Method for treating substance use disorder using a 4-(3-cyanophenyl)-6-pyridinylpyrimidine MGLU5 negative allosteric modulator

Abstract

The present disclosure relates to methods for treating a subject having a substance use disorder (SUD) with a 4-(3-cyanophenyl)-6-pyridinylpyrimidine mGlu5 negative allosteric modulator. Specifically, in some embodiments, the present disclosure relates to methods for treating a subject having SUD at risk of relapse to alcohol use. In some embodiments, the present disclosure relates to methods for promoting remission in a subject having SUD. In some embodiments, the SUD is a stimulant use disorder such as alcohol use disorder (AUD), opioid use disorder (OUD), or cocaine use disorder (CUD).

Description

Technical Field

[0001] Expression of Interest by the Government This invention was made with government support under Grant No. 1U01DA057118-01 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 355,451, filed Jun. 24, 2022, which is hereby incorporated by reference in its entirety for all purposes.

[0003] The present disclosure relates to methods for treating a subject having a substance use disorder with a 4-(3 - cyanophenyl)-6 - pyridinylpyrimidine mGlu5 negative allosteric modulator. Specifically, in some embodiments, the present disclosure relates to methods for treating a subject having a SUD at risk of relapse to alcohol use. In some embodiments, the present disclosure relates to methods for promoting remission in a subject having a SUD. In some embodiments, the SUD is a stimulant use disorder such as alcohol use disorder (AUD), opioid use disorder (OUD), or cocaine use disorder (CUD).

Background Art

[0004] Current evidence indicates that medications are not being used adequately in the treatment of substance use disorders such as stimulant use disorders, including alcohol use disorder (AUD), opioid use disorder (OUD), and cocaine use disorder (CUD). This is a concern because of the high prevalence of alcohol problems in the general population. For example, in the United States, the 12-month prevalence of AUD is estimated to be 4.6% among 12- to 17-year-olds and 8.5% among adults 18 years and older. The incidence of this disorder is higher among adult men (12.4%) than among adult women (4.9%). Alcohol problems affect the incidence, course, and treatment of many other medical and psychiatric conditions. Many addiction experts believe that patients with moderate or severe substance-related problems, such as alcohol-related problems, should be provided with pharmacologic support therapy on a regular basis.

[0005] The onset of SUD (e.g., AUD, OUD, CUD) is a multiphase process, initially characterized by repeated use episodes and leading to the final stage of addiction, including dependence / withdrawal syndromes. Relapse after abstinence is a complex phenomenon, involving more than just the physical urge to use substances. It is often accompanied by secondary anxiety and discomfort due to the downregulation of dopamine signaling and can be triggered by environmental cues such as stress and negative emotions. Medications used to treat substance use disorders may not be effective in preventing relapse. For example, methadone and buprenorphine, which act as agonists at opioid receptors, can be used in place of drug abuse and may help reduce substance use in individuals with SUD. Similarly, acamprosate, a medication used to treat alcohol use disorder, reduces overall alcohol use. However, methadone, buprenorphine, and acamprosate are not effective in preventing relapse after detoxification. Similarly, medications used to prevent or treat relapse to substances after abstinence are not necessarily effective in reducing substance consumption. For example, naltrexone, an opioid antagonist, is somewhat effective in suppressing relapse in people with alcohol use disorder but is less effective in people who are currently using alcohol.

[0006] The reinforcing or rewarding effects of substances are factors contributing to the tendency of abuse and may promote the onset and maintenance of SUD. Therefore, methods for reducing the reinforcing properties of substances (e.g., alcohol, opioids, cocaine) may be useful in the development of pharmacotherapies for treating SUD clinically. Similarly, relapse to substance seeking after abstinence is a factor in the behavioral pathology of SUD that can be triggered by conditioned reinforcement (cue-induced) processes. Therefore, new methods for reducing post-abstinence relapse of substance use are needed, as well as methods for reducing substance use triggers in SUD patients. SUMMARY OF THE INVENTION

[0007] The present disclosure provides a method for treating a subject having a substance use disorder (SUD) at risk of relapse to substance use, the method comprising administering to the subject a therapeutically effective amount of a compound of the following formula,

Chemical formula

[0008] The present disclosure also provides a method for promoting remission in a subject having SUD, the method comprising administering to the subject a therapeutically effective amount of a compound of the following formula,

Chemical formula

[0009] The present disclosure also provides for the use of a compound in a treatment for reducing sensitivity to one or more relapse triggers, the treatment comprising administering to a subject having an SUD at risk of relapse to substance use a therapeutically effective amount of the compound, The compound is of the formula,

Chemical formula

[0010] The present disclosure also provides for the use of a compound in the manufacture of a medicament for a treatment for reducing sensitivity to one or more relapse triggers, the treatment comprising administering the medicament to a subject having an SUD at risk of relapse to substance use, The compound is of the formula,

Chemical formula

[0011] The present disclosure also provides a compound for use in a method for reducing sensitivity to one or more relapse triggers, the method comprising administering to a subject having an SUD at risk of relapse to substance use a therapeutically effective amount of the compound, The compound is of the formula,

Chemical formula

[0012] The present disclosure also provides an agent for treatment to reduce sensitivity to one or more relapse triggers, the agent comprising a compound, and the treatment comprising administering the agent to a subject having a SUD at risk of relapse to substance use in a therapeutically effective amount of the compound. The compound has the following formula

Chemical formula

[0013] The present disclosure also provides the use of a compound in the manufacture of an agent for treatment to promote remission of SUD, the treatment comprising administering the agent to a subject having SUD. The compound has the following formula

Chemical formula

[0014] The present disclosure also provides the use of a compound in the treatment to promote remission of SUD, the treatment comprising administering a therapeutically effective amount of the compound to a subject having SUD. The compound has the following formula [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. In some embodiments, the SUD is AUD, OUD, and / or stimulant use disorder (e.g., CUD). In some embodiments, the SUD is AUD.

[0015] The present disclosure also provides a compound for use in a method of promoting remission of SUD, the method comprising administering a therapeutically effective amount of the compound to a subject having SUD, The compound has the following formula, [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. In some embodiments, the SUD is AUD, OUD, and / or stimulant use disorder (e.g., CUD). In some embodiments, the SUD is AUD.

[0016] The present disclosure also provides an agent for use in the treatment of promoting remission of SUD, the agent comprising the compound, and the treatment comprising administering the agent to deliver a therapeutically effective amount of the compound to a subject having SUD, The compound has the following formula, [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. In some embodiments, the SUD is AUD, OUD, and / or stimulant use disorder (e.g., CUD). In some embodiments, the SUD is AUD. BRIEF DESCRIPTION OF THE DRAWINGS

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Mode for Carrying Out the Invention

[0034] Substance use disorder (SUD) treatment can be divided into three stages: (1) from withdrawal to abstinence, the aim of which is to lead the patient to discontinue substance consumption; (2) abstinence and relapse prevention; and (3) reduction of substance consumption. For example, alcohol use disorder (AUD) treatment can be divided into three stages: (1) from withdrawal to abstinence, the aim of which is to lead the patient to discontinue alcohol consumption; (2) abstinence and relapse prevention; and (3) reduction of alcohol consumption. See, for example, Guglielmo, R et al. “Pharmacological treatments in alcohol use disorders: state of art and new perspectives.” La Clinica terapeutica vol. 166, 6 (2015): 262 - 70. The content of which is incorporated herein by reference. Different treatments and actually different drugs are used in these stages.

[0035] The present disclosure relates to abstinence and relapse prevention, and in particular, to methods for treating subjects having a substance use disorder (SUD) (such as stimulant use disorder like AUD, OUD, and / or CUD) with a 4-(3-cyanophenyl)-6-pyridinylpyrimidine mGlu5 negative allosteric modulator (e.g., Compound 1 or Compound 2). Treating a subject having a SUD at risk of relapse to substance use may reduce the subject's sensitivity to one or more relapse triggers. Also, treating a subject having a SUD with a 4-(3-cyanophenyl)-6-pyridinylpyrimidine mGlu5 negative allosteric modulator (e.g., Compound 1 or Compound 2) may promote remission in the subject.

[0036] The following description sets forth numerous exemplary configurations, methods, parameters, etc. However, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but rather is provided as an illustration of exemplary embodiments.

[0037] As used herein, the terms “including,” “containing,” and “comprising” are used in their open-ended, non-limiting sense.

[0038] The articles “a” and “an,” as used herein, refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, “an embodiment” refers to one element or two or more embodiments.

[0039] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” Of course, whether or not the term “about” is explicitly used, all quantities given herein are intended to refer to the actual given value, and also to approximations thereof which would be reasonably deduced by those skilled in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given values.

[0040] The present disclosure provides a method of treating a subject having a substance use disorder (SUD) (e.g., a stimulant use disorder such as AUD, OUD, and / or CUD), such as a subject at risk of relapse with respect to substance use and / or a subject in remission who needs assistance to maintain remission, with a compound (e.g., compound 1 or compound 2). In some embodiments, the method reduces the subject's substance intake. In some embodiments, the compound is compound 1.

[0041] Accordingly, the present disclosure also provides a method of treating a subject having an alcohol use disorder (AUD), such as a subject at risk of relapse with respect to alcohol use and / or a subject in remission who needs assistance to maintain remission, with a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., compound 1 or compound 2). In some embodiments, the method reduces the subject's alcohol intake. In some embodiments, the compound is compound 1.

[0042] The present disclosure also provides a method of treating a subject having an opioid use disorder (OUD), such as a subject at risk of relapse with respect to opioid use and / or a subject in remission who needs assistance to maintain remission, with a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., compound 1 or compound 2). In some embodiments, the method reduces the subject's opioid intake. In some embodiments, the compound is compound 1.

[0043] The present disclosure also provides a method of treating a subject having a substance use disorder, such as a subject at risk of relapse to stimulant use and / or a subject in remission who needs assistance in maintaining remission, e.g., a stimulant (e.g., cocaine) use disorder, with a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2). In some embodiments, the method reduces the subject's stimulant (e.g., cocaine) intake. In some embodiments, the substance use disorder is a cocaine use disorder (CUD). In some embodiments, the compound is Compound 1.

[0044] The present disclosure also provides a method of treating a subject having two, three, four, or more substance use disorders (SUDs), such as a subject at risk of relapse to use of two, three, four, or more substances and / or a subject in remission who needs assistance in maintaining remission, with a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2). In some embodiments, the method reduces the subject's intake of two, three, four, or more substances. In some embodiments, the subject has an alcohol use disorder (AUD) and an opioid use disorder (OUD). In some embodiments, the subject has a stimulant use disorder, such as AUD and CUD. In some embodiments, the subject has a stimulant use disorder, such as OUD and CUD. In some embodiments, the compound is Compound 1.

[0045] The present disclosure also provides a method of treating a subject having a substance use disorder (SUD) at risk of relapse to substance use, e.g., a stimulant use disorder such as AUD, OUD, and / or CUD, the method comprising administering a therapeutically effective amount of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative of the following formula (e.g., Compound 1 or Compound 2),

Chemical formula

[0046] The present disclosure also provides a method of promoting remission in a subject having a SUD (e.g., a stimulant use disorder such as AUD, OUD, and / or CUD), the method comprising administering to the subject a therapeutically effective amount of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative of the following formula, [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. In some embodiments, the administering results in remission for at least 3 months. In some embodiments, the administering results in remission for at least 12 months. In some embodiments, the SUD is AUD. In some embodiments, the compound is Compound 1.

[0047] As used herein, the terms “administered,” “administering,” or “administration” refer to directly administering to a subject in need of treatment a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof, or a composition thereof, contacting such an individual with such a compound, or otherwise exposing the individual to such a compound.

[0048] As used herein, the term "subject" includes mammals and non-mammals. Examples of mammals include any member of the mammalian class, humans, non-human primates such as chimpanzees, as well as other apes and monkey species, domestic animals such as cows, horses, sheep, goats, pigs, laboratory animals such as rabbits, dogs, and cats, and rodents such as rats, mice, and guinea pigs, but are not limited thereto. Examples of non-mammals include birds, fish, etc., but are not limited thereto. In some embodiments, the subject is a human. The term "patient" is used interchangeably with the term "subject" herein when the subject is a human.

[0049] The substance use disorder (SUD) disclosed herein refers to a substance-related disorder (SRD) that is a use disorder. Examples of SUD include alcohol use disorder (AUD), opioid use disorder (OUD), and stimulant use disorder. Stimulants include amphetamine-type substances and cocaine. An example of stimulant use disorder is cocaine use disorder (CUD).

[0050] As used herein, stimulant use disorders such as AUD, OUD, and CUD refer to mental disorders that can be diagnosed by a trained medical professional according to the diagnostic criteria presented in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the content of which is incorporated herein by reference.

[0051] SUD (e.g., stimulant use disorders such as AUD, OUD, and CUD) refers to a problematic pattern of substance use that results in clinically significant impairment or distress, as indicated by at least two of the following SUD symptoms (e.g., stimulant use disorder symptoms such as AUD symptoms, OUD symptoms, or CUD symptoms) occurring within 12 months. 1. The substance (e.g., alcohol, opioid, or stimulant such as cocaine) is often taken in amounts greater than intended or over a longer period of time. 2. There is a persistent desire to reduce or control the use of substances (such as stimulants like alcohol, opioids, or cocaine), or efforts to do so are unsuccessful. 3. A great deal of time is spent on activities necessary to obtain substances (such as stimulants like alcohol, opioids, or cocaine), use substances (such as stimulants like alcohol, opioids, or cocaine), or recover from their effects. 4. Craving, that is, a strong desire or impulse to use the substance (such as stimulants like alcohol, opioids, or cocaine). 5. Due to repeated use of substances (such as stimulants like alcohol, opioids, or cocaine), it is impossible to fulfill major role obligations at work, school, or home. 6. Substances (such as stimulants like alcohol, opioids, or cocaine) are continued despite the fact that they cause or worsen persistent or recurrent social or interpersonal problems as a result of their effects. 7. Important social, occupational, or recreational activities are given up or reduced due to the use of substances (such as stimulants like alcohol, opioids, or cocaine). 8. Substances (such as stimulants like alcohol, opioids, or cocaine) are repeatedly used in physically dangerous situations. 9. The use of substances (such as stimulants like alcohol, opioids, or cocaine) is continued despite knowledge that persistent or recurrent physical or psychological problems are likely to have been caused or worsened by alcohol. 10. Tolerance defined by any of the following: (a) Requiring a significantly increased amount of the substance to achieve intoxication or the desired effect. (b) The effect significantly decreasing with continued use of the same amount of the substance. 11. Withdrawal manifested by any of the following: (a) The withdrawal syndrome of the substance. (b) The substance (or, in the case of alcohol, a closely related substance such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms.

[0052] Some embodiments further include determining whether the subject has one, two, three or more SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) symptoms. Some embodiments further include treating the subject if the subject has one, two, three or more SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) symptoms. Some embodiments further include determining whether the subject has one or more SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) symptoms. Some embodiments further include treating the subject if the subject has one or more SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) symptoms. Some embodiments further include determining whether the subject has two or more SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) symptoms. Some embodiments further include treating the subject if the subject has two or more SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) symptoms.

[0053] Some embodiments further include reducing one or more stimulant use disorder (SUD) symptoms (e.g., stimulant use disorders such as alcohol use disorder (AUD), opioid use disorder (OUD), and / or cocaine use disorder (CUD)). Referring to the SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) symptom lists above, some embodiments reduce symptom 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, or any combination thereof. Some embodiments reduce symptom 1, 2, 4, or 5, or any combination thereof. Some embodiments reduce symptom 1. Some embodiments reduce symptom 2. Some embodiments reduce symptom 4. Some embodiments reduce symptom 5. Some embodiments reduce the intake of a substance (e.g., a stimulant such as alcohol, opioid, or cocaine) in a subject. Some embodiments reduce the alcohol intake in a subject having a SUD (e.g., a stimulant use disorder such as AUD, OUD, and / or CUD). In some embodiments, the method reduces the intake of a substance (e.g., a stimulant such as alcohol, opioid, or cocaine) in a subject having a SUD (e.g., a stimulant use disorder such as AUD, OUD, and / or CUD) at risk of relapse to the use of the substance. Some embodiments reduce withdrawal symptoms in a subject having AUD.

[0054] Substance use disorder (SUD), such as stimulant use disorder including alcohol use disorder (AUD), opioid use disorder (OUD), and / or cocaine use disorder (CUD), can be classified as mild SUD (with 2 - 3 symptoms; e.g., mild stimulant use disorder such as mild AUD, mild OUD, or mild CUD), moderate SUD (with 4 - 5 symptoms; e.g., moderate stimulant use disorder such as moderate AUD, moderate OUD, or moderate CUD), or severe SUD (with 6 or more symptoms; e.g., severe stimulant use disorder such as severe AUD, severe OUD, or severe CUD). Some embodiments include determining whether a subject has at least mild SUD (e.g., mild stimulant use disorder such as mild AUD, mild OUD, or mild CUD). Some embodiments include treating a subject having mild SUD (e.g., mild stimulant use disorder such as mild AUD, mild OUD, or mild CUD). Some embodiments include determining whether a subject has at least moderate SUD (e.g., moderate stimulant use disorder such as moderate AUD, moderate OUD, or moderate CUD). Some embodiments include treating a subject having moderate SUD (e.g., moderate stimulant use disorder such as moderate AUD, moderate OUD, or moderate CUD). Some embodiments further include determining whether a subject has severe SUD (e.g., severe stimulant use disorder such as severe AUD, severe OUD, or severe CUD). Some embodiments include treating a subject having severe SUD (e.g., severe stimulant use disorder such as severe AUD, severe OUD, or severe CUD). Some embodiments reduce the presence of one or more SUDs, such as stimulant use disorders including AUD, OUD, and / or CUD. Some embodiments reduce the severity of SUD (e.g., reducing severe SUD to mild SUD or reducing moderate SUD to mild SUD).

[0055] In some embodiments, the method further includes determining whether the subject meets the DSM-5 diagnostic criteria for SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD). In some embodiments, the method further includes determining whether the subject meets the DSM-5 diagnostic criteria for SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD), administering a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., compound 1 or compound 2) or a pharmaceutically acceptable salt thereof if the subject meets the DSM-5 criteria for SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD), and not administering a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., compound 1 or compound 2) or a pharmaceutically acceptable salt thereof if the subject does not meet the DSM-5 diagnostic criteria for SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD).

[0056] Subjects who develop SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) and later lose some or most of their symptoms do not necessarily have a cure for SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD). Rather, SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) often persists in a state called remission in subjects with SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD).

[0057] Remission, as used herein, refers to the state in a subject in which none of the criteria for a SUD (e.g., stimulant use disorder such as AUD, OUD, and / or CUD) are met (except that criterion A4, "craving, i.e., a strong desire or urge to use the substance," may be met) after the full criteria for a SUD (e.g., stimulant use disorder such as AUD, OUD, and / or CUD) were previously met. Early remission refers to remission that is at least 3 months but less than 12 months. Sustained remission refers to remission that is at least 12 months. As used herein, a subject in remission is understood to still be a subject with a SUD (e.g., stimulant use disorder such as AUD, OUD, and / or CUD).

[0058] As used herein, abstinence refers to a period during which a subject does not consume a substance (e.g., a stimulant such as alcohol, an opioid, and / or cocaine). Examples of tests performed to confirm abstinence include self-assessment tests and clinical tests (e.g., Timeline-Followback (TFLB) self-report substance consumption assessment, acute alcohol intake test, and chronic alcohol test, discussed in more detail below).

[0059] In some embodiments, the subject is abstinent. In some embodiments, the subject is already in a state of abstinence and at risk of relapse. In some of these embodiments, the method further comprises administering to the subject a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof after a period of abstinence by the subject. In some embodiments, the method further comprises performing a test to confirm abstinence.

[0060] In some embodiments, the abstinence period is at least 12 hours, and the subject has an exhaled or blood alcohol value of approximately 0. In some embodiments, the abstinence period is at least 1 day, at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 months, at least 6 months, or at least 12 months. In some embodiments, the abstinence period is at least 1 month. In some embodiments, the abstinence period is at least 3 months. In some embodiments, the abstinence period is at least 6 months. In some embodiments, the abstinence period is at least 12 months.

[0061] As used herein, relapse refers to the resumption of use of a substance (e.g., stimulants such as alcohol, opioids, and / or cocaine) after a prolonged period of abstinence. Clinically, vulnerability to relapse is generally associated with a strong craving or desire to use the substance. Relapse represents a common and significant problem in SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD). Indeed, given the high rates of habitual use in SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD), relapse is clearly a major obstacle to treatment efforts. For example, clinical research has found that people with alcohol dependence are more sensitive to these relapse triggers compared to control subjects, which likely increases their desire to drink.

[0062] In some embodiments, administration of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof prevents relapse for at least 3 months. In some embodiments, administration of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof prevents relapse for at least 12 months.

[0063] Some embodiments include using one or more tests to measure the use of a substance (e.g., stimulants such as alcohol, opioids, and / or cocaine). In some embodiments, the method reduces the intake of a substance (e.g., stimulants such as alcohol, opioids, and / or cocaine) by the subject, as measured by one or more tests (e.g., self-assessment tests and clinical tests). In some embodiments, the method includes one or more tests for determining relapse. Tests for relapse include self-assessment tests and clinical tests.

[0064] The Timeline-Followback (TFLB) self-report substance consumption assessment is a retrospective report of daily substance (e.g., stimulants such as alcohol, opioids, and / or cocaine) consumption over the past 30 days and is commonly used to assess relapse. TFLB is described in Sobell L, Sobell M. Timeline Followback: A Technique for Assessing Self Reported Ethanol Consumption. Vol. 17. Totowa, NJ: Humana Press, and Sobell LC, Sobell M (1996). Timeline Followback Method (Drugs, Cigarettes, and Marijuana), the contents of which are incorporated herein by reference. In some embodiments, one of the one or more tests for determining relapse is the Timeline-Followback self-report substance (e.g., stimulants such as alcohol, opioids, and / or cocaine) consumption assessment. Some embodiments include measuring a substance (e.g., stimulants such as alcohol, opioids, and / or cocaine) using the TFLB self-report substance consumption assessment. In some embodiments, the method reduces the intake of a substance (e.g., stimulants such as alcohol, opioids, and / or cocaine) by the subject, as measured by the TFLB self-report substance consumption assessment.

[0065] Clinical tests for relapse include urine drug tests, saliva drug tests (also known as oral fluid tests), and hair follicle drug tests. For opioids and stimulants (e.g., cocaine), the most common test used in clinics is the urine drug screening test.

[0066] Urine drug test: The urine drug test is the most commonly used method for detecting substance use, especially for opioids and stimulants (e.g., cocaine). To perform a urine drug test, a urine sample is collected from an individual into a sterile container. The sample is then analyzed using immunoassay techniques to detect the presence of drug metabolites. If the initial test yields a positive result, a confirmatory test is usually continued using gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS / MS) to ensure accuracy. The detection time of substances can vary. For example, opioids and cocaine can be detected in urine for 1 to 3 days, and ethanol (alcohol) can be detected 12 to 24 hours after use. Further details can be found in the following references, which are incorporated herein by reference. Center for Substance Abuse Treatment. Substance Abuse: Clinical Issues in Intensive Outpatient Treatment. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2006. (Treatment Improvement Protocol (TIP) Series, No. 47.) Appendix B. Urine Collection and Testing Procedures and Alternative Methods for Monitoring Drug Use. (https: / / www.ncbi.nlm.nih.gov / books / NBK64092 /

[0067] Saliva drug testing (oral fluid testing): Saliva drug testing is a non-invasive method for detecting drug use. To perform this test, a swab is used to collect saliva from an individual's mouth, typically from the inside of the cheek or under the tongue. The saliva sample is then analyzed for the presence of drugs using immunoassay technology. Similar to urine testing, positive results are usually confirmed by GC-MS or LC-MS / MS. The detection time of substances in saliva can vary. Opioids can be detected for up to 36 hours, while cocaine can be detected 24 - 48 hours after use. Further details can be found in the following references, which are incorporated herein by reference. Cone, E.J., & Huestis, M.A. (2007). Interpretation of Oral Fluid Tests for Drugs of Abuse. Annals of the New York Academy of Sciences, 1098(1), 51 - 103. https: / / doi.org / 10.1196 / annals.1384.037.

[0068] Hair drug testing: For hair drug testing, a small hair sample is usually collected from the head. This test provides a longer detection window compared to urine or saliva tests. Hair samples are analyzed using techniques such as enzyme-linked immunosorbent assay (ELISA) for screening and GC-MS or LC-MS / MS for confirmation. Hair drug testing can detect drug use over approximately 90 days depending on the length of the hair sample. Further details can be found in the following references incorporated herein by reference. Gryczynski J, Schwartz RP, Mitchell SG, O’Grady KE, Ondersma SJ. Hair drug testing results and self-reported drug use among primary care patients with moderate-risk illicit drug use. Drug Alcohol Depend. 2014 Aug 1;141:44-50. https: / / doi:10.1016 / j.drugalcdep.2014.05.001.

[0069] The detection time and range can vary depending on factors such as individual metabolism, frequency of drug use, and sensitivity of the testing method.

[0070] Clinical tests for AUD recurrence include acute alcohol intake tests and chronic alcohol use tests. Examples of tests are described in Nanau RM, Neuman MG., Biomolecules and biomarkers used in diagnosis of alcohol drinking and monitoring therapeutic interventions, Biomolecules, 2015;5(3):1339-1385, the content of which is incorporated herein by reference. In some embodiments, the method reduces the alcohol intake of the subject as measured by an acute alcohol intake test. In some embodiments, the method reduces the alcohol intake of the subject as measured by a chronic alcohol use test.

