); and POMS-Brief (Profile of Mood States-Brief)Safety Variables:

[0362] The safety variables assessing safety and tolerability of Compound (IIC) :• Adverse events, clinical laboratory results, electrocardiograms (ECGs), physical examination, vital signs measurements, peripheral capillary oxygen saturation (SpO2)• Neurological exam• C-SSRS: Columbia-Suicide Severity Rating ScaleExploratory Variables

[0363] The exploratory variables assessing sleep parameters as measured by PSG:• WASO by hour, TST by hour, NAW by hour• WASO in first half of night (WASO1H), WASO in second half of night (WASO2H)• Total minutes of stages Nl, N2, N3 and rapid eye movement (REM)• Percentage of stages Nl, N2, N3 and REM with TST denominator and with Time in Bed (TIB) denominator• REM latency• Number of transient arousal / shifts to wake or Nl

[0364] The exploratory variables assessing alcohol craving and mood:• PACS: Alcohol urge to drink as measured by the Penn Alcohol Craving Scale• HADS: Hospital Anxiety and Depression Scale

[0365] The exploratory variables assessing PK: Plasma concentrationsEfficacy AnalysisAnalysis Populations

[0366] Enrolled population: The group of subjects who sign informed consent.

[0367] Randomized safety population: The group of subjects who are randomized and receive at least 1 dose of the study drug and have at least 1 safety assessment.

[0368] Full analysis population: The group of subjects who are randomized, receive study drug, and have at least 1 valid efficacy measurement.

[0369] Per protocol population: The group of subjects who are included in the full analysis population but excluding those with major protocol deviations and those who do not receive the actual treatment they were randomized to receive.

[0370] PK analysis population: The group of subjects who are randomized, receive study drug, and have at least 1 measurable plasma concentration of Compound (IIC).

[0371] Subjects and profiles / metrics excluded from the analysis set are documented in the statistical analysis plan (SAP).Efficacy Analysis

[0372] Listings, tables, and figures of efficacy variables are based on the full analysis population.Primary Efficacy Analyses

[0373] Polysomnography recordings are collected and scored by a central reader. Sleep stages are scored following American Academy of Sleep Medicine (AASM) standardcriteria based on 30-second epochs. The 2 PSG nights at baseline and post baseline PSGs performed during each sleep lab visit are averaged before comparison.

[0374] The baseline, post baseline, and change from baseline of WASO are summarized by treatment group using descriptive statistics and presented graphically. The statistical analysis to compare change from baseline of Compound (IIC) versus placebo is performed by using a mixed model with factors of age group, treatment as fixed effects, baseline measurement of WASO as a covariate, and subject as a random effect. 90% confidence intervals (Cis) and P-values comparing placebo and each Compound (IIC) dose is summarized. Plots of the least squares (LS) mean change from baseline and 90% Cis, are produced by treatment group and visit. The impact of significant amount of missing data may be explored by using different imputation methods as sensitivity analyses.Secondary Efficacy Analyses

[0375] The baseline, post baseline, and change from baseline of all sleep variables as measured by PSG (including TST, SE, LPS, NAW), and all sleep variables as measured by CSD-M (including sleep quality, sTST, sWASO, sSOL, sSE, etc.) are summarized by treatment group with descriptive statistics and presented graphically.

[0376] PSG data is analyzed similarly as outlined above for the primary endpoint if they are continuous variables and follow normal distribution. Categorical endpoints are analyzed by logistic regression or Cochran-Mantel-Haenszel test if stratified by a factor and presented graphically if appropriate.

