Methods for treating neurological and psychiatric disorders

Abstract

The present invention provides an effective method of treating neurological and psychiatric diseases and disorders (eg, schizophrenia) with a lower incidence of adverse events. Compound 1, or a pharmaceutically acceptable salt thereof, is an antipsychotic drug with a non-D2 mechanism of action. Adverse events associated with antipsychotic drugs that target D2 dopamine receptors can be reduced by treating disorders with Compound 1, or a pharmaceutically acceptable salt thereof. JPEG2026035701000060.jpg6443

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 039,722, filed June 16, 2020, and U.S. Provisional Application No. 63 / 009,595, filed April 14, 2020, the contents of which are incorporated herein by reference in their entireties.

[0002] The present disclosure relates to methods for treating neurological and psychiatric diseases and disorders. [Background technology]

[0003] The D2 dopamine receptor is the primary target for both typical and atypical antipsychotics. Wang et al. NATURE 555, 269-273 (2018). However, many drugs that target the D2 dopamine receptor cause severe or potentially life-threatening side effects. Wang et al. Nature 555, 269-273 (2018). Despite decades of research into non-D2 mechanisms of action, developing safe and effective non-D2 antipsychotic therapies remains challenging. Girgis et al., J. Psychiatric Res. (2018), https: / / doi.org / 10.1016 / j.jpsychires.2018.07.006. Specifically, after conducting a comprehensive review of the literature on experimental treatments for schizophrenia, including 250 studies from 1970 to 2017, including glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormonal, dopaminergic, metabolic, vitamin / natural therapy, histaminergic, infectious / inflammatory, and various other mechanisms for treating schizophrenia, Girgis states, "Despite several promising [non-D2] targets, such as allosteric modulation of NMDA and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are undoubtedly effective and clinically ready for use in the treatment of schizophrenia." Therefore, there is a need for therapeutic agents that are effective in treating neurological and psychiatric diseases and disorders (e.g., schizophrenia) and have lower adverse event rates.

[0004] As disclosed herein, Compound 1 has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for a new drug for the treatment of patients with schizophrenia. Breakthrough Therapy Designation is intended to expedite the development and review of drugs for the treatment of serious or life-threatening diseases when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically meaningful endpoints compared to available therapies. The FDA granted Breakthrough Therapy Designation to Compound 1 based on the pivotal Phase 2 clinical trial data disclosed herein. Summary of the Invention

[0005] The present disclosure relates to methods for treating neurological and psychiatric diseases and disorders.

[0006] In some embodiments, a method of treating a patient having a neurological or psychiatric disease or disorder, said method comprising administering to said patient Compound 1 [ka] or a pharmaceutically acceptable salt thereof is orally administered in the evening or at night or around bedtime.

[0007] In some embodiments, a method for treating a neurological or psychiatric disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of Compound 1. [ka] or a pharmaceutically acceptable salt thereof in the evening, at night, or around bedtime, thereby minimizing adverse events in the patient. In some embodiments, the method minimizes adverse events associated with antipsychotic drugs that have affinity for dopamine D2 receptors.

[0008] In some embodiments, a method for treating a neurological or psychiatric disease or disorder in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the evening, at night, or around bedtime, wherein the method is substantially devoid of adverse events. In some embodiments, the risk of adverse events in the patient is about the same as or similar to that of a placebo.

[0009] In some embodiments, there is provided a method for treating a neurological or psychiatric disease or disorder in a patient, the method being substantially devoid of the adverse events of antipsychotics that have affinity for the dopamine D2 receptor, comprising administering to the patient a therapeutically effective amount of an antipsychotic that does not have direct affinity for the dopamine D2 receptor selected from Compound 1, or a pharmaceutically acceptable salt thereof, in the evening or at night or around bedtime.

[0010] In some embodiments, there is provided a method of minimizing adverse events in a patient in need of treatment for a neurological or psychiatric disease or disorder, the method comprising administering to the patient in the evening, at night, or around bedtime a therapeutically effective amount of an antipsychotic drug that does not have direct affinity for the dopamine D2 receptor, wherein the antipsychotic drug is Compound 1, or a pharmaceutically acceptable salt thereof, and the method minimizes adverse events associated with antipsychotic drugs that have affinity for the dopamine D2 receptor.

[0011] In some embodiments, a method for treating a neurological or psychiatric disease or disorder in a patient without exposing the patient to a risk of clinically significant adverse events is provided, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the evening, at night, or around bedtime, wherein the risk of the adverse events is associated with antipsychotic drugs with affinity for dopamine D2 receptors. In some embodiments, the disease or disorder is schizophrenia.

[0012] In some embodiments, provided is a method of administering an antipsychotic to a patient in need of treatment without incurring the risk of clinically significant adverse events, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the evening or at night or around bedtime, wherein the patient does not experience clinically significant adverse events.

[0013] In some embodiments, a method for treating a patient with a neurological or psychiatric disease or disorder that does not pose a risk of clinically significant adverse events is provided, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the evening, at night, or around bedtime. In some embodiments, the patient has schizophrenia.

[0014] In some embodiments, an adverse event refers to one or more of the following: a cardiovascular adverse event (e.g., atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, postural tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension, or orthostatic tachycardia), an extrapyramidal adverse event (e.g., akathisia, restlessness, joint stiffness, musculoskeletal stiffness, neck stiffness, postural tremor, or tremor), hyperprolactinemia, insomnia, anxiety, headache, schizophrenia, somnolence, agitation, nausea, diarrhea, and dyspepsia.

[0015] In some embodiments, the method is effective in treating a neurological or psychiatric disease or disorder in the patient. In some instances, the method improves one or more of the Positive and Negative Symptom Scale (PANSS) total score, the PANSS subscores (negative, positive, and overall psychopathology), the Clinical Global Impression-Severity (CGI-S) score, the Brief Negative Symptom Scale (BNSS) total score, and the Montgomery-Asberg Depression Rating Scale (MADRS) total score.