[0071] Clinical tests for acute alcohol intake include tests for ethanol (e.g., breath or blood alcohol tests), ethyl glucuronide (EtG), and ethyl sulfate (EtS). EtG and EtS are direct minor metabolites of ethanol and are considered good markers of acute short-term (up to 36 hours in blood, up to 5 days in urine) alcohol intake. The sensitivity of these tests is highest in heavy drinkers but decreases after 24 hours and with lower alcohol consumption. The results do not correlate precisely with the amount or frequency of ethanol use. False positive results occur in screening tests, so it is strongly recommended that all positive screening results be confirmed by an EtG / EtS confirmation test. There are no false positive results in the confirmation test. False negative results are very rare in EtG screening tests. The results of EtG and EtS are legally defensible. The 2012 SAMSHA Advisory includes the following preliminary guidance on what positive results may indicate. >1,000 ng / mL: heavy drinking on the same day or previously (e.g., 1 or 2 days prior), or light drinking on the same day; 500 - 1,000 ng / mL: heavy drinking previously (1 - 3 days prior), recent light drinking (e.g., in the past 24 hours), or recent strong "external exposure" (within 24 hours); 100 - 500 ng / mL: heavy drinking previously (1 - 3 days), light drinking previously (12 - 36 hours), or recent "external" exposure. Some embodiments include measuring alcohol use using an acute alcohol intake test. In some embodiments, the method reduces the alcohol intake of a subject as measured by an acute alcohol intake test. In some embodiments, one of one or more tests for determining recurrence is an acute alcohol intake test.

[0072] Chronic alcohol tests include tests for carbohydrate-deficient transferrin (CDT) and phosphatidylethanol (PEth), which are useful markers for monitoring abstinence and relapse after long-term use. Some embodiments include measuring alcohol use using a chronic alcohol test. In some embodiments, the method reduces the subject's alcohol intake as measured by a chronic alcohol test. In some embodiments, one of the one or more tests for determining relapse is a chronic alcohol use test.

[0073] Carbohydrate-deficient transferrin: CDT, an indirect metabolite of ethanol, is a serum marker of long-term heavy alcohol use (≥40 g per day for up to 2 weeks) or relapse. CDT concentrations generally correlate well with an individual's drinking pattern over the past 30 days and are most useful for monitoring long-term abstinence and detecting relapse. Factors that affect CDT values include body mass index (BMI), female gender, and smoking. The CDT test cannot be used in individuals suspected of having congenital glycosylation disorders.

[0074] Phosphatidylethanol: PEth is a direct ethanol metabolite and can be tested to detect long-term exposure (within 1 - 2 weeks or more). Since blood PEth levels are closely correlated with alcohol consumption, the PEth test can be used to monitor alcohol consumption, identify early signs of harmful alcohol consumption, and track cases of AUD or dependence.

[0075] As used herein, a relapse trigger refers to a craving for a substance (e.g., alcohol, opioids, and / or stimulants such as cocaine) and the impulse associated with a cue. Craving and cue refer to distinct concepts but are often associated with each other. A cue can induce a craving, but a craving can occur independently of a cue. A cue may also not necessarily induce a craving but may lead to the use of a substance (e.g., alcohol, opioids, and / or stimulants such as cocaine).

[0076] As used herein, craving refers to a strong desire or impulse for a substance (e.g., stimulants such as alcohol, opioids, and / or cocaine), which can occur at any time but is more likely to occur when in an environment where the substance has been previously obtained or used. Craving also involves classical conditioning and is associated with the activation of specific reward structures in the brain. The craving of a subject is queried by asking whether the subject has ever been driven by a strong impulse to consume the substance (e.g., stimulants such as alcohol, opioids, and / or cocaine) and thought of nothing else.

[0077] As used herein, cue refers to social, environmental, or emotional situations that cause people in recovery to recognize past use of a substance (e.g., stimulants such as alcohol, opioids, and / or cocaine). These cues can lead to strong impulses that can lead to relapse. Cues do not force a person to use a substance but increase the likelihood of use. Examples of cues include internal cues such as sadness, anxiety or stress, anger or irritation, physical pain or discomfort, smelling the odor of the substance, having financial problems, visiting a bar or restaurant where the patient used the substance, attending a party, seeing the substance (e.g., seeing an alcoholic beverage, interacting with people who use it, and experiencing mental or physical abuse).

[0078] Relapse can be a staged process with distinct stages. This can begin weeks and months before an individual consumes a substance (such as stimulants like alcohol, opioids, and / or cocaine). The goal of treatment is to recognize the early stages where the likelihood of success is greatest and help the individual gain control. As used herein, symptoms related to the initial stage of relapse are referred to as early relapse symptoms. Early relapse symptoms can include emotional and mental symptoms as described below. Melemis SM. Relapse Prevention and the Five Rules of Recovery. Yale J Biol Med. 2015 Sep 3;88(3):325 - 32., herein incorporated by reference. In some embodiments, administration of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (such as Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof results in the subject being free of early relapse symptoms for at least 3 months. In some embodiments, administration of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (such as Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof results in the subject being free of early relapse symptoms for at least 12 months.

[0079] Emotional early relapse symptoms include the following: (1) Irritability or grouchiness. Sometimes mood changes can occur due to emotional triggers or feelings of guilt about wanting to use again. (2) Withdrawing. (3) Not going to meetings / appointments. (4) Going to meetings / appointments but not sharing. (5) Focusing on others (focusing on others' problems or how others affect oneself). (6) Poor eating and sleeping habits. A common general factor in emotional relapse symptoms is inadequate self-care, which is broadly defined to include emotional, psychological, and physical care.

[0080] Spiritual early relapse symptoms include the following: (1) craving substances (e.g., stimulants such as alcohol, opioids, and / or cocaine), (2) thinking about people, places, and things related to past use, (3) minimizing or glorifying the effects of past use, (4) bargaining (bargaining means starting to think about scenarios in which an individual may use), (5) lying, (6) devising schemes to better control use, (7) seeking opportunities for relapse, (8) planning for relapse.

[0081] Compound Embodiments of the present disclosure relate to compounds of the following formula,

Chemical formula

[0082] In some embodiments, the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is Compound 1, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is Compound 2, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0084] As used herein, "pharmaceutically acceptable" generally refers to those that are useful for preparing pharmaceutical compositions that are generally safe, non-toxic and not undesirable biologically or otherwise, and includes those that are acceptable for both human pharmaceutical use and veterinary use. For example, some embodiments employ pharmaceutical compositions comprising Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0085] As used herein, "pharmaceutically acceptable salt" generally refers to salts that are generally safe, non-toxic and not undesirable biologically or otherwise, and includes those that are acceptable for both human pharmaceutical use and veterinary use. Some embodiments use a pharmaceutically acceptable salt of Compound 1. Some embodiments use a pharmaceutically acceptable salt of Compound 2.

[0086] When used in connection with a compound, the terms "effective amount" or "therapeutically effective amount" refer to an amount of the compound sufficient to provide the desired biological result. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD), or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein necessary to effect a clinically significant decrease in the signs, symptoms, or causes of relapse to substance (e.g., stimulant such as alcohol, opioid, and / or cocaine) use. Thus, the expression "effective amount" generally refers to an amount at which the active substance has a therapeutic effect.

[0087] Dosage The dosage of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof can be effective for the treatment of a subject having SUD (e.g., stimulant use disorders such as AUD, OUD, and / or CUD) as described herein. In some embodiments, the dosage is administered multiple times a day (e.g., ingested multiple times over the course of a day). In some embodiments, the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof is administered two, three, or four times a day. The sum of the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof administered multiple times a day is the dosage.

[0088] In some embodiments, the subject is administered a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof in an amount of about 5 mg / day to about 300 mg / day, about 10 mg / day to about 300 mg / day, about 20 mg / day to about 300 mg / day, about 30 mg / day to about 300 mg / day, about 40 mg / day to about 300 mg / day, about 50 mg / day to about 300 mg / day, about 60 mg / day to about 300 mg / day, about 70 mg / day to about 300 mg / day, about 5 mg / day to about 200 mg / day, about 10 mg / day to about 200 mg / day, about 20 mg / day to about 200 mg / day, about 30 mg / day to about 200 mg / day, about 40 mg / day to about 200 mg / day, about 50 mg / day to about 200 mg / day, about 60 mg / day to about 200 mg / day, about 70 mg / day to about 200 mg / day, about 5 mg / day to about 120 mg / day, about 10 mg / day to about 120 mg / day, about 20 mg / day to about 120 mg / day, about 30 mg / day to about 120 mg / day, about 40 mg / day to about 120 mg / day, about 50 mg / day to about 120 mg / day, about 60 mg / day to about 120 mg / day, about 70 mg / day to about 120 mg / day, about 5 mg / day to about 100 mg / day, about 10 mg / day to about 100 mg / day, about 20 mg / day to about 100 mg / day, about 30 mg / day to about 100 mg / day, about 40 mg / day to about 100 mg / day, about 50 mg / day to about 100 mg / day, about 60 mg / day to about 100 mg / day, about 70 mg / day to about 100 mg / day, about 5 mg / day to about 90 mg / day, about 10 mg / day to about 90 mg / day, about 20 mg / day to about 90 mg / day, about 30 mg / day to about 90 mg / day, about 40 mg / day to about 90 mg / day, about 50 mg / day to about 90 mg / day, about 60 mg / day to about 90 mg / day, about 70 mg / day to about 90 mg / day, about 5 mg / day to about 80 mg / day, about 10 mg / day to about 80 mg / day, about 20 mg / day to about 80 mg / day, about 30 mg / day to about 80 mg / day, about 40 mg / day to about 80 mg / day, about 50 mg / day to about 80 mg / day, about 60 mg / day to about 80 mg / day, about 70 mg / day to about 80 mg / day, about 5 mg / day to about 70 mg / day, about 10 mg / day to about 70 mg / day, about 20 mg / day to about 70 mg / day, about 30 mg / day to about 70 mg / day, about 40 mg / day to about 70 mg / day, about 50 mg / day to about 70 mg / day, or about 60 mg / day to about 70 mg / day.

[0089] In some embodiments, the subject is administered a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 200 mg / day, or about 300 mg / day.

[0090] Surprisingly, subjects administered compound 1 at 100 mg / day were found to have unexpectedly high compound exposure. Thus, in some embodiments, the subject is administered a dose of less than about 100 mg / day. In some embodiments, the subject is administered from about 5 mg / day to about 100 mg / day, from about 10 mg / day to about 100 mg / day, from about 20 mg / day to about 100 mg / day, from about 30 mg / day to about 100 mg / day, from about 40 mg / day to about 100 mg / day, from about 50 mg / day to about 100 mg / day, from about 60 mg / day to about 100 mg / day, from about 70 mg / day to about 100 mg / day, from about 5 mg / day to about 90 mg / day, from about 10 mg / day to about 90 mg / day, from about 20 mg / day to about 90 mg / day, from about 30 mg / day to about 90 mg / day, from about 40 mg / day to about 90 mg / day, from about 50 mg / day to about 90 mg / day, from about 60 mg / day to about 90 mg / day, from about 70 mg / day to about 90 mg / day, from about 5 mg / day to about 80 mg / day, from about 10 mg / day to about 80 mg / day, from about 20 mg / day to about 80 mg / day, from about 30 mg / day to about 80 mg / day, from about 40 mg / day to about 80 mg / day, from about 50 mg / day to about 80 mg / day, from about 60 mg / day to about 80 mg / day, from about 70 mg / day to about 80 mg / day, from about 5 mg / day to about 70 mg / day, from about 10 mg / day to about 70 mg / day, from about 20 mg / day to about 70 mg / day, from about 30 mg / day to about 70 mg / day, from about 40 mg / day to about 70 mg / day, from about 50 mg / day to about 70 mg / day, or from about 60 mg / day to about 70 mg / day of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., compound 1 or compound 2) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered a dose of from about 5 mg / day to about 100 mg / day of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., compound 1 or compound 2) or a pharmaceutically acceptable salt thereof.Some embodiments are methods of treating a subject having a SUD (e.g., a stimulant use disorder such as AUD, OUD, and / or SUD), comprising administering a dosage of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof of from about 5 mg / day to about 100 mg / day, from about 10 mg / day to about 100 mg / day, from about 20 mg / day to about 100 mg / day, from about 30 mg / day to about 100 mg / day, from about 40 mg / day to about 100 mg / day, from about 50 mg / day to about 100 mg / day, from about 60 mg / day to about 100 mg / day, from about 70 mg / day to about 100 mg / day, from about 5 mg / day to about 90 mg / day, from about 10 mg / day to about 90 mg / day, from about 20 mg / day to about 90 mg / day, from about 30 mg / day to about 90 mg / day, from about 40 mg / day to about 90 mg / day, from about 50 mg / day to about 90 mg / day, from about 60 mg / day to about 90 mg / day, from about 70 mg / day to about 90 mg / day, from about 5 mg / day to about 80 mg / day, from about 10 mg / day to about 80 mg / day, from about 20 mg / day to about 80 mg / day, from about 30 mg / day to about 80 mg / day, from about 40 mg / day to about 80 mg / day, from about 50 mg / day to about 80 mg / day, from about 60 mg / day to about 80 mg / day, from about 70 mg / day to about 80 mg / day, from about 5 mg / day to about 70 mg / day, from about 10 mg / day to about 70 mg / day, from about 20 mg / day to about 70 mg / day, from about 30 mg / day to about 70 mg / day, from about 40 mg / day to about 70 mg / day, from about 50 mg / day to about 70 mg / day, or from about 60 mg / day to about 70 mg / day.

[0091] In some embodiments, a subject is administered a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, or about 100 mg / day. In some embodiments, a subject is administered a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 40 mg / day. In some embodiments, a subject is administered a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 50 mg / day. In some embodiments, a subject is administered a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 60 mg / day. Some embodiments are methods of treating a subject having a SUD (e.g., a stimulant use disorder such as AUD, OUD, and / or SUD), the method comprising administering to the subject a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, or about 100 mg / day.

[0092] In some embodiments, the subject is administered a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof when the subject is in a feeding state (e.g., immediately after a meal). In some embodiments, the subject is administered a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof within about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, or about 5 hours after consuming a meal.

[0093] In some embodiments, the subject is administered a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof with the dose being gradually increased so that the subject adapts and higher doses are possible with minimal side effects.

[0094] In some embodiments, the subject is administered at about 1 / 4 of the dose for 1, 2, 3, 4, or 5 days, then at about 2 / 4 of the dose for 1, 2, 3, 4, or 5 days, then at about 1 / 4 of the dose for 1, 2, 3, 4, or 5 days, and thereafter at the full dose.

[0095] In some embodiments, the subject is administered at about 1 / 3 of the dose for 1, 2, 3, 4, or 5 days, then at about 2 / 3 of the dose for 1, 2, 3, 4, or 5 days, and thereafter at the full dose.

[0096] In some embodiments, the subject is administered at about 1 / 3 of the dose for 1 - 3 days, at about 2 / 3 of the dose for 4 - 6 days, and at the full dose from the 7th day onwards.

[0097] In some embodiments, the subject is administered at about 1 / 3 of the dose twice a day for 1 - 3 days, at about 2 / 3 of the dose twice a day for 4 - 6 days, at the full dose twice a day for 7 - 13 days, and at the full dose once a day from the 14th day onwards.

[0098] In some embodiments, the subject is administered 50 mg / day twice daily on days 1 to 3, approximately 100 mg / day twice daily on days 4 to 6, approximately 150 mg / day twice daily on days 7 to 13, and approximately 150 mg / day once daily after day 14.

[0099] In some embodiments, treatment achieves an average plasma concentration of about 10 ng / mL to about 300 ng / mL, about 50 ng / mL to about 300 ng / mL, about 10 ng / mL to about 200 ng / mL, about 10 ng / mL to about 150 ng / mL, about 50 ng / mL to about 150 ng / mL, about 75 ng / mL to about 150 ng / mL, about 100 ng / mL to about 150 ng / mL, about 10 ng / mL to about 100 ng / mL, about 50 ng / mL to about 100 ng / mL, about 75 ng / mL to about 100 ng / mL, about 10 ng / mL to about 75 ng / mL, or about 50 ng / mL to about 75 ng / mL. In some embodiments, treatment achieves an average plasma concentration of about 100 ng / mL.

[0100] Exemplary embodiments Embodiment I-1. A method of treating a subject having alcohol use disorder (AUD) at risk of relapse to alcohol use, comprising administering to the subject a therapeutically effective amount of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative of the following formula,

Chemical formula

[0101] Embodiment I-2. The method according to embodiment I-1, wherein the administration results in remission of AUD for at least 3 months.

[0102] Embodiment I-3. A method for promoting remission in a subject having alcohol use disorder (AUD), comprising administering to the subject a therapeutically effective amount of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative of the following formula,

Chemical formula

[0103] Embodiment I-4. The method according to embodiments I-2 and I-3, wherein the administration results in remission for at least 12 months.

[0104] Embodiment I-5. The method according to embodiments I-1 to I-4, wherein the administration prevents relapse for at least 3 months.

[0105] Embodiment I-6. The method according to embodiments I-1 to I-5, wherein the administration prevents relapse for at least 12 months.

[0106] Embodiment I-7. The method according to embodiments I-5 and I-6, wherein the method further comprises one or more tests for determining relapse.

[0107] Embodiment I-8. The method according to embodiment I-7, wherein one of the one or more tests for determining relapse is a timeline-follow-back self-reported alcohol consumption assessment.

[0108] Embodiment I-9. The method according to embodiments I-7 and I-8, wherein one of the one or more tests for determining relapse is an acute alcohol intake test.

[0109] Embodiment I-10. The method according to embodiments I-7 to I-9, wherein one of the one or more tests for determining recurrence is a chronic alcohol use test.

[0110] Embodiment I-11. The method according to embodiments I-1 to I-10, wherein the administration results in a subject having no early recurrence symptoms for at least 3 months.

[0111] Embodiment I-12. The method according to embodiments I-1 to I-11, wherein the administration results in a subject having no early recurrence symptoms for at least 12 months.

[0112] Embodiment I-13. The method according to embodiments I-1 to I-12, further comprising determining whether the subject meets the DSM-5 diagnostic criteria for AUD, and if the subject meets the DSM-5 criteria for AUD, administering a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof, and if the subject does not meet the DSM-5 diagnostic criteria for AUD, not administering a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof.

[0113] Embodiment I-14. The method according to embodiments I-1 to I-13, wherein a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof is administered to the subject after a period of abstinence by the subject.

[0114] Embodiment I-15. The method according to embodiment I-14, further comprising performing a test to confirm abstinence.

[0115] Embodiment I-16. The method according to embodiments I-14 and I-15, wherein the period of abstinence is at least 12 hours and the subject has a breath or blood alcohol value of about 0.

[0116] Embodiment I-17. The method according to Embodiments I-14 to I-16, wherein the abstinence period is at least 1 day, at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 months, or at least 6 months.

[0117] Embodiment I-18. The method according to Embodiments I-1 to I-17, wherein R is F or cyano.

[0118] Embodiment I-19. The 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is as follows,

Chemical formula

[0119] Embodiment I-20. The 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is as follows,

Chemical formula

[0120] Embodiment I-21. The method according to Embodiments I-1 to I-20, wherein the treatment achieves an average plasma concentration of about 100 ng / mL.

[0121] Embodiment I-22. The method according to Embodiments I-1 to I-21, wherein the subject is administered a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 30 mg / day to about 300 mg / day, about 50 mg / day to about 200 mg / day, about 50 mg / day to about 120 mg / day, about 50 mg / day to about 100 mg / day, about 60 mg / day to about 90 mg / day, about 60 mg / day to about 80 mg / day, or about 60 mg / day to about 70 mg / day.

[0122] Embodiment I-23. The method according to Embodiments I-1 to I-21, wherein the subject is administered a dose of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 200 mg / day, or about 300 mg / day.

[0123] Embodiment I-24. The method according to Embodiments I-22 and I-23, wherein for the subject, the dose administered for 1 to 3 days is about 1 / 3 of the dose, for 4 to 6 days is about 2 / 3 of the dose, and from the 7th day onwards is the full dose.

[0124] Embodiment I-25. The method according to Embodiment I-24, wherein for the subject, the dose administered on the 1st to 3rd days is about 1 / 3 of the dose given twice a day, for the 4th to 6th days is about 2 / 3 of the dose given twice a day, for the 7th to 13th days is the full dose given twice a day, and from the 14th day onwards is the full dose given once a day.

[0125] Embodiment I-26. The method according to Embodiment I-25, wherein for the subject, the dose administered on the 1st to 3rd days is 50 mg / day given twice a day, for the 4th to 6th days is about 100 mg / day given twice a day, for the 7th to 13th days is about 150 mg / day given twice a day, and from the 14th day onwards is about 150 mg / day given once a day.

[0126] Embodiment I-27. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative in the treatment for reducing sensitivity to one or more relapse triggers, the treatment comprising administering to a subject having an alcohol use disorder (AUD) at risk of relapse to alcohol use, a therapeutically effective amount of the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, wherein the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is a compound of the following formula,

Chemical formula

[0127] Embodiment I-28. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative in the manufacture of a medicament for the treatment for reducing sensitivity to one or more relapse triggers, the treatment comprising administering the medicament to a subject having an alcohol use disorder (AUD) at risk of relapse to alcohol use, wherein the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is a compound of the following formula,

Chemical formula

[0128] Embodiment I-29. A 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative for use in a method for reducing sensitivity to one or more relapse triggers, the method comprising administering to a subject having an alcohol use disorder (AUD) at risk of relapse to alcohol use, a therapeutically effective amount of the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, wherein the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is a compound of the following formula, [Chemistry] A 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, which is or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano.

[0129] Embodiment I-30. An agent for the treatment for reducing susceptibility to one or more relapse triggers, the agent comprising a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the treatment comprising administering the agent to a subject having alcohol use disorder (AUD) at risk of relapse to alcohol use, to deliver a therapeutically effective amount of the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative. The 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is a compound of the following formula [Chemistry] Or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano, the agent.

[0130] Embodiment I-31. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the agent of Embodiments I-27 to I-30, wherein the administration results in remission of AUD for at least 3 months.

[0131] Embodiment I-32. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative in the manufacture of an agent for the treatment for promoting remission of alcohol use disorder (AUD), the treatment comprising administering the agent to a subject having AUD. The 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is a compound of the following formula [Chemistry] Or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano, use.

[0132] Embodiment I-33. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative in the treatment for promoting remission of alcohol use disorder (AUD), wherein the treatment comprises administering a therapeutically effective amount of the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative to a subject having AUD, The 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is a compound of the following formula,

Chemical formula

[0133] Embodiment I-34. A 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative for use in a method for promoting remission of alcohol use disorder (AUD), wherein the method comprises administering a therapeutically effective amount of the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative to a subject having AUD, The 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is a compound of the following formula,

Chemical formula

[0134] Embodiment I-35. An agent for the treatment for promoting remission of alcohol use disorder (AUD), wherein the agent comprises a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the treatment comprises administering the agent to deliver a therapeutically effective amount of the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative to a subject having AUD, A 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is a compound of the following formula,

Chemical formula

[0135] Embodiment I-36. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and a medicament of Embodiments I-31 to I-35, wherein administration results in remission for at least 12 months.

[0136] Embodiment I-37. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and a medicament described in Embodiments I-27 to I-36, wherein administration prevents relapse for at least 3 months.

[0137] Embodiment I-38. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and a medicament of Embodiments I-27 to I-37, wherein administration prevents relapse for at least 12 months.

[0138] Embodiment I-39. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and a medicament described in Embodiments I-37 and I-38, wherein the method further includes one or more tests for determining relapse.

[0139] Embodiment I-40. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and a medicament described in Embodiment I-39, wherein one of the one or more tests for determining relapse is a timeline-follow-back self-report alcohol consumption assessment.

[0140] Embodiment I-41. One of one or more tests for determining recurrence is an acute alcohol intake test, a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the use of the agents described in Embodiments I-39 and I-40.

[0141] Embodiment I-42. One of one or more tests for determining recurrence is a chronic alcohol use test, a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the use of the agents described in Embodiments I-39 to I-41.

[0142] Embodiment I-43. Administration results in a subject having no early recurrence symptoms for at least 3 months, a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the use of the agents described in Embodiments I-27 to I-42.

[0143] Embodiment I-44. Administration results in a subject having no early recurrence symptoms for at least 12 months, a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the use of the agents of Embodiments I-27 to I-43.

[0144] Embodiment I-45. The method further includes determining whether a subject meets the DSM-5 diagnostic criteria for AUD, and if the subject meets the DSM-5 criteria for AUD, administering a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof, and if the subject does not meet the DSM-5 diagnostic criteria for AUD, not administering a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof, a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the use of the agents described in Embodiments I-27 to I-44.

[0145] Embodiment I-46. 4-(3-Cyanophenyl)-6-pyridinylpyrimidine derivatives, and use of the agents described in Embodiments I-27 to I-45, wherein the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof is administered to a subject after a period of abstinence by the subject.

[0146] Embodiment I-47. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the agent described in Embodiment I-46, wherein the method further comprises performing a test to confirm abstinence.

[0147] Embodiment I-48. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the agents described in Embodiments I-46 and I-47, wherein the period of abstinence is at least 12 hours and the subject has a breath or blood alcohol level of about 0.

[0148] Embodiment I-49. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the agents described in Embodiments I-46 to I-48, wherein the period of abstinence is at least 1 day, at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 months, or at least 6 months.

[0149] Embodiment I-50. Use of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the agents described in Embodiments I-27 to I-49, wherein R is F or cyano.

[0150] Embodiment I-51. The 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is as follows

Chemical formula

[0151] Embodiment I-52. The 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative is as follows,

Chemical formula

[0152] Embodiment I-53. The use of 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivatives and the medicaments of Embodiments I-27 to I-52, wherein the treatment achieves an average plasma concentration of about 100 ng / mL.

[0153] Embodiment I-54. The use of 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivatives and the medicaments of Embodiments I-27 to I-53, wherein the subject is administered a dose of 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (such as Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 30 mg / day to about 300 mg / day, about 50 mg / day to about 200 mg / day, about 50 mg / day to about 120 mg / day, about 50 mg / day to about 100 mg / day, about 60 mg / day to about 90 mg / day, about 60 mg / day to about 80 mg / day, or about 60 mg / day to about 70 mg / day.

[0154] Embodiment I-55. A method for treating a subject administered a dosage of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative (e.g., Compound 1 or Compound 2) or a pharmaceutically acceptable salt thereof at about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 200 mg / day, or about 300 mg / day, and the use of the 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative and the agent described in Embodiments I-27 to I-53.

[0155] Embodiment I-56. A method for treating a subject administered about 1 / 3 of the dosage on the 1st to 3rd days of administration, about 2 / 3 of the dosage on the 4th to 6th days of administration, and the full dosage after the 7th day of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the use of the agent described in Embodiments I-54 and I-55.