[0377] For CSD-M sleep diary data which is processed into weekly data, the statistical analysis to compare change from baseline of Compound (IIC) versus placebo is performed by using a mixed model with repeated measures (MMRM) with factors of age group, treatment, visit (first 2 nights, week 1, week 2, and week 3), and treatment-by-visit interaction as fixed effects, and baseline measurement as a covariate. 90% confidence intervals (Cis) and P-values comparing placebo and each Compound (IIC) dose are summarized. Plots of the least squares (LS) mean change from baseline and 90% Cis, are produced by treatment group and visit.Exploratory Analyses• Sleep parameters as measured by PSG• Alcohol urge to drink as measured by Penn Alcohol Craving Scale (PACS)• Hospital Anxiety and Depression Scale (HADS)

[0378] Listings, tables, and figures of sleep parameters as measured by PSG, PACS and HADS are based on the full analysis population. Descriptive statistics are tabulated by treatment and presented graphically. The analysis is performed similarly as outlined above for the primary endpoint or secondary endpoint as appropriate.Pharmacodynamic Analyses

[0379] Listings, tables, and figures of next day residual effects measured by DSST, KSS, and POMS-Brief are based on the full analysis population. Descriptive statistics are tabulated by treatment and presented graphically. The analysis is performed similarly as outlined above for the primary endpoint.Pharmacokinetic Analyses

[0380] Listings of individual plasma concentrations of Compound (IIC) are based on the PK analysis population.Safety Analyses

[0381] All safety data (AEs, clinical laboratory results, vital signs, SpO2, physical examinations, ECGs, neurological exam, and C-SSRS) are listed for subjects in the enrolled and randomized safety populations. AEs are categorized into preferred terms and associated system organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs (TEAEs) are defined as AEs that start after or increase in intensity after the first dose of study drug. TEAEs are summarized by presenting the incidence of AEs for each treatment group by the MedDRA preferred term, nested within System Organ Class for the safety population. Medical history is coded to MedDRA terms. Coded medical history terms are summarized for all subjects in the randomized safety population. Laboratory evaluations, vital signs and SpO2 are summarized by treatment and time point for the randomized safety population. Concomitant and prior medications are coded using the latest version of the WHO-DD and presented in tables and listings.Interim Analysis

[0382] After approximately half of the planned subjects have completed the end-of-study visit, an interim analysis maybe performed. Details are provided in the SAP.Results and Conclusions

[0383] Figs. 2-4 provide patient characteristics of insomnia patients in recovery from AUD: Fig. 2 presents the total score of Penn Alcohol Craving Score (PACS) at screening for the broad population, that is, all the subjects administered with 1 mg and 2 mg doses of Compound (IIC) and placebo; Fig. 3 presents the duration of Alcohol Use Disorder in the broad population; and Fig. 4 presents the length of alcohol cessation in insomnia patients in recovery from AUD.

[0384] The following tables present safety results in the subjects who participated in the study: Table 3 provides summary of deaths, other SAEs and other significant AEs in insomnia patients in recovery from AUD; and Table 4 provides summary of treatment- emergent adverse events (AEs) reported in at least 5% of subjects in any treatment group.Table 3Table 4

[0385] As shown by the above safety data, Compound (IIC) was generally well tolerated with 3 weeks of daily dosing at bedtime. The most frequent TEAE reported was somnolence (5.3% at 1 mg dose and 25.6% at 2 mg dose).

[0386] Figs. 5 & 6 provide sleep data (by PSG and by Diary) on reversion to baseline, confirming effects of Compound (IIC), upon blinded switch to placebo during the washout period.

[0387] Further, Compound (IIC) showed increases in N2 with lesser negative effect on N1 and N3 sleep and a reduction in time spent in REM sleep (Fig. 7). Fig. 8 shows that Compound (IIC) has no remarkable effect on REM latency.

[0388] Fig. 9 presents total PACS scores, and Fig. 10 provides total mood disturbance in broad population. As shown in the figures, the PACS scores were generally low and did not change with treatment of Compound (IIC), and mood disturbance scores did not change much over the treatment period.

[0389] In summary, the study proves that Compound (IIC) has beneficial effects on insomnia patients recovering from AUD.

[0390] The invention is not to be limited in scope by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within thescope of the appended claims. A number of references have been cited, the entire disclosures of which are incorporated herein by reference for all purposes.

