Treatment for schizophrenia

Abstract

Providing treatment for schizophrenia. [Solution] Compound (I): A method for treating schizophrenia is disclosed, comprising administering at least one compound selected from Compound (I) and its pharmaceutically acceptable salts. A pharmaceutical composition comprising at least one compound selected from Compound (I) and its pharmaceutically acceptable salts is also disclosed. A method for treating schizophrenia is disclosed herein, comprising administering more than 80 mg of at least one compound selected from Compound (I) and its pharmaceutically acceptable salts to a patient in need thereof.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 081,264, filed September 21, 2020, which is incorporated by reference in its entirety.

[0002] Disclosed herein are methods for treating schizophrenia. Also disclosed are modulators of G protein-coupled receptor 139 (GPR139), and pharmaceutical compositions comprising said modulators. [Background technology]

[0003] Schizophrenia is a serious mental disorder that affects approximately 1% of the population, with a lifetime prevalence estimated to range from 5.6 to 11.9 per 1,000 people (Sahu et al., 2016; Coyle, 2017; McGrath et al., 2008). Schizophrenia is characterized by psychosis, cognitive impairment, and social motivational deficits. For example, schizophrenia can be characterized by positive symptoms (e.g., hallucinations or delusions), negative symptoms (e.g., anhedonia, amotivation, blunted affect, decreased spontaneous speech, and social withdrawal), and cognitive impairments associated with schizophrenia (Owen et al., 2016). Cognitive symptoms of schizophrenia affect a wide range of domains, including, but not limited to, attention, working memory, and executive function. While positive symptoms of schizophrenia tend to relapse and remit, negative and cognitive symptoms of schizophrenia are often chronic and affect the patient's social functioning.

[0004] Dopamine D2 receptors are the primary direct therapeutic target in modern pharmacological treatments for schizophrenia. While these treatments are generally effective in treating the positive symptoms of schizophrenia, many patients do not respond adequately (Lally et al., 2016). Furthermore, treatments targeting dopamine D2 receptors have little significant therapeutic effect on the negative symptoms of schizophrenia (e.g., anhedonia, amotivation, and decreased interest in social interactions), and their effectiveness in treating the cognitive deficits often present in schizophrenia patients appears uncertain (Fusar-Poli et al., 2015; Sakurai et al., 2013).

[0005] Although negative and cognitive symptoms are highly predictive of quality of life and functional recovery (Hunter and Barry, 2012), there are no approved treatments for cognitive impairment associated with schizophrenia. Thus, there is a need for new treatments for schizophrenia.

[0006] GPR139 is a highly conserved, class A orphan G protein-coupled receptor belonging to the gamma rhodopsin family. GPR139 may be involved in Gs, Gq, and Gi signaling and appears to be constitutively active when recombinantly expressed in mammalian cells. GPR139 is abundantly expressed in the central nervous system (CNS), less so in the pancreas and pituitary gland, and at low levels in other peripheral tissues. GPR139 expression is particularly high in the habenula, along with the striatum, hypothalamus, and midbrain regions (Vedel et al., 2019).

[0007] The habenula is a highly conserved subcortical structure that plays a key role in reward and cognitive networks (Bianco and Wilson, 2009). It receives input from the basal ganglia and limbic system and sends output to midbrain and forebrain structures containing dopaminergic and serotonergic neurons. The habenula is involved in regulating downstream monoamine neurotransmitter activity (Liu et al., 2015), and habenula efferents have been shown to regulate both dopamine (DA) and serotonin (5HT) cell populations in the midbrain (Wang and Aghajanian, 1977; Christoph et al., 1986; Jhou et al., 2009; Sego et al., 2014). The habenula is involved in pain processing, reproductive behavior, nutrition, the sleep-wake cycle, stress response, and learning.

[0008] Several studies have suggested the involvement of the habenula in schizophrenia, and numerous human and animal studies have linked abnormal activity in the habenula to schizophrenia, often within the scope of negative or cognitive symptoms. Chronic treatment with cocaine or amphetamine damages the habenula's output pathways in rats, resulting in a schizophrenia-like state. Large-scale calcifications in the pineal gland and habenula are more common in patients with schizophrenia compared with normal controls. Additionally, fMRI studies have shown altered activation of the habenula in patients with schizophrenia. Furthermore, after errors in a difficult matching-to-sample task, the habenula was activated in control subjects but not in patients with schizophrenia.

[0009] Genetic data from humans and animals have linked GPR139 to schizophrenia. For example, six pairs of human monozygotic twins were discordant for schizophrenia, and a GPR139 copy number variant was reported in one of the twins (Castellani et al., 2014). In addition, GPR139- / - knockout mice performed comparable to wild-type mice on a range of standard tasks but were significantly impaired in tasks related to negative symptomatology (e.g., progressive ratio (motivation) and nest building (self-neglect)) and a novel object recognition model of working memory (Atienza et al., 2018). Therefore, modulators of GPR139 (e.g., GPR139 agonists) may be useful for the treatment of schizophrenia, including the treatment of negative and cognitive symptoms. Compound (I) is a GPR139 agonist of the following structure: [ka] See International Patent Application Publication No. WO2016 / 081736, which is incorporated herein by reference (e.g., Example 2). [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Application No. 2016 / 081736 Summary of the Invention [Means for solving the problem]

[0011] Disclosed herein is a method of treating schizophrenia, comprising administering greater than 80 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof to a patient in need thereof.

[0012] In some embodiments, more than 100 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 160 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 160 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered in the form of four tablets, each tablet containing 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof, has a mean C max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2500 ng / mL or less in a patient. max It is effective to achieve this.

[0014] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered to a patient with a mean C max is effective in achieving

[0015] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered to a patient at a concentration of 50% to 150% of a mean C of 1267 ng / mL. max It is effective to achieve this.

[0016] In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered in at least one tablet. In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered in more than one tablet (e.g., two, three, or four tablets). In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered in an oral suspension.

[0017] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered with water.

[0018] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered without food. In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered with food. In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered with a high-fat, high-calorie meal.

[0019] In some embodiments, the method further comprises administering at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, barbiturates, mGlu2 / 3 agonists, 5HT-2 antagonists, PDE10 antagonists, and GlyT1 inhibitors. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from antipsychotics.

[0020] Also provided herein is a method of treating schizophrenia, comprising administering to a patient in need thereof a loading dose of greater than 20 mg comprising at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof; and at least one weekly maintenance dose comprising at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof.

[0021] In some embodiments, at least one weekly maintenance dose is administered 5 to 9 days after the loading dose, hi some embodiments, at least one weekly maintenance dose is administered 7 days after the loading dose.

[0022] In some embodiments, the loading dose comprises 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 160 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose is administered in the form of four tablets, each tablet comprising 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the loading dose is administered to a patient with a mean C of at least 250 ng / mL. max In some embodiments, the loading dose is effective to achieve a mean C of 2500 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 500 ng / mL to 2500 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 50% to 150% of 1267 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 75% to 125% of 1267 ng / mL in the patient. max It is effective to achieve this.

[0024] In some embodiments, at least one weekly maintenance dose is half the loading dose.

[0025] In some embodiments, at least one weekly maintenance dose comprises 20 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, at least one weekly maintenance dose comprises 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, at least one weekly maintenance dose comprises 60 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, at least one weekly maintenance dose comprises 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, at least one weekly maintenance dose is administered in the form of two tablets, each containing at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, at least one weekly maintenance dose provides a patient with a mean C at steady state of at least 400 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 3000 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 400 ng / mL to 3000 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 50% to 150% of 1885 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 75% to 125% of 1885 ng / mL in the patient. max It is effective to achieve this.

[0027] In some embodiments, at least one weekly maintenance dose provides a mean C of at least 200 ng / mL in the patient.av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 2500 ng / mL or less in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 200 ng / mL to 2500 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 50% to 150% of 1353 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 75% to 125% of 1353 ng / mL in the patient. av,ss It is effective to achieve this.

[0028] In some embodiments, the mean AUC τ In some embodiments, the mean AUC at steady state in a patient is 400,000 ng·h / mL or less. τ In some embodiments, the mean AUC at steady state in a patient is 300,000 ng·h / mL or less. τ In some embodiments, the mean AUC at steady state in a patient is 30,000 ng·h / mL to 400,000 ng·h / mL. τ is 50% to 150% of 227,230 ng·h / mL. τ is 75% to 125% of 227,230 ng·h / mL.

[0029] In some embodiments, the loading dose comprises 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof, and at least one weekly maintenance dose comprises 20 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof, and at least one weekly maintenance dose comprises 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof, and at least one weekly maintenance dose comprises 60 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 160 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof, and at least one weekly maintenance dose comprises 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose is administered in the form of four tablets containing 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof, and at least one weekly maintenance dose is administered in the form of two tablets containing 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the loading dose is administered orally. In some embodiments, the loading dose is administered in at least one tablet. In some embodiments, the loading dose is administered in more than one tablet (e.g., two, three, or four tablets). In some embodiments, the loading dose is administered in an oral suspension.

[0031] In some embodiments, the loading dose is administered with water. In some embodiments, the loading dose is administered with food. In some embodiments, the loading dose is administered without food. In some embodiments, the loading dose is administered with food. In some embodiments, the loading dose is administered with a high-fat, high-calorie meal.

[0032] In some embodiments, at least one weekly maintenance dose is administered orally. In some embodiments, at least one weekly maintenance dose is administered in at least one tablet. In some embodiments, at least one weekly maintenance dose is administered in more than one tablet (e.g., 2, 3, or 4 tablets). In some embodiments, at least one weekly maintenance dose is administered in an oral suspension.

[0033] In some embodiments, at least one weekly maintenance dose is administered with water. In some embodiments, at least one weekly maintenance dose is administered without food. In some embodiments, at least one weekly maintenance dose is administered with food. In some embodiments, at least one weekly maintenance dose is administered with a high-fat, high-calorie diet.

[0034] In some embodiments, the method further comprises administering at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, barbiturates, mGlu2 / 3 agonists, 5HT-2 antagonists, PDE10 antagonists, and GlyT1 inhibitors. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from antipsychotics.

[0035] Also disclosed herein is a method for treating negative symptoms of schizophrenia, comprising administering at least one compound selected from Compound (I) and its pharmaceutically acceptable salts to a patient in need thereof. In some embodiments, the method of the present disclosure treats at least one negative symptom of schizophrenia selected from anhedonia, apathy, and decreased interest in social interactions.

[0036] Also disclosed herein is a method for treating cognitive symptoms of schizophrenia, comprising administering at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof to a patient in need thereof. In some embodiments, the disclosed method treats at least one cognitive symptom of schizophrenia selected from impaired verbal memory, impaired working memory, impaired motor function, impaired attention and processing speed, impaired verbal fluency, and impaired executive function. In some embodiments, the disclosed method modulates reward anticipation-related brain activity in the patient. In some embodiments, the disclosed method modulates cerebral blood flow in the patient. In some embodiments, the disclosed method increases ventral striatum activity during reward anticipation in the patient.

[0037] Also disclosed herein is a method for modulating dopamine release in a patient suffering from schizophrenia, comprising administering to the patient at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof. In some embodiments, the disclosed method reduces dopamine release in the patient after exposure to a stimulant drug.

[0038] Also disclosed herein is a pharmaceutical composition comprising at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises more than 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises more than 100 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 160 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the pharmaceutical composition is in the form of at least one tablet. In some embodiments, the pharmaceutical composition is in the form of more than one tablet (e.g., 2, 3, or 4 tablets). In some embodiments, the pharmaceutical composition is in the form of at least one immediate-release tablet.