[0016] In some embodiments, there is provided a method of treating a neurological or psychiatric disease or disorder in a patient, said method comprising administering to said patient a therapeutically effective amount of an antipsychotic drug that does not have direct affinity for dopamine D2 receptors in the evening, at night, or around bedtime, wherein said method is substantially devoid of adverse events in said patient, said adverse events being associated with the antipsychotic drug that has affinity for dopamine D2.

[0017] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is crystalline Form A of Compound 1 hydrochloride. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 shows the MMRM analysis of the change from baseline in PANSS total score for the study of Example 1.1. [Figure 2] FIG. 2 shows the MMRM analysis of the change from baseline in PANSS positive subscale scores for the study in Example 1.1. [Figure 3] FIG. 3 shows the MMRM analysis of the change from baseline in PANSS negative subscale scores for the study in Example 1.1. [Figure 4] FIG. 4 shows the MMRM analysis of the change from baseline in PANSS Global Psychopathology subscale scores for the study in Example 1.1. [Figure 5] FIG. 5 shows the MMRM analysis of the change from baseline in CGI-S scores for the study of Example 1.1. [Figure 6] FIG. 6 shows the MMRM analysis of the change from baseline in BNSS total score for the study of Example 1.1. [Figure 7] FIG. 7 shows the MMRM analysis of the change from baseline in MADRS total score for the study of Example 1.1. [Figure 8]FIG. 8 shows the median change in prolactin levels from baseline to week 4 for the study of Example 1.1. [Figure 9] FIG. 9 shows the PANSS total scores observed during the double-blind treatment (Example 1.1) and open-label extension study (Example 1.2). [Figure 10] FIG. 10 shows the PANSS positive subscores observed during the double-blind treatment (Example 1.1) and open-label extension study (Example 1.2). [Figure 11] FIG. 11 shows the PANSS negative subscores observed during the double-blind treatment (Example 1.1) and open-label extension study (Example 1.2). [Figure 12] FIG. 12 shows the PANSS total psychopathology subscores observed during the double-blind treatment (Example 1.1) and open-label extension study (Example 1.2). [Figure 13] FIG. 13 shows the CGI-S scores observed during the double-blind treatment (Example 1.1) and open-label extension study (Example 1.2). [Figure 14] FIG. 14 shows the BNSS total scores observed during the double-blind treatment (Example 1.1) and open-label extension study (Example 1.2). [Figure 15] FIG. 15 shows the MADRS total scores observed during the double-blind treatment (Example 1.1) and open-label extension study (Example 1.2). [Figure 16] FIG. 16 shows the change in prolactin levels from open-label baseline to week 26. [Figure 17] FIG. 17 shows the change in (A) weight and (B) body mass index (BMI) from open-label baseline to week 26. [Figure 18]FIG. 18 shows the change in lipids from open-label baseline to week 26: (A) total cholesterol (total), (B) triglycerides (total), (C) HDL (total), and (D) LDL (total). [Figure 19] FIG. 19 shows the change from open-label baseline to week 26 in glycemic indices: (A) glucose (total), and (B) HbA1c. [Figure 20] FIG. 20 shows (A) time to all-cause discontinuation in the study of Example 1.2 and (B) comparative data for other medications. [Figure 21] Figure 21 (FIG. 21) and Figure 22 (FIG. 22) show the XRPD patterns of crystalline form A of Compound 1 hydrochloride, where Figure 21 is an XRPD measured in transmission and Figure 22 is an XRPD measured in reflection. [Figure 22] Figure 21 (FIG. 21) and Figure 22 (FIG. 22) show the XRPD patterns of crystalline form A of Compound 1 hydrochloride, where Figure 21 is an XRPD measured in transmission and Figure 22 is an XRPD measured in reflection. [Figure 23] FIG. 23 is a DSC thermogram of crystalline form A of Compound 1 hydrochloride. [Figure 24A] FIG. 24A shows the mean (±SEM) number of infusions in the self-administration (cocaine substitution) test of Example 5. [Figure 24B] FIG. 24B shows the mean (±SEM) number of infusions in the self-administration (amphetamine substitution) study of Example 5. [Figure 24C] FIG. 24C shows the mean (±SEM) number of infusions in the self-administration (heroin substitution) study of Example 5. [Figure 25A] FIG. 25A shows the mean (±SEM) amphetamine-paired lever response rates for Compound 1 (po = orally) in the drug discrimination study of Example 5. [Figure 25B] FIG. 25B shows the mean (±SEM) response rates to Compound 1 in the drug discrimination study of Example 5. [Figure 26A] FIG. 26A shows the mean (±SEM) MDMA-paired lever response rates for Compound 1 in the drug discrimination study of Example 5. [Figure 26B] FIG. 26B shows the rate of amphetamine-paired lever responding relative to buspirone in the drug discrimination study of Example 5. [Figure 27A] FIG. 27A shows the mean (±SEM) number of active lever presses during the cue-induced reinstatement test session in the cocaine reinstatement study of Example 5. [Figure 27B] FIG. 27B shows the mean (±SEM) number of active lever presses during the cocaine prime-induced reinstatement test session in the cocaine reinstatement study of Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0019] All publications cited herein are incorporated by reference in their entirety.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Accordingly, the following terms are intended to have the following meanings:

[0021] As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0022] Unless otherwise specified, the word "includes" (or any variations thereof, such as "include," "including," etc.) is intended to be open-ended. For example, "A includes 1, 2, and 3" means that A includes, but is not limited to, 1, 2, and 3.