Claims

WHAT IS CLAIMED:

1. A method of treating alcohol use disorder in a human subject identified in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1, wherein said method reduces alcohol craving in said human subject compared to a corresponding alcohol craving level in a similarly situated human subject administered a placebo.

3. The method of claim 1 or 2, wherein said method reduces a frequency of alcohol consumption in said human subject compared to a corresponding frequency of alcohol consumption in a similarly situated human subject administered a placebo.

4. The method of any one of claims 1-3, wherein said method reduces a total volume of alcohol ingested by said human subject in a single sitting compared to a corresponding total volume of alcohol ingested by a similarly situated human subject administered a placebo.

5. The method of any one of claims 1-4, wherein said method reduces a total volume of alcohol ingested by said human subject during a period of 30 days compared to acorresponding total volume of alcohol ingested by a similarly situated human subject administered a placebo.

6. A method of preventing relapse to alcohol drinking in a human subject identified as in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof.

7. A method for maintenance of abstinence from alcohol drinking in a human subject in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof.

8. The method of claim 7, wherein the method achieves at least 5 more days of alcohol abstinence in said human subject compared to a number of days of alcohol abstinence in a similarly situated human subject administered a placebo.

9. The method of any one of claims 1-8, wherein said human subject is orally administered the therapeutically effective amount of the compound.

10. The method of any one of claims 1-9, wherein said human subject is daily administered the therapeutically effective amount of the compound.

11. The method of any one of claims 1-10, wherein the administration occurs before bedtime of said human subject.

12. The method of any one of claims 1-11, wherein said human subject also suffers from an insomnia.

13. The method of claim 12, wherein said insomnia is insomnia-type alcohol -induced sleep disorder, insomnia in alcohol use disorder, insomnia associated with alcohol cessation, or any combination thereof.

14. The method of claim 12 or 13, wherein said insomnia is insomnia in alcohol use disorder.

15. The method of any one of claims 12-14, wherein said method also treats or prevents the insomnia in said human subject.

16. The method of claim 15, wherein an average sleep efficiency of said human subject administered with the therapeutically effective amount of the compound on two consecutive days is at least about 1.04 times of the average sleep efficiency of a similarly situated human subject administered a placebo.

17. The method of claim 15, wherein an average total sleep time of said human subject administered with the therapeutically effective amount of the compound on two consecutive days is at least about 15 minutes greater than the average total sleep time of a similarly situated human subject administered a placebo.

18. The method of claim 15, wherein an average wake after sleep onset (WASO) of said human subject administered with the therapeutically effective amount of the compound on two consecutive days is at least about 20 minutes less than the average WASO of a similarly situated human subject administered a placebo.

19. The method of any one of claims 1-18, wherein said compound is a compound of formula(II)or a solvate thereof.

20. The method of any one of claims 1-19, wherein said compound is a compound of formula(HA):or a solvate thereof.

21. The method of any one of claims 1-19, wherein said compound is a compound of formula (IIB):or a solvate thereof.

22. The method of any one of claims 1-19, wherein said compound is a compound of formula(IIC):or a solvate thereof.

23. The method of any one of claims 1-22, wherein the therapeutically effective amount is from about 0.10 mg to about 10.0 mg.

24. The method of any one of claims 1-23, wherein the therapeutically effective amount is 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, or 3.0 mg.

25. The method of any one of claims 1-24, wherein the therapeutically effective amount is 1.0 mg.

26. A method to reduce stress or anxiety level in a human subject identified in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof.

27. The method of claim 26, wherein said compound is a compound of formula (IIC):or a solvate thereof.

28. The method of claims 26 or 27, wherein the human subject also suffers from AUD or insomnia associated with alcohol cessation.

29. The method of any one of claims 26-28, wherein the compound is administered during daytime and at a therapeutically effective amount of about 0.10 mg to about 1.0 mg.

30. The method of any one of claims 1-25, wherein the method reduces percentage of heavy drinking days experienced by a human subject who consumes alcohol, compared tocorresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo.