[0040] In some embodiments, the pharmaceutical composition is in the form of an oral suspension. In an embodiment of the present invention, for example, the following items are provided: (Item 1) More than 80 mg of Compound (I): [ka] and pharmaceutically acceptable salts thereof to a patient in need thereof. (Item 2) 2. The method according to item 1, wherein more than 100 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered. (Item 3) 3. The method according to item 1 or 2, wherein 120 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered. (Item 4) 3. The method according to item 1 or 2, wherein 160 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered. (Item 5) said at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof, has a mean C of at least 500 ng / mL in said patient; max The method according to any one of items 1 to 4, which is effective to achieve the above. (Item 6) The at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof, max The method according to any one of items 1 to 5, which is effective to achieve the above. (Item 7) The at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered to the patient to achieve a mean C max The method according to any one of items 1 to 6, which is effective for achieving the above. (Item 8) The at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered to the patient to achieve a mean C of 50% to 150% of 1267 ng / mL. max The method according to item 4, which is effective for achieving the above. (Item 9) 9. The method according to any one of items 1 to 8, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered orally. (Item 10) 10. The method according to any one of items 1 to 9, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered in at least one tablet. (Item 11) 10. The method according to any one of items 1 to 9, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered in an oral suspension. (Item 12) 12. The method according to any one of items 1 to 11, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered without food. (Item 13) 12. The method according to any one of items 1 to 11, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered with food. (Item 14) 14. The method of any one of items 1 to 13, further comprising administering at least one additional active pharmaceutical ingredient. (Item 15) 15. The method of claim 14, wherein the at least one additional active pharmaceutical ingredient is selected from antipsychotics. (Item 16) 16. The method of any one of items 1 to 15, comprising treating at least one negative symptom of schizophrenia. (Item 17) Item 17. The method of item 16, wherein the at least one negative symptom of schizophrenia is selected from anhedonia, loss of motivation, and decreased interest in social interactions. (Item 18) 18. The method of any one of items 1 to 17, comprising treating at least one cognitive symptom of schizophrenia. (Item 19) Item 19. The method of item 18, wherein the at least one cognitive symptom of schizophrenia is selected from verbal memory impairment, working memory impairment, motor function impairment, attention and processing speed impairment, verbal fluency impairment, and executive function impairment. (Item 20) 20. The method according to any one of items 1 to 19, comprising modulating reward anticipation-related brain activity in the patient. (Item 21) 21. The method according to any one of items 1 to 20, comprising regulating cerebral blood flow in the patient. (Item 22) 22. The method of any one of items 1 to 21, comprising increasing ventral striatum activity during reward anticipation in said patient. (Item 23) 23. The method of any one of items 1 to 22, comprising modulating dopamine release in said patient. (Item 24) More than 20 mg of Compound (I): [ka] and a pharmaceutically acceptable salt thereof; and A method of treating schizophrenia, comprising administering to a patient in need thereof at least one weekly maintenance dose comprising at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof. (Item 25) 25. The method of item 24, wherein the at least one weekly maintenance dose is administered 5 to 9 days after the loading dose. (Item 26) 26. The method of item 24 or 25, wherein the at least one weekly maintenance dose is administered 7 days after the loading dose. (Item 27) 27. The method according to any one of items 24 to 26, wherein the loading dose comprises 40 mg of at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof. (Item 28) 27. The method according to any one of items 24 to 26, wherein the loading dose comprises 80 mg of at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof. (Item 29) 27. The method according to any one of items 24 to 26, wherein the loading dose comprises 120 mg of at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof. (Item 30) 27. The method according to any one of items 24 to 26, wherein the loading dose comprises 160 mg of at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof. (Item 31) The loading dose provides a mean C of at least 250 ng / mL in the patient. max The method according to any one of Items 24 to 30, which is effective to achieve the above. (Item 32) The loading dose is administered to the patient in a manner that results in a mean C of 2500 ng / mL or less. max The method according to any one of Items 24 to 31, which is effective to achieve the above. (Item 33) The loading dose is administered to the patient at a mean C of 500 ng / mL to 2500 ng / mL. max The method according to any one of Items 24 to 32, which is effective to achieve the above. (Item 34) The loading dose is administered to the patient at a mean C of 50% to 150% of 1267 ng / mL. max The method according to item 30, which is effective to achieve the above. (Item 35) 35. The method of any one of items 24 to 34, wherein the at least one weekly maintenance dose is half of the loading dose. (Item 36) 35. The method of item 30 or 34, wherein the at least one weekly maintenance dose comprises 80 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof. (Item 37) and wherein the at least one weekly maintenance dose provides a mean Cmax of at least 400 ng / mL at steady state in the patient. max The method according to any one of Items 24 to 36, which is effective to achieve the above. (Item 38) and wherein the at least one weekly maintenance dose is administered to the patient to achieve a mean Cmax of 3000 ng / mL or less at steady state. maxThe method according to any one of Items 24 to 37, which is effective to achieve the above. (Item 39) The at least one weekly maintenance dose provides a mean Cmax of 400 ng / mL to 3000 ng / mL at steady state in the patient. max The method according to any one of items 24 to 38, which is effective to achieve the above. (Item 40) The at least one weekly maintenance dose provides a mean C of 50% to 150% of 1885 ng / mL at steady state in the patient. max Item 37. The method according to Item 36, which is effective for achieving the above. (Item 41) and wherein the at least one weekly maintenance dose achieves a mean C of at least 200 ng / mL in the patient. av,ss The method according to any one of Items 24 to 40, which is effective to achieve the above. (Item 42) and wherein the at least one weekly maintenance dose is administered to the patient to achieve a mean C of 2500 ng / mL or less. av,ss The method according to any one of Items 24 to 41, which is effective to achieve the above. (Item 43) The at least one weekly maintenance dose provides a mean C of 200 ng / mL to 2500 ng / mL in the patient. av,ss The method according to any one of Items 24 to 42, which is effective to achieve the above. (Item 44) The at least one weekly maintenance dose provides a mean C of 50% to 150% of 1353 ng / mL in the patient. av,ss 41. The method according to item 36 or 40, which is effective to achieve the above. (Item 45) Mean AUC at steady state in the patient τ is 400,000 ng·h / mL or less. (Item 46) Mean AUC at steady state in the patient τis 300,000 ng·h / mL or less. (Item 47) Mean AUC at steady state in the patient τ 47. The method according to any one of items 24 to 46, wherein the IL-10 is 30,000 ng·h / mL to 400,000 ng·h / mL. (Item 48) Mean AUC at steady state in the patient τ is 50% to 150% of 227,230 ng·h / mL. (Item 49) 49. The method of any one of items 24 to 48, wherein the loading dose is administered orally. (Item 50) 50. The method of any one of items 24 to 49, wherein the loading dose is administered in at least one tablet. (Item 51) 50. The method of any one of items 24 to 49, wherein the loading dose is administered in an oral suspension. (Item 52) 52. The method of any one of items 24 to 51, wherein the loading dose is administered without food. (Item 53) 52. The method of any one of items 24 to 51, wherein the loading dose is administered with food. (Item 54) 54. The method of any one of items 24 to 53, wherein the at least one weekly maintenance dose is administered orally. (Item 55) 55. The method of any one of items 24 to 54, wherein the at least one weekly maintenance dose is administered in at least one tablet. (Item 56) 55. The method of any one of items 24 to 54, wherein the at least one weekly maintenance dose is administered in an oral suspension. (Item 57) 57. The method of any one of items 24 to 56, wherein the at least one weekly maintenance dose is administered without food. (Item 58) 57. The method of any one of items 24 to 56, wherein the at least one weekly maintenance dose is administered with food. (Item 59) 59. The method of any one of items 24 to 58, further comprising administering at least one additional active pharmaceutical ingredient. (Item 60) 60. The method of claim 59, wherein the at least one additional active pharmaceutical ingredient is selected from antipsychotics. (Item 61) 61. The method of any one of items 24 to 60, comprising treating at least one negative symptom of schizophrenia. (Item 62) 62. The method of item 61, wherein the at least one negative symptom of schizophrenia is selected from anhedonia, amotivation, and decreased interest in social interactions. (Item 63) 63. The method of any one of items 24 to 62, comprising treating at least one cognitive symptom of schizophrenia. (Item 64) Item 64. The method of item 63, wherein the at least one cognitive symptom of schizophrenia is selected from verbal memory impairment, working memory impairment, motor function impairment, attention and processing speed impairment, verbal fluency impairment, and executive function impairment. (Item 65) 65. The method of any one of items 24 to 64, comprising modulating reward anticipation-related brain activity in the patient. (Item 66) 66. The method according to any one of items 24 to 65, comprising regulating cerebral blood flow in the patient. (Item 67) 67. The method of any one of items 24 to 66, comprising increasing ventral striatum activity during reward anticipation in said patient. (Item 68) 68. The method of any one of items 24 to 67, comprising modulating dopamine release in said patient. (Item 69) More than 80 mg of Compound (I): [ka] and at least one compound selected from: at least one pharmaceutically acceptable excipient A pharmaceutical composition comprising: (Item 70) 70. The pharmaceutical composition according to item 69, comprising more than 100 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof. (Item 71) 71. The pharmaceutical composition according to item 69 or 70, comprising 120 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof. (Item 72) 71. The pharmaceutical composition according to item 69 or 70, comprising 160 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof. (Item 73) 73. The pharmaceutical composition according to any one of items 69 to 72, wherein the pharmaceutical composition is in the form of at least one tablet. (Item 74) 73. The pharmaceutical composition according to any one of items 69 to 72, wherein the pharmaceutical composition is in the form of an oral suspension. [Brief explanation of the drawings]

[0041] [Figure 1] Figure 1 shows the plasma concentration-time profiles of Compound (I) in healthy participants and patients with stable schizophrenia after multiple oral doses of Compound (I) (Day 22). (A) 0-22 hours post-dose, and (B) the full profile. Healthy participants and patients with stable schizophrenia received 160 mg of Compound (I) on Day 1, followed by 80 mg of Compound (I) orally once weekly. Zero was used for values ​​below the limit of quantitation (<1.00 ng / mL).

[0042] [Figure 2]FIG. 2 shows the study design for a [11C]PHNO PET study of endogenous dopamine release in the brain of healthy human volunteers following administration of Compound (I) (20 mg or 40 mg).

[0043] [Figure 3] Figure 3 shows within-subject differences between Compound (I) and placebo in mean ventral striatum activation during the Monetary Incentive Delay (MID) reward task in patients with stable schizophrenia (mean ± standard deviation (SD) by visit). Checkmarks indicate that statistical success criteria were met (post-hoc probability of an increase over placebo exceeding 0.09 was at least 70%).

[0044] [Figure 4] FIG. 4 shows the total cerebral blood flow (CBF) (mean±standard error (SE)) in stable schizophrenic patients treated with Compound (I) (40 mg or 160 mg).

[0045] [Figure 5] FIG. 5 shows a manufacturing flow diagram for a tablet containing at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0046] Definition: As used herein, "a" or "an" element refers to one or more of that element; for example, "a compound" refers to one or more compounds or at least one compound unless otherwise specified. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0047] As used herein, the term "active pharmaceutical ingredient" or "therapeutic agent" ("API") refers to a biologically active compound.

[0048] As used herein, "administration" of an API to a patient refers to any route of introducing or delivering the API to the patient (e.g., oral delivery). Administration includes self-administration and administration by another.

[0049] As used herein, the term "agonist" refers to a molecule (e.g., an API) that binds to and activates a receptor (e.g., GPR139). As used herein, "agonist" refers to both full agonists and partial agonists.

[0050] As used herein, the term "anhedonia" refers to one or more deficits in pleasure function, such as a decreased willingness or ability to feel pleasure.

[0051] As used herein, the term "amotivation" refers to a decreased motivation to initiate and perform goal-directed behavior.

[0052] As used herein, “Compound (I)” refers to (S)-2-(4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide, which has the following structure: [ka]

[0053] Compound (I) may be referred to herein as a "drug," "active agent," "therapeutic agent," or "API."

[0054] As used herein, "condition," "disorder," or "disease" refers to any unhealthy or abnormal state.

[0055] As used herein, " effective amount " or " effective dose " refers to the amount of a molecule that, when administered in single or multiple doses, treats a patient suffering from a certain condition.Effective amount can be determined by the attending diagnostician by using known techniques and observing the results obtained under similar circumstances.In determining effective amount, the attending diagnostician will consider many factors, including but not limited to, the patient's species; its size, age, and general health; the specific condition, disorder, or disease involved; the degree or complications or severity of the condition, disorder, or disease, the response of individual patients; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosage regimen; the use of concomitant drug therapy; and other relevant circumstances.

[0056] As used herein, the amount represented by the term "mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof" refers to the total amount of Compound (I) (i.e., the free base) in milligrams plus an equivalent amount of one or more pharmaceutically acceptable salts of Compound (I) based on the weight of the free base.

[0057] As used herein, the term "increase" refers to a change of at least 5%, including, but not limited to, a change of 5%, a change of 10%, a change of 25%, a change of 30%, a change of 50%, a change of 75%, or a change of 100%.

[0058] As used herein, "mammal" refers to domesticated animals (e.g., dogs, cats, and horses) and humans. In some embodiments, the mammal is a human.

[0059] As used herein, the phrase "mean [X] in said patients" refers to the average value of [X] determined from one or more observations of [X] in said patients.

[0060] As used herein, the term "modulate" refers to a change, either positive or negative. Non-limiting examples of modulation include a 1% change, a 2% change, a 5% change, a 10% change, a 25% change, a 50% change, a 75% change, or a 100% change.

[0061] As used herein, the terms "patient" and "subject" are used interchangeably and refer to a mammal, e.g., a human.

[0062] As used herein, "pharmaceutically acceptable excipient" refers to a carrier or excipient useful in preparing a pharmaceutical composition. For example, pharmaceutically acceptable excipients include carriers and excipients that are generally considered safe and acceptable for mammalian pharmaceutical use. As a non-limiting example, a pharmaceutically acceptable excipient can be a solid, semi-solid, or liquid material that collectively functions as a vehicle or medium for an active ingredient. Some examples of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients, including diluents, vehicles, carriers, ointment bases, binders, disintegrants, lubricants, glidants, sweeteners, flavorings, gel bases, sustained-release matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coatings, and others.

[0063] As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic salt form of the compound of the present disclosure. Pharmaceutically acceptable salts of Compound (I) of the present disclosure include salts derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. Suitable pharmaceutically acceptable salts are, for example, those disclosed in Berge, SM et al., J. Pharma. Sci. 66:1-19 (1977). Non-limiting examples of pharmaceutically acceptable salts disclosed in this document include acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycollylarsanilate; hexylresorcinate; hydrabamine; hydrobromide; hydrochloride; hydroxynaphthoate; iodide; isethionate; lactate; lactobionate. ;malate;maleate;mandelate;mesylate;methyl bromide;methyl nitrate;methyl sulfate;mucate;napsylate;nitrate;pamoate (embonate);pantothenate;phosphate / diphosphate;polygalacturonate;salicylate;stearate;subacetate;succinate;sulfate;tannate;tartrate;teosylate;triethiodide;benzathine;chloroprocaine;choline;diethanolamine;ethylenediamine;meglumine;procaine;aluminum;calcium;lithium;magnesium;potassium;sodium;and zinc.

[0064] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid); salts formed with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid); and salts formed by other methods used in the art, such as ion exchange. Additional non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, hydroxybenzo ... Non-limiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4Examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0065] As used herein, the term "reduce" refers to a change down by at least 5%, including, but not limited to, a change down by 5%, a change down by 10%, a change down by 25%, a change down by 30%, a change down by 50%, a change down by 75%, or a change down by 100%.

[0066] As used herein, the terms "treat," "treating," or "treatment," when used in reference to a disorder or condition, include any effect that results in improvement of the disorder or condition (e.g., alleviating, reducing, modulating, ameliorating, or eliminating). Improvement or reduction in the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0067] As used herein, the term "weekly" means per week. In some embodiments, "weekly" means every 7 days ± 2 days.