[0023] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease or disorder, or one or more symptoms thereof, including, but not limited to, a therapeutic benefit. In some embodiments, treatment is administered after one or more symptoms have arisen, e.g., after an acute exacerbation of symptoms. In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a subject prior to the onset of symptoms (e.g., taking into account previous symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0024] Therapeutic benefit includes eradication and / or amelioration of the underlying disease being treated, and also includes eradication and / or amelioration of one or more symptoms associated with the underlying disease, such that an improvement is observed in the subject, even though the subject may still be afflicted by the underlying disease. In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disorder (e.g., reducing one or more symptoms caused by the disorder and / or attenuating the severity of the disorder); (b) delaying or halting the onset of one or more symptoms associated with the disorder (e.g., stabilizing the disorder and / or slowing the worsening or progression of the disorder); and / or (c) alleviating the disorder (e.g., causing a reduction in clinical symptoms, ameliorating the disorder, slowing the progression of the disorder, and / or increasing quality of life).

[0025] As used herein, "administering" or "administration" of Compound 1, or a pharmaceutically acceptable salt thereof, includes delivering Compound 1, or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, e.g., as described herein.

[0026] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount that is effective to elicit a desired biological or medical response, and includes the amount of a compound that, when administered to a subject for treating a disorder, is sufficient to effect such treatment of the disorder. The effective amount will vary depending on the disorder and its severity, as well as the age of the subject to be treated. An effective amount may be one or more doses (e.g., one dose or multiple doses may be required to achieve a desired therapeutic endpoint). An effective amount may be considered to be administered in an effective amount if, in combination with one or more other agents, a desired or beneficial result is likely to be achieved or is achieved. The appropriate dose of any co-administered compound may be reduced appropriately depending on the combined, additive, or synergistic effects of the compounds.

[0027] As used herein, "delaying" the onset of a disorder means to postpone, prevent, slow, stabilize, and / or postpone the onset of a disorder. The delay period depends on the individual's medical history and / or treatment and can be of varying lengths of time.

[0028] As used herein, "prevention" or "preventing" refers to a regimen that protects against the occurrence of a disorder, such that clinical symptoms of the disorder do not develop. Thus, "prevention" relates to administering a therapy to a subject before signs of the disease are detectable in the subject (e.g., administering a therapy in the absence of detectable symptoms of the disorder). The subject may be an individual at risk of developing a disorder.

[0029] As used herein, an "at risk" individual is one who is at risk of developing the disorder to be treated. This may be indicated, for example, by one or more risk factors, which are measurable parameters that correlate with the development of the disorder and are known in the art.

[0030] As used herein, the "subject" or "patient" to whom administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, toddlers, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or geriatrics)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, including, for example, cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or commercially relevant birds, including, for example, chickens, ducks, geese, quail, and / or turkeys. As used herein, "subject" and "patient" are interchangeable.

[0031] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other substances useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0032] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable risk-benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of Compound 1 include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed using other methods used in the art, such as ion exchange. Other 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, lanthanide ... Counterions include butbionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable counterions will be preferred for the preparation of pharmaceutical formulations, although other anions are quite acceptable as synthetic intermediates.Thus, X may be a pharmaceutically undesirable anion, such as iodide, oxalate, trifluoromethanesulfonate, and the like, when such salts are chemical intermediates.

[0033] As used herein, the term "pharmaceutically acceptable excipient" includes, but is not limited to, any binder, filler, adjuvant, carrier, additive, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, tonicity agent, solvent, emulsifier, anti-caking agent, flavoring agent, desiccant, plasticizer, disintegrant, lubricant, polymer matrix system, polymer coating system, and glazing agent, approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0034] As used herein, a "clinically significant" risk of an adverse event refers to a risk that is statistically significant greater than that of a placebo. If the risk of an adverse event or a particular adverse event is less than, the same as, or about the same as that of a placebo, the risk is not clinically significant.

[0035] As used herein, a "clinically meaningful" risk of an adverse event refers to a risk that is less than the risk of the same adverse event with an antipsychotic drug that has affinity for the dopamine D2 receptor, although the difference is not necessarily statistically significant. If the risk of an adverse event or a particular adverse event is less than with an antipsychotic drug that has affinity for the dopamine D2 receptor, the risk is not clinically significant. In some embodiments, the risk of a clinically meaningful adverse event can be determined by a person of ordinary skill in the art of treating and / or prescribing antipsychotic drugs to patients in need. In some embodiments, the risk of a clinically meaningful adverse event can be determined by comparative calculations across patient populations.

[0036] As used herein, a method that is "substantially devoid" of adverse events refers to a method that is associated with an adverse event rate that is less than, the same as, or about the same as a placebo.

[0037] As used herein, "minimizing" an adverse event refers to a statistically significant reduction in the incidence of an adverse event in a patient population compared to the typical incidence of the adverse event in a patient population treated with an antipsychotic drug having affinity for the D2 dopamine receptor. Such antipsychotic drugs (e.g., as defined herein) with affinity for the D2 dopamine receptor will have such therapeutic affinity for the D2 dopamine receptor that one skilled in the art might propose direct targeting of the D2 dopamine receptor as a primary mechanism of action (either alone or in combination with another receptor). The risk of the corresponding adverse event in a patient is correspondingly reduced. In some embodiments, the adverse event incidence refers to the frequency or rate of a particular adverse event for a patient population. In some embodiments, the adverse event incidence refers to the total number of adverse events experienced by an individual subject.

[0038] As used herein, "antipsychotic agents" are a group of medications specifically used to treat, prevent, or manage psychosis, e.g., schizophrenia or bipolar disorder, and more broadly in the treatment of various neurological and psychiatric disorders. First-generation antipsychotics are known as "typical antipsychotics" and include chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, pericyazine, promazine, thioridazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupenthixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopenthixol. Second-generation antipsychotics, known as "atypical antipsychotics," include aripiprazole, asenapine maleate, clozapine, iloperidone, lurasidone, olanzapine, olanzapine / fluoxetine, paliperidone, quetiapine, risperidone, and ziprasidone. Both typical and atypical antipsychotics target and have affinity for D2 dopamine receptors.