31. The method of any one of claims 1-25 and 30, wherein the method reduces the number of standard unit drinks ingested per day by the human subject who consumes alcohol, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject administered a placebo.

32. The method of any one of claims 1-25 and 30-31, wherein the method reduces a percentage of drinking days experienced by the human subject, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject administered a placebo.

33. The method of any one of claims 1-25 and 30-32, wherein the method disclosure increases a percentage of abstinent days experienced by the human subject, compared to a corresponding percentage of abstinent days experienced by a similarly situated human subject administered a placebo.

34. The method of any one of claims 1-25 and 30-33, wherein the method reduces the human subject’s WHO risk drinking level, compared to the WHO risk drinking level of a similarly situated human subject administered a placebo.

35. A method of treating alcohol use disorder in a human subject identified in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces a percentage of heavy drinking days experienced by the human subject over a period of time, compared to corresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo over the same period of time.

36. The method of claim 35, wherein the method reduces a percentage of heavy drinking days experienced by the human subject over the period of time by at least about 10%, compared to corresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo over the same period of time.

37. The method of claim 35 or claim 36, wherein the method reduces a percentage of heavy drinking days experienced by the human subject over the period of time by at least about 20%, compared to corresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo over the same period of time.

38. The method of any one of claims 35-37, wherein the method reduces a percentage of heavy drinking days experienced by the human subject over the period of time by at least about 25%, compared to corresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo over the same period of time.

39. A method of treating alcohol use disorder in a human subject identified in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces a number of standard unit drinks ingested per day by the human subject over a period of time, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is administered a placebo over the same period of time.

40. The method of claim 39, wherein the method reduces a number of standard unit drinks ingested per day by the human subject over the period of time by at least about 10%, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is administered a placebo over the same period of time.

41. The method of claim 39 or claim 40, wherein the method reduces a number of standard unit drinks ingested per day by the human subject over the period of time by at least about 25%, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is administered a placebo over the same period of time.

42. The method of any one of claims 39-41, wherein the method reduces a number of standard unit drinks ingested per day by the human subject over the period of time by at least about 30%, compared to a corresponding number of standard unit drinks ingested by a similarly situated human subject who is administered a placebo over the same period of time.

43. A method of treating alcohol use disorder in a human subject identified in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces the percentage of drinking days experienced by the human subject during a period of time, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject who is administered a placebo over the same period of time.

44. The method of claim 43, wherein the method reduces the percentage of drinking days experienced by the human subject during the period of time by at least about 10%, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject who is administered a placebo over the same period of time.

45. The method of claim 43 or claim 44, wherein the method reduces the percentage of drinking days experienced by the human subject during the period of time by at least about 20%, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject who is administered a placebo over the same period of time.

46. The method of any one of claims 43-45, wherein the method reduces the percentage of drinking days experienced by the human subject during the period of time by at least about 25%, compared to a corresponding percentage of drinking days experienced by asimilarly situated human subject who is administered a placebo over the same period of time.

47. A method of treating alcohol use disorder in a human subject identified in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces the human subject’s WHO risk drinking level during a period of time, compared to the WHO risk drinking level of a similarly situated human subject who is administered a placebo over the same period of time.

48. The method of claim 47, wherein the method reduces the human subject’s WHO risk drinking level by at least a level during the period of time, compared to the WHO risk drinking level of a similarly situated human subject who is administered a placebo over the same period of time.

49. The method of claim 47 or claim 48, wherein the method reduces the human subject’s WHO risk drinking level by at least two levels during the period of time, compared to the WHO risk drinking level of a similarly situated human subject who is administered a placebo over the same period of time.

50. A method of treating alcohol use disorder in a human subject identified in need thereof, comprising administering to said human subject a therapeutically effective amount of a compound, wherein said compound is a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces alcohol craving in a human subject during a period of time, compared to a corresponding alcohol craving in a similarly situated human subject who is administered placebo over the same period of time.