[0068] Exemplary embodiments: Without limitation, embodiments of the present disclosure include the following: 1. More than 80 mg of Compound (I): [ka] and pharmaceutically acceptable salts thereof to a patient in need thereof. 2. The method of embodiment 1, wherein more than 100 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered. 3. The method of embodiment 1 or 2, wherein 120 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered. 4. The method of embodiment 1 or 2, wherein 160 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered. 5. The at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof, has a mean C of at least 500 ng / mL in the patient. max The method of any one of embodiments 1 to 4, which is effective to achieve the following. 6. The at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof has a mean C of 2500 ng / mL or less in the patient. max The method of any one of embodiments 1 to 5, which is effective to achieve the following. 7. The at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof has a mean C of 500 ng / mL to 2500 ng / mL in the patient. max The method of any one of embodiments 1 to 6, which is effective to achieve the following: 8. The at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof is administered to the patient, and the patient has a mean C of 50% to 150% of 1267 ng / mL. max 5. The method of embodiment 4, wherein the method is effective to achieve 9. The method of any one of embodiments 1 to 8, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered orally. 10. The method of any one of embodiments 1 to 9, wherein the at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered in at least one tablet. 11. The method of any one of embodiments 1 to 9, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered in an oral suspension. 12. The method of any one of embodiments 1 to 11, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered without food. 13. The method of any one of embodiments 1 to 11, wherein the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof is administered with food. 14. The method of any one of embodiments 1 to 13, further comprising administering at least one additional active pharmaceutical ingredient. 15. The method of embodiment 14, wherein the at least one additional active pharmaceutical ingredient is selected from an antipsychotic. 16. The method of any one of embodiments 1-15, comprising treating at least one negative symptom of schizophrenia. 17. The method of embodiment 16, wherein the at least one negative symptom of schizophrenia is selected from anhedonia, amotivation, and decreased interest in social interactions. 18. The method of any one of embodiments 1-17, comprising treating at least one cognitive symptom of schizophrenia. 19. The method of embodiment 18, wherein the at least one cognitive symptom of schizophrenia is selected from verbal memory impairment, working memory impairment, motor function impairment, attention and processing speed impairment, verbal fluency impairment, and executive function impairment. 20. A method according to any one of embodiments 1 to 19, comprising modulating reward anticipation-related brain activity in the patient. 21. A method according to any one of embodiments 1 to 20, comprising regulating cerebral blood flow in the patient. 22. A method according to any one of embodiments 1 to 21, comprising increasing ventral striatal activity in the patient during reward anticipation. 23. A method according to any one of embodiments 1 to 22, comprising modulating dopamine release in the patient. 24. More than 20 mg of Compound (I): [ka] and a pharmaceutically acceptable salt thereof; and A method of treating schizophrenia, comprising administering to a patient in need thereof at least one weekly maintenance dose comprising at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof. 25. The method of embodiment 24, wherein the at least one weekly maintenance dose is administered 5 to 9 days after the loading dose. 26. The method of embodiment 24 or 25, wherein the at least one weekly maintenance dose is administered 7 days after the loading dose. 27. The method of any one of embodiments 24-26, wherein the loading dose comprises 40 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof. 28. The method of any one of embodiments 24-26, wherein the loading dose comprises 80 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof. 29. The method of any one of embodiments 24-26, wherein the loading dose comprises 120 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof. 30. The method of any one of embodiments 24-26, wherein the loading dose comprises 160 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof. 31. The loading dose achieves a mean C of at least 250 ng / mL in the patient. max The method of any one of embodiments 24 to 30, which is effective to achieve 32. The loading dose results in a mean C of 2500 ng / mL or less in the patient. max The method of any one of embodiments 24 to 31, which is effective to achieve 33. The loading dose is administered to the patient to achieve a mean C of 500 ng / mL to 2500 ng / mL. max The method of any one of embodiments 24 to 32, which is effective to achieve 34. The loading dose achieves a mean C of 50% to 150% of 1267 ng / mL in the patient. max 31. The method of embodiment 30, wherein the method is effective to achieve 35. The method of any one of embodiments 24-34, wherein the at least one weekly maintenance dose is half of the loading dose. 36. The method of embodiment 30 or 34, wherein the at least one weekly maintenance dose comprises 80 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof. 37. The at least one weekly maintenance dose is administered to the patient to achieve a mean Cmax of at least 400 ng / mL at steady state. max The method of any one of embodiments 24 to 36, which is effective to achieve 38. The at least one weekly maintenance dose is administered to the patient to achieve a mean Cmax of 3000 ng / mL or less at steady state. max The method of any one of embodiments 24 to 37, which is effective to achieve 39. The at least one weekly maintenance dose is administered to the patient to achieve a mean Cmax of 400 ng / mL to 3000 ng / mL at steady state. maxThe method of any one of embodiments 24 to 38, which is effective to achieve 40. The at least one weekly maintenance dose provides a mean C of 50% to 150% of 1885 ng / mL at steady state in the patient. max 37. The method of embodiment 36, wherein the method is effective to achieve 41. The at least one weekly maintenance dose is administered to the patient to achieve a mean C of at least 200 ng / mL. av,ss The method of any one of embodiments 24 to 40, which is effective to achieve 42. The at least one weekly maintenance dose is administered to the patient to achieve a mean C of 2500 ng / mL or less. av,ss The method of any one of embodiments 24 to 41, which is effective to achieve 43. The at least one weekly maintenance dose is administered to the patient to achieve a mean C of 200 ng / mL to 2500 ng / mL. av,ss The method of any one of embodiments 24 to 42, which is effective to achieve 44. The at least one weekly maintenance dose achieves a mean C of 50% to 150% of 1353 ng / mL in the patient. av,ss 41. The method of embodiment 36 or 40, wherein the method is effective to achieve 45. Mean AUC at steady state in the patient τ The method of any one of embodiments 24 to 44, wherein the IL-10 is 400,000 ng·h / mL or less. 46. ​​Mean AUC at steady state in the patient τ The method of any one of embodiments 24 to 45, wherein the IL-10 ... 47. Mean AUC at steady state in the patient τ The method of any one of embodiments 24 to 46, wherein the IL-10 is 30,000 ng·h / mL to 400,000 ng·h / mL. 48. Mean AUC at steady state in the patient τis 50% to 150% of 227,230 ng·h / mL. 49. The method of any one of embodiments 24 to 48, wherein the loading dose is administered orally. 50. The method of any one of embodiments 24-49, wherein the loading dose is administered in at least one tablet. 51. The method of any one of embodiments 24 to 49, wherein the loading dose is administered in an oral suspension. 52. The method of any one of embodiments 24 to 51, wherein the loading dose is administered without food. 53. The method of any one of embodiments 24-51, wherein the loading dose is administered with food. 54. The method of any one of embodiments 24 to 53, wherein the at least one weekly maintenance dose is administered orally. 55. The method of any one of embodiments 24-54, wherein the at least one weekly maintenance dose is administered in at least one tablet. 56. The method of any one of embodiments 24 to 54, wherein the at least one weekly maintenance dose is administered in an oral suspension. 57. The method of any one of embodiments 24 to 56, wherein the at least one weekly maintenance dose is administered without food. 58. The method of any one of embodiments 24 to 56, wherein the at least one weekly maintenance dose is administered with food. 59. The method of any one of embodiments 24 to 58, further comprising administering at least one additional active pharmaceutical ingredient. 60. The method of embodiment 59, wherein the at least one additional active pharmaceutical ingredient is selected from an antipsychotic. 61. The method of any one of embodiments 24-60, comprising treating at least one negative symptom of schizophrenia. 62. The method of embodiment 61, wherein the at least one negative symptom of schizophrenia is selected from anhedonia, amotivation, and decreased interest in social interactions. 63. A method according to any one of embodiments 24-62, comprising treating at least one cognitive symptom of schizophrenia. 64. The method of embodiment 63, wherein the at least one cognitive symptom of schizophrenia is selected from verbal memory impairment, working memory impairment, motor function impairment, attention and processing speed impairment, verbal fluency impairment, and executive function impairment. 65. A method according to any one of embodiments 24 to 64, comprising modulating reward anticipation-related brain activity in the patient. 66. A method according to any one of embodiments 24 to 65, comprising regulating cerebral blood flow in the patient. 67. A method according to any one of embodiments 24 to 66, comprising increasing ventral striatal activity in the patient during reward anticipation. 68. A method according to any one of embodiments 24 to 67, comprising modulating dopamine release in the patient. 69. More than 80 mg of Compound (I): [ka] and at least one compound selected from: at least one pharmaceutically acceptable excipient A pharmaceutical composition comprising: 70. The pharmaceutical composition of embodiment 69, comprising more than 100 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof. 71. A pharmaceutical composition according to embodiment 69 or 70, comprising 120 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof. 72. The pharmaceutical composition according to embodiment 69 or 70, comprising 160 mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof. 73. The pharmaceutical composition of any one of embodiments 69 to 72, wherein the pharmaceutical composition is in the form of at least one tablet (e.g., 1, 2, 3, or 4 tablets). 74. A pharmaceutical composition described in any one of embodiments 69 to 72, wherein the pharmaceutical composition is in the form of an oral suspension.

[0069] Some embodiments of the present disclosure relate to a method of treating schizophrenia, comprising administering more than 80 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof to a patient in need thereof.

[0070] In some embodiments, more than 85 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 90 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 95 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 100 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 105 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 110 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 115 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 125 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 130 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 135 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 140 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 145 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, more than 150 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered.In some embodiments, more than 155 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered, while in some embodiments, no more than 160 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered.

[0071] In some embodiments, less than 85 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 90 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 95 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 100 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 105 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 110 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 115 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 125 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 130 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 135 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 140 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 145 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 150 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered.In some embodiments, less than 155 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered. In some embodiments, less than 160 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered. In some embodiments, less than 165 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered. In some embodiments, less than 170 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered.

[0072] In some embodiments, 85 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 90 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 95 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 100 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 105 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 110 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 115 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 125 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 130 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 135 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 140 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 145 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered. In some embodiments, 150 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered.In some embodiments, 155 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered. In some embodiments, 160 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered.

[0073] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof, has a mean C max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 550 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 600 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 650 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 700 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 750 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 800 ng / mL in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 850 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 900 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 950 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1000 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1050 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1100 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1150 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1200 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1250 ng / mL in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1300 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1350 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1400 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1450 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1500 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1550 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1600 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1650 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1700 ng / mL in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1750 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1800 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1850 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1900 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 1950 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2000 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2050 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2100 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2150 ng / mL in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2200 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2250 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2300 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2350 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2400 ng / mL in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of at least 2450 ng / mL in a patient. max It is effective to achieve this.

[0074] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof, is administered to a patient with a mean C of 550 ng / mL or less. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 600 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 650 ng / mL or less in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 700 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 750 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 800 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 850 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 900 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 950 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1000 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1050 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1100 ng / mL or less in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1150 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1200 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1250 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1300 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1350 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1400 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1450 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1500 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1550 ng / mL or less in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1600 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1650 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1700 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1750 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1800 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1850 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1900 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 1950 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2000 ng / mL or less in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2050 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2100 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2150 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2200 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2250 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2300 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2350 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2400 ng / mL or less in a patient. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2450 ng / mL or less in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 2500 ng / mL or less in a patient. max It is effective to achieve this.

[0075] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered to a patient with a mean C max It is effective to achieve this.

[0076] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered to a patient at a concentration of 50% to 150% of a mean C of 1267 ng / mL. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 55% to 145% of 1267 ng / mL in patients. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 60% to 140% of 1267 ng / mL in patients. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 65% to 135% of 1267 ng / mL in patients. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 70% to 130% of 1267 ng / mL in patients. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 75% to 125% of 1267 ng / mL in a patient. maxIn some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 80% to 120% of 1267 ng / mL in patients. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 85% to 115% of 1267 ng / mL in patients. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 90% to 110% of 1267 ng / mL in patients. max In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is effective to achieve a mean C of 95% to 105% of 1267 ng / mL in patients. max It is effective to achieve this.

[0077] In some embodiments, the mean t 1 / 2z In some embodiments, the mean t in the patient is between 50 hours and 1000 hours. 1 / 2z In some embodiments, the mean t in the patient is between 100 h and 1000 h. 1 / 2z In some embodiments, the mean t in the patient is between 50 hours and 900 hours. 1 / 2z In some embodiments, the mean t in the patient is 50 hours to 800 hours. 1 / 2z In some embodiments, the mean t in the patient is between 50 hours and 700 hours. 1 / 2z In some embodiments, the mean t in the patient is 50 hours to 600 hours. 1 / 2z In some embodiments, the mean t in the patient is between 50 hours and 500 hours. 1 / 2z In some embodiments, the mean t in the patient is between 50 hours and 400 hours. 1 / 2z In some embodiments, the mean t 1 / 2zIn some embodiments, the mean t 1 / 2z In some embodiments, the mean t 1 / 2z is 200h to 300h.

[0078] In some embodiments, the mean t 1 / 2z In some embodiments, the mean t in the patient is at least 100 h. 1 / 2z In some embodiments, the mean t in the patient is at least 125 hours. 1 / 2z In some embodiments, the mean t in the patient is at least 150 h. 1 / 2z In some embodiments, the mean t at steady state in the patient is at least 175 h. 1 / 2z is at least 200h.

[0079] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered orally.

[0080] In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered in at least one tablet. In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered in at least one immediate release tablet. In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered in at least one immediate release tablet, further comprising mannitol and microcrystalline cellulose.

[0081] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered in more than one tablet (e.g., 2, 3, or 4 tablets). In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered in more than one immediate release tablet (e.g., 2, 3, or 4 immediate release tablets). In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered in more than one immediate release tablet (e.g., 2, 3, or 4 immediate release tablets) that further comprise mannitol and microcrystalline cellulose.

[0082] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered in an oral suspension. In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered in an oral suspension further comprising Tween® and methylcellulose.

[0083] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof is administered with water.

[0084] In some embodiments, at least one compound selected from Compound (I) and its pharmaceutically acceptable salts is administered without food. In some embodiments, the patient is fasting. In some embodiments, the patient has fasted for at least 10 hours before administration of at least one compound selected from Compound (I) and its pharmaceutically acceptable salts.

[0085] In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered with food. In some embodiments, at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof is administered with a high-fat, high-calorie meal. In some embodiments, the patient is in a fed state. In some embodiments, the patient has eaten or drunk at least 30 minutes before administration of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the method further comprises administering at least one additional active pharmaceutical ingredient selected from sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, mGlu2 / 3 agonists, 5HT-2 antagonists, PDE10 antagonists, and GlyT1 inhibitors.

[0087] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from an antipsychotic agent.

[0088] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from first generation antipsychotics, hi some embodiments, the at least one additional active pharmaceutical ingredient is selected from chlorpromazine, fluphenazine, haloperidol, and perphenazine.

[0089] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from second-generation antipsychotics, hi some embodiments, the at least one additional active pharmaceutical ingredient is selected from aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone.

[0090] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a long-acting injectable antipsychotic, hi some embodiments, the at least one additional active pharmaceutical ingredient is selected from aripiprazole, fluphenazine decanoate, haloperidol decanoate, paliperidone, and risperidone.

[0091] In some embodiments, the method comprises treating at least one negative symptom of schizophrenia. In some embodiments, the at least one negative symptom of schizophrenia is selected from anhedonia, amotivation, and decreased interest in social interactions. In some embodiments, the at least one negative symptom of schizophrenia is anhedonia. In some embodiments, the at least one negative symptom of schizophrenia is amotivation. In some embodiments, the at least one negative symptom of schizophrenia is decreased interest in social interactions.

[0092] In some embodiments, the method comprises treating at least one cognitive symptom of schizophrenia. In some embodiments, the at least one cognitive symptom of schizophrenia is selected from verbal memory impairment, working memory impairment, motor function impairment, attention and processing speed impairment, verbal fluency impairment, and executive function impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is verbal memory impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is working memory impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is motor function impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is attention and processing speed impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is verbal fluency impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is executive function impairment.

[0093] In some embodiments, the method comprises modulating reward anticipation-related brain activity in the patient.

[0094] In some embodiments, the method comprises modulating cerebral blood flow in the patient.

[0095] In some embodiments, the method comprises increasing ventral striatum activity in the patient during reward anticipation.

[0096] In some embodiments, the method comprises modulating dopamine release in the patient. In some embodiments, the method comprises decreasing dopamine release in the patient. In some embodiments, the method comprises decreasing dopamine release in the patient after exposure to a stimulant.

[0097] Some embodiments of the present disclosure relate to methods of treating schizophrenia, comprising administering to a patient in need thereof a loading dose of greater than 20 mg comprising at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof; and at least one weekly maintenance dose comprising at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof.

[0098] In some embodiments, at least one weekly maintenance dose is administered 5-9 days after the loading dose. In some embodiments, at least one weekly maintenance dose is administered 6-8 days after the loading dose. In some embodiments, at least one weekly maintenance dose is administered 5 days after the loading dose. In some embodiments, at least one weekly maintenance dose is administered 6 days after the loading dose. In some embodiments, at least one weekly maintenance dose is administered 7 days after the loading dose. In some embodiments, at least one weekly maintenance dose is administered 8 days after the loading dose. In some embodiments, at least one weekly maintenance dose is administered 9 days after the loading dose.