[0039] An "adverse event" is any untoward medical occurrence associated with the use of a drug in a human, whether or not it is considered drug-related. "Adverse events," as used herein, include events associated with antipsychotic drugs that have affinity for the dopamine D2 receptor. In some embodiments, the adverse event is drug-seeking behavior. In some embodiments, the drug-seeking behavior is abuse, misuse, addiction, physical dependence, and / or tolerance. In some embodiments, the adverse event is abuse, misuse, addiction, physical dependence, and / or tolerance. In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt thereof, does not clinically significantly increase the patient's tendency toward drug-seeking behavior. In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt thereof, does not clinically significantly increase the patient's tendency toward abuse, misuse, addiction, physical dependence, or tolerance. In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt thereof, does not clinically significantly increase the patient's tendency toward abuse, misuse, addiction, physical dependence, or tolerance. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is not a controlled substance. As used herein, the term "abuse" refers to the intentional non-therapeutic use of a drug, even on a single occasion, due to its undesirable psychological or physiological effects. As used herein, the term "misuse" refers to the intentional therapeutic use of a drug by an individual other than as directed by a healthcare provider or by an individual for whom the drug has not been prescribed. As used herein, the term "addiction" refers to a group of behavioral, cognitive, and physiological phenomena, including a strong desire to take a drug, difficulty controlling drug use (e.g., continuing drug use despite harmful consequences, prioritizing drug use over other activities and obligations), and possible tolerance or physical dependence. Physical dependence is not synonymous with addiction; a patient can be physically dependent on a drug without being addicted to it. Similarly, abuse is not synonymous with addiction. Tolerance, physical dependence, and withdrawal symptoms are all expected biological phenomena that result from chronic treatment with a particular drug.These phenomena do not in themselves indicate a state of addiction. As used herein, the term "physical dependence" refers to a state in which withdrawal signs and symptoms appear after abrupt cessation or significant drug reduction as a result of physiological adaptation to repeated drug use. As used herein, the term "tolerance" refers to a physiological state characterized by a decreased response to a drug after repeated administration (e.g., higher doses of the drug are required to produce the same effect previously achieved with lower doses). As used herein, the term "controlled substance" refers to a drug or other substance, or immediate precursor, listed in Schedules I, II, III, IV, or V of 21 U.S.C. §§ 811-814, which are incorporated herein by reference.

[0040] "Adverse events associated with antipsychotic agents with affinity to dopamine D2 receptors" are understood by those skilled in the art to be representative adverse events of D2 antipsychotic therapy. In some embodiments, the adverse events associated with antipsychotic agents with affinity to dopamine D2 receptors are any one or more of the class effects of antipsychotic drugs. In some embodiments, the adverse events associated with antipsychotic agents with affinity for dopamine D2 receptors are any one or more of the class effects of typical antipsychotic drugs. In some embodiments, the adverse events associated with antipsychotic agents with affinity for dopamine D2 receptors are any one or more of the class effects of atypical antipsychotic drugs. In some embodiments, the adverse events associated with antipsychotic agents with affinity for dopamine D2 receptors are any one or more of the class effects of atypical antipsychotic drugs. In some embodiments, the adverse events associated with antipsychotic agents with affinity for dopamine D2 receptors are cardiovascular adverse events or extrapyramidal adverse events. In some embodiments, adverse events associated with antipsychotics with affinity for the dopamine D2 receptor include cardiovascular adverse events (e.g., atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, postural orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension, or orthostatic tachycardia), extrapyramidal adverse events (e.g., akathisia, restlessness, joint stiffness, musculoskeletal stiffness, neck stiffness, postural tremor, or tremor), hyperprolactinemia, insomnia, anxiety, headache, schizophrenia, somnolence, agitation, nausea, diarrhea, and dyspepsia.

[0041] As used herein, "about" in reference to a time (e.g., bedtime) refers to the indicated time ±3 hours or less, e.g., the indicated time ±3 hours, the indicated time ±2 hours, the indicated time ±1 hour, the indicated time ±30 minutes, or the indicated time ±15 minutes.

[0042] "Bedtime," as used herein, refers to the time a subject normally goes to bed to sleep.

[0043] The present disclosure describes various embodiments. Those skilled in the art who review this disclosure will readily recognize that the various embodiments can be combined in any variation. For example, embodiments of the present disclosure include treatment of various disorders, patient populations, various dosages, administration of dosage forms, minimization of various adverse events, and improvement of various efficacy indicators. Any combination of the various embodiments is within the scope of the present disclosure.

[0044] Compound 1, as described herein for use in the methods of the disclosure, has the following structure: [ka] or a pharmaceutically acceptable salt thereof. Unless otherwise indicated or the context requires otherwise, in this disclosure, the term "Compound 1" refers to [ka] Also included are pharmaceutically acceptable salts of the compounds.