[0156] Embodiment I-57. A method for treating a subject administered about 1 / 3 of the dosage twice a day on the 1st to 3rd days of administration, about 2 / 3 of the dosage twice a day on the 4th to 6th days of administration, the full dosage twice a day on the 7th to 13th days of administration, and the full dosage once a day after the 14th day of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the use of the agent described in Embodiment I-56.

[0157] Embodiment I-58. A method for treating a subject administered 50 mg / day twice a day on the 1st to 3rd days of administration, about 100 mg / day twice a day on the 4th to 6th days of administration, about 150 mg / day twice a day on the 7th to 13th days of administration, and about 150 mg / day once a day after the 14th day of a 4-(3-cyanophenyl)-6-pyridinylpyrimidine derivative, and the use of the agent described in Embodiment I-57.

[0158] Set II Embodiment II-1. A method for treating a subject having a substance use disorder (SUD) at risk of relapse to substance use, the method comprising administering a therapeutically effective amount of a compound of the following formula [Chemical] or administering to a subject a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano, A method, wherein the administration reduces susceptibility to one or more relapse triggers.

[0159] Embodiment II-2. Use of a compound in the treatment for reducing susceptibility to one or more relapse triggers, wherein the treatment comprises administering to a subject having a substance use disorder (SUD) at risk of relapse to substance use a therapeutically effective amount of the compound, The compound is of the following formula, [Chemical] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano.

[0160] Embodiment II-3. Use of a compound in the manufacture of a medicament for the treatment for reducing susceptibility to one or more relapse triggers, wherein the treatment comprises administering to a subject having a substance use disorder (SUD) at risk of relapse to substance use a medicament, The compound is of the following formula, [Chemical] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano.

[0161] Embodiment II-4. A compound for use in a method for reducing susceptibility to one or more relapse triggers, wherein the method comprises administering to a subject having a substance use disorder (SUD) at risk of relapse to substance use a therapeutically effective amount of the compound, The compound is of the following formula, [Chemical] A compound which is or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano.

[0162] Embodiment II-5. An agent for the treatment for reducing sensitivity to one or more relapse triggers, the agent comprising a compound, and the treatment comprising administering the agent to a subject having a substance use disorder (SUD) at risk of relapse to substance use in a therapeutically effective amount of the compound. The compound has the following formula: [Chemical formula] An agent which is or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano.

[0163] Embodiment II-6. The method, use, compound, or agent according to any one of Embodiments II-1 to II-5, wherein the administration results in remission of SUD for at least 3 months.

[0164] Embodiment II-7. A method for promoting remission in a subject having a substance use disorder (SUD), comprising administering to the subject a therapeutically effective amount of a compound of the following formula: [Chemical formula] Or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. The method, wherein the administration results in remission for at least 3 months.

[0165] Embodiment II-8. Use of a compound in the manufacture of an agent for the treatment for promoting remission of a substance use disorder (SUD), the treatment comprising administering the agent to a subject having SUD. The compound has the following formula: [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano, use.

[0166] Embodiment II-9. Use of a compound in the treatment for promoting remission of substance use disorder (SUD), wherein the treatment comprises administering to a subject having SUD a therapeutically effective amount of the compound, The compound has the following formula,

Chemical formula

[0167] Embodiment II-10. A compound for use in a method for promoting remission of substance use disorder (SUD), wherein the method comprises administering to a subject having SUD a therapeutically effective amount of the compound, The compound has the following formula,

Chemical formula

[0168] Embodiment II-11. An agent for the treatment for promoting remission of substance use disorder (SUD), wherein the agent comprises a compound and the treatment comprises administering the agent to deliver a therapeutically effective amount of the compound to a subject having SUD, The compound has the following formula,

Chemical formula

[0169] Embodiment II-12. The method, use, compound for use, and medicament according to embodiments II-7 to II-11, wherein the administration results in remission for at least 12 months.

[0170] Embodiment II-13. The method, use, compound for use, and medicament according to embodiments II-1 to II-12, wherein the administration prevents relapse for at least 3 months.

[0171] Embodiment II-14. The method, use, compound for use, and medicament according to embodiments II-1 to II-13, wherein the administration prevents relapse for at least 12 months.

[0172] Embodiment II-15. The method, use, compound for use, and medicament according to embodiments II-13 and II-14, wherein the method or treatment further comprises one or more tests for determining relapse.

[0173] Embodiment II-16. The method, use, compound for use, and medicament according to embodiment II-15, wherein one of the one or more tests for determining relapse is a timeline-follow-back self-reported substance consumption assessment.

[0174] Embodiment II-17. The method, use, compound for use, and medicament according to embodiment II-15, wherein one of the one or more tests for determining relapse is a urine drug screening test, a saliva drug test, or a hair follicle drug test.

[0175] Embodiment II-18. The method, use, compound for use, and medicament according to embodiment II-15, wherein one of the one or more tests for determining relapse is an acute alcohol intake test.

[0176] Embodiment II-19. The method, use, compound for use, and medicament according to embodiment II-15, wherein one of the one or more tests for determining recurrence is a chronic alcohol use test.

[0177] Embodiment II-20. The method, use, compound for use, and medicament according to embodiments II-1 to II-19, wherein upon administration, the subject does not exhibit early recurrence symptoms for at least 3 months.

[0178] Embodiment II-21. The method, use, compound for use, and medicament according to embodiments II-1 to II-20, wherein upon administration, the subject does not exhibit early recurrence symptoms for at least 12 months.

[0179] Embodiment II-22. The method, use, compound for use, and medicament according to embodiments II-1 to II-21, further comprising determining whether the subject meets the DSM-5 diagnostic criteria for SUD, and if the subject meets the DSM-5 criteria for SUD, administering the compound or a pharmaceutically acceptable salt thereof, and if the subject does not meet the DSM-5 diagnostic criteria for SUD, not administering the compound or a pharmaceutically acceptable salt thereof.

[0180] Embodiment II-23. The method, use, compound for use, and medicament according to embodiments II-1 to II-22, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject after a period of abstinence by the subject.

[0181] Embodiment II-24. The method, use, compound for use, and medicament according to embodiment II-23, further comprising performing a test to confirm abstinence.

[0182] Embodiment II-25. The method, use, compound for use, and medicament according to Embodiments II-23 and II-24, wherein the abstinence period is at least 12 hours and the subject has a breath or blood alcohol level of about 0.

[0183] Embodiment II-26. The method, use, compound for use, and medicament according to Embodiments II-23 to II-25, wherein the abstinence period is at least 1 day, at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 months, or at least 6 months.

[0184] Embodiment II-27. The method, use, compound for use, and medicament according to Embodiments II-1 to II-26, wherein R is F or cyano.

[0185] Embodiment II-28. The compound is as follows

Chemical formula

[0186] Embodiment II-29. The compound is as follows

Chemical formula

[0187] Embodiment II-30. The method or treatment achieves an average plasma concentration of about 10 ng / mL to about 300 ng / mL, and the method, use, compound for use, and medicament according to Embodiments II-1 to II-29.

[0188] Embodiment II-31. The method, use, compound for use, and medicament according to embodiments II-1 to II-30, wherein the subject is administered a dose of a compound or a pharmaceutically acceptable salt thereof of from about 5 mg / day to about 300 mg / day, from about 30 mg / day to about 300 mg / day, from about 50 mg / day to about 300 mg / day, from about 5 mg / day to about 200 mg / day, from about 30 mg / day to about 200 mg / day, from about 50 mg / day to about 200 mg / day, from about 30 mg / day to about 120 mg / day, from about 50 mg / day to about 120 mg / day, from about 30 mg / day to about 100 mg / day, from about 50 mg / day to about 100 mg / day, from about 30 mg / day to about 90 mg / day, from about 50 mg / day to about 90 mg / day, from about 30 mg / day to about 80 mg / day, from about 50 mg / day to about 80 mg / day, from about 30 mg / day to about 70 mg / day, from about 50 mg / day to about 70 mg / day, from about 60 mg / day to about 90 mg / day, from about 60 mg / day to about 80 mg / day, or from about 60 mg / day to about 70 mg / day.

[0189] Embodiment II-32. The method, use, compound for use, and medicament according to embodiments II-1 to II-31, wherein the subject is administered a dose of a compound or a pharmaceutically acceptable salt thereof of about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 200 mg / day, or about 300 mg / day.

[0190] Embodiment II-33. The method, use, compound for use, and medicament according to embodiments II-31 to II-32, wherein for administration for 1 to 3 days, about 1 / 3 of the dose is administered, for administration for 4 to 6 days, about 2 / 3 of the dose is administered, and from the 7th day onwards, the full dose is administered.

[0191] Embodiment II-34. The method, use, compound for use, and medicament according to embodiment II-33, wherein for administration on days 1 to 3, about 1 / 3 of the dose is administered twice a day, for administration on days 4 to 6, about 2 / 3 of the dose is administered twice a day, for administration on days 7 to 13, the full dose is administered twice a day, and from the 14th day onwards, the full dose is administered once a day.

[0192] Embodiment II-35. The method, use, compound for use, and medicament according to Embodiment II-34, wherein the subject is administered 50 mg / day in two doses per day on the 1st to 3rd days, about 100 mg / day in two doses per day on the 4th to 6th days, about 150 mg / day in two doses per day on the 7th to 13th days, and about 150 mg / day in one dose per day after the 14th day.

[0193] Embodiment II-36. The method, use, compound for use, and medicament according to Embodiments II-1 to II-35, wherein the SUD is alcohol use disorder (AUD).

[0194] Embodiment II-37. The method, use, compound for use, and medicament according to Embodiments II-1 to II-17, II-20 to II-24, and II-26 to II-35, wherein the SUD is opioid use disorder (OUD).

[0195] Embodiment II-38. The method, use, compound for use, and medicament according to Embodiments II-1 to II-17, II-20 to II-24, and II-26 to II-35, wherein the SUD is stimulant use disorder.

[0196] Embodiment II-39. The method, use, compound for use, and medicament according to Embodiment II-38, wherein the stimulant use disorder is cocaine use disorder (CUD).

Examples

[0197] The following examples are provided to illustrate the present disclosure and should not be construed as limiting it. In these examples, all parts and percentages are by weight unless otherwise specified.

[0198] Example 1 - Effects of Compound 1 on Home Cage Alcohol Intake, Positive Reinforcing Properties of Alcohol, and Reinstatement (Relapse) of Cue-Induced Alcohol Seeking The following are additional examples regarding home cage alcohol intake, positive reinforcing properties of alcohol, and effects of Compound 1 on relapse.

[0199] Summary Background: The aim of this research was to investigate the preclinical efficacy of Compound 1, a novel mGluR5 negative allosteric modulator (NAM), in 1) chronic alcohol intake, 2) positive reinforcing properties of alcohol modeled by operant self-administration, and 3) reducing reinstatement of cue-induced operant alcohol seeking behavior as a relapse model in Wistar rats. Compound 1 is brain penetrant and exhibits high affinity for mGluR5 after systemic administration in rats, mice, and primates.

[0200] Methods and Results: Acute systemic administration of Compound 1 (0 - 10 mg / kg, IP) resulted in a dose-dependent decrease in home-cage sweetened alcohol intake. A comparison of Compound 1 (3 mg / kg) with mGluR5 NAM MPEP (3 mg / kg) and the opioid antagonist naltrexone (3 mg / kg) showed that all compounds significantly decreased home-cage alcohol intake after 1 h of access compared to vehicle controls, which had no statistically significant differences among the three test compounds. After 24 h of alcohol access, only Compound 1 showed efficacy in reducing sweetened alcohol intake. Overall, there was a tendency for a decrease in parallel water intake, but the dose of Compound 1 did not reach statistical significance for this control measure. Compound 1 did not affect acclimation to a novel environment, total locomotor activity, or anxiety-like behavior when evaluated in the open-field test. This suggests that the effects on home-cage alcohol intake and operant self-administration are not related to nonspecific behavioral effects. Repeated treatment with Compound 1 (3 mg / kg) for 7 days also decreased the mean home-cage alcohol intake over 1 week, but only during the first hour of access. Importantly, Compound 1 also decreased operant alcohol self-administration (e.g., the number of alcohol-reinforced lever presses) in a dose-dependent manner, indicating blockade of the positive reinforcing effects of alcohol. Finally, Compound 1 (10 mg / kg) blocked the reinstatement of cue-induced alcohol-seeking behavior, an animal model of relapse induced by exposure to environmental stimuli previously paired with alcohol use.

[0201] Conclusion: Compound 1 demonstrated preclinical efficacy in reducing spontaneous alcohol intake, operant alcohol self-administration (reinforcement / reward), and cue-induced reinstatement (relapse) in Wistar rats. When administered acutely, Compound 1 significantly decreased alcohol intake and operant self-administration and was similarly effective compared to naltrexone, an FDA-approved treatment for AUD. Compound 1 demonstrated improved efficacy in reducing preference for alcohol after a 24-hour access period. Control experiments (water intake, locomotor activity, anxiety-like behavior) did not show non-specific effects that could explain the decrease in alcohol intake, self-administration, or relapse-like behavior. These preclinical results support the conclusion that Compound 1 may be useful in the medical management of chronic alcohol intake and relapse.

[0202] Specific aims of these studies The aim of Study Objective 3.1 was to evaluate the preclinical efficacy of Compound 1 (3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile; AKA HTL0014242), a novel mGluR5 negative allosteric modulator, for reducing chronic spontaneous alcohol intake in rats. Two studies were conducted under two separate study objectives, namely, Objective 3.1 and Objective 3.2.

[0203] Study Objective 3.1. RO 3.1 had two aims. First Specifically, Aim 3.1a was to evaluate the preclinical efficacy of acute treatment with Compound 1 (0–10 mg / kg) for reducing spontaneous home-cage alcohol intake, as evaluated in Study 3.1.a. The behavioral effects of Compound 1 were compared to those of the mGluR5 negative modulator MPEP and the opioid antagonist naltrexone, an FDA-approved treatment for AUD. Additionally, the effective dose of Compound 1 was evaluated for potential non-specific behavioral effects in an open-field locomotor chamber that assesses motor function and other natural rodent behaviors. SecondFor objective 3.1b, the goal was to examine the effective dose of compound 1 (3 mg / kg) identified in study 3.1.a and evaluate the effect of the repeated treatment protocol.

[0204] Study objective 3.2. In study objective 3.2, studies were conducted to evaluate the preclinical efficacy of compound 1 to reduce the positive reinforcing and relapse-inducing effects of alcohol. First For this, preclinical efficacy data were collected on the ability of pretreatment with an acute dose range of compound 1 to reduce the positive reinforcing effect of alcohol during chronic operant self-administration. We also attempted to evaluate the efficacy of repeated treatment with a single effective dose of compound 1 determined from the acute dose-response curve. Second For this, the final goal of this project was to evaluate the preclinical efficacy of compound 1 to inhibit relapse-like behavior. Using a reinstatement procedure induced by cues, we modeled relapse that occurs when abstinent individuals encounter environmental stimuli previously paired with drug use. These "cues" are widely known to induce craving and relapse in abstinent drug users, including AUD patients. We showed that the mGluR5 NAM MPEP blocks cue-induced reinstatement in rats and that compound 1 shows similar efficacy.

[0205] Materials and Methods Animals: Male Wistar rats (Charles River Laboratories, INC) were used in these studies. The rats were housed and tested in a state-of-the-art rodent facility approved by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) at the University of North Carolina at Chapel Hill (UNC-CH) School of Medicine. The health status of the rats was monitored daily by the principal investigator and a veterinarian in the UNC Comparative Medicine Department. All experimental procedures were conducted in accordance with the NIH Guide to Care and Use of Laboratory Animals (Committee for the Update of the Guide for the Care and Use of Laboratory Animals, 2011) and the facility guidelines.

[0206] Rats were individually housed in standard plexiglass cages and allowed free access to standard rodent chow and water. Upon arrival from the vendor, rats were given 7 days to acclimate to the breeding facility, during which time their general health was monitored and they were weighed and cared for daily by the study physician to get used to human contact. The rats were then weighed daily within 1 hour of the experimental procedure to calculate the drug dose relative to body weight. The rats showed typical growth and development along with body weight throughout the experimental procedure. The colony was maintained at 21 ± 1 ° °C on a 12-hour light / dark cycle with lights on from 10:00 a.m. to 10:00 p.m. All behavioral experiments were conducted during the light portion of the light cycle.

[0207] Study Goals 3.1a and 3.1b - Effects of Acute Compound 1 on Home-Cage Alcohol Intake (Acute and Repeated Treatments) Home-cage alcohol intake method. Oral alcohol and water intake was examined using a two-bottle choice protocol that is standard in the art and commonly used in laboratories. Male Wistar rats (n = 12) were first adapted to drink from a 50-ml conical tube equipped with a standard stainless-steel ball-bearing sipper tube that restricted spillage. Two bottles were then placed in the cage daily. One bottle contained the alcohol solution and the other contained water. Bottles with fresh solution were weighed daily before and after the 24-hour access period. After drug treatment, the bottles were weighed 1 hour and 24 hours after access. Weekly, the rats had access to sweetened alcohol and water for 4 - 5 days and water only for the remaining days.

[0208] Wistar rats were trained to drink alcohol using the well-characterized and widely used sucrose fading technique, as they do not spontaneously consume pharmacologically appropriate doses of alcohol. Briefly, rats were first exposed to alcohol (10% v / v) + sucrose (5% w / v) and water in two bottles. Then, over a period of 6 weeks, the concentrations of alcohol and sucrose were gradually adjusted to alcohol (8% v / v) + sucrose (2% w / v) to achieve a pharmacologically appropriate dose of alcohol intake. Rats were maintained at this concentration throughout the experimental period in both acute (3.1.a) and chronic (3.1.b) home cage drinking tests. The use of sweetened alcohol solutions in preclinical studies generally provides face validity for the binge-drinking - intoxication stage of alcohol addiction in humans, where sweeteners are added to alcohol.

[0209] Compound 1 treatment. After establishing baseline intakes of sweetened alcohol and water, rats were acclimated to intraperitoneal injection. All rats (N = 12) received three acclimation injections of vehicle (10% w / v kolliphor in BCD (10%)) before measuring the dose-response curve of Compound 1 and alcohol intake. Then, the dose-response curve of Compound 1 was conducted in a randomized dose order according to the modified Latin square method. Rats were given a minimum interval of 1 - 2 days between injections to ensure that normal drinking was re-established in the absence of drug administration. Each dose of Compound 1 (0 - 10 mg / kg) was administered via intraperitoneal injection, and rats were returned to their home cages for 1 hour, after which sweetened alcohol and water were returned. Alcohol intake was measured in grams by weighing the drinking bottles after 1 hour and 24 hours of access. One rat that did not drink the solution and completely emptied both bottles daily was excluded from the data. Thus, the results are presented for the final group of N = 11 rats.

[0210] Spontaneous locomotor activity: Examination of non-specific behavioral effects. After completion of the dose-response curve for Compound 1, the potential non-specific effects of Compound 1 (3 mg / kg) were evaluated using an open-field spontaneous locomotor test. This test assesses the potential effects on locomotor activity and anxiety-like behavior. Rats were administered Compound 1 (0 or 3 mg / kg, intraperitoneally) in a randomized balanced order. After a 1-hour pretreatment period (matching the pretreatment period used in the drinking test), rats were placed in an open-field apparatus and spontaneous locomotor activity was computer-monitored for 1 hour. To evaluate anxiety-like behavior, activity in the central zone of the open field was analyzed.

[0211] Efficacy comparison with MPEP and naltrexone. After the spontaneous locomotor test, the effects of the mGluR5 negative modulator MPEP (3 mg / kg, intraperitoneally) and the opioid antagonist naltrexone (3 mg / kg, intraperitoneally) were evaluated against alcohol drinking as a positive control. The drugs were administered on separate days in a balanced order.

[0212] Repeated treatment with Compound 1. To evaluate the effect of repeated treatment with Compound 1 on home-cage alcohol drinking, baseline intakes of sweetened alcohol and water, as well as acclimation to intraperitoneal injection, were performed as described above in separate groups of male Wistar rats (n = 12). During acclimation to intraperitoneal injection, rats were transferred to a 7-day-a-week alcohol access schedule to allow for chronic daily treatment. Then, according to an A-B-A experimental design, rats were administered vehicle (for 4 consecutive days), Compound 1 (3 mg / kg, for 7 consecutive days), and then vehicle (for 4 consecutive days) for a total of 15 days. Access to alcohol was provided 1 hour after injection of vehicle or Compound 1. Alcohol and water intakes were measured as described above 1 hour and 24 hours after access. One rat that was unable to consume alcohol was excluded from the data. Therefore, the results are reported for the final group of N = 11 rats.

[0213] Study Objectives 3.2a and 3.2b - Effects of Compound 1 on Alcohol Reinforcement (Reward) and Relapse Behavioral Apparatus Twelve operant conditioning chambers (30.5 cm × 24.1 cm × 21.0 cm, Med Associates, Georgia, Vermont) designed for rats were placed in a dedicated indoor acoustic attenuation cubicle to limit potential external influences from external environmental variables. Each cubicle was equipped with an exhaust fan to provide ventilation and block external noise. The chambers were electronically connected to a Microsoft Windows-based computer programmed using software developed by the researcher to control the session and record the number of lever press responses at 100 millisecond intervals.

[0214] The right wall of each chamber contained a liquid container and a response lever called the active lever (Med Associates). A syringe pump (PHM-100, Med Associates) that delivered 0.1 ml of an alcohol solution (ethanol 8% v / v + sucrose 2% w / v) into the container over 1.66 seconds was activated by a lever press response on the active lever. Entry of the head into the liquid container was recorded when the infrared light beam was interrupted. A stimulus light located above the response lever was lit during pump operation. Pressing the lever during delivery of the reinforcer was recorded but did not result in a programmed outcome. The opposite wall of each chamber housed a response lever called the inactive lever. Responses to the inactive lever were recorded but did not result in a programmed outcome. The behavior of this lever serves as a control for movement disruption and other non-specific effects of the test compound.

[0215] Operant alcohol self-administration: Training and baseline Alcohol self-administration training was conducted using the general methods reported so far and was verified to evaluate the mechanism of the reinforcing effect of alcohol (Schroeder JP, Overstreet DH, Hodge CW. The mGluR5 antagonist MPEP decreases operant ethanol self-administration during maintenance and after repeated alcohol deprivations in alcohol-preferring (P) rats. Psychopharmacology (2005) 179:262-270). First, rats were exposed to an alcohol solution (ethanol 8% v / v + sucrose 2% w / v) and water placed in the drinking bottles of the home cage for 1 week. This provides habituation to the novel taste and initial experience of the drug. Next, during the first 3 days of training, rats were placed in the self-administration chamber for 16-hour sessions to establish reliable lever-pressing behavior. We have shown that this autoshaping method, which depends on exploratory behavior, produces a robust alcohol-reinforced lever-press response in rodents. Throughout the training and the entire experiment, each lever-press response produced an alcohol solution on a fixed ratio 1 (FR-1) reinforcement schedule. After the first training, rats were allowed to self-administer the alcohol solution spontaneously for 30 days during 30-minute sessions daily (Monday to Friday) to establish a stable vertical baseline.

[0216] Operant Alcohol Self-Administration: Drug Testing Examine the effectiveness of compound 1 in reducing the potentiating or rewarding effects of alcohol. After establishing stable baseline self-administration behavior, the effects of pre-session treatment with the novel mGluR5 negative allosteric modulator compound 1 (0, 0.3, 1, 3, and 10 mg / kg, IP) were evaluated against operant alcohol self-administration behavior (n = 12 rats). To control for potential handling or injection effects, rats (n = 12) were first given three habituation injections of vehicle (10% w / v kolliphor in BCD (10%)), after which the dose-response curve for compound 1 was evaluated. Doses of compound 1 (0 - 10 mg / kg) were administered within subjects according to a randomized Latin square dosing method to control for potential order effects. All doses were administered 1 hour before the start of the operant self-administration session based on known receptor occupancy data in rats after systemic injection. Drug testing was performed only on Tuesdays and Fridays of each week when behavior was stable (compared to baseline) on the intervening non-drug days. Parameters of operant performance were measured, including total lever press responses, number of head entries into the liquid receptacle, and the operant response rate, a direct measure of positive reinforcement function.

[0217] Comparison of effectiveness with MPEP and naltrexone. After completion of the acute dose-response curve for compound 1, the effects of the mGluR5 antagonist MPEP (3 and 10 mg / kg, IP) and the opioid antagonist naltrexone (3 mg / kg, IP) were evaluated in the same rats, and a comparison was made between compound 1 and compounds known to reduce operant alcohol self-administration. MPEP has a similar mechanism of action via mGluR5, and importantly, naltrexone is FDA-approved as a therapeutic for AUD in humans, providing comparative data with a validated therapeutic compound. The effects of MPEP were evaluated first, followed by naltrexone. As with the testing of compound 1, each drug was administered 1 hour before the behavioral session and only on Tuesdays or Fridays under stable baseline conditions. The same vehicle (10% w / v kolliphor in BCD (10%)) was used for all test compounds.

[0218] Repeated treatment with compound 1. To evaluate the effect of repeated treatment with compound 1 on operant alcohol self-administration, as described above, another group of rats (n = 12) was trained to self-administer alcohol. After reaching a stable baseline of operant behavior, acclimation to intraperitoneal injection was performed as described above. During acclimation to intraperitoneal injection, the rats showed a severe stress response to the injection and the study was terminated. Then, another group of rats (n = 12) was trained to self-administer alcohol and a new injection protocol (e.g., 2-hour pretreatment time) was initiated. This method also resulted in a stress response and reduced alcohol self-administration. In the final attempt to evaluate repeated treatment, we re-established baseline behavior in the same rats and orally administered compound 1 (0 and 10 mg / kg) with a previously reported palatable food pellet. Doses were administered according to an A-B-A (vehicle-compound 1-vehicle) experimental design, with each vehicle treatment exposed for 5 consecutive days and compound 1 exposed for 7 days. There was no observable stress response using this exposure method. Operant self-administration (number of alcohol-reinforced lever presses) was recorded during daily 15-minute inspection sessions (n = 12 rats).