[0099] In some embodiments, the first weekly maintenance dose is administered 7 days after the loading dose, and the second weekly maintenance dose is administered 14 days after the loading dose.

[0100] In some embodiments, the first weekly maintenance dose is administered 5 to 9 days after the loading dose, and the second weekly maintenance dose is administered 12 to 16 days after the loading dose.

[0101] In some embodiments, the first weekly maintenance dose is administered 7 days after the loading dose, the second weekly maintenance dose is administered 14 days after the loading dose, and the third weekly maintenance dose is administered 21 days after the loading dose.

[0102] In some embodiments, the first weekly maintenance dose is administered 5 to 9 days after the loading dose, the second weekly maintenance dose is administered 12 to 16 days after the loading dose, and the third weekly maintenance dose is administered 19 to 23 days after the loading dose.

[0103] In some embodiments, each weekly maintenance dose is administered 5 to 9 days after the preceding dose comprising at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof.

[0104] In some embodiments, the loading dose comprises more than 30 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 50 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 60 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 70 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 90 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 100 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 110 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 130 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 140 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises more than 150 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the loading dose comprises 30 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 50 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 60 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 70 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 90 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 100 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 110 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 130 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 140 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 150 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 160 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the loading dose is administered to a patient with a mean C of at least 250 ng / mL. max In some embodiments, the loading dose is effective to achieve a mean C of at least 300 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 350 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 400 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 450 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 500 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 550 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 600 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 650 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 700 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 750 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 800 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 850 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 900 ng / mL in the patient.max In some embodiments, the loading dose is effective to achieve a mean C of at least 950 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1000 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1050 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1100 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1150 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1200 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1250 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1300 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1350 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1400 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1450 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1500 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1550 ng / mL in the patient. maxIn some embodiments, the loading dose is effective to achieve a mean C of at least 1600 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1650 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1700 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1750 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1800 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1850 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1900 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 1950 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2000 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2050 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2100 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2150 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2200 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2250 ng / mL in the patient.max In some embodiments, the loading dose is effective to achieve a mean C of at least 2300 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2350 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2400 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of at least 2450 ng / mL in the patient. max It is effective to achieve this.

[0107] In some embodiments, the loading dose is administered to a patient with a mean C of 300 ng / mL or less. max In some embodiments, the loading dose is effective to achieve a mean C of 350 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 400 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 450 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 500 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 550 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 600 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 650 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 700 ng / mL or less in the patient. maxIn some embodiments, the loading dose is effective to achieve a mean C of 750 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 800 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 850 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 900 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 950 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1000 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1050 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1100 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1150 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1200 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1250 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1300 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1350 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1400 ng / mL or less in the patient. maxIn some embodiments, the loading dose is effective to achieve a mean C of 1450 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1500 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1550 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1600 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1650 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1700 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1750 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1800 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1850 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1900 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 1950 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2000 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2050 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2100 ng / mL or less in the patient. maxIn some embodiments, the loading dose is effective to achieve a mean C of 2150 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2200 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2250 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2300 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2350 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2400 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2450 ng / mL or less in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 2500 ng / mL or less in the patient. max It is effective to achieve this.

[0108] In some embodiments, the loading dose is administered to a patient with a mean C of 500 ng / mL to 2500 ng / mL. max It is effective to achieve this.

[0109] In some embodiments, the loading dose is administered to a patient at a mean C of 50% to 150% of 1267 ng / mL. max In some embodiments, the loading dose is effective to achieve a mean C of 55% to 145% of 1267 ng / mL in patients. max In some embodiments, the loading dose is effective to achieve a mean C of 60% to 140% of 1267 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 65% to 135% of 1267 ng / mL in the patient.max In some embodiments, the loading dose is effective to achieve a mean C of 70% to 130% of 1267 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 75% to 125% of 1267 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 80% to 120% of 1267 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 85% to 115% of 1267 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 90% to 110% of 1267 ng / mL in the patient. max In some embodiments, the loading dose is effective to achieve a mean C of 95% to 105% of 1267 ng / mL in the patient. max It is effective to achieve this.

[0110] In some embodiments, at least one weekly maintenance dose is half the loading dose. In some embodiments, at least one weekly maintenance dose is 30% to 70% of the loading dose. In some embodiments, at least one weekly maintenance dose is 35% to 65% of the loading dose. In some embodiments, at least one weekly maintenance dose is 40% to 60% of the loading dose. In some embodiments, at least one weekly maintenance dose is 45% to 65% of the loading dose.

[0111] In some embodiments, at least one weekly maintenance dose comprises 20 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, at least one weekly maintenance dose comprises 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, at least one weekly maintenance dose comprises 60 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, at least one weekly maintenance dose comprises 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, at least one weekly maintenance dose provides a patient with a mean C at steady state of at least 400 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 500 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 600 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 700 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 800 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 900 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 1000 ng / mL in the patient. maxIn some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 1100 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 1200 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 1300 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 1400 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 1500 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 1600 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 1700 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 1800 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 1900 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 2000 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 2100 ng / mL. maxIn some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 2200 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 2300 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of at least 2400 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 2500 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 2600 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 2700 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 2800 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state in the patient of at least 2900 ng / mL. max It is effective to achieve this.

[0113] In some embodiments, at least one weekly maintenance dose is administered to a patient to achieve a mean C at steady state of less than or equal to 500 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 600 ng / mL or less in the patient. maxIn some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 700 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 800 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 900 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1000 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1100 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1200 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1300 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1400 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1500 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1600 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1700 ng / mL or less in the patient. maxIn some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1800 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 1900 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 2000 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 2100 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 2200 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 2300 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 2400 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 2500 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 2600 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 2700 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of less than or equal to 2800 ng / mL in the patient. maxIn some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 2900 ng / mL or less in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 3000 ng / mL or less in the patient. max It is effective to achieve this.

[0114] In some embodiments, at least one weekly maintenance dose provides a patient with a mean C at steady state of 400 ng / mL to 3000 ng / mL. max It is effective to achieve this.

[0115] In some embodiments, at least one weekly maintenance dose provides a patient with a mean C at steady state of 50% to 150% of 1885 ng / mL. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 55% to 145% of 1885 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 60% to 140% of 1885 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 65% to 135% of 1885 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 70% to 130% of 1885 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 75% to 125% of 1885 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 80% to 120% of 1885 ng / mL in the patient.max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 85% to 115% of 1885 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 90% to 110% of 1885 ng / mL in the patient. max In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C at steady state of 95% to 105% of 1885 ng / mL in the patient. max It is effective to achieve this.

[0116] In some embodiments, at least one weekly maintenance dose provides a mean C of at least 200 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 2500 ng / mL or less in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 200 ng / mL to 2500 ng / mL in the patient. av,ss It is effective to achieve this.

[0117] In some embodiments, at least one weekly maintenance dose is administered to a patient with a mean C of 50% to 150% of 1353 ng / mL. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 55% to 145% of 1353 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 60% to 140% of 1353 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 65% to 135% of 1353 ng / mL in the patient. av,ssIn some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 70% to 130% of 1353 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 75% to 125% of 1353 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 80% to 120% of 1353 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 85% to 115% of 1353 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 90% to 110% of 1353 ng / mL in the patient. av,ss In some embodiments, at least one weekly maintenance dose is effective to achieve a mean C of 95% to 105% of 1353 ng / mL in the patient. av,ss It is effective to achieve this.

[0118] In some embodiments, the mean AUC τ In some embodiments, the mean AUC at steady state in a patient is 400,000 ng·h / mL or less. τ In some embodiments, the mean AUC at steady state in a patient is 300,000 ng·h / mL or less. τ is 30,000ng·h / mL to 400,000ng·h / mL.

[0119] In some embodiments, the mean AUC τ is 50% to 150% of 227,230 ng·h / mL. τis 55% to 145% of 227,230 ng·h / mL. τ is 60% to 140% of 227,230 ng·h / mL. τ is 65% to 135% of 227,230 ng·h / mL. τ is 70% to 130% of 227,230 ng·h / mL. τ is 75% to 125% of 227,230 ng·h / mL. τ is 80% to 120% of 227,230 ng·h / mL. τ is 85% to 115% of 227,230 ng·h / mL. τ is 90% to 110% of 227,230 ng·h / mL. τ is 95% to 105% of 227,230 ng·h / mL.

[0120] In some embodiments, the mean t 1 / 2z In some embodiments, the mean t in the patient is between 50 hours and 500 hours. 1 / 2z In some embodiments, the mean t at steady state in a patient is between 50 h and 450 h. 1 / 2z In some embodiments, the mean t in the patient is between 50 hours and 400 hours. 1 / 2z is 50h to 350h.

[0121] In some embodiments, the mean t 1 / 2zIn some embodiments, the mean t in a patient at steady state is 100 h to 500 h. 1 / 2z In some embodiments, the mean t in the patient at steady state is 150 h to 500 h. 1 / 2z is 200h to 500h.

[0122] In some embodiments, the mean t 1 / 2z is 150h to 350h.

[0123] In some embodiments, the mean t 1 / 2z In some embodiments, the mean t at steady state in a patient is at least 100 h. 1 / 2z In some embodiments, the mean t at steady state in a patient is at least 125 h. 1 / 2z In some embodiments, the mean t at steady state in a patient is at least 150 h. 1 / 2z In some embodiments, the mean t at steady state in the patient is at least 175 h. 1 / 2z In some embodiments, the mean t at steady state in the patient is at least 200 h. 1 / 2z In some embodiments, the mean t at steady state in the patient is at least 225 h. 1 / 2z is at least 250h.

[0124] In some embodiments, the loading dose comprises 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof, and at least one weekly maintenance dose comprises 20 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof, and at least one weekly maintenance dose comprises 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof, and at least one weekly maintenance dose comprises 60 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the loading dose comprises 160 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof, and at least one weekly maintenance dose comprises 80 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof.

[0125] In some embodiments, the loading dose is administered orally.

[0126] In some embodiments, the loading dose is administered in at least one (e.g., 1, 2, 3, or 4) tablet. In some embodiments, the loading dose is administered in at least one (e.g., 1, 2, 3, or 4) immediate-release tablet. In some embodiments, the loading dose is administered in at least one (e.g., 1, 2, 3, or 4) immediate-release tablet further comprising mannitol and microcrystalline cellulose.

[0127] In some embodiments, the loading dose is administered in an oral suspension. In some embodiments, the loading dose is administered in an oral suspension further comprising Tween® and methylcellulose.

[0128] In some embodiments, the loading dose is administered with water.

[0129] In some embodiments, the loading dose is administered without food. In some embodiments, the patient is fasted. In some embodiments, the patient fasts for at least 10 hours prior to administration of the loading dose.

[0130] In some embodiments, the loading dose is administered with food. In some embodiments, the loading dose is administered with a high-fat, high-calorie meal. In some embodiments, the patient is in a fed state. In some embodiments, the patient has eaten or drunk at least 30 minutes prior to administration of the loading dose.

[0131] In some embodiments, at least one weekly maintenance dose is administered orally.

[0132] In some embodiments, the at least one weekly maintenance dose is administered in at least one (e.g., 1, 2, 3, or 4) tablet. In some embodiments, the at least one weekly maintenance dose is administered in at least one (e.g., 1, 2, 3, or 4) immediate-release tablet. In some embodiments, the at least one weekly maintenance dose is administered in at least one (e.g., 1, 2, 3, or 4) immediate-release tablet further comprising mannitol and microcrystalline cellulose.

[0133] In some embodiments, at least one weekly maintenance dose is administered in an oral suspension, hi some embodiments, at least one weekly maintenance dose is administered in an oral suspension further comprising Tween® and methylcellulose.

[0134] In some embodiments, at least one weekly maintenance dose is administered without food. In some embodiments, the patient is fasting. In some embodiments, the patient fasts for at least 10 hours before administration of at least one weekly maintenance dose.

[0135] In some embodiments, at least one weekly maintenance dose is administered with water. In some embodiments, at least one weekly maintenance dose is administered with food. In some embodiments, at least one weekly maintenance dose is administered with a high-fat, high-calorie meal. In some embodiments, the patient is in a fed state. In some embodiments, the patient has eaten or drunk at least 30 minutes before administering at least one weekly maintenance dose.

[0136] In some embodiments, the method further comprises administering at least one additional active pharmaceutical ingredient selected from sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, mGlu2 / 3 agonists, 5HT-2 antagonists, PDE10 antagonists, and GlyT1 inhibitors.

[0137] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from an antipsychotic agent.

[0138] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from first generation antipsychotics, hi some embodiments, the at least one additional active pharmaceutical ingredient is selected from chlorpromazine, fluphenazine, haloperidol, and perphenazine.

[0139] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from second-generation antipsychotics, hi some embodiments, the at least one additional active pharmaceutical ingredient is selected from aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone.

[0140] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a long-acting injectable antipsychotic, hi some embodiments, the at least one additional active pharmaceutical ingredient is selected from aripiprazole, fluphenazine decanoate, haloperidol decanoate, paliperidone, and risperidone.

[0141] In some embodiments, the method comprises treating at least one negative symptom of schizophrenia. In some embodiments, the at least one negative symptom of schizophrenia is selected from anhedonia, amotivation, and decreased interest in social interactions. In some embodiments, the at least one negative symptom of schizophrenia is anhedonia. In some embodiments, the at least one negative symptom of schizophrenia is amotivation. In some embodiments, the at least one negative symptom of schizophrenia is decreased interest in social interactions.

[0142] In some embodiments, the method comprises treating at least one cognitive symptom of schizophrenia. In some embodiments, the at least one cognitive symptom of schizophrenia is selected from verbal memory impairment, working memory impairment, motor function impairment, attention and processing speed impairment, verbal fluency impairment, and executive function impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is verbal memory impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is working memory impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is motor function impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is attention and processing speed impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is verbal fluency impairment. In some embodiments, the at least one cognitive symptom of schizophrenia is executive function impairment.

[0143] In some embodiments, the method comprises modulating reward anticipation-related brain activity in the patient.

[0144] In some embodiments, the method comprises modulating cerebral blood flow in the patient.

[0145] In some embodiments, the method comprises increasing ventral striatum activity in the patient during reward anticipation.

[0146] In some embodiments, the method comprises modulating dopamine release in the patient. In some embodiments, the method comprises decreasing dopamine release in the patient. In some embodiments, the method comprises decreasing dopamine release in the patient after exposure to a stimulant.

[0147] Pharmaceutical Composition Some embodiments of the present disclosure relate to a pharmaceutical composition comprising at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises more than 80 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises more than 100 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 120 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 160 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the pharmaceutical composition is in the form of at least one (e.g., 1, 2, 3, or 4) tablet. In some embodiments, the pharmaceutical composition is in the form of at least one (e.g., 1, 2, 3, or 4) immediate-release tablet. In some embodiments, the pharmaceutical composition is in the form of at least one (e.g., 1, 2, 3, or 4) immediate-release tablet comprising mannitol and microcrystalline cellulose.