[0045] The chemical name of Compound 1 is (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (sometimes abbreviated as "(S)-TPMA"), or a pharmaceutically acceptable salt thereof. Those skilled in the art will recognize various compound nomenclatures. Thus, Compound 1 may also be identified as (S)-1-(4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine, (S)-1-(5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine, or others, or a pharmaceutically acceptable salt thereof. For example, Compound 1, or a pharmaceutically acceptable salt thereof, identified as SEP-0363856 or SEP-856, has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) as a new drug for the treatment of patients with schizophrenia. Breakthrough Therapy Designation is intended to expedite the development and review of drugs for the treatment of serious or life-threatening diseases when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically meaningful endpoints compared with available therapies. The FDA granted Breakthrough Therapy Designation to Compound 1, or a pharmaceutically acceptable salt thereof, based on pivotal Phase 2 clinical trial data disclosed herein. Compound 1, or a pharmaceutically acceptable salt thereof, is an antipsychotic with an indirect D2 mechanism of action and exhibits broad efficacy in animal models of psychosis and depression. The molecular targets involved in the antipsychotic and antidepressant efficacy of Compound 1, or a pharmaceutically acceptable salt thereof, are trace amine associated receptor-1 (TAAR1) and 5HT 1A It is understood that the compound 1 has agonist activity at both α and β receptors. For example, as described in Dedic et al. The Journal of Pharmacology and Experimental Therapeutics 371, 1-14 (2019), compound 1 was tested against several panels of known molecular targets (ion channels, G protein-coupled receptors (GPCRs), and enzymes), and at 10 μM, compound 1 exhibited α 2A , α 2B , D2, 5-HT 1A, 5-HT 1B , 5-HT 1D , 5-HT 2A , 5-HT 2B , 5-HT 2C and 5-HT7 receptors, exhibiting >50% inhibition of specific binding. Further receptor panel screening and complementary functional testing revealed that compound 1 exhibits variable activity at several receptors. The human TAAR1 receptor (EC 50 , maximum effect (E max ) = 101.3% ± 1.3%) and 5-HT 1A Receptor (EC 50 = 2.3 μM, values ​​range from 0.1 to 3 μM, E max =74.7%±19.6%). In the D2 receptor functional assay, Compound 1 exhibited an agonism of 10.44±4 μM (cAMP, E max = 23.9% ± 7.6%) and 8 μM (β-arrestin recruitment, E max =27.1%) 50 Without being bound to a particular mechanism of action, Compound 1 is also theorized to act as a presynaptic dopamine modulator.

[0046] Compound 1 can be used in the methods described herein as a free base or in the form of a pharmaceutically acceptable salt. In some embodiments, the hydrochloride (HCl) salt of Compound 1 is used in the methods described herein.

[0047] Compound 1, or a pharmaceutically acceptable salt thereof, can be obtained according to the production methods described in PCT Patent Publication No. WO2011 / 069063 (U.S. Patent No. 8,710,245, issued April 29, 2014) or PCT Patent Publication No. WO2019 / 161238, which are incorporated herein by reference in their entirety for all purposes, or methods analogous thereto.

[0048] Compound 1, or a pharmaceutically acceptable salt thereof, may be in amorphous or crystalline form. In some embodiments, a crystalline form of Compound 1, or a pharmaceutically acceptable salt thereof, is used in the methods described herein. In some embodiments, crystalline Form A of the HCl salt of Compound 1 is used in the methods described herein.

[0049] In some embodiments, crystalline Form A of the HCl salt of Compound 1 is characterized by a powder x-ray diffraction pattern comprising peaks in 2-theta at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°C, and 25.1±0.2°C, and in some embodiments, further comprising peaks at 20.2±0.2° and 20.8±0.2°, and in some embodiments, further comprising peaks at 20.2±0.2° and 20.8±0.2°, and prominent peaks at two or more of 17.9±0.2°, 24.8±0.2°, and 27.1±0.2°. An example of a method for preparing crystalline Form A of the HCl salt of Compound 1 is provided in Example 4.

[0050] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is substantially enantiomerically pure. In some examples, a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, comprises about 90%, 95%, 97%, 99%, 99.5%, 99.7%, or 99.9% or more of Compound 1 relative to the total amount of Compound 1 and its (R)-enantiomer in the composition. In some embodiments, the substantially enantiomerically pure crystalline Form A of the HCl salt of Compound 1 is used in the methods described herein.

[0051] Also provided herein are pharmaceutical compositions and dosage forms comprising Compound 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The compositions and dosage forms provided herein may further comprise one or more additional active ingredients. Compound 1, or a pharmaceutically acceptable salt thereof, may be administered as part of a pharmaceutical composition, as described herein.

[0052] Selecting the right medication to treat a neurological or psychiatric disease or disorder involves finding a medication that causes few or no adverse events in patients. As disclosed herein, physicians who want to avoid a trial-and-error approach to treating a neurological or psychiatric disease or disorder can select Compound 1 from available antipsychotics and treat patients without the risk of clinically significant adverse events. For example, this can be important for patients at risk for QT prolongation, as QT prolongation is a serious adverse event that can result in death. As disclosed herein, Compound 1, unlike some antipsychotic drugs with affinity for the dopamine D2 receptor, does not pose the risk of clinically significant QT prolongation, potentially allowing for safer dosing in patients at high risk for QT prolongation. The risk of QT prolongation in patients who have not previously received neurological or psychiatric medication may be unknown. However, in some embodiments provided herein, Compound 1 can be administered without the risk of clinically significant QT prolongation. Other adverse events, such as other cardiovascular events, may take some time to manifest, such as weight gain, changes in blood lipids, or blood glucose levels. Over time, such events can lead to cardiovascular problems in patients. Administration of Compound 1 can prevent or significantly reduce adverse events.

[0053] The present disclosure relates to methods of treating neurological and psychiatric diseases and disorders, such as schizophrenia.

[0054] In some embodiments, a method of treating a patient having a neurological or psychiatric disease or disorder, said method comprising administering to said patient Compound 1 [ka] or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, there is provided a method for treating a neurological or psychiatric disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. [ka] and minimizing adverse events in the patient, comprising administering to the patient a therapeutically effective amount of a steroid drug, wherein the therapeutically effective amount of a steroid drug is a steroid drug, and ...

[0056] In some embodiments, a method for treating a neurological or psychiatric disease or disorder in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the method is substantially devoid of adverse events. In some embodiments, the method poses a risk of adverse events in the patient that is approximately the same as or similar to that of a placebo.

[0057] In some embodiments, a method for treating a neurological or psychiatric disease or disorder in a patient is provided, the method being substantially devoid of the adverse events of antipsychotics that have affinity for the dopamine D2 receptor, comprising administering to the patient a therapeutically effective amount of an antipsychotic that does not have direct affinity for the dopamine D2 receptor, selected from Compound 1, or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, a method of minimizing adverse events in a patient in need of treatment for a neurological or psychiatric disease or disorder is provided, comprising administering to the patient a therapeutically effective amount of an antipsychotic drug that does not have direct affinity for dopamine D2 receptors, wherein the antipsychotic drug is Compound 1, or a pharmaceutically acceptable salt thereof, and wherein the method minimizes adverse events associated with antipsychotic drugs that have affinity for dopamine D2 receptors. In some embodiments, the method reduces the incidence of such adverse events compared to treatment with an antipsychotic drug that has affinity for dopamine D2 receptors.