[0219] Restart of alcohol seeking behavior induced by cue Operant alcohol self-administration training. Male Wistar rats (n = 12) were trained to self-administer alcohol in an operant conditioning chamber with two levers as described above. A total of n = 11 rats completed the experiment. One rat was unable to acquire the initial behavior. During all operant self-administration sessions (training and 30-day baseline period), a compound stimulus consisting of a visual cue light located above the response lever and an auditory stimulus of pump activation from a fixed spatial location was presented in response to a response to the lever paired with alcohol (Figure 9A, left panel). Responses to the non-active lever did not result in programmed consequences. The fluid cup was inspected at the end of each session to confirm the intake. Extinction. After 30 days of baseline, the self-administration behavior was extinguished by removing all programmed consequences of lever press responses (i.e., cue light, pump sound, and absence of sweetened alcohol delivery) (Figure 9A, middle panel). The extinction training was continued for 7 days, and at the end of it, the total responses on the active lever decreased from 80 responses per session to 3 responses, which did not differ from the total of the non-active lever and was consistent with the complete extinction of alcohol-reinforced lever press responses.

[0220] Reinstatement testing induced by cue. The next day, rats were subjected to a reinstatement test in which, following lever press responses, cue light and auditory pump sounds (as during training) were presented, but ethanol reinforcement was not performed in order to examine alcohol seeking behavior induced by cue (cue-induced reinstatement method, Figure 9A, right panel). One hour prior to the reinstatement session, rats were divided into two equal subgroups and administered compound 1 (0 or 10 mg / kg, IP) to determine whether compound 1 altered cue-induced reinstatement of alcohol seeking behavior compared to vehicle controls. The groups were matched for body weight, total baseline responses, and extinction performance prior to drug testing. After this test, the rats were returned to baseline conditions. After reestablishing baseline performance, rats received a second extinction procedure followed by a second reinstatement test in a crossover design in which rats that had received vehicle during the first test were administered compound 1 (10 mg / kg) and rats that had previously received compound 1 were administered vehicle.

[0221] Behavioral data analysis The main behavioral parameter of operant ethanol self-administration was the number of lever presses. Self-administration and extinction data were analyzed separately by one-way or two-way analysis of variance (ANOVA) using factors of drug dose, lever (active vs. inactive), and time where appropriate (GraphPad Software Inc., La Jolla, CA, USA). Where appropriate, multiple comparisons were performed using the Sidak or Dunnett multiple comparison tests.

[0222] Results Study objective 3.1a - On home cage alcohol intake Acute Compound 1 Effect of Alcohol intake (1-hour access). Rats consumed an average EtOH dose of 0.596 ± 0.09 g / kg (mean ± SEM) during the first hour of access after vehicle pretreatment. Repeated measures analysis of variance (RM-ANOVA) showed that acute administration of compound 1 (0 - 10 mg / kg) significantly decreased spontaneous home-cage alcohol intake by Wistar rats (F(5, 50) = 3.040, P = 0.0180). By a post-hoc multiple comparison procedure, it was shown that compound 1 (1, 3, and 10 mg / kg) significantly decreased alcohol intake compared to the vehicle control, respectively (Figure 1A). The greatest decrease in EtOH intake was seen after the 3 mg / kg dose of compound 1. The effect of compound 1 (3 mg / kg) was compared with MPEP (3 mg / kg) and naltrexone (3 mg / kg) as positive controls. RM-ANOVA showed that overall drug treatment significantly decreased alcohol intake (F(3, 30) = 7.74, P = 0.0006). By a multiple comparison procedure, it was shown that all three drugs significantly decreased alcohol intake at 1 hour of access compared to the vehicle control (Figure 1B). Thus, compound 1 demonstrated high efficacy in reducing spontaneous alcohol intake during the first hour of access when rodent motivation peaks.

[0223] Alcohol intake (24-hour access). RM-ANOVA showed that acute pretreatment with Compound 1 (0 - 10 mg / kg) significantly decreased alcohol intake measured after 24-hour access (F(5, 50) = 2.429, P = 0.0478). Follow-up multiple comparison procedures showed that Compound 1 (1 and 3 mg / kg) significantly decreased alcohol intake after 24-hour access, respectively (Figure 1C). The tendency for a decrease in EtOH intake after Compound 1 (10 mg / kg) did not achieve statistical significance. Comparison of Compound 1 to equivalent doses of MPEP and naltrexone showed that overall drug treatment significantly decreased alcohol intake at 24-hour measurement intervals (F(3, 30) = 3.058, P = 0.0433). Interestingly, follow-up multiple comparisons showed that only Compound 1 (3 mg / kg) maintained efficacy at 24-hour measurement intervals (Figure 1D), indicating an improvement in the efficacy of Compound 1 compared to FDA-approved agents for the treatment of similar acting compounds (MPEP) and AUD (naltrexone). Results after 24-hour access indicate that Compound 1 (1 or 10 mg / kg) has significant efficacy for decreasing spontaneous alcohol intake over a long period after treatment.

[0224] Water intake (1-hour and 24-hour access). RM-ANOVA showed compound 1 (0 - 10 mg / kg) or compound 1 (3 mg / kg) compared to MPEP and naltrindole. The tendency for a decrease in water intake did not reach statistical significance (Figures 2A - 2B). At the 24-hour measurement interval, RM-ANOVA identified an overall decrease in H2O intake after pretreatment across the full dose range of compound 1 (0 - 10 mg / kg) (F(5, 50) = 6.542, P < 0.0001). However, post-hoc multiple comparisons did not identify significant changes at any dose of compound 1 compared to vehicle (Figure 2C). This suggests that an overall trend with little variability (both slight increases and decreases) contributed to the main effect. Finally, there was no effect of compound 1 (3 mg / kg) or the comparator compounds on H2O intake after 24-hour access (Figure 2D). These results show a favorable profile indicating a lack of non-specific effects of compound 1 on general fluid consumption.

[0225] Open-field locomotor activity test for non-specific behavioral effects. Pharmacological manipulations can alter rodent behavior by producing effects non-specific to locomotor ability, learning and memory, or emotional processing. The open-field test is a widely used method for assessing all of these potential non-specific effects in a single test. In this method, rodents are injected with the test compound, placed in an open-field apparatus, and the interruption of light beams is computer-analyzed to record locomotor behavior in real time (Figure 3A). Results showed that compound 1 (3 mg / kg) did not affect initial exploration or habituation to a novel open-field environment compared to vehicle controls (Figure 3B). Similarly, compound 1 (3 mg / kg) did not affect summary measures of total distance traveled (Figure 3C) or total time spent walking (Figure 3D) compared to vehicle controls. This indicates that normal learning, memory, and motor function are intact and not altered by drug treatment.

[0226] To evaluate potential non-specific changes in emotional processing, spontaneous movement data were analyzed for potential changes in locomotor activity in the central zone of the open field (Figure 4A). Rats showed normal avoidance of the central zone after treatment with Compound 1 (3 mg / kg) compared to vehicle (Figures 4B and 4C). Overall, the important negative control results shown in Figures 3 and 4 indicate that Compound 1 did not reduce alcohol intake via non-specific changes in locomotor ability, cognitive function (spatial learning and memory), or emotional processing.

[0227] Study Objective 3.1b - Effects on Repeated Compound 1 home cage alcohol intake Alcohol intake (1-hour access). Rats consumed an average EtOH dose of 0.73 ± 0.08 g / kg (mean ± SEM) during the first hour of access after vehicle pretreatment (Days 1 - 4, Figure 5A). Repeated measures analysis of variance (RM-ANOVA) showed that repeated administration of Compound 1 (3 mg / kg) significantly reduced spontaneous home cage alcohol intake in Wistar rats (F(14,140) = 2.303, P = 0.0071). A follow-up multiple comparison procedure of data from individual treatment days showed that Compound 1 (3 mg / kg) decreased alcohol intake only on Day 5 compared to vehicle on Day 4, but there was a trend towards decreased intake on Days 2 - 5 and Day 7 (Figure 5A). Alcohol intake remained somewhat decreased on Day 12 after vehicle administration, suggesting a residual effect of Compound 1 treatment. Subsequently, alcohol intake returned to baseline values on Days 12 - 15 after vehicle treatment, suggesting that the effect of Compound 1 did not extend beyond Day 12.

[0228] To further evaluate the effect of compound 1 as a whole, daily alcohol intake data from each condition (Veh-1, compound 1, and Veh-2) were converted to the overall average of each rat's performance. RM-ANOVA showed that compound 1 (3 mg / kg) significantly decreased alcohol intake (F(1.689, 16.89) = 4.284, P = 0.0366). The follow-up multiple comparison procedure showed that the average alcohol intake during the 7-day compound 1 treatment phase was lower than that in both Veh-1 and Veh-2 conditions (Figure 5B). These results indicate the preclinical efficacy of repeated compound 1 treatment to reduce alcohol intake during the first hour of access.

[0229] Alcohol intake (24-hour access). Rats consumed an average EtOH dose of 4.04 ± 0.48 g / kg (mean ± SEM) 2 hours after the start of access following vehicle pretreatment (days 1 - 4, Figure 5C). Repeated measures ANOVA (RM-ANOVA) of daily drinking data showed that repeated administration of compound 1 (3 mg / kg) significantly decreased alcohol intake (F(14, 140) = 3.315, P = 0.0001) compared to the average vehicle value (Figure 5C). Similar to the 1-hour data above, the follow-up multiple comparison procedure of data from individual treatment days showed that compound 1 (3 mg / kg) decreased alcohol intake only on day 5 compared to the vehicle on day 4 (Figure 5C). Visual inspection of drinking data during compound 1 treatment showed a tendency to increase consistent with the development of tolerance (Figure 5C, middle panel). Also, similar to the 1-hour results, alcohol intake tended to decrease on day 12, but there was no significant difference from the first vehicle days by Dunnett's test. Figure 5D shows no effect of compound 1 (3 mg / kg) when the data were averaged across treatment conditions.

[0230] Water intake (1-hour and 24-hour access). RM-ANOVA showed that repeated treatment with compound 1 (3 mg / kg) resulted in a significant overall decrease in H2O intake after 1-hour access compared to vehicle control (F(14,140) = 2.073, P = 0.0167). However, multiple comparison procedures were unable to identify significant changes on specific treatment days (Figure 6A). This result is likely due to non-significant trends in H2O intake on various days. However, when evaluated by averaging H2O intake across three experimental phases, RM-ANOVA showed that compound 1 decreased water intake (F(2,20) = 9.959, P = 0.0010), and this overall effect was shown to be due to a significant difference between the treatment phase of compound 1 and both vehicle control conditions (Figure 6B). This analysis increased statistical power due to fewer post hoc comparisons and was likely to detect differences.

[0231] After 24-hour access, RM-ANOVA detected an overall decrease in H2O intake produced by compound 1 (3 mg / kg) treatment (F(14,140) = 3.396, P < 0.0001). Multiple comparison procedures showed that this overall effect was caused by significant decreases in H2O intake on days 7 and 11 (Figure 6C). This effect dissipated after returning to vehicle administration between days 12 - 15 of treatment (Figure 6C). This effect on H2O intake was also evident when data were averaged across experimental phases. RM-ANOVA: (F(1.824,18.24) = 7.370, P = 0.0054). Holm-Sidak's multiple comparison test found that the overall effect was caused by a decrease in H2O intake by compound 1 compared to only the first vehicle condition (Figure 6D). Overall, these decreases in H2O intake were modest and did not affect overall health as measured by experimenter and veterinary observations.

[0232] Study Objective 3.2.a - Acute and Repeated Dosing Strategies - Operant Self-Administration (Positive Reinforcement) Effect of acute compound 1 on operant self - administration. Rats were trained for ethanol lever presses in an operant conditioning chamber as described above (Figure 7A). Under baseline conditions, rats made an average of 103 responses on the ethanol lever. Pretreatment with compound 1 (0.3 - 10 g / kg, IP) dose - dependently reduced alcohol - reinforced lever press responses during a 15 - minute test session [RM - ANOVA (F(2.917,29.17)=3.810, P = 0.0211)] (Figure 7B). Dunnett's test showed that compound 1 (10 mg / kg) significantly decreased alcohol intake after 24 - hour access (Figure 7B, asterisk). Comparison of compound 1 (3 and 10 mg / kg) with MPEP and naltrexone (3 mg / kg) at the same doses showed that compound 1 (10 mg / kg) and naltrexone (3 mg / kg) had similar efficacy for reducing alcohol - reinforced lever press responses (Figure 7C). Tukey's multiple comparisons showed that compound 1 (10 mg / kg) and naltrexone (3 mg / kg) reduced the EtOH - reinforced response (Figure 7C, asterisk). Compound 1 (10 mg / kg) and naltrexone (3 mg / kg) did not differ from each other and showed equivalent efficacy.

[0233] Important Point These data indicate the following: 1) Compound 1 dose - dependently reduces the positive reinforcing effect of alcohol, and 2) Compound 1 shows similar efficacy to FDA - approved naltrexone in reducing alcohol reinforcement.

[0234] Effect of repeated treatment with compound 1 on operant self - administration. Rats (n = 12) were trained for lever presses for EtOH reinforcement as described above. After establishing stable baseline behavior and habituation to IP injection, vehicle was injected daily 1 hour before an operant self - administration session as part of an A - B - A (vehicle - compound 1 - vehicle) experimental protocol. Unfortunately, all rats in the group showed a large stress response to daily injection, so the study was terminated.

[0235] A second group of rats (n = 12) was purchased and an alternative injection strategy (e.g., a 2-hour pre-session interval between injection and testing) was used. Unfortunately, the new group of rats also showed a stress response to daily injections under the modified protocol.

[0236] In a final attempt to salvage the study, injections were discontinued in the second group of rats and EtOH self-administration behavior was stabilized over a one-week period. Compound 1 (0 or 10 mg / kg) was then orally delivered via palatable food pellets 2 hours prior to each daily session according to the proposed A-B-A study protocol. The oral pellet method of drug delivery has been successfully used for activation of the Tet-on viral vector and serves as a model for oral drug delivery methods via palatable substances, which are widely used in the art.

[0237] Under these conditions, rats (n = 12) rapidly consumed pellets containing compound 1 (0 mg / kg, vehicle), and behavior remained stable during the 5-day test. During the next 7 days, rats were administered compound 1 (10 mg / kg, oral) in the palatable food pellets, followed by 5 days back to vehicle (A-B-A design). Daily results are shown in Fig. 8A, indicating that the EtOH-reinforced lever press responses were stable during the first vehicle exposure (days 1–5). Administration of compound 1 (10 mg / kg) did not alter operant alcohol self-administration (days 6–12). Returning to vehicle at the final stage (days 13–17) indicated that, although behavior varied somewhat from day to day, it did not show a consistent upward or downward trajectory. Fig. 8B shows a summary plot averaging data from all rats across each experimental stage (A-B-A). Statistical analysis by one-way ANOVA did not show a significant effect of treatment on the multi-day mean of the EtOH-reinforced lever press responses, F(2, 33) = 0.7387, P = 0.4855. Overall, this experiment did not show an effect of compound 1 (10 mg / kg, oral pellet) on the reinforcing effects of alcohol. However, the lack of an apparent effect should be interpreted cautiously and could be due to differences in pharmacokinetics and / or receptor occupancy between this oral consumption method and the more standard IP injection method that generates a well-characterized profile of compound 1 [other studies in this report, as well as (Bennet KA, Sergeev E, MacSweeney CP, Bakker G, and Cooper AE. Understanding the relationship between exposure and receptor occupancy of metabotropic glutamate receptor 5 negative allosteric modulators across various preclinical and clinical studies. The Journal of Pharmacology and Experimental Therapeutics (2021) 377:157–168.)]. Therefore, a full interpretation of these results requires additional pharmacokinetic and behavioral testing.

[0238] Study Aim 3.2.b. - Reinstatement (relapse) of alcohol seeking induced by cue Baseline self-administration. On the last day of baseline, rats (n = 11) responded significantly more on the EtOH (active) lever compared to the simultaneously available inactive lever (t(21) = 5.781, P < 0.0001) (Figure 9B, baseline is indicated by B on the x-axis).

[0239] Extinction of alcohol self-administration. During 7 days of extinction, responses to the lever that previously produced ethanol reinforcement, and environmental cues (stimulus light and pump sound) did not produce programmed outcomes. Overall, rats emitted more responses on the previous active lever during extinction (F(1, 21) = 32.35, P < 0.0001). However, consistent with extinction of behavior, responses to the previous active lever decreased as a function of days (F(7, 147) = 28.18, P < 0.0001) and did not differ from responses to the inactive lever after day 1 (Figure 9B). Also, there was a statistical interaction between time and lever (F(7, 147) = 27.25, P < 0.0001), indicating that the main change in behavior was a time-dependent decrease in responses on the active lever. These data show extinction of ethanol reinforcement responses when all consequences of lever presses were removed for 7 days (i.e., equivalent responses to the lever that previously produced ethanol and the inactive lever).

[0240] Restart of alcohol-seeking behavior induced by cue: blockade by Compound 1. On the 8th day of treatment, half of the rats were administered vehicle and the other half were administered Compound 1 (10 mg / kg), and then a reinstatement test was conducted in which responses on the active lever resulted in the presentation of a distinct cue (stimulus light above the lever and pump sound) that had been paired with ethanol delivery during baseline (Figure 9A). Analysis of the total response data by one-way RM-ANOVA showed a significant effect of the treatment (vehicle vs Compound 1) condition (F(2,20)=3.849, P=0.0385). Multiple comparison procedures showed that responses to the lever that had previously been active increased after vehicle treatment, indicating reinstatement induced by the cue that was blocked by Compound 1 (Figure 9C). The data were also analyzed using each rat as its own control, comparing performance during extinction, and group means were generated. These results showed a reinstatement effect of approximately 400% of the extinction value performance that was completely blocked by Compound 1 (F(2,16)=6.146, P=0.0105) (Figure 9D). Overall, the behavioral data indicate a potent cue-induced reinstatement of alcohol-seeking behavior after vehicle treatment that was blocked by Compound 1, an mGluR5 inhibitor (Figure 9C).

[0241] Conclusion Purpose of These Studies:These studies were conducted to evaluate the preclinical efficacy of compound 1, an mGluR5 negative allosteric modulator, as a drug therapy for AUD. We utilized a rat behavioral paradigm that is highly relevant to human disorders and addresses important therapeutic indications. First, the experiment determined whether compound 1 demonstrates efficacy in reducing chronic alcohol intake within the home cage. Second, using the state-of-the-art operant alcohol self-administration method (Schroeder JP, Overstreet DH, Hodge CW. mGluR5 antagonist MPEP reduces operant ethanol self-administration during maintenance and after repeated alcohol deprivation in alcohol-preferring (P) rats. Psychopharmacology (2005) 179:262-270), we determined whether compound 1 shows efficacy in reducing the positive reinforcing effects of alcohol, a fundamental requirement for abuse liability (Stolerman, 1992). Third, we evaluated the potential efficacy of compound 1 in reducing relapse-like behavior in rats. This was achieved by assessing the impact of pretreatment with compound 1 on the reinstatement of cue-induced alcohol-seeking behavior (Cannady R, Fisher KR, Durant B, Besheer J, Hodge CW. Enhancement of AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement. Addiction Biology (2013) 18:54-65.). This paradigm uses operant conditioning to evaluate the ability of environmental stimuli previously paired with alcohol to trigger alcohol-seeking behavior, which models cue-induced craving common to humans with AUD. The following sections present an overview of the results and translational conclusions related to these three preclinical domains.

[0242] Therapeutic Indications : Reduction of chronic alcohol intake The results of Study 3.1a showed that acute administration of compound 1 (0 - 10 mg / kg) led to a dose - dependent decrease in home - cage alcohol intake, which is highly consistent with the previously reported effects of FDA - approved naltrexone and acamprosate in a rat model of alcohol intake. In this study, compound 1 resulted in equivalent efficacy compared to MPEP (an equivalent mGluR5 inhibitor) and naltrexone (FDA - approved as an AUD treatment) when evaluated after 1 - hour alcohol access. However, at 24 hours, only compound 1 showed efficacy in reducing alcohol intake, indicating improved efficacy compared to the FDA - approved compound naltrexone. The positive efficacy results obtained with compound 1 occurred in the absence of non - specific effects on water intake, locomotor activity, cognition, or anxiety - like behavior. This suggests that the effects of mGluR5 inhibition in active alcohol drinkers are relatively specific to alcohol use. Study 3.1b evaluated the effect of repeated compound 1 (3 mg / kg) treatment on alcohol intake. There was a strong effect on the first day of treatment, and the efficacy was somewhat lost on subsequent treatment days. Parallel conclusion: Overall, these results indicate that compound 1 shows significant pre - clinical efficacy for the reduction of chronic alcohol intake using the home - cage intake method, which is standard in the field. Therefore, compound 1 may reduce chronic alcohol use in a clinical population with AUD.

[0243] Therapeutic Indications : Reduce the positive reinforcing effect of alcohol that promotes repetitive drug - seeking behavior The basic behavioral process of reinforcement reflects the tendency for all animals, human and non-human, to repeat responses that produce desired outcomes. Thus, the reinforcement mechanism is fundamental to the repetitive nature of alcohol-seeking behavior in both the initial overdrinking / intoxication and subsequent dependence stages of addiction. The results of Study 3.2a showed that acute administration of Compound 1 (0 - 10 mg / kg) produced a dose-dependent reduction in alcohol-reinforced lever press responses. We compared the efficacy of Compound 1 to MPEP (a similar mGluR5 inhibitor) and naltrexone (an opioid antagonist approved by the FDA for the treatment of AUD). Compound 1 and naltrexone showed comparable efficacy in reducing the positive reinforcing effects of alcohol. Study 3.2b attempted to evaluate the effects of repeated treatment with Compound 1, but the rats showed an excessive stress response to repeated IP injections, and alternative strategies for drug delivery (oral food pellets) were not effective. Parallel conclusion: These results indicate that acute treatment with Compound 1 reduces the positive reinforcing effects of alcohol, as represented by a reduction in chronic operant alcohol self-administration. This finding has great translational value because the reinforcing effects of alcohol are known to promote the chronic, repeated alcohol use that characterizes AUD. Thus, treatment with Compound 1 may be useful for the medical management of excessive chronic alcohol use in humans with AUD.

[0244] Therapeutic Indications : Reduction in the reinstatement of alcohol-seeking behavior induced by cue Relapse of alcohol seeking after abstinence is a characteristic behavioral pathology of AUD and is often caused by conditioned reinforcement (elicited by cues) processes. Clinical studies have shown that cues associated with alcohol use promote craving and relapse in alcoholic patients during abstinence. Thus, an important issue in this field is to identify agents that interfere with this behavioral process. In this study, rats were trained to self-administer alcohol in an operant conditioning chamber. Each lever press response produced an alcohol and stimulus complex (stimulus light, pump sound). After establishing a stable chronic baseline of alcohol self-administration, an extinction procedure in which lever press responses did not produce programmed outcomes was implemented, and thus lever press responses on the active lever extinguished to less than 4 responses per session. On the reinstatement test day, lever press responses produced the stimulus complex only (without alcohol), and the ability of cue exposure to trigger relapse-like behaviors (e.g., increased non-reinforced lever presses) was evaluated. The results showed that compound 1 (10 mg / kg) significantly decreased the reinstatement of cue-induced alcohol seeking behavior. Parallel conclusion: These findings indicate that treatment with compound 1 blocks the ability of previously alcohol-use-related cues to trigger relapse-like behaviors. Since exposure to environmental stimuli previously associated with alcohol use is a major cause of relapse in the clinical AUD population, this result strongly supports the potential value of compound 1 as an agent for relapse prevention in humans.

[0245] Example 2 - Evaluation of Compound 1 for Attenuating Cocaine Dependence Using the Conditioned Place Preference (CPP) Test in Rats First: Conditioned place preference (CPP) is a commonly used behavioral test for evaluating an animal's preference for an environment associated with a positive reinforcer. After CPP training, animals spend more time in the environment associated with the positive reinforcer compared to other environments without the positive reinforcer. This behavior can be used to evaluate the rewarding or aversive properties of drugs or stimuli.

[0246] Objective: This study was designed to evaluate the efficacy of Compound 1 in attenuating cocaine dependence using a conditioned place preference (CPP) test in male Sprague-Dawley rats.

[0247] Materials and Methods Animals: Male Sprague Dawley rats (Envigo, Indiana, 275 - 299 g) were group-housed upon arrival (2 rats per cage). All rats were examined and handled to confirm appropriate health and fitness. A 12 / 12 light / dark cycle was maintained during the examination (lights on at 7:00 AM). The room temperature was maintained at 20 - 23 °C and the relative humidity at approximately 50%. During the examination period, solid feed (LabDiet #5001) and water were provided ad libitum. The examinations were conducted during the light / dark cycle of the animals.

[0248] Formulations: Cocaine (10 mg / kg) was dissolved in saline and injected IP at a dose volume of 1 ml / kg. Cocaine was administered immediately before training on days 3, 5, 7, and 9 of training.

[0249] 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP, 3 mg / kg) was dissolved in saline and injected IP at a dose volume of 1 ml / kg 30 minutes before the examination on day 10 (bias test).

[0250] Compound 1 (1, 3, and 10 mg / kg) was formulated in 10% Solutol HS15 and 90% (10% aqueous 2-hydroxypropyl-β-cyclodextrin) and injected IP at a dose volume of 2 ml / kg on day 10 (bias test). Compound 1 was administered 30 minutes before the examination.

[0251] CPP Protocol: The chamber used in this study contained two compartments [(60 cm (L) × 40 cm (W) × 24 cm (H)]. The compartments used for each animal and drug combination were pre-assigned, counterbalanced, and adjusted as needed in a re-balancing procedure after the first day (see details below). Inside the chamber, two separate compartments were created using visual and physical features. For example, one compartment may have had a flat plastic floor with white stripes, while the other may have had a textured floor and black stripes. The chamber was cleaned with 70% alcohol between runs.

[0252] Inspection sessions were recorded on the first and tenth days, and the time (seconds) spent in each chamber was determined.

[0253] Day 1 Pre-adjustment / Acclimation: Animals were allowed to freely explore the entire test chamber for 20 minutes. Animals that showed a strong preference for one compartment (spending more than 75% of the time in one compartment) were excluded.

[0254] Re-balancing Procedure: If the between-group difference in the time spent in one compartment is more than 15%, the animals are re-balanced after scoring on the first day. Animals that did not meet the criteria (spending more than 75% of the time in one compartment) are replaced to complete the balance.