51. The method of claim 50, wherein the reduces alcohol craving in a human subject during the period of time by at least about 10% based on an alcohol urge questionnaire (AUQ), a desire for alcohol visual analog scale (DFA-VAS), and / or an anxiety visual analog scale (Anxiety-VAS), compared to a corresponding alcohol craving based on the AUQ, DFA- VAS, and / or Anxiety-VAS, in a similarly situated human subject who is administered placebo over the same period of time.

52. The method of claim 50 or claim 51, wherein the method reduces alcohol craving in a human subject during the period of time by at least about 20% based on the AUQ, DFA- VAS, and / or Anxiety-VAS, compared to a corresponding alcohol craving based on the AUQ, DFA-VAS, and / or Anxiety-VAS, in a similarly situated human subject who is administered placebo over the same period of time.

53. The method of any one of claims 50-52, wherein the method reduces alcohol craving in a human subject during the period of time by at least about 25% based on the AUQ, DFA- VAS, and / or Anxiety-VAS, compared to a corresponding alcohol craving based on the AUQ, DFA-VAS, and / or Anxiety-VAS, in a similarly situated human subject who is administered placebo over the same period of time.

54. The method of any one of claims 35-53, wherein the therapeutically effective amount of the compound is a dose of about 0.5 mg to about 6 mg.

55. The method of any one of claims 35-54, wherein the compound of formula (I) or pharmaceutically acceptable salt or solvate thereof is a compound of formula (IIC).

56. The method of any one of claims 35-55, wherein the therapeutically effective amount of the compound is a dose of about 0.5 mg, about 1 mg, or about 2 mg.

57. The method of any one of claims 35-56, wherein the therapeutically effective amount of the compound is orally administered to the human subject at a daily basis.

58. A method of reducing alcohol consumption in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces a percentage of heavy drinking days experienced by the human subject over a certain period of time, compared to a corresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo over the same period of time.

59. A method of reducing alcohol consumption in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces the number of standard unit drinks ingested per day by the human subject over a certain period of time, compared to a corresponding percentage of heavy drinking days experienced by a similarly situated human subject administered a placebo over the same period of time.

60. A method of reducing alcohol consumption in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces a percentage of drinkingdays experienced by the human subject over a certain period of time, compared to a corresponding percentage of drinking days experienced by a similarly situated human subject administered a placebo over the same period of time.

61. A method of reducing alcohol consumption in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces the human subject’s WHO risk drinking level over a certain period of time, compared to a similarly situated human subject administered a placebo over the same period of time.

62. A method of reducing alcohol craving in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the method reduces the human subject’s urge to drink alcohol over a period of time, compared to a similarly situated human subject administered a placebo over the same period of time.

63. A method of reducing alcohol craving in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the method decreases the human subject’s desire to drink alcohol over a period of time, compared to a similarly situated human subject administered a placebo over the same period of time.

64. A method of reducing alcohol craving in a human subject identified in need thereof, comprising administering to the human subject a therapeutically effective amount of a compound, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the method decreases the human subject’s anxiety level over a period of time, compared to a similarly situated human subject administered a placebo over the same period of time.

65. The method of any one of claims 58-64, wherein the human subject is identified as having AUD.

66. The method of any one of claims 58-64, wherein the human subject has not been identified as having AUD.

67. The method of any one of claims 58-66, wherein the therapeutically effective amount of the compound comprises about 0.5 mg to about 6 mg.

68. The method of any one of claims 58-67, wherein the compound is a compound of formula (IIC).

69. The method of any one of claims 58-68, wherein the therapeutically effective amount of the compound comprises about 0.5 mg, about 1 mg, or about 2 mg.

70. The method of any one of claims 58-69, wherein the therapeutically effective amount of the compound is orally administered to the human subject daily.

71. The method of any one of claims 1-70, wherein the method reduces symptoms of alcohol withdrawal in the human subject.

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