[0059] In some embodiments, provided is a method for treating a neurological or psychiatric disease or disorder in a patient without exposing the patient to a risk of a clinically significant adverse event, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the risk of the adverse event is associated with an antipsychotic drug having affinity for the dopamine D2 receptor.

[0060] In some embodiments, a method of administering an antipsychotic drug to a patient in need of treatment without incurring the risk of clinically significant adverse events is provided, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the patient does not experience clinically significant adverse events. In some embodiments, the method treats a neurological or psychiatric disease or disorder (e.g., schizophrenia) in the patient.

[0061] In some embodiments, there is provided a method of treating a neurological or psychiatric disease or disorder in a patient, said method comprising administering to said patient a therapeutically effective amount of an antipsychotic drug that does not have direct affinity for dopamine D2 receptors, wherein said method is substantially devoid of adverse events in said patient, said adverse events being associated with the antipsychotic drug that has affinity for dopamine D2.

[0062] In some embodiments, there is provided use of Compound 1, or a pharmaceutically acceptable salt thereof, in the treatment of a neurological or psychiatric disease or disorder, as generally described herein, e.g., with minimized adverse events. Also provided is Compound 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurological or psychiatric disease or disorder, as generally described herein, e.g., with minimized adverse events. Also provided is use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological or psychiatric disease or disorder, as generally described herein, e.g., with minimized adverse events.

[0063] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily for a 29-day treatment period. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily for a 26-week or 30-week treatment period.

[0064] In some embodiments, adverse events refer to any one or more of the following: cardiovascular adverse events (atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, postural orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension, orthostatic tachycardia), extrapyramidal adverse events (akathisia, restlessness, joint stiffness, musculoskeletal stiffness, neck stiffness, postural tremor, tremor), hyperprolactinemia, insomnia, anxiety, headache, schizophrenia, somnolence, agitation, nausea, diarrhea, and dyspepsia.

[0065] In some embodiments, the disclosed methods are effective in treating a neurological or psychiatric disease or disorder in the patient. In some instances, the methods improve one or more of the Positive and Negative Symptom Scale (PANSS) total score, PANSS subscores (negative, positive, and overall psychopathology), Clinical Global Impression-Severity (CGI-S) score, Brief Negative Symptom Scale (BNSS) total score, and Montgomery-Asberg Depression Rating Scale (MADRS) total score.

[0066] In some embodiments, the method results in one or more of the following: a reduction in PANSS total score from baseline, e.g., a reduction in PANSS total score from baseline of at least 1, 2, 3, 4, 5, 7, 10, 15, or 17 (e.g., at least 17.2), or a reduction in PANSS total score from baseline of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%; or a PANSS total score effect size of at least 0.1, 0.2, 0.3, or 0.4 (e.g., at least 0.45); or a statistically significantly improved PANSS responder rate compared to placebo (e.g., a responder rate at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20% higher than placebo); a reduction in the PANSS negative subscale score from baseline, e.g., a reduction in the PANSS negative subscale score from baseline of at least 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, or 3 (e.g., at least 3.1), or a reduction in the PANSS negative subscale score from baseline of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%, or an effect size of the PANSS negative subscale score of at least 0.1, 0.2, 0.3, or 0.35 (e.g., at least 0.37); a reduction in PANSS positive subscale score from baseline, e.g., a reduction in PANSS positive subscale score from baseline of at least 1, 2, 3, 4, or 5 (e.g., at least 5.5), or a reduction in PANSS positive subscale score from baseline of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%; or an effect size in PANSS positive subscale score of at least 0.1, 0.2, or 0.3 (e.g., at least 0.32); a reduction in the PANSS Composite Psychopathology subscale score from baseline, e.g., a reduction in the PANSS Composite Psychopathology subscale score from baseline of at least 1, 2, 3, 4, 5, 7, or 9 (e.g., at least 9), or a reduction in the PANSS Composite Psychopathology subscale score from baseline of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%, or an effect size in the PANSS Composite Psychopathology subscale score of at least 0.1, 0.2, 0.3, 0.4, or 0.5 (e.g., at least 0.51); a decrease in CGI-S score from baseline, e.g., a decrease in CGI-S score from baseline of at least 0.2, 0.4, 0.6, 0.8, or 1 (e.g., at least 1), or a decrease in CGI-S score from baseline of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20% or an effect size of CGI-S score of at least 0.1, 0.2, 0.3, 0.4, or 0.5 (e.g., at least 0.52); a reduction in BNSS total score from baseline, e.g., a reduction in BNSS total score from baseline of at least 1, 2, 3, 4, 5, 6, or 7 (e.g., at least 7.1), or a reduction in BNSS total score from baseline of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%; or an effect size of BNSS total score of at least 0.1, 0.2, 0.3, 0.4, or 0.45 (e.g., at least 0.48); and A reduction in the MADRS total score from baseline, e.g., a reduction in the MADRS total score from baseline of at least 0.5, 1, 1.5, 2, 2.5, or 3 (e.g., at least 3.3), or a reduction in the MADRS total score from baseline of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%; or an effect size of the MADRS total score of at least 0.1, 0.2, or 0.3 (e.g., at least 0.32).

[0067] In some embodiments, the reduction in PANSS (total or subscore), CGI-S, BNSS, or MADRS score is measured after a 29-day treatment period.