[0255] Days 2 - 9 Adjustment: All animals were treated with saline on days 2, 4, 6, and 8, and with cocaine or saline on days 3, 5, 7, and 9, according to the assigned group. Animals were confined to the assigned compartment (the compartment combined with saline or cocaine) for 20 minutes after administration.

[0256] Day 10 Adjusted Bias Test: Animals are administered either saline, MTEP, or Compound 1 (1, 3, and 10 mg / kg) once according to the assignment. After administration, the animals can freely explore the test chamber for 20 minutes with the partition door open. Their activities exploring the chamber are recorded for analysis. [Table 1]

[0257] Statistical Analysis: Statistical analysis was performed using GraphPad Prism 9. A blinded scorer scored the amount of time each animal spent exploring each chamber on Day 1 and Day 10 for the treatment groups. For the bias test data, one-way analysis of variance (ANOVA) followed by Dunnett's post hoc test was used. Significance was set at p < 0.05, and values exceeding two standard deviations of the mean were considered statistical outliers and excluded from the analysis. Additionally, if animals spent more than 85% or less than 15% of the time in one compartment without any obvious signs of sedation or spontaneous motor dysfunction, they were excluded from the analysis. As a result of this criterion to ensure reliable data, more than half of the subjects were removed from these two groups based on the criterion, and the Compound 1, 3 mg / kg, and 10 mg / kg groups were excluded from the analysis due to low n values (see the attached Excel spreadsheet).

[0258] Results Percentage of time in drug-paired compartments: Figure 10 shows the percentage of time spent in drug-paired compartments on Day 1 (baseline) and Day 10 (bias test). On Day 10, one-way ANOVA found a significant main effect of treatment [F(3,48) = 4.708, p < 0.01]. Dunnett's post hoc test showed a significant increase in the time spent in drug-paired compartments in the cocaine-saline group compared to the saline-saline group, indicating that 10 mg / kg of cocaine effectively induced CPP. Dunnett's test also showed that the cocaine-MTEP group and the cocaine-compound 1 (1 mg / kg) group spent significantly less time in drug-paired compartments than the cocaine-saline group (p < 0.05 and p < 0.01, respectively), suggesting attenuation of cocaine-induced CPP.

[0259] Preference score: Figure 11 shows the difference in time spent in drug-paired and saline-paired compartments on Day 1 (baseline) and Day 10 (bias test). On Day 10, one-way ANOVA found a significant main effect of treatment [F(3,48) = 4.709, p < 0.01]. Dunnett's post hoc test showed a significant increase in the time difference in drug-paired compartments in the cocaine-saline group compared to the saline-saline group, indicating that 10 mg / kg of cocaine effectively induced CPP. Dunnett's test also showed that the cocaine-MTEP group and the cocaine-compound 1 (1 mg / kg) group had a significantly lower time difference than the cocaine-saline group (p < 0.05 and p < 0.01, respectively), suggesting attenuation of cocaine-induced CPP.

[0260] Summary The purpose of this study was to evaluate the effectiveness of compound 1 in the CPP paradigm using cocaine as an enhancer. Significant CPP was found in the cocaine-treated group, indicating the effectiveness of this assay in showing a tendency for cocaine abuse. The results also showed that cocaine-induced CPP was attenuated by treatment with 3 mg / kg of MTEP and compound 1 (1 mg / kg), suggesting that compound 1 has potential for the treatment of cocaine abuse.

[0261] The groups of compound 1 at 3 mg / kg and 10 mg / kg were excluded from data analysis because more than half of the subjects in these two groups showed extreme values (spending more than 85% or less than 15% of the time in a single chamber), which is unlikely to occur in saline or vehicle-treated rats. The extreme values occurred because these rats mainly randomly stayed in one compartment. The side effects caused by the doses of compound 1 (3 mg / kg and 10 mg / kg) may have obscured the effectiveness of the compound. Statistical table [Table 2] [Table 3] [Table 4] [Table 5]

[0262] Example 3 - Evaluation of compound 1 for attenuating cocaine dependence using an intravenous self-administration (SA) model in rats First: Cocaine abuse represents a major health problem worldwide. Cocaine rehabilitation has proven to be very difficult not only because of the addictive properties of cocaine, but also because of the possibility of relapse after a period of abstinence. Several preclinical models have been developed to evaluate the abuse potential of compounds and / or their effectiveness in the treatment of drug dependence. Intravenous self-administration is widely accepted as a valid tool in this field. Using different protocols under this model, it is possible to evaluate whether a new compound is effective in attenuating cocaine self-administration, and also to evaluate the effectiveness of a new compound in preventing or reducing the resumption of drug-seeking behavior after the extinction of cocaine self-administration.

[0263] Objective: The objective of this study was to evaluate the efficacy of Compound 1 against cocaine self-administration in rats.

[0264] Materials and Methods Animals: Adult male Sprague-Dawley rats (300 - 325 g at arrival) from Envigo (Indiana, USA) were used. Upon arrival, rats were singly housed in standard cages with filter tops and acclimated for at least 7 days prior to treatment. All rats were examined and treated before the start of the study. During the study period, a 12-hour / 12-hour light / dark cycle was maintained. The room temperature was 21 - 23 °C and the relative humidity was maintained at 30 - 70%. Water was freely available during the study period.

[0265] Test compound: Cocaine hydrochloride (Sigma-Aldrich, USA) was dissolved in physiological saline (0.9% NaCl). More specifically, cocaine was made at 1.05 mg / ml, which corresponds to 0.3 mg / kg / injection per 350 g rat. The injection rate was 0.1 ml / injection.

[0266] Compound 1 was formulated in 10% Solutol HS15 + 90% (aqueous solution of 10% hydroxypropyl) beta-cyclodextrin. The compound was administered IP 30 minutes before the test. The dose volume of Compound 1 was 2 ml / kg. Initially, three doses of 1, 3, and 10 mg / kg were used for the fixed ratio decrement test (Phase I). For the subsequent reinstatement test (Phase II), 3 mg / kg of Compound 1 was used. During the 30-minute treatment period, a slight decrease in muscle tension was observed, but the rats did not become sedated.

[0267] 3 mg / kg of the reference compound MTEP (3-((2-methyl-4-thiazolyl)ethynyl)pyridine, a selective allosteric antagonist of mGluR5) was prepared in physiological saline and administered IP at a dose volume of 1 ml / kg.

[0268] Apparatus: Intravenous self - administration of drugs was conducted in an experimental chamber within an acoustically attenuated cubicle equipped with an exhaust fan (Med Associates, Vermont). Each chamber included two response levers located on one wall of the chamber. The stimulus light was positioned above each lever, and the house light was located at the top of the opposite wall. A pellet dispenser was placed between the two levers for the delivery of food pellets (Bio - Serv’s Dustless Precision Pellets #F0165, 45 mg). An infusion pump mounted above each chamber delivered the drug solution via a Tygon tube connected to a single - channel fluid swivel mounted on a balance arm above the operant chamber. The output of the liquid swivel was attached to the externalized end of the intravenous catheter.

[0269] Surgery and catheter maintenance: First, jugular vein catheters (Access Technologies, USA) were implanted in the rats. After surgery, the catheters were flushed daily with 0.2 ml of a heparin - enrofloxacin solution to avoid clogging and ensure smooth drug infusion. The flush liquid was prepared in 50 - ml volume units containing 1500 U of heparin and 320 mg of enrofloxacin (Baytril®). The solution was stored in a refrigerator at 4 °C in a sterile vial. After recovering from the catheter - insertion surgery, the rats were food - restricted (about 15 or 20 g / day) and maintained at approximately 85% of their age - matched control body weight with free access to food throughout the study. Starting on the third day of food restriction, the rats were trained to press the active lever (one of the two levers) to obtain food.

[0270] In the study, methohexital sodium (Brevital®, Henry Schein Animal Health, USA) was used twice for catheter evaluation and indirect injection confirmation. Brevital is a short-acting barbiturate that shows obvious signs of sedation within seconds when injected through a catheter. Animals that did not show immediate signs of sedation were suspected of having catheter malfunction and were removed from the experiment. In this study, the Brevital® test at the end of acquisition training showed that 23 out of 24 rats had functional catheters.

[0271] Cocaine self-administration acquisition: All rats took about 10 days to meet the criteria for food training (consuming 50 food pellets in a 1-hour session), thereby preparing them for drug training. Then, the rats were allowed to self-administer cocaine solution by pressing an active lever on a fixed ratio (FR) reinforcement schedule. In this study, FR5 was used. That is, the lever was pressed five times for each drug injection. Each drug injection lasted for 1.0 second. A 20-second timeout period was provided following each drug injection, during which no drug was delivered even if the active lever was pressed. The stimulating light above the active lever was on during the timeout period. Each training or test session lasted for 1 hour.

[0272] Phase I: Evaluation of Compound 1 using a conventional fixed ratio protocol After establishing a stable cocaine self-administration baseline (variation in daily drug injections less than 20% for 3 consecutive days, at least 6 drug injections per session) through 20 days of acquisition training, the rats were ready for compound testing. Compound testing was conducted twice a week (typically Tuesdays and Fridays), and baseline cocaine training was maintained on other days. Since 23 rats were more than needed (12 rats can provide reliable data), 16 rats were randomly selected for the compound testing in Phase I. The 7 rats that were not selected continued to receive daily cocaine training.

[0273] An in - plan where all rats received all treatments was applied with a Latin - square testing schedule. There were six treatment groups in this study: (1) saline, (2) MTEP 3 mg / kg, (3) compound vehicle, (4) compound 1 (1 mg / kg), (5) compound 1 (3 mg / kg), (6) compound 1 (10 mg / kg).

[0274] Stage II: Evaluation of compound 1 using a reinstatement protocol After completion of Stage I, rats were retrained with cocaine for one week to ensure a stable baseline. Then the rats underwent a 6 - day extinction training procedure where only saline infusion occurred when the active lever was pressed. On the other hand, for reinstatement induced by a pharmacological stressor, the rats were divided into three groups of approximately equal size. All rats were injected once with the alpha - 2 adrenergic antagonist yohimbine (2 mg / kg) and then immediately placed in the training box. Thirty minutes before the yohimbine treatment, one group of rats was administered saline, another group was administered an MTEP 3 mg / kg injection, and the third group was administered compound 1 at 3 mg / kg.

[0275] Reinstatement induced by yohimbine was re - examined two more times in the same rats under a continuous extinction procedure 3 days and 6 days after the first test (there was an additional 2 - day extinction training between the first and second reinstatement tests and between the second and third reinstatement tests). Using a 3×3 within - subject design, each given animal passed through all three treatments (saline, MTEP, and compound 1) over three rounds of testing.

[0276] Data analysis: Prism software package version 9 was used for statistical analysis and graphing. The number of active lever - press responses during each session was recorded and compared between treatment groups.

[0277] The effectiveness of Compound 1 and MTEP against cocaine self - administration in Stage I was analyzed using a one - way ANOVA mixed - effects model (REML) of ANOVA, followed by Dunnett's post - hoc test (repeated - measures ANOVA was not fully applicable due to some outlier data points being removed). A one - way ANOVA mixed - effects model (REML) of ANOVA, followed by Tukey's post - hoc test, was used in Stage II. An effect was considered significant if P < 0.05. Data were presented as mean and standard error of the mean (s.e.m).

[0278] Statistical outliers exceeding the group mean ± (2 × standard deviation) were excluded from the analysis. Also, for restart, the extinction time was shortened (9 days + extended optionally for 6 days). In this study, 3 rounds of restart tests were conducted and the extinction period was shortened as we wanted to maintain the restart force. Thus, during the last extinction session, the extinction criteria were loosened from 6 or fewer injections to 9 or fewer injections. By this criterion, 17 out of 21 rats were eligible for the drug test in Stage II. This adjustment did not change the data quality.

[0279] Results Cocaine acquisition: As shown in Figure 12, cocaine acquisition training continued for 20 days. The number of injections increased steadily, and the curve had already reached a plateau after 15 days of acquisition training. To ensure sufficient acquisition, an additional five - day training was added.

[0280] Effect of the compound on cocaine self - administration: The effect of the compound on cocaine self - administration is illustrated in Figure 13. A significant main effect of treatment was found using a one - way ANOVA mixed - effects model (REML) of ANOVA, followed by Dunnett's post - hoc test (saline treatment as a reference) (F[2.525,35.86]=74.77, P < 0.001). Post - hoc comparisons showed that MTEP 3 mg / kg significantly decreased cocaine injections. All three doses of Compound 1 also showed effectiveness in significantly attenuating cocaine self - administration. The potency of the compound increased progressively at higher doses.

[0281] Effect of a compound on cocaine relapse induced by pharmacological stressors: Based on data from Phase I and signs of potential side effects of Compound 1 at a dose of 10 mg / kg (decrease in muscle tone), a dose of 3 mg / kg was selected for Phase II. The effect of Compound 1 in the presence of yohimbine, a pharmacological stressor, induced relapse, a model of recurrence (Figure 14). One-way analysis of variance using the restricted maximum likelihood (REML) mixed effects model found a significant effect of treatment (F[1.777,26.66]=150.7, P<0.001). In this case, Tukey's post hoc test was used because multiple comparisons with different reference groups were required. Multiple comparisons showed that extinction training caused a significant (approx. 80%) decrease in cocaine infusion (P<0.001). Yohimbine 2 mg / kg induced significant relapse (P<0.001). Both MTEP 3 mg / kg and Compound 1 (3 mg / kg) co-administered with yohimbine almost completely prevented cocaine relapse (Ps<0.001).

[0282] Summary This study examined the efficacy of test compound 1 and reference compound MTEP in a rat model of cocaine self-administration.

[0283] Acquisition of cocaine self-administration was well established after 20 days of training. Examination of MTEP 3 mg / kg and Compound 1 at 1, 3, and 10 mg / kg using a conventional FR5 protocol all showed significant efficacy in attenuating cocaine infusion.

[0284] After 6 days of extinction of the self-administration response, yohimbine 2 mg / kg, a pharmacological stressor, resulted in significant relapse of cocaine self-administration (P<0.001). Both reference compound MTEP 3 mg / kg and Compound 1 (3 mg / kg) significantly prevented the occurrence of relapse (Ps<0.001).

[0285] This study showed promising results in a rat model of cocaine self - administration. Compound 1 effectively reduced cocaine infusion in rats and prevented the resumption of cocaine seeking behavior. These findings suggest that Compound 1 may have potential for the treatment of cocaine abuse. Statistical table Phase I - Effect of the compound on cocaine self - administration [Table 6] [Table 7] Phase II: Effect of the compound on cocaine resumption: [Table 8] [Table 9]

[0286] Example 4 - Evaluation of the effectiveness of Compound 1 against oxycodone dependence using an intravenous self - administration (SA) model in rats First: Opioid abuse represents a major health problem worldwide. Opioid rehabilitation has proven to be very difficult not only because of the addictive properties of cocaine but also because of the potential for relapse after the abstinence period. Several pre - clinical models have been developed to evaluate the abuse potential of compounds and / or their effectiveness in the treatment of drug dependence. Intravenous self - administration is widely accepted as an effective tool in this field. Under this model, different protocols can be used to evaluate whether a new compound shows effectiveness in reducing cocaine self - administration and also to evaluate the effectiveness of a new compound in preventing or reducing the resumption of drug - seeking behavior after the extinction of opioid self - administration.

[0287] Objective: The objective of this study was to evaluate the efficacy of Compound 1 against oxycodone self-administration in rats.

[0288] Materials and Methods Animals. Adult male Sprague-Dawley rats (300 - 325 g at arrival) from Envigo (Indiana, USA) were used. Upon arrival, rats were singly housed in standard cages with filter tops and acclimated for at least 7 days prior to treatment. All rats were examined and treated before the start of the study. During the study, a 12-hour / 12-hour light / dark cycle was maintained. The room temperature was 21 - 23 °C and the relative humidity was maintained at 30 - 70%. Water was freely available during the study period.

[0289] Test Substances · Oxycodone (0.05 mg / kg / injection; Sigma-Aldrich, USA) was dissolved in saline and injected at a rate of 0.1 ml / injection. · Compound 1 (0.3, 1, and 3 mg / kg) was formulated in 10% Solutol HS15 + 90% (10% aqueous hydroxypropyl)-β-cyclodextrin and injected IP 30 minutes before testing at a dose volume of 2 ml / kg. In the rechallenge study, only 3 mg / kg was used. · MTEP (3-((2-Methyl-4-thiazolyl)ethynyl)pyridine; 3 mg / kg) was dissolved in saline and injected IP 30 minutes before testing at a dose volume of 2 ml / kg.

[0290] Methods Apparatus. Intravenous self-administration of drugs was performed in an experimental chamber within an acoustically attenuated cubicle (Med Associates, Vermont) equipped with an exhaust fan. Each chamber included two response levers located on one wall of the chamber. The stimulus light was located above each lever, and the house light was located at the top of the opposite wall. A pellet dispenser was placed between the two levers for the delivery of food pellets (Bio-Serv’s Dustless Precision Pellets #F0165, 45 mg). An infusion pump mounted above each chamber delivered the drug solution via a Tygon tube connected to a single-channel fluid swivel mounted on a balance arm above the operant chamber. The output of the fluid swivel was attached to the externalized end of an intravenous catheter.

[0291] Surgery and catheter maintenance: Rats were first implanted with jugular vein catheters (Access Technologies, USA). After surgery, the catheters were flushed daily with 0.2 ml of heparin-enrofloxacin solution to avoid blockage and ensure smooth drug injection. The flushing liquid was prepared in 50-ml volume units containing 1500 U of heparin and 320 mg of enrofloxacin (Baytril®). The solution was stored in a sterile vial in a 4°C refrigerator. After recovery from the catheter insertion surgery, the rats were food-restricted (about 15 or 20 g / day) and maintained at approximately 85% of the control body weight corresponding to their age with free access to food throughout the study. Starting on the third day of food restriction, the rats were trained to obtain food by pressing an active lever (one of two levers). During the study, methohexital sodium (Brevital®, Henry Schein Animal Health, USA) was used several times for catheter evaluation and indirect injection confirmation. Brevital is a short-acting barbiturate, and when injected through the catheter, obvious signs of sedation appear within seconds. Animals that did not show immediate signs of sedation were suspected of catheter malfunction and removed from the experiment. Rats were first implanted with jugular vein catheters (Access Technologies, USA). After surgery, the catheters were flushed daily with 0.2 ml of heparin-enrofloxacin solution to avoid blockage and ensure smooth drug injection. The flushing liquid was prepared in 50-ml volume units containing 1500 U of heparin and 320 mg of enrofloxacin (Baytril®). The solution was stored in a sterile vial in a 4°C refrigerator. After recovery from the catheter insertion surgery, the rats were food-restricted (about 15 or 20 g / day) and maintained at approximately 85% of the control body weight corresponding to their age with free access to food throughout the study. Starting on the third day of food restriction, the rats were trained to obtain food by pressing an active lever (one of two levers). During the study, methohexital sodium (Brevital®, Henry Schein Animal Health, USA) was used several times for catheter evaluation and indirect injection confirmation.Brevital is a short-acting barbiturate that, when injected through a catheter, shows clear signs of sedation within seconds. Animals that did not show immediate signs of sedation were suspected of having catheter malfunction and were removed from the experiment. In this study, the Brevital (registered trademark) test was conducted several times at the end of acquisition training, and it was shown that 16 out of 20 rats had functional catheters and their data were eligible for analysis.

[0292] Acquisition of oxycodone self-administration. After reaching the criteria for food training (ingesting 50 food pellets in a 1-hour session), rats self-administered oxycodone solution by pressing an active lever on a fixed ratio (FR) reinforcement schedule. In this study, FR3 was used. That is, the lever was pressed three times for each drug injection. Each drug injection lasted for 1.0 second. A 20-second timeout period was provided following each drug injection, during which no drug was delivered even if the active lever was pressed. The stimulating light above the active lever was on during the timeout period. Each training or test session lasted for 1 hour.

[0293] Evaluation of compound 1 on oxycodone self-administration. The test began after establishing a stable oxycodone self-administration baseline (variation in the daily dose of drug injection less than 20% for 3 consecutive days, at least 6 drug injections per session) through 20 days of acquisition training. The compound tests were conducted twice a week (typically, Tuesdays and Fridays), and the baseline oxycodone training was maintained on other days. 16 rats were used in the study. A within-subject design in which each rat received all treatments was applied with a Latin square test schedule. There were 6 treatment groups in this study: 1) saline, 2) MTEP 3 mg / kg, 3) compound vehicle, 4) compound 1 (0.3 mg / kg), 5) compound 1 (1 mg / kg), 6) compound 1 (3 mg / kg).

[0294] Evaluation of Compound 1 for oxycodone reinstatement. After the inspection was completed, the rats were retrained with oxycodone for one week to ensure a stable baseline. The rats were then subjected to a 6-day extinction during which only saline infusion occurred when the active lever was pressed. On the other hand, the rats were divided into three groups: all rats were injected once with the alpha-2 adrenergic antagonist yohimbine (2 mg / kg) in a 0-minute pretreatment (the rats were immediately placed in the training box). Thirty minutes before the yohimbine treatment, one group of rats was administered saline, another group was administered an MTEP injection of 3 mg / kg, and the third group was administered Compound 1 (3 mg / kg). The reinstatement induced by yohimbine was re-examined two more times in the same rats 3 days and 6 days after the first inspection under a continuous extinction procedure.

[0295] Statistical analysis. Prism 9.40 software package version 9 was used for statistical analysis and graphing. The number of active lever responses during each session was recorded and compared between treatment groups. A one-way ANOVA mixed effects model (REML), followed by Dunnett's post hoc test, was used to analyze the effectiveness of Compound 1 and MTEP on oxycodone self-administration in Phase I (repeated measures ANOVA was not fully applicable due to some outlier data points being removed), and a one-way ANOVA mixed effects model (REML), followed by Tukey's post hoc test, was used in Phase II. An effect was considered significant if P < 0.05. The data were presented as the mean and the standard error of the mean (s.e.m). Statistical outliers exceeding the mean of the group ± (2 × standard deviation) were excluded from the analysis.

[0296] Results Oxycodone acquisition. The oxycodone acquisition training continued for 20 days as shown in Figure 15. The number of infusions decreased slightly from the activity level during the first three days of food training and maintained an average of about 10 - 14 infusions / session until the training ended.

[0297] Effect of Compound 1 on oxycodone self - administration. The effect of Compound 1 on oxycodone self - administration is shown in Figure 16. A one - way ANOVA mixed - effects model (REML), followed by Dunnett's post - hoc test, found a significant main effect of treatment (F[3.247,47.41]=17.73, P < 0.001). Post - hoc comparisons showed that MTEP 3 mg / kg significantly decreased self - administered oxycodone infusions compared to vehicle treatment. All three doses of Compound 1 also significantly attenuated oxycodone self - administration.

[0298] Effect of Compound 1 on oxycodone reinstatement. The effect of Compound 1 on yohimbine - induced reinstatement is shown in Figure 17. A one - way ANOVA using a mixed - effects model (REML) found a significant effect of treatment (F[1.886,26.88]=55.96, P < 0.001). Tukey's post - hoc analysis showed that extinction training caused a significant (about 70%) decrease in oxycodone infusions (P < 0.001). Yohimbine 2 mg / kg induced significant reinstatement (P < 0.001 compared to extinction value). Both MTEP 3 mg / kg and Compound 1 (3 mg / kg) attenuated yohimbine - induced oxycodone reinstatement (Ps < 0.001 compared to vehicle - yohimbine group).

[0299] Summary This study examined the efficacy of Compound 1 in attenuating oxycodone self - administration and reinstatement.

[0300] Acute injection of Compound 1 (0.3, 1, and 3 mg / kg) significantly decreased oxycodone self - administration. After extinction of the self - administration response, the pharmacological stressor yohimbine (2 mg / kg) produced a significant reinstatement of oxycodone self - administration. Compound 1 (3 mg / kg) significantly prevented the occurrence of reinstatement. MTEP also attenuated oxycodone self - administration and reinstatement. These results suggest that Compound 1 may be effective in the treatment of oxycodone abuse. Statistical table

Table 10

Table 11

[0301] Example 5 - Phase 1, Randomized, Placebo - Controlled, Multiple - Ascending - Dose (MAD) Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Compound 1 in Healthy Subjects Example 5 presents the protocol for an interrupted multiple - ascending - dose (MAD) trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of Compound 1 in healthy subjects. In the following paragraphs, Example 5 is described in the future tense for brevity, and the trial was interrupted on Day 9 after dosing of 6 patients. Exposure beyond expectation was observed at a dose level of 100 mg / day (i.e., 50 mg, twice a day). Example 6 presents the protocol for a planned and amended Phase 1 MAD trial.

[0302] Study Objectives and Evaluation Items - For study objectives and evaluation items, refer to Table 12. There are up to 4 dose cohorts, and within each cohort, subjects are randomly assigned to receive either active drug or placebo. Subjects are administered active drug or placebo twice daily for 14 days (note: only the AM dose is administered on Day 14).

[0303] In this study, genetic samples are collected for exploratory pharmacogenetic studies that may be conducted to investigate the relationship between genetic factors (genotype) and clinical evaluation (phenotype). If conducted, these studies aim to better identify genetic factors that can predict response to treatment with Compound 1, predict relative susceptibility to drug - drug interactions, predict genetic predisposition to side effects, or provide more detailed information about Compound 1 in the disease state and how subjects may respond to Compound 1.

Table 12

[0304] Test Design Adaptation Characteristics and Risk Management of the Test Plan The basis with the following adaptation characteristics is based on this clinical test hypothesis formation approach. The following categories are adapted as follows. [Table 13]

[0305] The decision-making process for the above adaptation test category is as follows. (1) The safety and tolerability of Compound 1 and new data from the completed or ongoing MAD cohort are reviewed at an interim in a blinded manner by the SRC. (2) The results of the adaptation test category are documented by the SRC.

[0306] Based on the above, it can be implemented without delay and without obtaining approval from the Institutional Review Board (IRB). If any of the adaptation characteristics are outside the pre-specified boundaries above, review and approval by the IRB before implementation are essential.

[0307] Maximum Tolerated Dose (MTD) The Maximum Tolerated Dose (MTD) is defined as the highest dose that can be administered without clinically significant adverse events (AEs). The MTD is determined by dose escalation until the stopping criteria are met, as outlined in the section on stopping rules.

[0308] The MTD is defined as the highest dose that does not cause unacceptable side effects. If no such toxicity is observed, the dose administered in Cohort 3 is considered the MTD.