[0149] In some embodiments, the pharmaceutical composition is in the form of at least one tablet comprising a core composition comprising at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof; and a coating layer coating the core composition.

[0150] In some embodiments, the core composition further comprises mannitol. In some embodiments, the core composition further comprises microcrystalline cellulose. In some embodiments, the core composition further comprises hydroxypropyl cellulose. In some embodiments, the core composition further comprises croscarmellose sodium.

[0151] In some embodiments, the core composition further comprises mannitol and microcrystalline cellulose. In some embodiments, the core composition further comprises mannitol and hydroxypropyl cellulose. In some embodiments, the core composition further comprises mannitol and croscarmellose sodium.

[0152] In some embodiments, the core composition further comprises mannitol, microcrystalline cellulose, and hydroxypropyl cellulose. In some embodiments, the core composition further comprises mannitol, microcrystalline cellulose, and croscarmellose sodium.

[0153] In some embodiments, the core composition further comprises mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and croscarmellose sodium.

[0154] In some embodiments, the core composition comprises, by weight of the core composition, 5% to 25% of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the core composition comprises, by weight of the core composition, 7.5% to 22.5% of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof. In some embodiments, the core composition comprises, by weight of the core composition, 10% to 20% of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the core composition further comprises 55% to 75% mannitol by weight of the core composition. In some embodiments, the core composition further comprises 60% to 75% mannitol by weight of the core composition. In some embodiments, the core composition further comprises 65% to 75% mannitol by weight of the core composition. In some embodiments, the core composition further comprises 60% to 70% mannitol by weight of the core composition.

[0156] In some embodiments, the core composition further comprises 5% to 15% microcrystalline cellulose by weight of the core composition. In some embodiments, the core composition further comprises 7.5% to 12.5% ​​microcrystalline cellulose by weight of the core composition. In some embodiments, the core composition further comprises 10% microcrystalline cellulose by weight of the core composition.

[0157] In some embodiments, the core composition further comprises 2.5% to 7.5% croscarmellose sodium by weight of the core composition, hi some embodiments, the core composition further comprises 5% croscarmellose sodium by weight of the core composition.

[0158] In some embodiments, the core composition further comprises 1% to 5% hydroxypropyl cellulose by weight of the core composition, hi some embodiments, the core composition further comprises 3% hydroxypropyl cellulose by weight of the core composition.

[0159] In some embodiments, the core composition further comprises 0.5% to 1.5% magnesium stearate by weight of the core composition, hi some embodiments, the core composition further comprises 1% magnesium stearate by weight of the core composition.

[0160] In some embodiments, the core composition comprises, by weight of said core composition: 5% to 25% of at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof; 55% to 75% mannitol; and 5% to 15% microcrystalline cellulose Includes.

[0161] In some embodiments, the core composition comprises, by weight of said core composition: 10% to 20% of at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof; 60% to 75% mannitol; and 7.5% to 12.5% ​​microcrystalline cellulose Includes.

[0162] In some embodiments, the pharmaceutical composition is in the form of one tablet. In some embodiments, the pharmaceutical composition is in the form of two tablets. In some embodiments, the pharmaceutical composition is in the form of three tablets. In some embodiments, the pharmaceutical composition is in the form of four tablets. In some embodiments, the pharmaceutical composition is in the form of five tablets. In some embodiments, the pharmaceutical composition is in the form of six tablets.

[0163] In some embodiments, the pharmaceutical composition is in the form of two tablets, each tablet containing 40 mg of at least one compound selected from Compound (I) and a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the pharmaceutical composition is in the form of four tablets, each tablet containing 40 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof.

[0165] In some embodiments, the pharmaceutical composition is in the form of an oral suspension. In some embodiments, the pharmaceutical composition is in the form of an oral suspension comprising Tween® and methylcellulose.

[0166] The proportion and nature of any pharmaceutically acceptable excipient can be determined by the selected route of administration and standard pharmaceutical practice. Except insofar as any conventional pharmaceutically acceptable excipient is incompatible with Compound (I), for example, by producing some undesirable biological effect or otherwise reacting in a deleterious manner with any other component(s) of the pharmaceutical composition, the use of any conventional pharmaceutically acceptable excipient is intended to be within the scope of this disclosure.

[0167] Some non-limiting examples of materials that can function as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, and corn oil. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances used in pharmaceutical formulations.

[0168] Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C.B. Boylan, 1988-1999, Marcel Dekker, New York, also disclose additional non-limiting examples of pharmaceutically acceptable excipients and known techniques for preparing and using the same.

[0169] In the treatment of patients in need thereof, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof may be administered in any form and by any route that makes the API bioavailable. For example, in some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof may be administered by various routes, such as oral administration (e.g., via tablets or capsules). In some embodiments, when an aqueous suspension is used for oral administration, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof may be formulated with emulsifiers and suspending agents.

[0170] In some embodiments, at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof may be administered parenterally, for example, by inhalation, subcutaneous, intramuscular, intravenous, intraarterial, transdermal, intranasal, rectal, vaginal, ocular, topical, sublingual, buccal, intraperitoneal, intraadiposally, intrathecal, or by local delivery (e.g., via a catheter or stent). In some embodiments, the sterile injectable form of the pharmaceutical composition of the present disclosure may be an aqueous or oily suspension. These suspensions may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, the sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Non-limiting examples of acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. As an additional non-limiting example, sterile, fixed oils can be employed as a solvent or suspending medium.

[0171] Those skilled in the art can easily select an appropriate form and route of administration depending on the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances. In some embodiments, the pharmaceutical compositions of the present disclosure can be administered to a patient in the form of a tablet, capsule, cachet, paper, lozenge, wafer, elixir, ointment, transdermal patch, aerosol, inhalant, suppository, solution, or suspension.

[0172] A claim or description including "or" or "and / or" between at least one member of a group is deemed to be applicable if one, more than one, or all of the members of the group are present in, used in, or otherwise relevant to a given product or process, unless stated otherwise or otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which two or more, or all members of the group are present in, used in, or otherwise relevant to a given product or process.

[0173] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the enumerated claims is incorporated into another claim. For example, any claim that depends on another claim can be modified to include at least one limitation found in any other claim that depends from the same dependent claim. Where elements are presented as a list (e.g., in the form of a Markush group), each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. Generally, when the present disclosure or aspects of the disclosure are indicated as including certain elements and / or features, it should be understood that embodiments of the disclosure or aspects of the disclosure consist of (or consist essentially of) those elements and / or features. For purposes of simplicity, these embodiments have not been specifically described in these terms herein. When ranges are presented, both ends are inclusive. Furthermore, unless otherwise stated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​stated as ranges may, in different embodiments of the present disclosure, be deemed to refer to any specific value or subrange within the stated range, to one-tenth of the unit of the lower value of that range, unless clearly contrary to the context.

[0174] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein which equivalents are intended to be encompassed by the following claims. [Example]

[0175] The following examples are intended to be illustrative and not to limit the scope of the disclosure in any way. Abbreviation % percent % CV Coefficient of Variation % AE Adverse Event ANOVA analysis of variance ASL Arterial Spin Labeling AUC Area under the plasma concentration time curve AUC 24 AUC from 0 to 24 hours AUC 96 AUC from 0 to 96 hours AUC τ AUC during the dosing interval BACS Brief Assessment of Cognition in Schizophrenia BOLD blood oxygen level dependence BMI Body Mass Index BNSS Brief Negative Symptom Scale C av,ss Mean steady-state plasma concentration C max Maximum plasma concentration C trough Observed plasma concentrations at the end of the dosing interval Ca caudate nucleus CBF cerebral blood flow CL / F Apparent clearance after extravascular administration CSSRS Columbia Suicide Severity Rating Scale CYP3A4 cytochrome P450 3A4 d-APMH dextroamphetamine DSM Diagnostic and Statistical Manual of Mental Disorders FIH First in Human fMRI Functional Magnetic Resonance Imaging g grams GAD Generalized Anxiety Disorder GCP Good Clinical Practice GP globus pallidus h time IA interim analysis ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IRB Institutional Review Board kg kilogram m 2 square meters MC methylcellulose mg milligram MID Monetary Incentive Delay min Mini International Neuropsychiatric Interview mL milliliter mm millimeters MNI Montreal Neurological Institute Institute) MP-RAGE Magnetization-prepared rapid gradient-echo MRD Multiple Ascending Dose MR magnetic resonance MRI Magnetic Resonance Imaging NAcc nucleus accumbens NSFS negative symptom factor score PANSS Positive and Negative Symptom Rating Scale Syndrome Scale) pCASL pseudo-continuous ASL PET Positron Emission Tomography PK Pharmacokinetics PD Pharmacodynamics Pu putamen R ac(AUC) accumulation ratio (AUC τ (based on R ac(Cmax) Accumulation ratio (C max (based on RBA Relative Bioavailability RF radio waves ROI Region of Interest s seconds SAP Statistical Analysis Plan SD standard deviation SE standard error SN substantia nigra SPECT Single Photon Emission Computed Tomography SPM Statistical Parametric Mapping SRD Single Ascending Dose SRTM Simplified Reference Tissue Model t 1 / 2z Terminal elimination half-life t max First C max Time to reach TAC time activity curve TEAE Treatment-emergent adverse events V z / F Apparent terminal volume of distribution after extravascular administration VSt Ventral striatum (VSt) VTA ventral tegmental area

[0176] Example 1: Phase 1 First-in-Human Safety, Tolerability, and Pharmacokinetic Study of Compound (I) A Phase 1 first-in-human (FIH) study was conducted at a single site in the United States to evaluate the safety, tolerability, and pharmacokinetics (PK) of Compound (I). Specifically, Compound (I) was studied in healthy participants and in participants with stable schizophrenia as an add-on study to antipsychotic medication to assess the safety, tolerability, and PK of single and multiple doses. The Phase 1 study also evaluated the oral bioavailability of Compound (I) in healthy participants administered a tablet formulation compared to an oral suspension formulation under fasting conditions, and the effect of a high-fat, high-calorie meal on the PK of a single dose of the tablet formulation of Compound (I). Additional exploratory pharmacodynamic analyses were conducted in patients with stable schizophrenia to inform future studies.

[0177] In a Phase 1 study, Compound (I) was rapidly absorbed in both healthy volunteers and patients with stable schizophrenia after single and repeated oral administration. After single and repeated oral administration of Compound (I), the urinary 6β-hydroxycortisol / cortisol ratio was not significantly different from placebo, suggesting that CYP3A4 was not induced. Compound (I) was generally well tolerated, and no severe or serious adverse safety signals were reported.

[0178] Test Design

[0179] The study followed IRB rules as stated in GCP rules and guidelines, and all applicable local regulations. The study was conducted with the utmost respect for individual participants and in accordance with the ethical principles originating from the Declaration of Helsinki, the requirements and definitions of the ICH Harmonized Tripartite Guidelines on GCP, and all applicable local regulations. All participants signed and dated informed consent forms prior to any protocol-specific screening procedures.

[0180] As shown in Table 1, the study consisted of four parts: (1) Part 1 (single ascending dose [SRD], alternating panel design and sequential panel design); (2) Part 2 (multiple ascending dose [MRD], sequential panel design); (3) Part 3 (open-label parallel design); and (4) Part 4 (single-dose cohorts). Cohorts in Parts 1 and 2 were randomized to receive either Compound (I) or placebo in a 6:2 ratio. Cohorts in Part 3 were randomized in a 1:1 ratio, while cohorts in Part 4 were randomized in a 2:1 ratio.

[0181] [Table 1-1] [Table 1-2]

[0182] Part 1 was a double-blind, SRD study in healthy adults using an alternating panel design (Cohorts 1 and 2) and a sequential panel design (Cohorts 3–5). Cohorts 1 and 2 were two-period, alternating panel, double-blind portions of a study of Compound (I) or a matching placebo administered as an oral suspension (5 mg, 10 mg, 20 mg, or 40 mg) with a washout period of at least 7 days between treatment periods. Cohorts 3–5 were sequential panel, double-blind portions to evaluate the SRD of Compound (I) (80, 120, or 160 mg, respectively) or a matching placebo. Although planned, all doses after the 80 mg dose were determined based on safety, tolerability, and PK data emerging from the preceding cohorts.

[0183] A sentinel group was used for Cohort 1, Period 1, with the first two participants assigned 1:1 to receive either Compound (I) or placebo to ensure adequate safety and tolerability before dosing the remaining participants in this cohort. The remaining six participants were dosed after review of safety and tolerability data 24 hours after dosing. Subsequent cohorts were dosed based on a minimum of 21 days of safety, tolerability, and available PK data from the preceding cohort.

[0184] Part 2 was an MRD study in healthy adults to evaluate plasma exposure and accumulation of Compound (I) in four cohorts (1-4). Part 2 did not begin until 21 days of safety, tolerability, and available PK data had been collected from Cohort 3 in Part 1.

[0185] In Part 2, participants received either placebo on all dosing days or Compound (I) as an oral suspension, with a loading dose on day 1 and maintenance doses of half the initial dose on days 8, 15, and 22. Baseline measurements were taken on day -2, and study-specific measurements were taken after oral dose administration on days 1, 8, 15, and 22.

[0186] Participants were required to stay at the study site for 5 days for each cycle of Compound (I). For the loading dose, participants were required to remain at the study site from days -2 to 3, and for the maintenance doses on days 7-10, 14-17, and 21-24. Study-specific measurements were performed within the 48-hour post-dose period before participants were discharged. After discharge on day 24, participants returned for follow-up visits on days 26, 29, 36, 43, 50, 57, and 64. The final study-termination visit occurred 12-16 days after the last safety and PK follow-up.

[0187] Part 3 was a randomized, open-label, single-dose, parallel-design study to evaluate the effect of food on the bioavailability and PK of a tablet formulation of Compound (I) compared with an oral suspension formulation of Compound (I) in healthy participants. The immediate-release tablets contained mannitol, microcrystalline cellulose, and other commonly used excipients. Participants were randomized 1:1 to receive a single 40 mg dose of Compound (I) as a tablet either after a 10-hour overnight fast or 30 minutes after the start of a high-fat, high-calorie breakfast.

[0188] Participants were required to remain at the study site for an additional 48 hours post-dose for safety and PK assessments, with follow-up visits on days 4-5 and 17-21. Blood samples were collected over a 96-hour period post-dose to measure plasma concentrations of Compound (I).

[0189] Part 4 was a double-blind, once-weekly, parallel-group design in patients with stable schizophrenia. Part 4 did not begin until 21 days of safety, tolerability, and PK data had been collected in Part 2.

[0190] Participants were randomly assigned 2:1 to receive either Compound (I) or placebo. Participants receiving Compound (I) received a loading dose on Day 1 and maintenance doses at half the initial dose on Days 8, 15, and 22. Participants in the placebo group received placebo on all study dosing days.