[0068] In some embodiments, the reduction in scores is measured after a 30-week treatment period. In some embodiments, the methods of the disclosure result in (i) a reduction of at least about 30 in the PANSS total score from baseline after 30 weeks of treatment; (ii) a reduction of at least about 10 in the PANSS positive subscale score from baseline after 30 weeks of treatment; (iii) a reduction of at least about 5 in the PANSS negative subscale score from baseline after 30 weeks of treatment; (iv) a reduction of at least about 15 in the PANSS global psychopathology subscale score from baseline after 30 weeks of treatment; (v) a reduction of at least about 1.5 in the CGI-S score from baseline after 30 weeks of treatment; (vi) a reduction of at least about 10 in the BNSS total score from baseline after 30 weeks of treatment; and / or (vii) a reduction of at least about 5 in the MADRS total score from baseline after 30 weeks of treatment.

[0069] In some embodiments, the methods of the disclosure reduce the number of adverse events leading to discontinuation during a treatment period, e.g., 29 days, 26 weeks, or 30 weeks. For example, in some embodiments, the methods result in less than 50%, less than 40%, or less than 35% of patients discontinuing treatment due to adverse events over a 26-week or 30-week treatment period.

[0070] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. In some embodiments, the patient experiences an acute exacerbation of schizophrenia. In some embodiments, treating schizophrenia comprises ameliorating the symptoms of schizophrenia. In some embodiments, treating schizophrenia comprises treating the negative symptoms of schizophrenia.

[0071] In some embodiments, the neurological or psychiatric disease or disorder is psychiatric symptoms associated with Parkinson's disease.

[0072] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia spectrum disorder, negative symptoms of schizophrenia, attenuated psychotic syndrome, prodrome of schizophrenia, delusional disorder, psychosis, psychotic disorder, delirium, Tourette's syndrome, post-traumatic stress disorder, behavioral disorder, affective disorder, depression, bipolar disorder, major depressive disorder, dysthymia, mania, seasonal affective disorder, obsessive-compulsive disorder, narcolepsy, REM behavior disorder, substance abuse or dependence, Lesch-Nyhan disease, Wilson's disease, autism, agitation and psychosis of Alzheimer's disease, or Huntington's chorea.

[0073] In some embodiments, the neurological or psychiatric disease or disorder is selected from schizophrenia, attenuated psychotic syndrome, schizophrenia prodrome, schizoid personality disorder, and schizotypal personality disorder.

[0074] In some embodiments, the neurological or psychiatric disease or disorder is agitation and psychosis associated with Alzheimer's disease. In some embodiments, the patient has dementia. In some embodiments, the neurological or psychiatric disease or disorder is dementia-related psychosis.

[0075] In some embodiments, the psychosis is selected from organic psychosis, drug-induced psychosis, psychotic symptoms associated with Parkinson's disease, and agitated psychosis.

[0076] In some embodiments, the neurological or psychiatric disease or disorder is a bipolar disorder selected from bipolar disorder and bipolar depression.

[0077] In some embodiments, the patient has an inadequate response to an antipsychotic that is at least one typical antipsychotic or at least one atypical antipsychotic. In some embodiments, the patient has an inadequate response to an antipsychotic, and the antipsychotic is a typical antipsychotic or an atypical antipsychotic. In some embodiments, the patient has not responded adequately to an antipsychotic agent, and the antipsychotic agent is a typical antipsychotic agent (e.g., chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, pericyazine, promazine, thioridazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupenthixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, zuclopenthixol) or an atypical antipsychotic agent (e.g., aripiprazole, asenapine maleate, clozapine, iloperidone, lurasidone, olanzapine, olanzapine / fluoxetine, paliperidone, quetiapine, risperidone, ziprasidone).

[0078] In some embodiments, the patient is elderly.

[0079] In some embodiments, treating a neurological or psychiatric disease or disorder comprises ameliorating the symptoms of said neurological or psychiatric disease or disorder.

[0080] In some embodiments, the patient is characterized by one or more of the following: the patient is an adult; The patient has been diagnosed with schizophrenia for at least six months; The patient has experienced an acute exacerbation of psychotic symptoms for at least two months; The patient has been hospitalized no more than two times for treatment of an acute exacerbation of schizophrenia; The patient has a baseline PANSS total score of at least 80; The patient has a baseline PANSS score of at least 4 with two or more of the following: delusions, conceptual disorganization, hallucinatory behavior, and unnatural thought content; and The patient has a baseline CGI-S score of at least 4.

[0081] In some embodiments, an adverse event refers to one or more of the following: a cardiovascular adverse event (e.g., atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, postural orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension, or orthostatic tachycardia), an extrapyramidal adverse event (e.g., akathisia, restlessness, joint stiffness, musculoskeletal stiffness, neck stiffness, postural tremor, or tremor), hyperprolactinemia, insomnia, anxiety, headache, schizophrenia, somnolence, agitation, nausea, diarrhea, and dyspepsia.

[0082] The D2 dopamine receptor is the primary target for both typical and atypical antipsychotics. Wang et al. NATURE 555, 269-273 (2018). Unfortunately, many drugs targeting the D2 dopamine receptor cause severe and potentially life-threatening side effects due to indiscriminate activity against related receptors. Wang et al. Nature 555, 269-273 (2018). Currently available antipsychotic drugs with affinity for D2 dopamine receptors include typical antipsychotics such as chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, pericyazine, promazine, thioridazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupenthixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopenthixol, and atypical antipsychotics such as aripiprazole, asenapine maleate, clozapine, iloperidone, lurasidone, olanzapine, olanzapine / fluoxetine, paliperidone, quetiapine, risperidone, and ziprasidone. Adverse events associated with typical and atypical antipsychotics include cardiovascular adverse events (e.g., atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, postural orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension, or orthostatic tachycardia), extrapyramidal adverse events (e.g., akathisia, restlessness, joint stiffness, musculoskeletal stiffness, neck stiffness, postural tremor, or tremor), and hyperprolactinemia, insomnia, anxiety, headache, schizophrenia, somnolence, agitation, nausea, diarrhea, and dyspepsia.