[0309] Overall Test Plan This trial is a randomized, double-blind, placebo-controlled, fixed-sequence MAD trial. This trial is conducted at a single clinical research unit (CRU). This examination consists of three cohorts with options for additional cohorts (intermediate dose cohort or escalating cohort). Each cohort consists of 8 subjects (active: placebo is 6:2), and the maximum total sample size is approximately 32 subjects. Subjects participate in only one cohort.

[0310] Screening is conducted within approximately 28 days prior to the initially scheduled administration of the investigational drug. Screening data are reviewed to determine subject eligibility. Subjects who meet all selection criteria, do not conflict with any exclusion criteria, and consent to participate are admitted to the CRU for pre-dose baseline evaluation. All baseline safety results should be available prior to the first administration of the investigational drug.

[0311] Subjects fast overnight for 10 hours prior to morning dosing and then continue to fast for 2 hours. Subjects fast for 2 hours prior to dosing and 2 hours after evening dosing. For cohort 3, on day 13, subjects consume a standardized high-fat, high-calorie meal 30 minutes prior to dosing.

[0312] Each subject is randomly assigned to one of the following cohorts. Cohort 1: Group 1 (6 subjects): 50 mg of Compound 1 twice daily (bid), Group 2 (2 subjects): placebo (matching Compound 1) twice daily. Cohort 2: Group 3 (6 subjects): 100 mg of Compound 1 twice daily, Group 4 (2 subjects): placebo (matching Compound 1) twice daily. Cohort 3: Group 5 (6 subjects): 150 mg of Compound 1 twice daily, Group 6 (2 subjects): placebo (matching Compound 1) twice daily.

[0313] If low bioavailability occurs in Cohorts 1 and 2 and results in lower than expected predicted exposure (C avg、ss <100 ng / mL) in Cohort 3, the planned dosing schedule can be adjusted to allow for administration of a 200 mg dose in Cohort 3.

[0314] Assess safety and collect blood samples for PK throughout the confinement period. The subject is discharged from the CRU on the 18th day. The subject returns to the CRU on the 25th day for follow-up visits and the test termination procedure.

[0315] The maximum period of participation for subjects, including screening, is approximately 53 days.

[0316] Subjects who terminate the test early will have follow-up procedures implemented at the time of early termination.

[0317] Based on the safety and tolerability findings in any of the cohorts, a 14-day dose escalation cohort (7-day escalation + 7-day stable dosing) may be added as an additional cohort to evaluate the impact on TEAE.

[0318] Describe the test activity schedule (SoA) in Table 16.

[0319] Test treatment The following treatments are administered according to Table 14 below. (1) IP: Oral tablets of Compound 1. (2) Placebo: A matching placebo

Table 14

[0320] Subject population Subjects who meet all the selection criteria and do not conflict with any of the exclusion criteria at the time of screening may be eligible to participate in this examination. Continuing eligibility is evaluated at the time of admission to the clinical facility, prior to the first administration of the investigational drug.

[0321] Screening failure is defined as participants who consented to participate in the clinical trial but were not subsequently randomly assigned to the test intervention or were not registered for the test.

[0322] Selection criteria Provision of an informed consent form (ICF) with signature and date

[0323] Willingness to follow all study procedures and declaration of availability during the study period

[0324] Healthy adult males or females

[0325] In the case of males, meet one of the following criteria:

[0326] a) Be capable of reproduction, use one of the recognized contraceptive methods, and agree not to provide sperm from the first administration of the test drug until at least 90 days after the follow-up visit. The recognized contraceptive methods include one of the following. Abstinence from heterosexual intercourse, male condom containing a spermicide, or male condom containing a vaginal spermicide (gel, foam, or suppository)

[0327] Or b) Be incapable of reproduction; be defined as surgically sterile (i.e., have had a vasectomy at least 180 days before the first administration of the test drug)

[0328] In the case of females, meet one of the following criteria:

[0329] (1) Physiological postmenopausal state defined as follows: Absence of menstruation for at least 12 months before the first administration of the test drug (without alternative medical conditions), and follicle-stimulating hormone (FSH) value of 40 mIU / mL or more at the time of screening;

[0330] Or (2) Surgically induced postmenopausal state defined as follows: Bilateral oophorectomy, salpingectomy, tubal ligation, and / or hysterectomy

[0331] 18 years of age or older and 59 years of age or younger at the time of informed consent

[0332] Body mass index (BMI) of 18.5 kg / m 2 ~32.0 kg / m 2 Within the range

[0333] Minimum body weight of 50.0 kg or more

[0334] Non-smokers or former smokers (a former smoker is defined as a person who has completely discontinued the use of nicotine products for at least 90 days before the first administration of the test drug)

[0335] During the trial, it is necessary to have the intention to refrain from coffee or beverages containing caffeine

[0336] When the principal investigator of the clinical trial determines that there are no clinically significant diseases in the medical history, or no evidence of clinically significant findings in the physical examination (including vital signs) and / or ECG

[0337] Except for results outside the standard range that the principal investigator of the clinical trial (or the designee) considers not clinically significant at the time of screening and check-in, the clinical test results are within the standard range of the laboratory

[0338] After a 5-minute rest, the supine blood pressure and pulse rate are within the following ranges: systolic blood pressure 90 - 140 mmHg, diastolic blood pressure 50 - 90 mmHg, and pulse rate 45 - 90 bpm at the time of screening and on Day - 1

[0339] Exclusion Criteria Women who are breastfeeding

[0340] Women who are pregnant as determined by a pregnancy test at the time of screening or before the first administration of the test drug

[0341] Women who have used oral, patch, or vaginal ring systemic contraceptives within 28 days before the first administration of the test drug

[0342] Women who have used hormone replacement therapy within 28 days before the first administration of the test drug

[0343] Women who are using the following systemic contraceptives: injections or implants, or hormone-releasing intrauterine devices during the 13 weeks before the first administration of the test drug and during the trial

[0344] Drinking beverages containing excessive amounts of tea, coffee, cocoa, and / or caffeine (more than 2 cups per day)

[0345] Using tobacco or nicotine-containing products (including, but not limited to, cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, or nicotine gum) within 90 days prior to the first administration of the investigational drug and being unable to refrain from using nicotine-containing products until the follow-up visit

[0346] Past or current medical history of mental disorders, behavioral disorders, or neurodevelopmental disorders as defined by the 10th Revision of the International Classification of Diseases (ICD-10). Subjects with a family history of major mental disorders, behavioral disorders, or neurodevelopmental disorders will be excluded unless the principal investigator (or designee) determines and the medical monitor clinically agrees that it is not significant (NCS).

[0347] Past or clinical symptoms of metabolic disorders, allergic disorders, skin disorders, liver disorders, kidney disorders, blood disorders, lung disorders, gastrointestinal disorders, neurological disorders, respiratory disorders, or endocrine disorders, except when the principal investigator (or designee) determines it to be NCS and the medical monitor agrees

[0348] Activity or past history of cardiovascular or cerebrovascular diseases, including hypertension, angina pectoris, ischemic heart disease, transient ischemic attack, peripheral artery disease, evidence of myocardial ischemia, stroke, and peripheral arterial disease sufficient to require treatment to cause and / or maintain a stable condition

[0349] Past history of severe hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, except when approved by the principal investigator (or designee)

[0350] Active neoplastic disease within 5 years of screening or past history of any neoplastic disease (except basal cell carcinoma of the skin, squamous cell carcinoma, or carcinoma in situ that has been reliably treated with standard therapy)

[0351] Active infection (e.g., sepsis, pneumonia, abscess) or severe infection (e.g., hospitalization required, or parenteral antibiotic treatment required) within 6 weeks prior to administration

[0352] History of gastric or intestinal surgery or resection that potentially alters absorption and / or excretion of orally administered drugs (appendectomy and hernia repair without complications are allowed)

[0353] Any of the following at screening and / or prior to first dose:

[0354] QT interval corrected for heart rate using the Fridericia method (QTcF), QRS duration, PR interval outside the normal range confirmed by repeated measurements, considered an NCS by the PI, and without the consent of the medical monitor;

[0355] Findings that make QTc measurement difficult or QTc data uninterpretable;

[0356] History of risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of QT prolongation syndrome);

[0357] Maintenance therapy with any drug, or significant history of drug dependence or alcohol abuse (more than 3 units of alcohol per day, acute or chronic excessive alcohol intake);

[0358] Positive test results for alcohol, cotinine, and / or abused drugs at screening or prior to first dose of the drug;

[0359] Positive screening results for HIV Ag / Ab combo, hepatitis B surface antigen, or hepatitis C virus test;

[0360] Other clinically significant abnormalities in clinical test results at screening that, in the opinion of the principal investigator of the clinical trial, increase the risk of subject participation, endanger complete participation in the trial, or compromise the interpretation of trial data

[0361] IP intake 28 days before the first investigational drug administration

[0362] Use of prescription drugs that raise concerns about the participant's health, based on the opinion of the responsible investigator, 28 days before the first investigational drug administration

[0363] Use of St. John's wort 28 days before the first dose of the investigational drug and during the trial

[0364] Intake of foods or beverages that change CYP1A2 activity, such as barbecue or cruciferous vegetables like broccoli and cauliflower, within 14 days before (the first) check-in (a list of prohibited foods will be provided to the subjects)

[0365] Intake of foods or beverages containing Seville oranges, grapefruit, or pomegranate within 7 days before (the first) check-in

[0366] Subjects who cannot consume vegetarian, vegan, and / or high-fat breakfasts (only for participants in the food effect evaluation)

[0367] Administration of blood products within 2 months before check-in

[0368] Donation of 1 unit of blood or more than 500 mL of blood to the American Red Cross or an equivalent organization within 56 days before the first investigational drug administration

[0369] Donation of plasma within 7 days before the first investigational drug administration

[0370] Poor peripheral vein access

[0371] History of prior or significant allergy to Compound 1 or any related formulation (including the excipients of the formulation), and severe allergic reactions (such as angioedema) to any drug

[0372] Subjects who, in the opinion of the principal investigator of the clinical trial (or the designee, if applicable, including the opinion of the subject's general physician), should not participate in this study

[0373] Subjects who were hospitalized for any reason within 30 days before the start of the examination

[0374] Subjects who are staff members of the clinical trial facility or directly involved in the conduct of the clinical trial, as well as their families, or subjects employed by the sponsor of the clinical trial

[0375] Withdrawal criteria Before the first treatment administration Before the first treatment administration, subjects to be administered are determined according to the inclusion / exclusion criteria. Subjects who withdraw before the first treatment administration will not be followed up and will not receive the trial end / early termination evaluation. Other safety evaluations can be conducted as necessary.

[0376] Subjects may freely withdraw their consent to participate in the trial at any time without prejudice to their rights. The reasons for withdrawal or the reasons for deciding to discontinue participation are documented.

[0377] After the first treatment administration Subjects may voluntarily withdraw from the trial or be excluded from the trial at any time at the discretion of the principal investigator of the clinical trial or the sponsor of the clinical trial. The principal investigator of the clinical trial may withdraw a subject at any time if it is determined that continuing the trial poses a significant safety risk to the subject or if their actions are determined to be harmful to the trial environment. If such a withdrawal occurs, or if the subject does not return for a visit, the principal investigator of the clinical trial must determine the main reason for the subject's early withdrawal from the trial and record that reason in the subject's trial documents.

[0378] Subjects will be unenrolled if any of the following criteria are met.

[0379] A change in compliance with the inclusion / exclusion criteria determined by the principal investigator of the clinical trial (or designee) that is clinically relevant and affects the safety of the subject

[0380] Clinically relevant signs, symptoms, or co-morbidities that justify subject withdrawal in the opinion of the principal investigator (or designee).

[0381] Non-compliance with study restrictions that the principal investigator (or designee) considers likely to affect subject safety or study evaluation / purpose.

[0382] Subjects report an SAE that the principal investigator (or designee) determines may be related to the IP.

[0383] Subjects experience an increase in ALT ≥ 3 x ULN with total bilirubin ≥ 2 x ULN, or an increase in AST ≥ 3 x ULN with ALP ≥ 1.5 x ULN.

[0384] If the subject's QTcF increases by more than 60 milliseconds from baseline (if applicable, pre-dose on Day 1 of each treatment period), and the QTcF, confirmed by the mean of at least two additional ECG recordings performed at at least 5-minute intervals, is greater than 500 milliseconds, or if there are other clinically significant conduction disturbances or arrhythmias. All ECGs for this determination must be performed under strict resting conditions. Subjects must rest in the supine position for 10 minutes prior to ECG collection.

[0385] If a subject meets any of the above withdrawal criteria, the sponsor's medical monitor may consider it necessary to unblind.

[0386] If the subject withdraws, a notification will be sent to the sponsor, and the date and reason for withdrawal will be recorded in the subject's electronic case report form (eCRF). If the subject withdraws, the principal investigator should make every effort to conduct a final study visit 7 days after the last dose of the investigational product and complete the evaluations and procedures outlined in the SOA. Other procedures may be carried out at the discretion of the principal investigator (or designee) and / or the sponsor. If the subject is hospitalized, these procedures should be carried out before the subject is discharged, if possible. The principal investigator (or designee) may also request that the subject return for additional follow-up. All withdrawn subjects will be followed until all AEs have resolved or until the principal investigator (or designee) determines that the unresolved AE has stabilized.

[0387] Subjects who withdraw for reasons unrelated to the investigational product may be replaced after consultation between the principal investigator and the sponsor. Subjects who withdraw as a result of an AE considered related to the investigational product are usually not replaced.

[0388] The principal investigator may exclude a subject from the study based on the recommendation of the PK facility and / or the sponsor due to unexpected events (e.g., missed blood sampling, AE, dietary deviation, concomitant medication intake) that may result in inadequate characterization of the PK profile.

[0389] If a clinically significant disease (including a diagnosis of COVID-19) is detected during the study, the principal investigator (or proxy) should cooperate with the sponsor to determine the most appropriate course of action for the individual. The evaluation includes, but is not limited to, the following.

[0390] The safety of the subject and other study participants

[0391] The potential impact of the disease on the results collected during the study and the ability to appropriately analyze or interpret those results

[0392] The possibility of interrupting participation and resuming after recovery

[0393] Suggestions of selection criteria or exclusion criteria that conflict with possible measures

[0394] Meaning of compliance with regulatory guidelines that may be affected by determined measures, such as group effect analysis

[0395] Calculation of sample size, current number of subjects, and possibility of subject replacement

[0396] The evaluation and decision of subject deletion are recorded in the clinical trial file, reported to the clinical trial sponsor, and considered in the clinical trial report if necessary.

[0397] Stopping rules Participation in the clinical trial can be terminated by the responsible investigator (or proxy) or the clinical trial sponsor in charge of the trial for any of the following reasons in Table 15.

Table 15

[0398] Clinical trial termination rules The responsible investigator must immediately contact the clinical trial sponsor regarding whether to interrupt the administration when an AE or abnormal clinical test indicates that subsequent continuous administration to subjects is not allowed or will endanger the safety of the subjects. The clinical trial sponsor alone can interrupt the administration at any time regardless of the reason.

[0399] Clinical trial termination rules:

[0400] 1. When one case of SAE related to Compound 1 occurs

[0401] 2. In two subjects within the same cohort, in the case of a "severe" non-serious adverse reaction (i.e., a severe non-serious adverse event that is considered to be at least possibly related to Compound 1), regardless of whether it is within the same system-organ class.

[0402] 3. One or more subjects meet the Hy's Law defined as an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥ 2 × ULN (confirmed by repeated tests), and no other reasons are found to explain the combination of increases (e.g., an increase in serum alkaline phosphatase (ALP) indicating cholestasis, viral hepatitis, or administration of another drug).

[0403] 4. The occurrence of one death due to the investigational treatment.

[0404] If any of the above scenarios occur, the trial is immediately put on hold. Subsequently, further consideration is carried out within the SRC, and a safety review is conducted. After the SRC review, if the principal investigator and the sponsor of the trial determine that it is safe to continue, the trial can proceed. If the trial is terminated, the MTD is declared at a dose level lower than its escalating dose.

[0405] Lifestyle and / or dietary requirements Subjects are prohibited from consuming food and beverages containing grapefruit, pomelo, and / or pomegranate seeds for 7 days before the first dose and during the trial.

[0406] Subjects shall consume only the food provided by the trial facility during restraint at the CRU.

[0407] Subjects are not permitted to use tobacco or nicotine-containing products (including but not limited to cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, or nicotine gum) within 90 days before the first administration of the investigational drug and must refrain from nicotine-containing products until the follow-up visit.

[0408] Subjects are prohibited from consuming alcohol for 48 hours before each dose and during each trial period. Throughout the trial, if there is any doubt about alcohol consumption, an alcohol test can be performed if requested by the principal investigator.

[0409] Subjects are prohibited from consuming foods or beverages that change CYP1A2 activity (e.g., barbecue dishes or cruciferous vegetables such as broccoli and cauliflower, etc.) within 7 days before check-in (a list of prohibited foods is provided to the subjects).

[0410] Subjects must refrain from caffeine for 48 hours before check-in and are prohibited from drinking coffee or caffeine-containing beverages during the test period.

[0411] Sexually active men are informed about the possibility of male-mediated fetal toxicity related to the investigational drug. Male subjects are expected to use acceptable contraceptive methods and not provide sperm as described in the selection criteria section.

[0412] Subjects are informed that female partners of childbearing potential are strongly recommended to use one of the following two contraceptive methods: systemic contraceptives (contraceptive pills, injectable / implantable / insertable hormonal contraceptive products, transdermal patches) or intrauterine contraceptive devices.

[0413] Combination therapy In addition to drugs prohibited by the exclusion criteria section, subjects are also prohibited from consuming over-the-counter (OTC) products for 14 days before the first dose and throughout the test period.

[0414] Drugs that are substrates, inhibitors, or inducers of CYP1A2 are specifically prohibited (including but not limited to those containing caffeine, tizanidine, theophylline, naproxen, fluvoxamine, cimetidine, fluoroquinolone, or ticlopidine).

[0415] At the discretion of the principal investigator of the clinical trial, occasional use at a dose of 2 grams / day or less of paracetamol / acetaminophen is permitted.

[0416] Except for drugs that may be necessary for the treatment of AE, no other treatments or drugs other than the investigational drug are permitted from the first dose until all test activities and evaluations are completed.

[0417] Subjects are instructed to notify the test site about new drugs taken after the start of the test treatment. All drugs and important non-drug therapies (including physical therapy and transfusions) administered after the subject has received the test treatment must be recorded in the Case Report Form (CRF). The drug name and dosage taken are described. The principal investigator, substitute, and / or sponsor of the clinical trial will determine whether the subject is permitted to continue the trial depending on the drugs used, the time of drug intake, etc.

[0418] Test treatment Investigational drug: All investigational drugs, including placebo, are provided by the sponsor of the clinical trial. Compound 1 (50 mg oral capsule) is provided by the sponsor of the clinical trial. Details of the preparation, administration method, and final amount of the investigational drug are described in detail in the test-specific procedures. Placebo: Placebo capsules matching Compound 1 are supplied by the sponsor of the clinical trial. The weight is the same as that of the sponsor's oral capsule of Compound 1, and the composition contains excipients that may prevent abuse and is the same, but does not contain Compound 1.

[0419] Investigational drug management Packaging, labeling, and dispensing: The sponsor of the clinical trial is responsible for ensuring that the IP is manufactured in accordance with the regulations and requirements of the current Good Manufacturing Practice and Good Quality Practice rules for pharmaceuticals and quasi-drugs applied. The IP is labeled in accordance with the requirements of local laws and regulations. The IP is dispensed by the pharmacy of the CRU unless the sponsor of the clinical trial supplies the pharmacy with pre-labeled individual dose samples.

[0420] Storage and Handling: All investigational products are shipped from the client or client resources to the CRU pharmacy. Compound 1 should be stored at 2°C to 8°C and kept in a sealed container. If the expiration date has passed, the product should not be used and should not be frozen. The CRU pharmacy maintains inventory records of received IP, stores (within a secure restricted area), and dispenses the IP. The IP is provided only to the subjects under study.

[0421] Method of Assigning Subjects to Treatment Groups Randomization codes are generated using a computer program according to the study protocol, number of subjects, and number of treatments. Within each cohort, subjects are randomized to receive Compound 1 or placebo (3:1). The random assignment of each IP to each subject is done to balance the examinations. Once generated, the randomization codes are final and will not be modified.

[0422] Subjects who signed the ICF and did not receive investigational treatment despite being randomized may be replaced. Subjects who signed the ICF, were randomized, and received investigational treatment but then withdrew from the study, dropped out, or were discontinued will not be replaced.

[0423] Blinding Randomization codes are not available to the personnel in the bioanalytical facility until the bioanalytical phase of the study is completed. The treatment assignments are not known to the study participants.

[0424] Furthermore, randomization codes are not available to physicians and clinical staff involved in AE collection, monitoring, revision, or evaluation, and clinical staff who may influence the results of the study (including pharmacokineticists (or substitutes)) until all CRFs are approved, signed, and the bioanalytical phase of the study is completed.

[0425] The preparation of the product is done by personnel not directly involved in the clinical aspects of the study.

[0426] The randomization code must not be broken, except in emergency situations where the investigator needs to identify the subject's trial treatment for further treatment of the subject or to complete an SAE report. The randomization information is held by the designated individual. The date and reason for unblinding must be recorded.

[0427] The results of PK analysis are available only to those responsible for evaluating safety data before proceeding to the next dose level.

[0428] Responsibility for the description of the investigational medicinal product Complete and accurate inventory records of all investigational medicinal products are maintained. This includes receipt confirmation (quantity and condition) of each shipment of the investigational product, dispensing records for subjects, and return or destruction of the investigational product.

[0429] At the end of the inspection, all unused investigational medicinal products and all drug containers are returned to the sponsor of the trial, unless the sponsor approves other arrangements. Responsibility for the description of the drug is carried out at the end of the trial.

[0430] Administration of the investigational medicinal product The investigational medicinal product is administered twice a day (at 12-hour intervals) on days 1 to 13 and once in the morning on day 14. The date and time of each administration are recorded. For each subject, all scheduled post-administration activities and evaluations are carried out relative to the time of the first administration of the investigational medicinal product.

[0431] The oral dose of the assigned formulation is administered to the subject with approximately 240 mL of water at ambient temperature. The tablets must be swallowed whole and must not be chewed or broken.

[0432] Treatment compliance The investigational medicinal product is dispensed only to eligible subjects and is administered under the supervision of the trial staff. Treatment compliance is verified in accordance with the facility's standard operating procedures (SOPs).

[0433] Diet Food intake is controlled for each confinement period and for all subjects.

[0434] Subjects need to fast overnight for 10 hours before morning dosing and for at least 2 hours after dosing. Also, subjects need to fast for 2 hours before and 2 hours after evening dosing. On day 13, in one cohort (determined after the first cohort is completed), subjects are dosed with Compound 1 30 minutes after the start of a standardized high-fat, high-calorie meal, which is consistent with the description of the meal outlined in the FDA Draft Guidance for Industry. Evaluation of the Effects of Food on Drugs in IND and NDA - Clinical Pharmacology Considerations (accessed May 19, 2022). A high-fat meal is defined as a meal that provides approximately 800 - 1000 calories with approximately 500 - 600 calories derived from fat. An example of a high-fat meal consists of 2 eggs fried in butter, 2 slices of bacon, 2 slices of buttered toast, 4 ounces of hash brown potatoes, and 8 ounces of whole milk. Substitution of this test meal may be done provided that the meal can consume the same amount of calories from protein, carbohydrates, and fat and that the amount and texture of the meal are equivalent. Subjects must eat the entire content of this meal within 30 minutes.

[0435] Fluid The intake of liquids other than water is controlled for each restraint period and for all subjects.

[0436] Each dose of Compound 1 is administered with approximately 8 ounces or 240 mL or water. Water may be drunk as needed except from 1 hour before dosing to 1 hour after dosing (excluding water consumed for dosing).

[0437] Other protocol restrictions Subjects remain in bed (seated or semi-reclining) for at least the first 4 hours after drug administration. However, if an AE occurs, the subject may be placed in an appropriate position. During this interval and after 4 hours, subjects are allowed to get up under supervision. Subjects do not engage in strenuous activity at any time during the restraint period.

[0438] Test procedures The outline of each participant's test activities is detailed in Table 16.

[0439] The subject may leave the clinical facility on the 20th day. However, if the principal investigator or the responsible agent determines it is necessary, the subject may be advised to stay at the clinical facility for safety reasons.

[0440] Unless otherwise specified in the protocol, during this trial, all activities related to the quality of this trial shall follow the standard operating procedures (SOP) of the research facility available. When the nominal times of multiple events occur simultaneously, the events shall be shifted using their acceptable windows (the acceptable windows for each evaluation are specified in the following sections of this protocol), and priority shall be given to events related to the main trial evaluation items.

[0441] Deviations from the protocol procedures shall be documented in the original text and summarized for reporting in the clinical trial report.

Table 16-1

Table 16-2

[0442] Safety Evaluation Safety evaluations include physical examinations, mental evaluations, vital signs, 12-lead ECG, clinical laboratory tests, and AE monitoring. At the discretion of the principal investigator, additional safety evaluations may be conducted as necessary to ensure the safety of the subjects.

[0443] The principal investigator or the responsible agent shall be present at the clinical facility for at least the first 4 hours after the first drug administration and shall be available at all times during the trial period.

[0444] Medical History The medical history at screening includes all questions by medical and clinical staff regarding the health status of the subject and related past medical events / experiences. The medical history includes all demographic data (age, gender, race, weight, height, and BMI) and baseline characteristics. Alcohol and smoking habits are also recorded.

[0445] Physical examination The physical examination is performed by medically qualified and licensed individuals as outlined in Table 16.

[0446] The physical examination includes a general examination of the following body systems (minimum) unless a symptom-directed physical examination is indicated: head and neck, cardiovascular, respiratory, gastrointestinal, a brief neurological examination, and overall appearance.

[0447] Vital signs Vital signs are measured as outlined in Table 16. Vital signs are measured within 1 hour before dosing. Vital signs during the study are evaluated within ±20 minutes of the nominal time point.

[0448] Blood pressure and pulse rate are measured after at least 3 minutes in the supine position.

[0449] 12-Lead electrocardiogram As outlined in Table 16, a 12-lead ECG is performed.