[0191] Participants were required to stay at the study site for 5 days for each cycle of Compound (I). For the loading dose, participants were required to remain at the study site from days -2 to 3, and for the maintenance doses, participants were required to remain at the study site on days 7-10, 14-17, and 21-24. Study-specific measurements were performed within the 48-hour post-dose period before participants were discharged. After discharge on day 24, participants returned for follow-up visits on days 26, 29, 36, 43, 50, 57, and 64. The final study-termination visit occurred 12-16 days after the last safety and PK follow-up.

[0192] Key inclusion criteria

[0193] The study enrolled men and women aged 18 to 55 years at the time of informed consent, with a body mass index (BMI) of 18 to 32 kg / m for healthy participants. 2 , and 18–40.5 kg / m for participants with schizophrenia. 2 It was.

[0194] In Part 4, participants met criteria for schizophrenia as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) by the Mini-Instruction Interview for Mental Illness (MINI), a Positive and Negative Symptom Scale (PANSS) total score ≤90, and a PANSS N1, N2, N3, N4, N6, G7, and G16 sum ≥15 at screening and baseline. Additionally, participants were required to be receiving a stable dose of antipsychotic medication for at least 2 months.

[0195] Safety evaluation

[0196] Safety measures in the Phase 1 study included treatment-emergent adverse events (TEAEs), physical examination, weight, height, BMI, vital signs, and clinical laboratory assessments. These included a laboratory evaluation, pregnancy monitoring, and ECG procedures.

[0197] A TEAE was defined as any adverse event that occurred or worsened after the first dose of Compound (I) and within 6 weeks after the last dose of Compound (I). Participants who experienced two or more different TEAEs were counted only once. A frequent TEAE was defined as an adverse event occurring in at least two participants in any treatment. Participants were assessed for mood and alertness (BL-VAS) and suicidality (C-SSRS).

[0198] Pharmacokinetic evaluation

[0199] Plasma and urinary concentrations of Compound (I), as well as cortisol and 6β-hydroxycortisol, were measured by high-performance liquid chromatography and tandem mass spectrometry. One 4 mL blood sample was collected at each scheduled assessment. For participants receiving placebo, C (as determined from measurements in the first dose group) was collected before dosing and to ensure that no additional participants were receiving active treatment. max Blood samples were analyzed only around the time of the event. Serial urine samples were collected for cohorts 1-5 in part 1 and cohorts 1-4 in part 2. Urine samples for participants who received placebo were not analyzed. Urine samples were collected for cohorts 1-4 in part 2 and for all patients in part 4 to determine cortisol and 6β-hydroxycortisol. Samples for participants randomized to placebo were analyzed for these parameters.

[0200] Pharmacokinetic parameters were determined from concentration-time profiles for all evaluable participants. Actual sampling times were used in all calculations. Pharmacokinetic parameters were calculated by noncompartmental analysis using Phoenix WinNonLin v8.0 or SAS v9.4.

[0201] Pharmacodynamic evaluation

[0202] Exploratory pharmacodynamic assessments in Part 4 included the Positive and Negative Symptom Scale (PANSS) total score, subscale scores, and factor scores; the Brief Assessment of Cognition in Schizophrenia (BACS) total score; the Clinical Global Impression-Severity Scale (CGI-S) and Clinical Global Impression-Global Improvement (CGI); the Brief Negative Symptom Scale (BNSS) total score; and the Transient Pleasure Experiences Scale (TEPS) total score.

[0203] statistics

[0204] In the Phase 1 study, three analysis sets were used: (1) safety set (all participants who received at least one dose of study drug); (2) PK set (all participants who received study drug and provided sufficient data for at least one PK parameter); and (3) PD set (Part 4 only) (participants who received study drug and provided sufficient data for one baseline and one planned post-baseline PD parameter).

[0205] The target sample sizes for Part 1 Cohorts 1–5 and Part 2 Cohorts 1–4 were based on precedent from other FIH trials, not on a formal assessment of statistical power. A sample size of 8 participants per cohort was considered sufficient to investigate the study objectives and to characterize any potential effects on safety parameters.

[0206] PK outcomes were summarized using descriptive statistics.

[0207] Demographic and other baseline characteristics, and study enrollment

[0208] Demographic and general characteristics were generally similar between the placebo and active treatment arms (Table 2).

[0209] One participant in the 160 / 80 mg Compound (I) cohort in Part 4 (MRD study in patients with stable schizophrenia) did not receive a dose on Day 15. The pharmacokinetic concentration on Day 22 for this subject was excluded from the mean plasma concentration-time profile, and related pharmacokinetic parameters were excluded from statistical analysis.

[0210] One participant in the 160 / 80 mg Compound (I) cohort in Part 4 (MRD study in patients with stable schizophrenia) discontinued the study after dosing on Day 1. PK parameters for this participant were excluded from statistical analysis.

[0211] Another participant in the 160 / 80 mg Compound (I) cohort in Part 4 (MRD study in patients with stable schizophrenia) discontinued the study after dosing on Day 22. max , C max , observed plasma concentration at the end of the dosing interval, AUC 24 , AUC 48 , and AUC 96 All PK parameters for this participant were excluded from the summary and statistical analyses, except for

[0212] [Table 2]

[0213] Safety evaluation

[0214] No clinically significant changes in baseline characteristics were observed during the study. Of the 114 randomized participants, all participants received at least one dose of Compound (I) and were included in the safety set. Except for two participants who experienced moderate TEAEs (one in Part 2 and one in Part 3), the TEAEs experienced by participants were mild. No deaths, serious adverse events, or other significant TEAEs were reported. Headaches tended to occur more frequently with Compound (I) compared with placebo, and their frequency appeared to increase with higher doses. There were no discontinuations due to TEAEs.

[0215] In Part 1 (SRD Study), 4 participants (40.0%) receiving placebo and 6 participants (20.0%) receiving Compound (I) experienced TEAEs during the study. None of the TEAEs were considered related to study drug by the investigator.

[0216] In Part 2 (MRD study), 3 participants (37.5%) who received placebo, and 19 participants in total (59.4%), experienced a TEAE during the study (Table 3). One TEAE was moderate, while all other TEAEs were mild.

[0217] In Part 3 (relative bioavailability / food effect study) (9 participants who received a single dose of Compound (I) after at least a 10-hour overnight fast), 1 (11.1%) experienced a TEAE. 2 participants (22.2%) who received a single dose of Compound (I) after a high-fat, high-calorie breakfast experienced a TEAE. 1 participant experienced a moderate TEAE, while all other TEAEs were mild. No deaths, serious AEs, or other TEAEs were reported.

[0218] In Part 4 (MRD study in patients with stable schizophrenia), 6 participants (75.0%) who received placebo and 15 participants in total (62.5%) experienced TEAEs during the study (Table 4). Similar frequencies of study drug-related TEAEs were reported by patients with schizophrenia who received placebo (50.0%) and patients with schizophrenia who received Compound (I) (56.3%). All TEAEs were mild.

[0219] [Table 3]

[0220] [Table 4]

[0221] Pharmacokinetics of Compound (I)

[0222] Compound (I) is rapidly absorbed after single and repeated oral administration in healthy and schizophrenic patients. max The C was 0.99-3.00 hours. At higher doses (≥120 mg), a second peak was occasionally observed. The C was 0.99-3.00 hours with increasing doses (5-160 mg) after a single oral dose of Compound (I) in healthy patients. max The increases in C and AUC were less than dose-proportional. max Values ​​(observed up to 96 hours post-dose for Cohorts 1 and 2, and up to 168 hours post-dose for Cohorts 3-5) are shown in Table 5. Mean C for participants in several cohorts in Parts 2 and 4 max The values ​​(observed up to 168 hours after administration) are shown in Table 6.

[0223] [Table 5]

[0224] [Table 6]

[0225] Saturation of plasma PK was observed at 160 mg (the highest dose level tested). Steady-state exposure for Compound (I) was 160 mg AUC τ Value and C max As shown by the values, the C of Compound (I) after a single oral dose of Compound (I) tablet formulation under fasted and fed conditions was not achieved after the initial loading dose. max and AUC 96 The ratios for t were 0.841 and 0.942, respectively, indicating that there was no significant food effect on systemic exposure. max The median values ​​were also similar under fed and fasted conditions.

[0226] In Part 1 (SRD study), Compound (I) was rapidly absorbed over the dose range of 5 to 80 mg, with t max The median time to presentation ranged from 0.99 to 3.00 hours. A second peak was observed in some participants at the 120 mg and 160 mg dose levels, with t max The median values ​​increased to 13.0 and 13.5 hours, respectively. The mean t 1 / 2z The C for Compound (I) ranged from 210 to 296 hours for the dose range of 20 to 160 mg. max and AUC 24 The increase in C for 160 mg of Compound (I) was less than proportional. max The values ​​and AUC were comparable to or lower than those for Compound (I) 120 mg, suggesting saturation of plasma PK.

[0227] The average t for compound (I) 1 / 2zreflects the extended half-life of Compound (I) in humans. Species variability in the rate and extent of metabolic pathways for Compound (I) was observed in separate studies in rats, dogs, monkeys, and humans following single oral dose administration of Compound (I) at 5-15 mg / kg. In this study, the mean human half-life of Compound (I) (approximately 11 days) was significantly longer than the mean half-life of 2-4 hours observed in rats and dogs.

[0228] PK parameters in healthy participants after MRD (Part 2) are shown in Table 7. In Table 7, t max The median and min-max values ​​(denoted as (a) and (b) in the table, respectively) are shown for t. Compound (I) was also rapidly absorbed in Part 2, with t max The median time was 1.75 to 3.00 hours (Figure 1). max was approximately 48 hours at an 80 mg loading dose and a 40 mg maintenance dose of Compound (I), or at a 160 mg loading dose and an 80 mg maintenance dose of Compound (I). The steady-state (Day 22) systemic exposure of Compound (I) increased approximately dose-proportionally, with a mean steady-state t for Compound (I). 1 / 2z ranged from 170 to 302 hours.

[0229] In Part 3 (Relative Bioavailability / Food Effect Study), mean Compound (I) systemic exposure for tablet formulations was comparable between fasted and fed conditions, demonstrating minimal food effect. max The median time (2.00 hours under fasting and fed conditions) was comparable to that for Compound (I) oral suspension (1.82 hours). max The estimates (36 hours and approximately 24 hours) were delayed compared to other participants within each treatment group.

[0230] PK parameters for stable schizophrenic patients (Part 4) are shown in Table 8. In Table 8, t maxThe median and minimum-maximum values ​​(denoted as (a) and (b) in the table, respectively) are shown, and the values ​​marked with (c) are based on a sample size of 13 due to early termination and dropout of subjects. In Part 4 (MRD study in patients with stable schizophrenia), the t max The median time was 1.80 hours for schizophrenia patients and 3.00 hours for healthy participants. max The mean steady-state t for compound (I) was comparable to the median (Figure 1). 1 / 2z were 334 hours and 271 hours for schizophrenia and healthy participants, respectively. In addition, in patients with schizophrenia, the mean t 1 / 2z was 334 hours, compared with 210-296 hours in healthy participants in Part 1 (SRD study) and 170-302 hours in healthy participants in Part 2 (MRD study). Peak systemic exposure of Compound (I) was 23-30% lower in participants with schizophrenia compared with healthy participants, and total systemic exposure of Compound (I) was 22-27% lower in participants with schizophrenia compared with healthy participants. [Table 7] [Table 8]

[0223] Example 2: Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: 11 C]PHNO PET evaluation of compound (I) Molecular imaging techniques using dopamine D2 receptor (D2R) radioligands have been shown to be suitable for detecting pharmacologically induced dopamine release in healthy nonhuman primates (Dewey et al., 1993; Innis et al., 1992) and human brains (Laruelle, 2000; Laruelle et al., 1995). Depletion of synaptic dopamine with α-methyl-p-tyrosine produces PET and SPECT signal changes opposite to those produced by dopamine-enhancing drugs such as amphetamine or levodopa (Laruelle et al., 1997; Verhoeff et al., 2002; Verhoeff et al., 2001); the magnitude of the signal change correlates with the magnitude of the dopamine change as measured by microdialysis (Breier et al., 1997; Laruelle et al., 1997). Using this methodology, differences between patients with neuropsychiatric disorders and healthy individuals have been shown (Abi-Dargham et al., 1998; Breier et al., 1997; Tedroff et al., 1996). D2R agonist radioligands, e.g., 11 C]PHNO (Brown et al., 1997; Wilson et al., 2005) and [ 11 C]NPA, like dopamine itself, binds primarily to D2R in its G protein-coupled (G-coupled) state, enabling the high sensitivity of the agonist ligand to detect changes in synaptic dopamine concentrations ( Narendran et al., 2004 ; Willeit et al., 2006 ).

[0224] To assess endogenous dopamine release in the human brain after treatment with Compound (I), [ 11 A human PET study using [C]PHNO was used. In this study, Compound (I) readily crossed the blood-brain barrier and demonstrated dose-dependent modulation of dopamine release in healthy human volunteers. Administration of dextroamphetamine (d-APMH) resulted in [C]PHNO-induced dopamine release, as predicted by elevated synaptic dopamine concentrations. 11 C]PHNO BP ND Pretreatment with compound (I) resulted in a robust decrease in [ 11C]-PHNO ΔBP ND The magnitude of the d-AMPH-induced dopamine release was reduced, consistent with a decrease in the release of extracellular dopamine after d-AMPH administration. Plasma concentrations of d-AMPH were similar in d-AMPH-alone and d-AMPH + Compound (I) PET scans, and the plasma concentrations of d-AMPH were significantly higher in d-AMPH + Compound (I) PET scans.

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[0225] Study design and subjects

[0226] Twelve male volunteers (age 39.8 ± 11.4 years) were screened and recruited to the study by Hammersmith Medicines Research (London). All imaging evaluations were performed at the Imanova Centre for Imaging Sciences (now Invicro) (London, UK). The study was supported by the London-Brent Research Ethics Committee. The study was approved by the Committee (reference 16 / LO / 1493) and permission for the administration of radioisotopes was obtained from the UK Administration of Radioactive Substances Advisory Committee (reference: 630 / 3764 / 35313).

[0227] T1-weighted magnetic resonance imaging (MRI) scans of the brain performed at screening were used to obtain the anatomical information required for PET data analysis. Each subject underwent three [ 11C]PHNO PET scans were performed: one at baseline, one 3 hours after a single oral dose of dextroamphetamine (d-AMPH, 0.5 mg / kg), and one approximately 5 hours after a single oral dose of Compound (I) (20 or 40 mg) and 3 hours after an oral dose of dextroamphetamine (d-AMPH) (0.5 mg / kg) (Figure 2).

[0228] Two subjects underwent only a baseline PET scan but no further PET scans due to failure of radioligand production; data from these subjects were not included in the analysis.