[0450] The pre-dose ECG needs to be completed 1 hour before morning dosing. All other ECG evaluations need to be completed within ±20 minutes of the nominal time point.

[0451] Pharmacogenetic and exploratory biomarker sampling As outlined in Table 16, a blood sample is taken on Day 1 for CYP 1A2 genotyping. Blood samples are also taken on Day 1 and at specified times during the treatment period (per Table 16) for exploratory biomarker analysis.

[0452] Clinical laboratory evaluations Clinical examination evaluations are conducted as outlined in Table 16.

[0453] The clinical examination evaluations conducted in this study are shown in Table 17. Additional clinical examinations may be conducted by the clinical laboratory as part of a larger standard test panel (not essential for subject safety).

Table 17

[0454] The principal investigator or responsible agent evaluates each abnormal value and determines whether it is clinically significant. Clinically important clinical test values after administration are reported as AEs at the discretion of the principal investigator or responsible agent, if applicable. Only the test results and / or abnormal results required by the protocol are entered into the clinical database and reported in the clinical study report based on the reporting requirements.

[0455] Brief Psychiatric Rating Scale (BPRS) The BPRS scale is designed for the evaluation of psychiatric symptoms or disorders (e.g., depression, anxiety, hallucinations, and abnormal behavior).

[0456] This scale must be administered by a psychiatrist or other individual appropriately qualified by education or training. The evaluation is conducted as outlined in Table 16.

[0457] The BPRS should be completed before administration of Compound 1 and at approximately 6.00 and 24.00 hours after administration on Days 1, 7, and 14.

[0458] Clinical Assessment of Dissociative States Scale (CADSS) The CADSS scale is designed for the evaluation of dissociation in adults.

[0459] This scale must be administered by a psychiatrist or other individual appropriately qualified by education or training. The evaluation is conducted as outlined in Table 16.

[0460] CADSS should be completed before compound 1 administration and at approximately 6.00 and 24.00 hours after administration on days 1, 7, and 14.

[0461] Columbia Suicide Severity Rating Scale (C-SSRS) The C-SSRS is a questionnaire designed for the assessment of suicidal thoughts and behaviors in youth and adults.

[0462] To monitor the history (from the past two years to the present) or emergence of suicidal thoughts and behaviors, subjects receive a C-SSRS assessment at the time points shown in Table 16.

[0463] This questionnaire must be administered by a psychiatrist or other individual appropriately qualified by education or training.

[0464] The C-SSRS should be completed before administration of compound 1 and evaluated at 1, 3, 5, 7, 9, 11, 13, 15, 17, on the 18th day before discharge, and at follow-up / EOS visit.

[0465] If a positive result for suicidal tendency on the C-SSRS is obtained after screening (defined by subjects who answer "yes" to question 4 or 5 in the suicidal thoughts part of the C-SSRS), the subject is evaluated by the principal investigator of the trial or a medically qualified sub-investigator of the trial regarding continuation of the trial.

[0466] If a subject has a suicidal desire during the trial, the principal investigator of the trial or a medically qualified sub-investigator of the trial should provide appropriate treatment to the subject.

[0467] Modified Mini-Mental State Examination (3MS)

[0468] The 3MS is a test designed for the assessment of dementia in adults.

[0469] This examination must be performed by a psychiatrist or other individual appropriately qualified by education or training. The evaluation is to be conducted as outlined in Table 16.

[0470] 3MS should be completed at approximately 24.00 hours before the administration of Compound 1 and on Days 1, 7, and 14 after administration.

[0471] Visual Analog Alert Scale (VAS) The VAS Alert Scale is designed to evaluate the subject's level of arousal across a continuous scale with values from 0 to 10.

[0472] This scale must be performed by a psychiatrist or other individual appropriately qualified by education or training. The evaluation is to be conducted as outlined in Table 16.

[0473] VAS should be completed at approximately 4.00, 6.00, and 12.00 hours before the administration of Compound 1 and on Days 1, 7, and 14 after administration. This evaluation is also to be conducted on Day 18 before discharge.

[0474] Salvage Therapy In the event of a medical emergency, a crash cart equipped with necessary resuscitation equipment including intravenous naloxone will be made available.

[0475] Pharmacokinetic Evaluation A total of 37 blood samples will be collected for PK evaluation. The complete blood sampling schedule is shown in Table 18.

Table 18

[0476] Blood samples are collected by direct venipuncture into labeled tubes containing the appropriate anticoagulant as specified by the bioanalytical facility. As an option for the subject or if determined necessary by clinical staff, blood samples may be collected from an indwelling cannula placed in the subject's vein.

[0477] The time of PK blood sample collection is calculated relative to the time of treatment administration. The actual time of all PK blood draws is recorded and reported for all subjects.

[0478] The window for timed PK blood sample collection is shown in Table 19. PK samples collected outside the pre-specified frame are recorded as protocol deviations. Since the actual time is used for PK analysis, deviations are reflected in the analysis unless otherwise instructed during data review.

Table 19

[0479] The concentration of Compound 1 for PK evaluation is obtained via bioanalysis of plasma derived from blood samples collected during the study using a validated bioanalytical method.

[0480] Pharmacokinetics Sample Handling, Storage, and Shipping Blood samples for PK determination are processed, stored, and shipped according to the sample handling instructions provided by the bioanalytical facility.

[0481] Documentation of Adverse Events Definitions AE is defined as any adverse medical event in subjects administered the investigational drug and is not necessarily causally related to the treatment. Thus, an AE can be any unfavorable, unintended sign (including, for example, abnormalities in clinically significant clinical laboratory findings), symptom, or disease that is temporally related to the use of the investigational drug, whether or not related to the investigational drug.

[0482] A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that the drug caused the AE. "Reasonable possibility" means that there is evidence suggesting a causal relationship between the drug and the AE. A suspected adverse reaction implies a lower degree of certainty of causality than an adverse reaction that means any AE caused by the drug.

[0483] AE can be the following.

[0484] New disease

[0485] Worsening of coexisting diseases

[0486] The effects of the investigational drug including the comparator. Clinical laboratory value abnormalities, as well as significant changes from baseline within the normal range that the principal investigator of the clinical trial deems clinically important.

[0487] Surgical procedures themselves are not AEs. These are therapeutic measures for conditions that require surgery. A condition that requires surgery is an AE if it occurs or is detected during the study period. Planned surgical procedures permitted by the clinical trial protocol, and the conditions leading to these procedures, are not AEs if the condition was known prior to the start of the study treatment. In the latter case, the condition should be reported as part of the medical history.

[0488] SAEs or reactions are harmful medical events that occur at any dose and are as follows:

[0489] Resulting in death,

[0490] Life-threatening,

[0491] Requiring hospitalization or prolongation of hospitalization,

[0492] Persistent or significant disability or incapacity (defined as a marked impairment of the ability to perform normal life functions),

[0493] Congenital or birth defects,

[0494] An important medical event that may place the subject at risk or that may require intervention to prevent one of the other outcomes described above (at the medical discretion of the principal investigator of the clinical trial).

[0495] Severity assessment All AEs are evaluated in accordance with the FDA's industry guidance on toxicity assessment for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials.

[0496] All efforts are made to obtain an appropriate assessment of severity.

[0497] Causality assessment The principal investigator of the clinical trial uses the guidelines shown in Table 20 to determine the relationship between the AE and the investigational medicinal product. [Table 20]

[0498] Monitoring of adverse events For the purposes of this trial, the AE monitoring period extends from screening to the visit at the end of the study (EOS). From screening to the first administration of the trial medicinal product, AEs are recorded, as required, as screening events or as part of the medical history. AEs occurring after the start of the trial medicinal product are shown as treatment-emergent adverse events (TEAEs) in the clinical study report.

[0499] Subjects are questioned about their state of health at the start of each trial period and before leaving the clinical facility. Open-ended questions are asked.

[0500] All AEs spontaneously reported by the subjects, observed by the clinical staff, or elicited by general questions during the trial are recorded for all subjects and reported on the case report form (CRF).

[0501] All efforts are made to obtain appropriate follow-up of the subjects, as required. If a subject chooses to withdraw from the trial, safety precautions are notified.

[0502] AEs unresolved at the time of the last visit require evaluation and follow-up until the AE has resolved, a reasonable explanation for its persistence has been found, or it is considered to have resolved in a mild and safe manner.

[0503] In the case of an AE considered to be related to the investigational drug, every effort is made to determine the final outcome.

[0504] It is the responsibility of the principal investigator of the clinical trial to ensure that subjects experiencing an AE receive appropriate follow-up, treatment as necessary, and that all measures are properly documented.

[0505] The classification of AEs is carried out according to the System Organ Class (SOC) and Preferred Term (PT) using the International Conference on Harmonisation (ICH) medical dictionary for regulatory activities (MedDRA) version 25.0 or higher.

[0506] Concomitant medications are coded using the World Health Organization's (WHO) drug dictionary (WHO-DDE, from March 2021 onwards).

[0507] Reporting of pregnancy Pregnancy in female trial subjects shall be reported to the sponsor within 24 hours of its discovery by the principal investigator of the clinical trial or the proxy (in the case of pregnancy occurring during or immediately after the trial period). Since the fetus / embryo may have been exposed to the investigational drug through the parent, and for the safety of the subject, the pregnancy is followed up to determine the outcome, including whether it is a miscarriage or spontaneous abortion, details of the delivery, presence or absence of birth defects, congenital anomalies, or maternal and / or neonatal complications.

[0508] Pregnancy occurring within 90 days after follow-up visit in the female partner of a male trial subject shall be reported to the sponsor within 24 hours of the clinical facility becoming aware that the pregnancy occurred during or immediately after the trial period. Since the fetus / embryo may have been exposed to the investigational drug through the parent, and for the safety of the subject's female partner, the pregnancy is followed up to determine the outcome, including whether it is a miscarriage or spontaneous abortion, details of the delivery, presence or absence of birth defects, congenital anomalies, or maternal and / or neonatal complications.

[0509] Record pregnancies and report them to the sponsor from the clinical facility. Pregnancy follow-up is appropriately recorded to ensure the quality and completeness of the data belonging to the investigational product, and also includes the assessment of the possibility of a causal relationship between the investigational product and the pregnancy outcome. SAE occurring during pregnancy are reported on the SAE report form.

[0510] Reporting of Serious Adverse Events The CRU notifies the sponsor of the SAE, regardless of causality, within 24 hours of recognizing its occurrence.

[0511] If a non-serious AE worsens during follow-up and ultimately meets the criteria for an SAE, that AE should be recorded as a new SAE.

[0512] The initial SAE report must be as complete as possible, including the current illness and details of the SAE, as well as an assessment of the causal relationship between the event and the investigational product. Information not available at the time of the initial report (e.g., the end date of the AE, clinical test values received after reporting, or an overview of discharge) must be documented. All follow-up information must be reported promptly as soon as the relevant information becomes available.

[0513] An SAE is considered "unexpected" if the AE is not described in the investigator's brochure, or if it is not described by the observed specificity or severity, or if the investigator's brochure is not required or not available, or if it does not match the risk information described in the general study plan or elsewhere in this application. "Unexpected" as used in this definition also refers to an AE that is mentioned in the investigator's brochure as occurring with a certain class of drugs or being expected from the pharmacological properties of the drug, but is not specifically mentioned as occurring with the particular drug under investigation.

[0514] The CRU determines whether an unexpected serious related AE needs to be reported to the Institutional Review Board (IRB). In that case, the investigator or staff reports the event by fax or email within 15 calendar days of recognizing the event.

[0515] The sponsor shall determine whether it is necessary to make an urgent report of the SAE to the relevant regulatory authority. In that case, the sponsor shall report the incident to the institution and all the clinical trial responsible physicians participating.

[0516] During the clinical part of this trial, if the sponsor obtains reports of new and unexpected AEs (regardless of whether they are related to this trial), the sponsor shall advise the CRU about those events through the responsible physician of the trial.

[0517] Data analysis and statistical considerations Analysis population Safety population The safety population includes all subjects who have received at least one administration of either the investigational drug or the placebo.

[0518] Count the number of included subjects, discontinued subjects, and subjects who completed the trial. The main reasons for discontinuation are provided.

[0519] Pharmacokinetic population In most cases, the determination of which subjects are included in the PK analysis is made before the start of sample analysis by the bioanalytical facility.

[0520] The PK population is described in the SAP. Generally, the PK population includes all subjects who have been administered the investigational drug or an equivalent drug and have at least one post - administration concentration value evaluable in any biological matrix.

[0521] Demographic data and other baseline characteristics

[0522] The statistics of demographic data and baseline data are detailed in the SAP.

[0523] Safety Safety evaluation items The safety evaluation items are evaluated by the number, severity, and type of TEAEs.

[0524] Safety analysis Safety statistical analysis is performed using clinical examinations and vital signs, ECG, physical examinations, mental evaluations, and measurements of other safety parameters.

[0525] Safety statistical methods Statistics regarding the summary of AEs and safety results are fully detailed in the SAP.

[0526] Pharmacokinetics PK analysis is performed according to the SOP. The handling and statistical analysis of pharmacokinetic data are fully detailed in the SAP.

[0527] Pharmacogenetic statistical methods Exploratory pharmacogenetic tests are designed to investigate the relationship between genetic factors (genotypes) collected during clinical trials and clinical evaluations (phenotypes). Without prior evidence of strong associations, exploratory analysis is used to evaluate several possible associations. Various statistical tests (chi-square test, ANCOVA, linear regression, and logistic regression) are used in the analysis. Additional data from subsequent clinical tests are often needed to confirm the associations. Alternatively, if the number of subjects enrolled in this trial is too small to complete appropriate statistical analysis, these data may be combined, if necessary, with data from other trials to expand the dataset for analysis.

[0528] Planned interim analysis No formal interim analysis is performed, and the blinded safety data are reviewed by the principal investigator and the medical monitor of the sponsor after completion of each dose value of Compound 1.

[0529] The SAP describes the planned interim analysis in more detail.

[0530] Sample size determination No formal sample size analysis was performed. To achieve the objectives of this trial, it is estimated that approximately 24 subjects are sufficient.

[0531] Equivalent Although the present disclosure has been described in conjunction with the specific embodiments above, many alternatives, modifications, and other variations will be apparent to those of ordinary skill in the art. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present disclosure.

[0532] Example 6 - Modifications to a Phase 1, randomized, placebo-controlled, multiple ascending dose (MAD) trial to evaluate the safety, tolerability, and pharmacokinetics of Compound 1 in healthy subjects Example 6 presents another randomized, placebo-controlled, multiple ascending dose (MAD) trial protocol. Example 6 is the same as Example 5, except that the trial will evaluate Compound 1 at 50 mg once daily for 14 consecutive days in Cohort 2, and the dose in subsequent cohorts may be increased based on new safety and pharmacokinetic data. This trial also includes an exploratory objective to evaluate the role of inhibition of the cytochrome P1A2 (CYP1A2) enzyme on the determination of steady-state exposure of Compound 1.

[0533] Example 7 - A Phase 2, randomized, global, double-blind, placebo-controlled, parallel-group trial to evaluate whether Compound 1 reduces cocaine use in patients diagnosed with cocaine use disorder. This is a randomized, subject- and treating investigator-blind, parallel-group, placebo-controlled trial to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of Compound 1 in subjects with at least moderate CUD who use cocaine by inhalation (intranasally) as the primary route of administration.

[0534] Study Design / Methods The trial consists of a 14-day screening period, followed by a 14-day baseline period, a 12-week outpatient treatment period, and the end of the study visit approximately 14 days after the last dose of study drug. The total duration for each subject in the trial is approximately 18 weeks, including screening and baseline. The entire trial is conducted on an outpatient basis.

[0535] Screening period: After signing the informed consent form, eligible individuals undergo medical history, physical examination, clinical laboratory tests, and other evaluations to determine their eligibility for the study. Individuals who meet all inclusion criteria and do not meet any exclusion criteria are enrolled in the study.

[0536] Baseline period: Before randomization, all enrolled subjects undergo baseline (pretreatment) evaluations including safety laboratory tests, quantification of substance use, and a health questionnaire. After confirmation of study eligibility, individuals enter the treatment period.

[0537] Treatment period: Enrolled individuals are randomized to receive either Compound 1 or the corresponding placebo once daily for 12 weeks. Subjects record their daily cocaine consumption throughout the treatment period. At regular intervals, participants return to the clinical research facility for safety, PK, PD, and efficacy evaluations.

[0538] End of study: Approximately 2 weeks after completion of treatment, subjects return to the clinical research facility for the end-of-study visit. At this time, each individual undergoes follow-up evaluations including physical examination, safety tests, cocaine use, and other health questionnaires.

[0539] Objectives and assessments Primary: To evaluate the treatment effect of 12 weeks of Compound 1 administration on reduction of cocaine use. Assessment: Percentage of cocaine use days by timeline follow-back (TLFB) cocaine self-report.

[0540] Secondary Objective 1: (1) Evaluate the effects of Compound 1 on the following. (a) Other criteria for cocaine use, (b) criteria for alcohol use. Evaluation items: (1) The proportion of positive urine measurements of benzoylecgonine (BE), (2) changes from baseline in cocaine and other substance cravings according to the BSCS (Brief Substance Craving Scale), (3) changes from baseline in the proportion of heavy drinking days per week as evaluated by the TLFB, (4) changes from baseline in the proportion of heavy drinking days in a month (a heavy drinking day is defined as a day when the patient consumes 5 or more standard alcoholic beverages if male and 4 or more standard alcoholic beverages if female).

[0541] Secondary Objective 2: Evaluate the safety and tolerability of Compound 1. Evaluation items: Vital signs, ECG parameters, clinical safety clinical laboratory parameters (chemistry / hematology / urine tests), (serious) AE reports, suicidal ideation (CSSR-S), BPRS.

[0542] Secondary Objective 3: Evaluate the pharmacokinetics of Compound 1 in subjects with CUD. Evaluation item: Plasma concentration of Compound 1.

[0543] Exploratory Objective 1: Evaluate the frequency of use of other drugs, alcohol, and nicotine before and during 12 weeks of Compound 1 treatment. Evaluation items: (1) Hair drug tests for cocaine, amphetamine, methamphetamine, MDMA, MDEA, MDA, methylphenidate, ketamine, and EtG, (2) changes from baseline to the 3rd month in alcohol biomarkers of consumption and / or relapse (LFT, CDT%, and urinary EtG), (3) Fagerström test for nicotine dependence and urinary cotinine.

[0544] Exploratory Objective 2: Examine whether differences in response to Compound 1 are confirmed by individual genetic variations in genes related to drug metabolism and transporters, CUD, and drug target pathways. Evaluation item: Association of single genetic variants or genetic risk scores with outcome criteria (pharmacogenetic blood samples).

[0545] Objective of exploration 3: To evaluate the effect of 12-week administration of Compound 1 versus placebo on (a) depressive symptoms, (b) anxiety symptoms, (c) stress, (d) sleep, and (e) overall function. Evaluation items: (1) Patient-reported outcomes (PRO) and wearable device data: (a) Beck Depression Inventory-II (BDI-II), (b) State-Trait Anxiety Inventory (STAI) and digital evaluation of heart rate variability, (c) digital evaluation of skin electrical activity, (d) Insomnia Severity Index (ISI) and digital evaluation of total sleep duration and overall sleep quality, (2) Clinician-reported outcomes: (e) CGI-S and CGI-I.

[0546] Population Major selection criteria: Patients meeting the following selection criteria are eligible to participate in the trial.

[0547] (1) Adult male or female subjects aged 18 to 65 years.

[0548] (2) Must use cocaine by inhalation (transnasal) as the main route of administration.

[0549] (3) Have met the DSM-5 diagnosis of at least moderate CUD (4 or more criteria) (using the SCID-5-CT diagnostic interview) during the 3 months immediately prior to signing the informed consent form.

[0550] (4) Recent cocaine use confirmed by a positive urine screening for one or more benzoylecgonines (BE).

[0551] (5) Must seek treatment for cocaine dependence and have the desire to reduce or discontinue cocaine use according to the goals evaluated at baseline.

[0552] As evaluated by the self-reported TLFB, cocaine use must be abstained from at least 3 days before the first dose (day 1). Two urine drug screening samples at Visit 2 (second screening) and Visit 3 (baseline) must show a decrease in BE value or both must be negative.

[0553] Main exclusion criteria: Patients who meet any of the following exclusion criteria are excluded from participating in the study.

[0554] For items 4 or 5 in the suicidal ideation section of the C-SSRS, score "Yes" if this ideation occurred in the past 6 months; for any item in the suicidal behavior section, score "Yes" (excluding "non-suicidal self-injury behavior" which is also included in the suicidal behavior section) if this behavior occurred in the past 2 years.

[0555] (1) For items 4 or 5 in the suicidal ideation section of the C-SSRS, score "Yes" if this ideation occurred in the past 6 months; for any item in the suicidal behavior section, score "Yes" (excluding "non-suicidal self-injury behavior" which is also included in the suicidal behavior section) if this behavior occurred in the past 2 years.

[0556] (2) Have a current diagnosis of moderate or severe substance use disorder (in accordance with DSM-5) for stimulants other than alcohol, cannabis, opioids, or cocaine. Note: Nicotine use is permitted. Current use of alcohol and / or cannabis is permitted. Current use of amphetamines and / or heroin is excluded, but lifetime use is permitted.

[0557] (3) Currently or lifetime meet the DSM-5 criteria for schizophrenia or mental disorder or organic mental disorder. Note: Subjects diagnosed with other mental disorders can be included at the discretion of the PI as long as co-treatment for the co-existing mental disorder does not prevent completion of the study or increase the risk to the patient by participating in the examination.

[0558] (4) Have received treatment for a substance use disorder (e.g., disulfiram, acamprosate, methylphenidate, modafinil, topiramate, immediate-release dextroamphetamine, or baclofen) in the past 90 days.

[0559] (5) Require treatment with psychoactive drugs including antiepileptic drugs (except for drugs used for short-term treatment of insomnia) Note: SSRIs and benzodiazepines are acceptable if they have an appropriate stable dose for at least 1 month before the test treatment administration.

[0560] Dosage form and route of administration Subjects will be assigned in a 1:1 ratio to one of the following two treatment groups. (1) Test product: Compound 1 mg capsules (dose not determined) (2) Reference product: Placebo capsules.

[0561] Route of administration: Compound 1 or placebo will be administered orally.

[0562] Evaluation criteria Efficacy (pharmacodynamics): (1) Proportion of days of cocaine use by TLFB cocaine self-report, (2) Alcohol consumption by TLFB, (3) Alcohol self-report (HDD / week and month), (4) Measurement of benzoylecgonine (BE), the major metabolite of cocaine in urine.

[0563] Pharmacokinetics: (5) Plasma concentration of Compound 1 before and after morning administration.

[0564] Safety: (6) Physical examination including vital signs, height, and weight, (7) Clinical laboratory evaluations (chemistry / hematology / urinalysis), (8) Electrocardiogram (ECG), (9) Suicidal thoughts and behaviors evaluated by the Columbia Suicide Severity Rating Scale (C-SSRS), (10) Brief Psychiatric Rating Scale (BPRS), (11) Reporting of serious adverse events (SAEs) and adverse events (AEs).

[0565] Other evaluations: (12) Hair drug testing for cocaine, amphetamine, methamphetamine, MDMA, MDEA, MDA, methylphenidate, ketamine) and ethyl glucuronide (EtG), (13) Alcohol biomarkers (LFT, CDT%, urinary EtG), (14) Pharmacogenetic blood samples,

[0566] Patient-reported outcomes (PRO): (15) Beck Depression Inventory-II (BDI-II), (16) State-Trait Anxiety Inventory (STAI), (17) Insomnia Severity Index (ISI), (18) Brief Substance Craving Scale (BSCS).

[0567] Clinician-reported outcomes (CRO): (17) Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I), (18) Digital evaluation via wearable / smartphone (using data passively collected from smart devices / sensors), (19) Total sleep duration and overall sleep quality, (20) Heart rate variability (HRV), (21) Electrodermal activity (EDA).

[0568] Determination of sample size Enroll approximately 90 subjects and ensure that 70 subjects (35 subjects for compound 1 and 35 subjects for placebo) complete the study. Assume a standard deviation of 25% and a dropout rate of 30%, with a power of 90% at a type I error of 5%.

[0569] Example 8 - A Phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate whether compound 1 reduces opioid use in patients diagnosed with opioid use disorder This is a randomized, subject- and treating investigator-blind, parallel-group, placebo-controlled trial to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of compound 1 in subjects with at least moderate OUD. Eligible patients are currently receiving buprenorphine treatment for OUD, desire opioid abstinence, are willing to undergo a taper of buprenorphine, and are able to discontinue buprenorphine as needed.

[0570] Study Design / Methodology This study consists of a screening period of up to 3 days (conducted in parallel with buprenorphine taper), followed by a 12-week outpatient treatment period, and a visit for EOS assessment approximately 14 days after the last dose of the study drug. The total duration for each subject in the study is approximately 14.5 weeks including screening. The entire study is conducted on an outpatient basis.

[0571] Screening / Baseline Period: After signing the informed consent form, eligible individuals undergo a medical history, physical examination, clinical laboratory tests, and other evaluations to determine eligibility for study participation. Individuals who meet all inclusion criteria and do not meet any of the exclusion criteria are enrolled in this study. During this time, relevant patients undergo buprenorphine taper / cessation.

[0572] Treatment Period: Enrolled individuals are randomized to receive either Compound 1 or the corresponding placebo once daily for 12 weeks. Subjects record their daily opioid consumption throughout the treatment period. At regular intervals, participants return to the clinical trial site for safety, PK, PD, and efficacy evaluations.

[0573] End of Study: Approximately 2 weeks after treatment completion, subjects return to the clinical trial site for the end-of-study visit. At this time, each individual undergoes follow-up evaluations including a physical examination, safety tests, opioid use, and other health questionnaires.

[0574] Objectives and Evaluation Items Primary Objective: To evaluate the treatment effect of 12-week administration of Compound 1 in reducing opioid use. Evaluation Item: Percentage of opioid use days by timeline follow-back (TLFB) opioid self-report.

[0575] Secondary Objective 1: Evaluate the effect of Compound 1 on the following over a 12-week period. (a) Other criteria for opioid use, (b) criteria for alcohol use. Evaluation items: (1) Measurement of opioid metabolites in urine and hair, (2) Changes from baseline in opioid and other substance cravings by the BSCS (Brief Substance Craving Scale), (3) TLFB alcohol self-report, urine analysis (ethyl glucuronide (EtG)), (4) Changes from baseline in the percentage of heavy drinking days per week as evaluated by TLFB, (5) Changes from baseline in the percentage of heavy drinking days in a month (Heavy drinking days are defined as days when the patient consumed 5 or more standard alcoholic beverages if male and 4 or more standard alcoholic beverages if female). This data is calculated from TLFB data, and the 3-month mark is the point of interest.

[0576] Secondary Objective 2: Evaluate the safety and tolerability of Compound 1. Evaluation items: Vital signs, ECG parameters, clinical safety clinical laboratory parameters (chemistry / hematology / urinalysis), (serious) AE reports, suicidal ideation (CSSR-S), BPRS.

[0577] Secondary Objective 3: Evaluate the PK of Compound 1 in subjects with OUD. Evaluation item: Plasma concentration of Compound 1.

[0578] Exploratory Objective 1: Evaluate the frequency of use of other drugs, as well as alcohol and nicotine, before and during 12 weeks of treatment with Compound 1. Evaluation items: (1) Hair drug tests for amphetamine, methamphetamine, MDMA, MDEA, MDA, methylphenidate, ketamine, and EtG, (2) Changes from baseline to the 3-month mark in consumption and / or relapse alcohol biomarkers (LFT, CDT%, and urine EtG), (3) Fagerström test for nicotine dependence and urine cotinine.

[0579] Objective of Exploration 1: To examine whether differences in response to Compound 1 are identified due to individual genetic variations in genes related to drug metabolism and transporters, OUD, and drug target pathways. Evaluation Items: Association with single genetic variants or genetic risk scores and outcome criteria (pharmacogenetic blood samples).

[0580] Objective of Exploration 1: (a) To evaluate the effect of Compound 1 over 12 weeks on depressive symptoms, (b) anxiety symptoms, (c) stress, (d) sleep, and (e) overall function. Evaluation Items: (1) Patient-reported outcomes (PRO) and wearable device data: (a) Beck Depression Inventory-II (BDI-II), (b) State-Trait Anxiety Inventory (STAI) and digital evaluation of heart rate variability, (c) digital evaluation of skin electrical activity, (d) Insomnia Severity Index (ISI) and digital evaluation of total sleep duration and overall sleep quality, (2) Clinician-reported outcomes: (e) CGI-S and CGI-I.

[0581] Population Major Selection Criteria: Patients meeting the following selection criteria are eligible to participate in the study.

[0582] (1) Adult male or female subjects aged 18 to 65 years.

[0583] (2) Have opioid use disorder meeting the criteria defined by the Mini International Neuropsychiatric Interview (MINI 7.0.2) for mental disorders, more than three months before screening.

[0584] (3) Currently in an inpatient opioid discontinuation program with buprenorphine taper, and the subject intends to and is able to discontinue before randomization to this trial.

[0585] (4) Have the intention to reduce or stop opioid use and must declare the intention to abstain from opioids without using currently approved treatments for opioid use disorder.

[0586] (5) Self-report of opioid use in the 30 days before screening was confirmed by a positive urine screen (verified by facility records).

[0587] Main exclusion criteria: Patients who meet any of the following exclusion criteria are excluded from participation in the study.

[0588] (1) For items 4 or 5 in the suicidal ideation section of the C-SSRS, score "yes" if this ideation occurred in the past 6 months; for any item in the suicidal behavior section, score "yes" excluding "non-suicidal self-injury behavior" (items also included in the suicidal behavior section) if this behavior occurred in the past 2 years.

[0589] (1) Have a current diagnosis of moderate or severe substance use disorder (DSM-5 compliant) other than OUD or tobacco use disorder within 3 months before screening.

[0590] (2) Positive urine drug screen for cocaine and / or methamphetamine.

[0591] (3) A current diagnosis other than opioid use disorder that requires chronic opioid treatment.

[0592] (4) Current medication-assisted treatment with methadone or naltrexone.

[0593] (5) Received extended-release buprenorphine (Sublocade) within 300 days of enrollment.

[0594] (6) Acute opioid withdrawal symptoms defined by a COWS score greater than 4.

[0595] (7) Currently or ever meet the DSM-5 criteria for schizophrenia or a mental disorder or an organic mental disorder. Note: Subjects diagnosed with other mental disorders may be included at the discretion of the PI if co-treatment for the co-existing mental disorder does not interfere with study completion or increase the risk to the patient from participation in the study.

[0596] (8) Have received treatment for substance use disorders other than buprenorphine in the past 90 days (e.g., disulfiram, acamprosate, methylphenidate, modafinil, topiramate, immediate-release dexamphetamine, or baclofen).

[0597] (9) Have relapsed more than 5 times in the past.

[0598] (10) Require treatment with psychoactive drugs including antiepileptic drugs (excluding drugs used for short-term treatment of insomnia). Note: SSRIs and benzodiazepines are acceptable if they have an appropriate stable dose for at least 1 month before the test treatment administration.

[0599] Dosage form and administration route Subjects are assigned to one of the following two treatment groups at a ratio of 1:1: (1) Test product: Compound 1 capsule (dose undetermined), (2) Reference product: Placebo capsule

[0600] Administration route: Compound 1 or placebo is administered orally.

[0601] Evaluation criteria Efficacy (pharmacodynamics): (1) Proportion of opioid use days by TLFB opioid self-report, (2) Alcohol consumption by TLFB (paper and electronic), (3) Alcohol self-report (HDD / week and month), (4) Measurement of opioid metabolites in urine.

[0602] Pharmacokinetics: (5) Plasma concentration of Compound 1 before and after morning administration.

[0603] Safety: (6) Physical examination including vital signs, height, and weight, (7) Clinical laboratory evaluation (chemistry / hematology / urine test), (8) Electrocardiogram (ECG), (9) Suicidal thoughts and behaviors evaluated by the Columbia Suicide Severity Rating Scale (C-SSRS), (10) Reporting of serious adverse events (SAEs) and adverse events (AEs).

[0604] Other evaluations: (11) Hair drug testing for opioids, amphetamines, methamphetamine, MDMA, MDEA, MDA, methylphenidate, ketamine) and ethyl glucuronide (EtG), (12) Alcohol biomarkers (LFT, CDT%, urinary EtG), (13) Pharmacogenetic blood samples.

[0605] Patient-reported outcomes (PRO): (14) Beck Depression Inventory (BDI-II), (15) State-Trait Anxiety Inventory (STAI), (16) Insomnia Severity Index (ISI), (17) Brief Substance Craving Scale (BSCS).

[0606] Clinician-reported outcomes (CRO): (18) Clinical Global Impression - Severity (CGI-S) and Improvement (CGI-I).

[0607] Digital evaluation via wearable / smartphone (using data passively collected from smart devices / sensors): (19) Total sleep duration and overall sleep quality, (20) Heart rate variability (HRV), (21) Electrodermal activity (EDA).

[0608] Determination of sample size Enroll approximately 90 subjects and ensure that 70 subjects (35 subjects for compound 1 and 35 subjects for placebo) complete the study. Assume a standard deviation of 25% and a dropout rate of 30%, with a power of 90% at a type I error of 5%.

[0609] Example 9 - A Phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate whether compound 1 reduces alcohol use in patients diagnosed with alcohol use disorder This is a randomized, subject- and treating investigator-blind, parallel-group, placebo-controlled trial to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of compound 1 in subjects with at least moderate alcohol use disorder (AUD).

[0610] Study design / methods The trial consists of a 14-day screening period, followed by a 7-day baseline period, a 12-week outpatient treatment period, and the end of the trial visit approximately 14 days after the last study drug administration. The total duration for each subject in the trial is approximately 16 weeks including screening and baseline. The entire trial is conducted outpatient.

[0611] Screening period: After signing the informed consent form, eligible individuals undergo a medical history, physical examination, clinical laboratory tests, and other evaluations to determine eligibility for the trial. Individuals who meet all inclusion criteria and do not meet any of the exclusion criteria are enrolled in this trial.

[0612] Baseline period: Before randomization, all enrolled subjects undergo baseline (pretreatment) evaluations including safety clinical laboratory tests, quantification of substance use, and a health questionnaire. After confirmation of trial eligibility, the individuals enter the treatment period.

[0613] Treatment period: Enrolled individuals are randomized to receive either Compound 1 or the corresponding placebo once daily for 12 weeks. Subjects record their daily alcohol consumption throughout the treatment period. At regular intervals, participants return to the clinical trial facility for safety, PK, PD, and efficacy evaluations.

[0614] End of trial: Approximately 2 weeks after treatment completion, subjects return to the clinical trial facility for the end-of-trial visit. At this time, each individual undergoes follow-up evaluations including a physical examination, safety tests, alcohol use, and other health questionnaires.

[0615] Primary objective: To evaluate the therapeutic effect of 12 weeks of Compound 1 administration in reducing alcohol consumption and promoting abstinence. Evaluation item: Change from baseline in the proportion of heavy drinking days (HDD) per week. HDD is defined as 5 or more standard alcoholic beverages for men and 4 or more standard alcoholic beverages for women.

[0616] Secondary objective 1: To evaluate the effect of 12-week compound 1 administration versus placebo on other measures of alcohol use. Evaluation items: (1) Change from baseline in the proportion of monthly heavy drinking days (HDDs), (2) Change from baseline in the proportion of abstinent days per week, (3) Change in total alcohol consumption from baseline to week 12 based on average daily alcohol consumption in grams per day (calculating the reduction for WHO drinking risk levels above level 1 and above level 2), (4) Time to initial HDD, (5) Change from baseline to week 12 in alcohol biomarkers of consumption and / or relapse (LFT, GGT, CDT%, and urinary EtG), (6) Proportion of participants who have not had an HDD or have been completely abstinent once a month, (7) Change from baseline in alcohol craving as evaluated by the Alcohol Craving Questionnaire - Short Form - Revised (ACQ-SF-R).

[0617] Secondary objective 2: To evaluate the safety and tolerability of compound 1. Evaluation items: Vital signs, ECG parameters, clinical safety clinical laboratory parameters (chemistry / hematology / urinalysis), (serious) AE reports, suicidal ideation (CSSR-S), BPRS, CADSS.

[0618] Secondary objective 3: To evaluate the PK of compound 1 in subjects with AUD. Evaluation item: Plasma concentration of compound 1.

[0619] Exploratory objective 1: To evaluate the frequency of other substances (cannabis, nicotine) before and during 12-week compound 1 treatment. Evaluation items: (1) TLFB for cannabis and nicotine, (2) Urine test for cannabis, (3) Number of packs of cigarettes per day, (4) Fagerström test for nicotine dependence and urinary cotinine.

[0620] Exploratory objective 2: To examine whether differences in response to compound 1 are identified by individual genetic variations in genes related to drug metabolism and transporters, AUD, and the drug target pathway. Evaluation item: Association of single genetic variants or genetic risk scores with outcome criteria (pharmacogenetic blood samples).

[0621] Objective of the exploration 3: To evaluate the effect of 14-week administration of Compound 1 vs placebo on (a) depressive symptoms, (b) anxiety symptoms, (c) quality of life, (d) stress, (e) sleep, and (f) overall function. Evaluation items: (1) Patient-reported outcomes (PRO) and wearable device data: (a) Beck Depression Inventory-II (BDI-II), (b) State-Trait Anxiety Inventory (STAI) and digital evaluation of heart rate variability, (c) 12-item Short Form Health Survey (SF-12), (d) Pittsburgh Sleep Quality Index (PSQI), (e) Short Inventory of Problems (SIP), (f) digital evaluation of skin electrical activity. (2) Clinician-reported outcomes: (g) CGI-S and CGI-I.

[0622] Population Major selection criteria: Patients meeting the following selection criteria are eligible to participate in the study.

[0623] (1) Adult male or female subjects aged 18 to 65 years.

[0624] (2) Have met the DSM-5 diagnosis of at least moderate AUD (4 or more criteria) (using the SCID-5-CT diagnostic interview) during the 3 months immediately prior to signing the informed consent form.

[0625] (3) Must have the desire to seek treatment for alcohol dependence and reduce or discontinue alcohol use according to the goals evaluated at baseline.

[0626] (4) Screening and must not have had at least 4 heavy drinking days over the past 4 weeks as evaluated by the Timeline Follow-back (TLFB) scale at baseline (heavy drinking is defined as more than 4 drinks per day (or more than 40 g) for women and more than 5 drinks per day (or more than 50 g) for men) [Standard drink is defined as 12 ounces (350 ml) of 5% beer, 5 ounces (150 ml) of 12% wine, or 1.5 ounces (44 ml) of 80 proof (40%) distilled spirits]. Alcohol consumption is converted to grams by multiplying by 10 from the standard drink amount according to the WHO guidelines for estimating the harm related to alcohol consumption. (World Health Organization. International Guide for Monitoring Alcohol Consumption and Related Harm. WHO Press, Geneva, 2000).

[0627] (5) Abstain from alcohol use for at least 3 days (up to 7 days) before the first dose (day 1) as evaluated by self-reported TLFB, urinary EtG, and measurements with a breathalyzer (BAC by breathalyzer is 0.00 at baseline).

[0628] Main exclusion criteria: Patients who meet any of the following exclusion criteria are excluded from participation in the study.

[0629] (1) For items 4 or 5 in the suicidal ideation section of the C-SSRS, score "yes" if this ideation occurred in the past 6 months, and for any item in the suicide behavior section, score "yes" excluding "non-suicidal self-injury behavior" (items also included in the suicide behavior section) if this behavior occurred in the past 2 years.

[0630] (2) Experienced acute alcohol withdrawal syndrome (especially hand tremors or seizures) within the past 6 months.

[0631] (3) If, in the opinion of the principal investigator of the clinical trial, or it is determined that there is a significant risk of acute withdrawal syndrome with a CIWA-Ar (Wiehl WO, Hayner G, and Galloway G. Haight Ashbury free clinics’ drug detoxification protocols - part 4: alcohol. Journal of Psychoactive Drugs (1994) 26:57 - 9.) score over 10, or if there is a previous history of alcohol withdrawal seizures or delirium tremens, or if the patient has other conditions that would increase the risk of seizures.

[0632] (4) Have a current diagnosis of moderate or severe substance use disorder (in accordance with DSM - 5) for alcohol, cannabis, opioids, or other stimulants excluding alcohol. Note: Nicotine use is permitted. Current use of cannabis is permitted. Current use of amphetamines, cocaine, and / or heroin is excluded, but lifetime use is permitted).

[0633] (5) Meet the current or lifetime DSM - 5 criteria for any other current Axis I disorder of mental disorder or neurocognitive disorder excluding major depressive disorder, panic disorder, obsessive - compulsive disorder, bipolar disorder, schizophrenia, or eating disorder, or post - traumatic stress disorder.

[0634] (6) Have received treatment for substance use disorder (e.g., disulfiram, acamprosate, methylphenidate, modafinil, topiramate, immediate - release dexamphetamine, or baclofen) in the past 90 days.

[0635] (7) Require treatment with psychoactive medications including anti - seizure medications (excluding medications used for short - term treatment of insomnia). Note: SSRIs and benzodiazepines are permitted if they have an appropriate stable dose for at least 1 month prior to the investigational treatment administration.

[0636] Dosage form and route of administration The subjects are assigned to one of the following two treatment groups in a 1:1 ratio. (1) Test product: 1 capsule of Compound 1 (dose not determined), (2) Reference product: placebo capsule.

[0637] Route of administration: Compound 1 or placebo is administered orally.

[0638] Evaluation criteria Efficacy / pharmacodynamics: (1) Change from baseline in the percentage of heavy drinking days (HDD) per week, as evaluated by TLFB, (2) Alcohol Craving Questionnaire - Short Form - Revised (ACQ - SF - R), (3) Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA - AR), (4) Percentage of alcohol use days as delivered by TLFB, (5) Alcohol consumption as delivered by TLFB.

[0639] Pharmacokinetics: (6) Plasma concentration of Compound 1 before and after morning dosing.

[0640] Safety: (7) Physical examination including vital signs, height, and weight, (8) Clinical laboratory evaluations (chemistry / hematology / urinalysis), (9) Electrocardiogram (ECG), (10) Suicidal thoughts and behaviors as evaluated by the Columbia - Suicide Severity Rating Scale (C - SSRS), (11) Brief Psychiatric Rating Scale (BPRS), (12) Reporting of serious adverse events (SAE) and adverse events (AE).

[0641] Other evaluations: (13) Hair drug testing for alcohol, amphetamines, methamphetamine, MDMA, MDEA, MDA, methylphenidate, ketamine, and ethyl glucuronide (EtG), (14) Alcohol biomarkers (LFT, CDT%, urinary EtG, GGT), (15) TLFB for cannabis, (16) Number of cigarette packs per day, (17) Pharmacogenetic blood samples.

[0642] Patient - reported outcomes (PRO): (18) Beck Depression Inventory - Second Edition (BDI - II), (19) State - Trait Anxiety Inventory (STAI), (20) 12 - item Short - Form Survey (SF - 12), (21) Pittsburgh Sleep Quality Index (PSQI), (22) Short Inventory of Problems (SIP).

[0643] Clinical investigator reported outcome (CRO): (23) Clinical Global Impression - Severity (CGI - S) and Improvement (CGI - I), (24) Clinical Assessment of Dissociation Scale (CADSS),

[0644] Digital assessment via wearable / smartphone (using data passively collected from smart devices / sensors): (a) Total sleep duration and overall sleep quality, (b) Heart rate variability (HRV), (c) Electrodermal activity (EDA)

[0645] Determination of sample size The sample size of this study is approximately 70 subjects (35 subjects for Compound 1 and 35 subjects for placebo). This sample size provides at least 80% power in a two - sided test with a significance level of α = 0.05 and detects a large effect - size difference (0.84) in the proportion of heavy drinking days per week from baseline to week 12 between the Compound 1 group and the placebo group.

Claims

**Claim 1** A method of treating a subject having a substance use disorder (SUD) at risk of relapse with respect to substance use, comprising administering to the subject a therapeutically effective amount of a compound of the following formula, 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano, wherein said administration reduces sensitivity to one or more relapse triggers. **Claim 2** Use of a compound in the treatment for reducing sensitivity to one or more relapse triggers, said treatment comprising administering to a subject having a substance use disorder (SUD) at risk of relapse with respect to substance use a therapeutically effective amount of said compound, wherein said compound is of the following formula, [Chemical 2] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. **Claim 3** Use of a compound in the manufacture of a medicament for the treatment for reducing sensitivity to one or more relapse triggers, said treatment comprising administering to a subject having a substance use disorder (SUD) at risk of relapse with respect to substance use said medicament, wherein said compound is of the following formula, 【Chemical Formula 3】 or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. **Claim 4** A compound for use in a method for reducing sensitivity to one or more relapse triggers, said method comprising administering to a subject having a substance use disorder (SUD) at risk of relapse with respect to substance use a therapeutically effective amount of said compound, wherein said compound is of the following formula, 【Chemical 4】 or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. **Claim 5** A medicament for the treatment for reducing sensitivity to one or more relapse triggers, said medicament comprising a compound, said treatment comprising administering to a subject having a substance use disorder (SUD) at risk of relapse with respect to substance use said medicament for delivering a therapeutically effective amount of said compound, wherein said compound is of the following formula, 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. **Claim 6** The method, use, compound, or medicament according to any one of claims 1 to 5, wherein said administration results in remission of said SUD for at least 3 months. **Claim 7** A method for promoting remission in a subject having a substance use disorder (SUD), comprising administering to the subject a therapeutically effective amount of a compound of the following formula, [Chemical Formula 6] or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano, said administration resulting in remission for at least 3 months. **Claim 8** Use of a compound in the manufacture of a medicament for the treatment for promoting remission of a substance use disorder (SUD), said treatment comprising administering said medicament to a subject having said SUD, said compound being of the following formula, 【Chemical Formula 7】 or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. **Claim 9** Use of a compound in the treatment for promoting remission of a substance use disorder (SUD), said treatment comprising administering to a subject having said SUD a therapeutically effective amount of said compound, said compound being of the following formula, 【Chemical 8】 or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. **Claim 10** A compound for use in a method for promoting remission of a substance use disorder (SUD), said method comprising administering to a subject having said SUD a therapeutically effective amount of said compound, said compound being of the following formula, 【Chemical Formula 9】 or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. **Claim 11** A medicament for the treatment for promoting remission of a substance use disorder (SUD), said medicament comprising a compound, said treatment comprising administering said medicament to a subject having said SUD to deliver a therapeutically effective amount of said compound, said compound being of the following formula, 【Chemical Formula 10】 or a pharmaceutically acceptable salt thereof, wherein R is H, Me, F, Cl, or cyano. **Claim 12** The method, use, compound for use, or medicament according to any one of claims 7 to 11, wherein said administration results in remission for at least 12 months. **Claim 13** The method, use, compound for use, or medicament according to any one of claims 1 to 12, wherein said administration prevents relapse for at least 3 months. **Claim 14** The method, use, compound for use, or medicament according to any one of claims 1 to 13, wherein said administration prevents relapse for at least 12 months. **Claim 15** The method or treatment according to claim 13 or 14, further comprising one or more tests for determining relapse, use, compound for use, or medicament.

16. The method, use, compound for use, or medicament according to claim 15, wherein one of the one or more tests for determining relapse is a timeline - follow - back self - reported substance consumption assessment.

17. The method, use, compound for use, or medicament according to claim 15, wherein one of the one or more tests for determining relapse is a urine drug screening test, a saliva drug test, or a hair follicle drug test.

18. The method, use, compound for use, or medicament according to claim 15, wherein one of the one or more tests for determining relapse is an acute alcohol intake test.

19. The method, use, compound for use, or medicament according to claim 15, wherein one of the one or more tests for determining relapse is a chronic alcohol use test.

20. The method, use, compound for use, or medicament according to any one of claims 1 to 19, wherein upon said administration, the subject shows no early relapse symptoms for at least 3 months.

21. The method, use, compound for use, or medicament according to any one of claims 1 to 20, wherein upon said administration, the subject shows no early relapse symptoms for at least 12 months.

22. The method, use, compound for use, or medicament according to any one of claims 1 to 21, further comprising determining whether the subject meets the DSM - 5 diagnostic criteria for the SUD, administering the compound or a pharmaceutically acceptable salt thereof if the subject meets the DSM - 5 criteria for the SUD, and not administering the compound or a pharmaceutically acceptable salt thereof if the subject does not meet the DSM - 5 diagnostic criteria for the SUD.

23. The method, use, compound for use, or medicament according to any one of claims 1 to 22, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject after a period of abstinence by the subject.

24. The method, use, compound for use, or medicament according to claim 23, further comprising performing a test to confirm abstinence.

25. The method, use, compound for use, or medicament according to claim 23 or 24, wherein the abstinence period is at least 12 hours and the subject has an exhaled or blood alcohol level of about 0.

26. The method, use, compound for use, or medicament according to any one of claims 23 to 25, wherein the abstinence period is at least 1 day, at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 months, or at least 6 months.

27. The method, use, compound for use, or medicament according to any one of claims 1 to 26, wherein R is F or cyano.

28. The compound is as follows 【Chemical Formula 11】 or a pharmaceutically acceptable salt thereof, the method, use, compound for use, or medicament according to any one of claims 1 to 27.

29. The compound is as follows 【Chemical Formula 12】 or a pharmaceutically acceptable salt thereof, the method, use, compound for use, or medicament according to any one of claims 1 to 27.

30. The method or the treatment according to any one of claims 1 to 29, which achieves an average plasma concentration of about 10 ng / mL to about 300 ng / mL.

31. The subject is administered a dose of the compound or a pharmaceutically acceptable salt thereof of about 5 mg / day to about 300 mg / day, about 30 mg / day to about 300 mg / day, about 50 mg / day to about 300 mg / day, about 5 mg / day to about 200 mg / day, about 30 mg / day to about 200 mg / day, about 50 mg / day to about 200 mg / day, about 30 mg / day to about 120 mg / day, about 50 mg / day to about 120 mg / day, about 30 mg / day to about 100 mg / day, about 50 mg / day to about 100 mg / day, about 30 mg / day to about 90 mg / day, about 50 mg / day to about 90 mg / day, about 30 mg / day to about 80 mg / day, about 50 mg / day to about 80 mg / day, about 30 mg / day to about 70 mg / day, about 50 mg / day to about 70 mg / day, about 60 mg / day to about 90 mg / day, about 60 mg / day to about 80 mg / day, or about 60 mg / day to about 70 mg / day, the method, use, compound for use, and medicament according to any one of claims 1 to 30.

32. The method, use, compound for use, or medicament according to any one of claims 1 to 31, wherein the subject is administered a dose of the compound or a pharmaceutically acceptable salt thereof of about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 200 mg / day, or about 300 mg / day.

33. The method, use, compound for use, or medicament according to any one of claims 31 to 32, wherein for administration for 1 to 3 days, about 1 / 3 of the dose is administered, for administration for 4 to 6 days, about 2 / 3 of the dose is administered, and from the 7th day onwards, the full dose is administered.

34. The method, use, compound for use, or medicament according to claim 33, wherein for administration on the 1st to 3rd days, about 1 / 3 of the dose is administered twice a day, for administration on the 4th to 6th days, about 2 / 3 of the dose is administered twice a day, for administration on the 7th to 13th days, the full dose is administered twice a day, and from the 14th day onwards, the full dose is administered once a day.

35. The method, use, compound for use, or medicament according to claim 34, wherein for administration on the 1st to 3rd days, 50 mg / day is administered twice a day, for administration on the 4th to 6th days, about 100 mg / day is administered twice a day, for administration on the 7th to 13th days, about 150 mg / day is administered twice a day, and from the 14th day onwards, about 150 mg / day is administered once a day.

36. The method, use, compound for use, or medicament according to any one of claims 1 to 35, wherein the SUD is alcohol use disorder (AUD).

37. The method, use, compound for use, or medicament according to any one of claims 1 to 17, 20 to 24, and 26 to 35, wherein the SUD is opioid use disorder (OUD).

38. The method, use, compound for use, or medicament according to any one of claims 1 to 17, 20 to 24, and 26 to 35, wherein the SUD is stimulant use disorder.

39. The method, use, compound for use, or medicament according to claim 38, wherein the stimulant use disorder is cocaine use disorder (CUD).

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