[0229] MRI acquisition

[0230] All subjects had MRI scans (including T1-weighted scans) obtained at screening. Scans were performed using a Siemens 3T MRI magnet (Siemens The MRI scans were acquired using a 3D magnetization-prepared rapid gradient echo (MP-RAGE) scan in the sagittal plane with the following parameters: repetition time = 2300 ms, echo delay time = 2.98 ms, flip angle = 9°, isotropic voxels = 1.0 mm × 1.0 mm × 1.0 mm, 160 slices, total scan time = 5 min, 3 s. The MR scans were reviewed by a neuroradiologist to exclude any clinically relevant brain abnormalities. The T1 MRI data were used as part of the PET data analysis, as described below.

[0231] [ 11 Preparation of [C]-PHNO

[0232] [ 11 C]PHNO was prepared as previously described ( Searle et al., 2010 ; Wilson et al., 2005 ). 11 C]-propionyl chloride with despropyl-PHNO. The final product was purified by solid-phase extraction and reconstituted in a solution of 10% ethanol in saline.

[0233] PET data acquisition

[0234] Subjects were placed in the PET scanner after an intravenous cannula was inserted into an antecubital or forearm vein. A soft pad and head restraint were used to minimize head movement during data acquisition. All dynamic 11 [C]PHNO PET scans were acquired on a Siemens Biograph 6 PET / CT scanner (Hi-Rez (PET / CT1) or TruePoint with TrueV (Siemens Healthcare, Erlangen, Germany)). All scans for a particular subject were acquired on the same scanner. A low-dose computed tomography (CT) scan was performed immediately before each PET study to estimate signal decay. 11 After intravenous bolus injection of [C]PHNO, dynamic emission data were acquired over 90 minutes with increasing duration of 26 frames. Dynamic images were reconstructed with a 5 mm isotropic Gaussian filter on a 128 × 128 matrix using Fourier rebinning and a 2D filtered discrete inverse Fourier transform algorithm, resulting in 2 mm isotropic voxels with a 2.6x zoom. Appropriate corrections for attenuation, randomness, and scatter were applied.

[0235] Analysis method

[0236] All imaging data were analyzed using the MIAKAT™ ( Gunn et al., 2016 ) software package (version 4.2.6.1) implemented using MATLAB® (version R2016a; The Mathworks Inc., Natick, MA, USA), and FSL (version 5.0.4; FMRIB, Oxford, UK; Jenkinson et al., 2005 ; Smith et al., 2004 ) functions for brain extraction, and SPM12 (Wellcome Trust Centre for Neuroimaging) for image segmentation and registration.

[0237] Image Processing

[0238] Each subject's structural MRI image undergoes brain extraction, gray matter segmentation, and co-registration to a standard reference space (MNI152; Grabner et al., 2006). The MNI152 template brain image and associated atlas (CIC atlas; Tziortzi et al., 2011) are nonlinearly warped to the control MR image, allowing for automatic definition of regions of interest (ROIs).

[0239] The first set of ROIs defined were the ventral striatum (VSt), putamen (Pu), and cerebellum. VSt and Pu were defined as the regions of the brain that were most closely related to the cerebellum after d-AMPH challenge. 11 C]-(+)-PHNO BP ND Among these ROIs, those previously selected were based on a previous study that found the most reproducible and robust reductions in cerebellum (Shotbolt et al., 2012). The cerebellum was used as a reference region. An additional set of ROIs was also evaluated, including the caudate nucleus (Ca), globus pallidus (GP), and substantia nigra (SN).

[0240] Dynamic PET imaging was registered to each subject's MRI scan and corrected for motion using a frame-by-frame registration process with a normalized mutual information cost function. ROIs defined on the MRI images were applied to the dynamic PET data to obtain regional time-activity curves (TACs).

[0241] Dynamic modeling

[0242] The Simplified Reference Tissue Model (SRTM) (Lammertsma and Hume, 1996) 11 It has been demonstrated to be suitable for modeling [C]-PHNO PET data (Ginovart et al., 2006; Graff-Guerrero et al., 2010; Searle et al., 2010; Tziortzi et al., 2011; Willeit et al., 2006). Regional TAC data extracted from PET images were fitted using a basis function implementation of SRTM (Gunn et al., 1997), thereby yielding, for each PET scan, the binding potential relative to the unsubstituted component (BP) as a measure of specific binding. ND ) was estimated (Innis et al., 2007).

[0243] After d-AMPH challenge 11 Decreased specific binding of [C]-PHNO

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[0244] After the combination of Compound (I) and d-AMPH, 11 Decreased specific binding of [C]-PHNO

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[0245] Effect of Compound (I) (ΔΔBP ND )of,

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[0246] All statistical comparisons were performed using Student's t test for each ROI, paired tests for within subject comparisons, and unpaired tests for between-group comparisons.

[0247] result

[0248] Image data were successfully acquired for 32 PET scans in 12 study subjects. Two subjects had baseline [ 11Only [C]PHNO PET scans were acquired. The remaining 10 subjects each had three [ 11 [C]PHNO PET scans were acquired. For all scans, radiochemical purity was >95%, the mean injected radioactivity was 120 ± 26 MBq, and the mean injected PHNO mass was 18.4 ± 3.0 ng / kg. The maximum difference in injected mass for the three scans in each subject was <5%.

[0249] The acquired PET images showed the expected anatomically heterogeneous signal, which is consistent with the known distribution of D2 / D3 receptors and previous [ 11 For all scans, acceptable SRTM models were obtained that fit the tissue TAC data, and for the major ROIs, the BP ND Values ​​were well determined (<10% COV).

[0250] d-AMPH challenge significantly increased BP in all analyzed ROIs. ND A decrease in

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[0251] [Table 9]

[0252] Pretreatment with Compound (I) attenuated the effect of d-AMPH challenge in all tested ROIs. This effect was significant in Pu and VSt, as well as in SN (Table 10, *=p<0.05). A dose effect of Compound (I) was observed in Pu and GP, where ΔΔBP in the 40 mg group was significantly higher. ND was significantly greater than that in the 20 mg group (one-tailed t-test, p<0.01). ND There was no relationship between plasma concentrations of

[0253] [Table 10]

[0254] The mechanism underlying the modulation of dopamine release by Compound (I) is unclear, and it appears to be observed in all regions tested. GPR139 expression has been shown to correlate with D2R expression in a range of brain regions, and these two receptors have been shown to interact in stable cell lines (Wang et al., 2019). Similar interactions have been demonstrated with MC3 and MC5 receptors (Noehr et al., 2017) and the μ-opioid receptor (Wang et al., 2019), indicating that GPR139 can heterodimerize with other GPCRs and regulate their signaling. Thus, modulation of D2R autoreceptors by Compound (I) may decrease synaptic dopamine release.

[0255] Example 3: Randomized, double-blind, placebo-controlled, two-period crossover proof of activity study to evaluate the effect of Compound (I) on motivational anhedonia as an add-on to antipsychotic medication in subjects with stable schizophrenia This phase 2 study evaluated the mechanism of action and efficacy of Compound (I) in patients with schizophrenia experiencing moderate to severe negative symptoms. Specifically, the study was designed to assess the effects of Compound (I) on motivational anhedonia and cognitive function using both cognitive task performance and neuroimaging markers. To assess reward and cognition in patients with schizophrenia, a series of specific tests was used, including both performance tests and task-induced fMRI BOLD assessments. The MID was used to assess brain reward function because abnormal activation during the MID task has consistently been reported in patients with schizophrenia, particularly in areas regulated by the habenula, such as the ventral tegmental area (VTA) (Nielsen et al., 2012) and nucleus accumbens (NAcc) (Radua et al., 2015). Importantly, differences in NAcc and ventral striatum brain activity during the MID task were also directly associated with the severity of negative symptoms (Juckel et al., 2006; Radua et al., 2015). Outside the scanner, cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) tool ( Keefe et al., 2004 ).

[0256] Compound (I) was safe and well-tolerated in subjects with stable schizophrenia in a Phase 2 study. Compound (I) modulated reward task activation after 14 days of exposure, but not acutely. Changes in striatal response were associated with changes in both positive symptoms (Nielsen et al., 2012) and negative symptoms (Juckel et al., 2006; Radua et al., 2015). Compound (I) also exhibited variable effects on cerebral blood flow, with a broad and robust decrease on day 1 compared with placebo, followed by an increase on day 14, reflecting the opposite direction of the API's effect on reward responses. BACS performance was unaffected by Compound (I) treatment, and performance on this task was not correlated with any changes in extracted BOLD values.

[0257] In this study, exploratory analyses of changes in symptomatology as measured by the PANSS and BNSS did not reveal any relationship between reward anticipatory responses and symptom severity, except for a negative association between anhedonia and ventral striatum response at day 14, which did not survive multiple comparison correction. However, studies reporting associations between symptom change and ventral striatum response have typically assessed patients over longer timescales (e.g., 6 weeks). Therefore, longer treatment periods may be necessary to understand the impact of these imaging changes on symptoms and behavior.

[0258] methodology

[0259] This study was a randomized, double-blind, placebo-controlled, two-period, crossover Phase 2 study to evaluate the PD efficacy, safety, tolerability, and pharmacokinetics (PK) of a single dose of oral Compound (I) in adult subjects with schizophrenia, particularly negative symptoms characterized by decreased motivation. The primary objectives were (1) to determine whether the motivation / reward deficits observed in schizophrenia are attenuated by add-on administration of Compound (I) to antipsychotic medication in subjects with stable schizophrenia; and (2) to determine whether cognitive impairments associated with schizophrenia are improved by add-on administration of Compound (I) to antipsychotic medication in subjects with stable schizophrenia. Secondary objectives were to determine the safety and tolerability of Compound (I) as add-on treatment to antipsychotic medication in subjects with stable schizophrenia.

[0260] The study consisted of two treatment periods, each of which consisted of a single dose of study drug. To reduce the possibility of residual Compound (I) affecting the PD endpoint, there was a 35-day (+7-day) washout interval between the two doses. Treatment Period 2 began at the end of the washout period of Treatment Period 1. Because subjects were not confined in this study, they attended the clinic for the following visits: a screening visit (between days -35 and -2) covering a complete medical and psychiatric examination; a baseline assessment visit (day -1 of each treatment period) covering baseline motivation / reward and cognitive testing, excluding functional magnetic resonance imaging (fMRI); dosing and first study visit (day 1 of each treatment period); a second study visit (day 14 of each treatment period); a follow-up visit (treatment period 2 only, day 49 [± 4] post-dose); an end-of-period 1 visit (day 35 [+7] post-dose in period 1); and study withdrawal was at the final visit, 77 ± 7 days post-dose in period 2.

[0261] The study population included subjects with stable schizophrenia aged 18 to 60 years who met the study inclusion and exclusion criteria. On Day 1 of Period 1, eligible subjects were randomized 1:1 to one of two treatment sequences and received each study medication according to the randomized sequence. Randomization was stratified by study center. The initial dose of Compound (I) was 40 mg and was adjusted up to a maximum of 160 mg based on available PK and safety data from the first-in-human cohort. The decision criteria were predefined in the statistical analysis plan (SAP) before unblinding.

[0262] During the screening visit (Days -35 to -2), subjects who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia and were receiving stable antipsychotic therapy for at least two months completed medical and psychiatric examinations, electrocardiograms (ECGs), and laboratory safety tests. At the baseline assessment visit (Day -1) in Period 1, subjects completed a series of motivational / reward and cognitive practice sessions to minimize potential practice effects at subsequent treatment visits and to familiarize themselves with the magnetic resonance imaging (MRI) tasks. In both study periods, subjects were also tested on the Day -1 baseline assessment (excluding fMRI). Practice sessions were conducted prior to the baseline assessment in Period 1 only. Subjects who met all inclusion criteria and no exclusion criteria received study drug or placebo in the clinic according to the randomization schedule on Day 1 of treatment Periods 1 and 2.

[0263] On the first day of each treatment period, subjects underwent PD testing for a total of approximately four hours, beginning approximately two hours after administration of the study drug. Blood samples were collected at designated times after administration to assess the PK of Compound (I). Six hours after administration, the final PK collection was conducted, after which subjects left the study site. On the 14th day of each treatment period, subjects underwent a second set of PD testing, along with single-timepoint PK collection. PK samples were also collected on the 49th day and at the final visit of the second treatment period. The PD testing was conducted in three blocks separated by two breaks. The first block included the Grip Effort task, the Progressive Ratio Test, and the Brief Assessment of Cognition in Schizophrenia (BACS). The BACS is a reliable and sensitive battery of tests specifically designed to efficiently assess key cognitive deficits in patients with schizophrenia; therefore, the BACS is suitable for repeated testing in clinical trial settings (Keefe et al., 2004). It has been shown to have excellent internal consistency and test-retest reliability compared with alternative tests of neuropsychological status (Chianetta et al., 2008). The following cognitive domains, which have been consistently found to be impaired in schizophrenia, were assessed in this study: verbal memory; working memory; motor function; attention and processing speed; verbal fluency; and executive function. A composite score was calculated from each of the subset scores and used as one endpoint.

[0264] After the break, subjects underwent a second block of imaging studies, including non-contrast arterial spin-labeling MRI and brain perfusion using fMRI scans to monitor changes in blood oxygen level-dependent (BOLD) signal. fMRI was performed in a resting state (resting-state fMRI) and a two-task (two-task fMRI) using a monetary incentive delay (MID) reward task and a set-shifting task. After the break, subjects underwent a third block, including the Effort Expenditure for Rewards Task (EEfRT) and an empathic accuracy task. Subjects also completed the Positive and Negative Symptoms Scale (PANSS), the Brief Negative Symptom Scale (BNSS), and the Clinical Global Impression (CGI) scales (CGI Severity and CGI Improvement) as part of the PD assessment.

[0265] Pharmacogenomic assessments, as appropriate, were performed on blood samples taken on Day 1 (prior to Compound (I) or placebo administration) for DNA in Period 1 only, and on Day 1 (prior to Compound (I) or placebo administration) and Day 14 for RNA in both treatment periods.

[0266] participants

[0267] Twenty-three subjects were enrolled in the double-blind treatment period: 23 subjects in the safety analysis set, 22 subjects in the PK analysis set, and 23 subjects in the PD analysis set. One subject voluntarily withdrew after receiving Compound (I) due to failure to complete the MRI procedure, and one subject withdrew after receiving placebo due to failure to meet the inclusion criteria for a positive urine drug screen.

[0268] Sixty-six adult men or women (not of childbearing age, lactating, or parenting) with schizophrenia, aged 18–60 years, recruited from a local mental health service in the Greater London area, were screened for the study. Screening procedures occurred 2–35 days before the first administration and scanning session. Inclusion criteria required a diagnosis of DSM-5-defined schizophrenia by the Mini-Interview for Mental Illnesses (MINI) and no other active diagnoses of a serious psychiatric illness (e.g., bipolar disorder, depression, GAD, etc.) as defined by DSM-5 (including meeting criteria for a substance use disorder or a history of alcohol abuse within 1 month prior to screening). Participants had to be receiving a stable dose of an antipsychotic medication other than clozapine for at least 2 months prior to screening and had a score ≤90 on the PANSS. To ensure the presence of negative symptomatology, the PANSS (N1 blunted affect, N2 emotional withdrawal, N3 poor rapport, N4 Passive social withdrawal, N6 A negative symptom factor score (NSFS) of ≥ 15 was required, based on G7 lack of spontaneity and flow of conversation, G7 motor retardation, and G16 active social avoidance. To ensure symptom stability, the PANSS was re-administered the day before randomization, and participants with a change of > 20% in NSFS score or total PANSS score between screening and day -1 were excluded.

[0269] Participants who were deemed to be at risk for suicide during the screening window according to the Columbia-Suicide Severity Rating Scale (CSSRS) (positive answers to ideation questions 4 or 5, any suicidal behavior in the last 6 months, or a suicide attempt within the 6 months prior to screening) were also excluded. Subjects were also excluded if they had a history or reasonable suspicion of a medical condition that may contraindicate taking Compound (I) or that may interfere with the performance of the study, or if they currently had a diagnosis of a serious psychiatric illness other than schizophrenia and were in the acute phase / episode.

[0270] Assessment of overall physical suitability for the study included medical history, complete physical examination, vital signs, electrocardiogram, blood and urine chemistry profile, serology (HIV1, HIV2, hepatitis B and / or C, and pregnancy), alcohol and drug abuse tests, and concomitant medications. Only participants judged by the study physician to be in good physical health were included. Exclusion criteria included a history of cancer, liver function test values ​​>ULN, and a positive drug abuse or alcohol breath test on the screening or study day. Participants also had to agree to adhere to contraceptive guidelines during their participation to avoid pregnancy during the study.

[0271] The MRI scan visit during the screening window was conducted to familiarize participants with the scanning session. T1- and T2-weighted images were acquired and reviewed by a neuroradiologist to rule out any structural brain abnormalities or other abnormalities that would interfere with the interpretation of the functional brain imaging results.

[0272] Twenty-three screened participants (17 men) met the eligibility criteria and were randomized to the double-blind treatment trial (age range: 21-60 years, mean age: 43.8 ± 12.1 years). Most subjects were Black or African American, African British, Black British, or Black British of Caribbean descent (69.6%). The mean body mass index was 30.3 kg / m 2Medical history was unremarkable across subjects, with the most frequent comorbid medical conditions being hypertension, back pain, muscle spasms, seasonal allergies, and asthma.

[0273] Duration of treatment

[0274] The study consisted of two treatment periods in a randomized, double-blind, placebo-controlled, crossover design, during which participants received a single dose of Compound (I) or placebo. Given the long half-life of Compound (I), there was a washout interval of 35 to 42 days between the two doses.

[0275] Participants who passed the screening procedure and were suitable to participate attended the NIHR Clinical Research Facility at King's College Hospital, London, for the following visits:

[0276] Baseline Assessment Visit (Day -1 of each treatment period): Final screening assessments (blood tests, urine tests, drug and alcohol screening) were completed, as well as baseline cognitive exercises and testing, baseline psychiatric measures, and familiarization with scanner tasks.

[0277] Dosing and First Study Visit (Day 1 of each treatment period): Following a physical health check by a study physician (drug and alcohol screening, ECG, vitals, and physical examination), subjects received a single dose of either Compound (I) or placebo between 10:30 AM and 12:00 PM. BACS was performed approximately 2.5 hours after dosing, and the fMRI session began 3.5 hours after dosing.

[0278] Second Study Visit (Day 14 of each treatment period): Two weeks after the dosing date, participants returned to complete the BACS and another fMRI session (identical to the first session), which took place at the same time as the Day 1 study session.

[0279] End of Period 1 Visit (Days 35-42) and Beginning of Period 2: One visit at the end of Period 1 / beginning of Period 2 served as the baseline assessment visit (Day -1) for Period 2, after which visits on Days 1 and 14 were repeated as above, with participants receiving the reverse of the treatment they received in Period 1.

[0280] Follow-up Visit (Day 49 [± 4 days] post-dose, Period 2): Safety follow-up, including physical and psychiatric health assessment.

[0281] Study Withdrawal Visit (77±7 ​​days post-dose in Period 2): Day 49 follow-up.

[0282] Administration

[0283] Administration involved participants drinking one bottle of oral suspension containing either Compound (I) (40 or 160 mg of Compound (I) mixed with 70 mL of Tween® / MC vehicle) or placebo (70 mL of Tween® / MC vehicle) (Table 11). Participants were instructed to drink the entire contents of the bottle and then rinse the bottle twice with 35 mL of water, which the participant also consumed. The initial dose level selected was 40 mg, which was adjusted to 160 mg after a planned interim analysis of available PK and safety data from the first-in-human cohort data. As a result, the first seven participants received the 40 mg dose of Compound (I), and the remaining 17 participants received the 160 mg dose.

[0284] [Table 11]

[0285] PD analysis

[0286] The PD analysis set consisted of all subjects who received at least one dose of study drug and had at least one evaluable primary or exploratory measure.

[0287] The BOLD signal in the mean of left and right ventral striatum activation in the MID reward task 3.5 hours after dosing on day 1, and the BACS composite score on day 14 were the primary PD measures.

[0288] The BACS consisted of six subsets of items: verbal memory, numerical permutation, token movement, verbal fluency, symbols, and the Tower of London.

[0289] The observed BOLD signal was summarized by treatment (Compound (I) (total and by dose) and placebo) and time (N, mean, median, SD, minimum, and maximum). BACS composite scores were summarized for baseline, post-dose, and change from baseline by treatment, dose, and time.

[0290] Each of the major PD measures was analyzed using a Bayesian normal linear model, with effects for sequence, period, treatment, time (as categorical variables), treatment × time interactions, subject within treatment sequence, and baseline (for BACS only). For BOLD fMRI, the observed value was the response variable in the model. For BACS, the observed value and change from baseline were modeled separately. Missing values ​​were not entered and, under the assumption of missing at random, were not included in the model. A spread normal distribution with mean 0 and variance 106 was used as the prior distribution for the regression coefficients, and a spread inverse gamma distribution with shape and scale parameters of 0.01 was used for the residual variance.

[0291] Posterior means, SDs, and 90% confidence intervals (highest posterior density intervals) were extracted for each treatment and time, along with the posterior mean treatment.

[0292] Bayesian and linear mixed-effects models for repeated measures analysis were performed for BOLD fMRI MID and BACS. Linear mixed-effects models for repeated measures analysis were performed for BNSS and Grip A summary table and data list of observed values ​​and changes from baseline (except for BOLD fMRI MID) for each PD measure were provided.

[0293] The criteria for a positive outcome in IA were a 70% (or higher) posterior probability of a difference between Compound (I) and placebo >0.09 in ventral striatum activation in MID fMRI 3.5 hours after administration on Day 1, or a 70% (or higher) posterior probability of a difference between Compound (I) and placebo >2 points in the BACS composite score on Day 14.

[0294] Penalty kick results

[0295] The PK set consisted of all subjects who received at least one dose of study drug and had at least one measurable plasma concentration.

[0296] Plasma concentrations of Compound (I) were tabulated with descriptive statistics (mean, median, SD, % coefficient of variation, minimum, and maximum) for each treatment and dose level at each scheduled time point. Individual subject plasma concentration data were listed.

[0297] Plasma PK parameters of Compound (I) were determined from the concentration-time profiles for all evaluable subjects. Actual sampling times, rather than scheduled sampling times, were used in all calculations involving sampling time. The following PK parameters were calculated using noncompartmental analysis with Phoenix WinNonLin (version 6.3 or higher): area under the plasma concentration-time curve from time 0 to time t, area under the plasma concentration-time curve from time 0 to infinity (AUC∞ ), maximum observed plasma concentration (C max ), first C max Time to reach (t max ), and the half-life of the terminal elimination phase.

[0298] Following oral administration of a single dose of Compound (I) (40 mg or 160 mg) to subjects with schizophrenia, Compound (I) was rapidly absorbed, with t max The median values ​​were 1.83 hours and 1.92 hours. max A dose-dependent increase in mean C (and area under the plasma concentration-time curve) was observed with a 4-fold increase in Compound (I) dose. max values ​​increased 2.8-fold (549 ng / mL and 1523 ng / mL for 40 mg and 160 mg, respectively), and the mean AUC ∞ The values ​​increased 3.5-fold (217 h·μg / mL and 763 h·μg / mL for 40 mg and 160 mg, respectively).

[0299] safety

[0300] The safety analysis set consisted of all subjects who were enrolled and received at least one dose of study drug. Safety measures included adverse events, physical examination, vital signs, clinical laboratory assessments, ECG, and C-SSRS.

[0301] Subjects experienced TEAEs at similar frequencies in the placebo and Compound (I) treatment groups, and there were no patterns of differences between Compound (I) and placebo for any individual TEAE. No subjects discontinued study drug treatment due to TEAEs, and there were no deaths or serious adverse events. No TEAEs were classified as serious. There were no concerning trends with Compound (I) treatment compared to placebo in clinical laboratory tests, vital signs, ECG, physical examination, or C-SSRS.

[0302] Overall, Compound (I) was safe and well tolerated in subjects with stable schizophrenia.

[0303] Main objective results

[0304] On Day 1, Compound (I) reduced activation in the ventral striatum compared with placebo. The posterior mean and SD for the difference between the fMRI BOLD endpoint on Day 1 for placebo and the fMRI BOLD endpoint for Compound (I) at the 40 mg, 160 mg, and overall dose levels were -0.1 (0.21), -0.15 (0.14), and -0.14 (0.11), respectively (Figure 3). The posterior probabilities of an increase above placebo in the fMRI BOLD endpoint on Day 1 greater than 0.09 were 0.1706, 0.0373, and 0.0209. Due to the study design, the results did not demonstrate superiority of Compound (I) over placebo.

[0305] On day 14, there was a dose-dependent increase in activation compared to placebo (Figure 3). The fMRI BOLD endpoint, i.e., mean activation of the left and right ventral striatum regions of interest (ROIs) during the MID reward task on day 14, met the predefined criteria for a "positive" signal for the 160 mg dose and overall. The posterior probabilities of a treatment difference greater than 0.09 for BOLD MID fMRI for these dose levels were 0.4657, 0.8314, and 0.7913, indicating superiority of Compound (I) over placebo on day 14. However, this set of criteria was proposed for the results on day 1, and therefore, overall, this study did not meet the "positive" criteria.

[0306] The posterior mean (SD) for the difference between the BACS composite score at placebo and the BACS composite score at the 40 mg, 160 mg, and overall dose levels of Compound (I) on Day 14 was -0.23 (2.95), -0.84 (1.87), and -0.61 (1.50), respectively. The posterior probabilities of a population increase over placebo in the BACS composite score on Day 14 of greater than 2 points were 0.2079, 0.0633, and 0.0413. Due to the study design, the results were insufficient to demonstrate superiority of Compound (I) over placebo.

[0307] mean whole cerebral blood flow

[0308] Although the literature on blood flow changes in schizophrenia populations is conflicting, the general pattern appears to be a decrease in cortical gray matter blood flow when compared to healthy controls, with both increases and decreases reported in subcortical regions as well ( Zhu et al., 2017 ).

[0309] Whole-brain maps of regional cerebral blood flow (CBF) were obtained using previously reported ASL methodology (Hawkins et al., 2018; Dai et al., 2008). Briefly, images were acquired using a pseudo-continuous arterial spin-labeling sequence (pCASL) with a multi-shot, segmented 3D stack of an axial spiral (8-arm) readout, resulting in a spatial resolution of 2 × 2 × 3 mm. Three contrast-labeled pairs were used to derive perfusion-weighted subtraction images. The duration of the labeling RF pulse was 1.5 seconds, with a 1.5-second post-labeling delay. The sequence included background suppression to maximally reduce static tissue signal. Proton density images were acquired in 48 seconds using the same acquisition parameters as those used to calculate the CBF maps, in standard physiological units (mL blood / 100 g tissue / min). Two trials were acquired per visit and averaged after preprocessing.

[0310] The T2-weighted images were co-registered to the T1-weighted images before creating a DARTEL template. The proton density images from each session were then co-registered to the T2-weighted images. The parameters for this transformation were then applied to the CBF maps, and the DARTEL flow field was applied to normalize the CBF maps to MNI space, followed by smoothing with a 6 mm FWHM kernel.

[0311] Mean whole-brain cerebral blood flow (CBF) was extracted using the SPM MNI whole-brain mask in the MarsBar and analyzed at each time point with a mixed two-way ANOVA (treatment (placebo / drug) within-subject factor, dose level (40 mg / 160 mg) between-subject factor) (Figure 4). On day 1, there was a significant effect of treatment (F(1,18) = 5.978, p = 0.025), but no treatment × dose interaction (F(1,18) = 2.306, p = 0.146). On day 14, there was no significant effect of treatment (F(1,15) = 3.558, p = 0.079), and no treatment × dose interaction (F(1,15) = 2.973, p = 0.105).

[0312] Example 4: Compound (I) tablet formulation Tablets containing 40 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof were developed for use in the relative bioavailability / food effect study discussed in Example 1. These tablets had the composition shown in Table 12, where (a) refers to components removed during processing and qs stands for sufficient quantity. Components labeled (b) are components of the premixed coating materials Opadry® Red 03F45081 and Opadry® Yellow 03F42240.

[0313] Wet granulation process is used to prepare tablets containing at least one compound selected from Compound (I) and its pharmaceutically acceptable salt.This process is composed of the common manufacturing method widely used in the pharmaceutical industry.Process conditions are set based on historical knowledge of the manufacturing process for similar formulations using the same equipment.

[0314] [Table 12]

[0315] To prepare tablets containing at least one compound selected from Compound (I) and its pharmaceutically acceptable salts, a binder solution is prepared by dissolving hydroxypropyl cellulose in purified water by stirring.At least one compound selected from Compound (I) and its pharmaceutically acceptable salts, mannitol, and microcrystalline cellulose are loaded into a fluidized bed granulator.The loaded powder is granulated in the fluidized bed granulator by spraying the binder solution.The granules are dried in the fluidized bed granulator.The dried granules are then passed through a screen mill or sieved through a suitable sieve.The milled granules are then blended with croscarmellose sodium, magnesium stearate, and microcrystalline cellulose in a diffusion mixer, and then the blended granules are compressed into tablets using a tablet press. Tablets were coated by pan coating with an aqueous film coating solution containing Opadry® Red 03F45081 and Opadry® Yellow 03F42240 and inspected visually or by automated inspection. The manufacturing flow diagram is shown in Figure 5.

[0316] Further non-limiting examples of tablet compositions comprising at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof, prepared according to the procedures described above, include those listed in Table 13. The exemplary compositions in Table 13 contain 20 mg or 40 mg of at least one compound selected from Compound (I) and pharmaceutically acceptable salts thereof.

[0317] [Table 13]

Claims

[Claim 1] The invention described in the specification.

Images