[0083] In some embodiments, the antipsychotic-related adverse event is any one or more of the following adverse events in the class effect, as defined by the EBGM ranking using FAERS. In some embodiments, the antipsychotic-related adverse event is any one or more of the following: hyperprolactinemia, abnormal blood prolactin, increased blood prolactin, galactorrhea, cogwheel rigidity, obesity, metabolic syndrome, akathisia, oromandibular dystonia, parkinsonism, sialorrhea, eye rotation, obsessive-compulsive disorder, muscle rigidity, type 2 diabetes, diabetes, overweight, parkinsonian gait, tongue spasm, and tardive dyskinesia. Diarrhea, bradykinesia, tics, psychomotor developmental delay, extrapyramidal disorder, enuresis, impaired glucose tolerance, hypersalivation, dystonia, diabetes, restlessness, torticollis, impaired fasting glucose, autosomal recessive dyscrasia, elevated body mass index, hyperactivity, viral hepatitis, dyskinesia, increased blood triglycerides, electrocardiogram QT prolongation, sleep abnormalities, orthostatic hypertension, bruxism, increased appetite, excessive eye blinking, chronic pancreatitis, weight gain, dyslipidemia, restless legs syndrome, tongue biting, or stiff neck.

[0084] In some embodiments, Compound 1 is used to treat hyperprolactinemia, abnormal blood prolactin levels, increased blood prolactin levels, galactorrhea, cogwheel rigidity, obesity, metabolic syndrome, akathisia, oromandibular dystonia, parkinsonism, sialorrhea, eye rotation attacks, obsessive-compulsive disorder, muscle rigidity, type 2 diabetes, diabetes, overweight, parkinsonian gait, tongue spasms, tardive dyskinesia, bradykinesia, tics, psychomotor developmental delay, extrapyramidal disorders, enuresis, Does not clinically significantly increase the risk of any one or more of the following adverse events: impaired glucose tolerance, hypersalivation, dystonia, diabetes, restlessness, torticollis, impaired fasting glucose, autosomal recessive eczema, elevated body mass index, hyperactivity, viral hepatitis, dyskinesia, elevated blood triglycerides, prolonged QT interval on electrocardiogram, sleep disorders, orthostatic hypertension, bruxism, increased appetite, excessive eye blinking, chronic pancreatitis, weight gain, dyslipidemia, restless legs syndrome, tongue biting, or stiff neck.

[0085] Compound 1, or a pharmaceutically acceptable salt thereof, does not have direct affinity for D2 dopamine receptors. As described herein (e.g., in the Examples below), when administered to patients, Compound 1, or a pharmaceutically acceptable salt thereof, did not cause the high incidence of adverse events and serious adverse events associated with typical or atypical antipsychotics that target D2 dopamine receptors. Surprisingly, as described in the Examples herein (e.g., Examples 1.1 and 1.2), despite its potent efficacy, Compound 1 had an adverse event profile similar to that of placebo. In particular, the incidence of cardiovascular adverse events (e.g., QT prolongation, orthostatic hypotension, orthostatic tachycardia), extrapyramidal adverse events, hyperprolactinemia, insomnia, anxiety, and headache experienced by patients was not clinically significant (i.e., less than, the same as, or approximately the same as, or similar to, placebo).

[0086] In some embodiments, the disclosed methods minimize cardiovascular adverse events. In some embodiments, the methods are substantially devoid of cardiovascular adverse events. In some embodiments, the risk of the cardiovascular adverse events in the patient is about the same as or similar to placebo. In some embodiments, the methods result in cardiovascular events in 5% or less of patients. In some embodiments, the methods result in cardiovascular adverse events in 4.2% or less of patients. In some embodiments, the methods result in cardiovascular adverse events in 5% or less (e.g., 4.2% or less) of patients during a 29-day treatment period. In some embodiments, the methods result in cardiovascular adverse events in 6% or less (e.g., 5.8% or less) of patients during a 26-week treatment period. In some embodiments, the methods result in cardiovascular adverse events in patients at a rate no greater than placebo by 1%.

[0087] In some embodiments, the patient is at increased risk of adverse cardiovascular events from administration of an antipsychotic drug with direct affinity for the dopamine D2 receptor. In some embodiments, the patient has a history of cardiovascular disease. In some embodiments, the patient has a history of adverse cardiovascular events from previous antipsychotic therapy. In some embodiments, the patient is susceptible to adverse cardiovascular events from antipsychotic drugs with direct affinity for the dopamine D2 receptor.

[0088] In some embodiments, the patient is not actively monitored for cardiovascular adverse events during the treatment period. In some embodiments, the patient is not monitored by electrocardiogram monitoring during the treatment period. In some embodiments, the patient is not warned about cardiovascular adverse events. In some embodiments, the patient is not concurrently treated for cardiovascular adverse events.

[0089] In some embodiments, the cardiovascular adverse event is considered to be atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, postural tachycardia syndrome, elevated blood pressure, hypertension, hypotension, or hot flashes. In some embodiments, the cardiovascular adverse event is considered to be atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, postural tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension, or orthostatic tachycardia.

[0090] In some embodiments, the disclosed methods minimize extrapyramidal adverse events. In some embodiments, the methods are substantially devoid of extrapyramidal adverse events. In some embodiments, the risk of the extrapyramidal adverse events in the patient is about the same as or similar to placebo. In some embodiments, the methods result in extrapyramidal adverse events in 5% or less of patients. In some embodiments, the methods result in extrapyramidal adverse events in 3.3% or less of patients. In some embodiments, the methods result in extrapyramidal adverse events in 5% or less of patients during a 29-day treatment period. In some embodiments, the methods result in extrapyramidal adverse events in 5% or less (e.g., 3.2% or less) of patients during a 26-week treatment period. In some embodiments, the methods result in extrapyramidal adverse events in no greater proportion than placebo.

[0091] In some embodiments, the patient is at increased risk for extrapyramidal adverse events from administration of an antipsychotic drug with direct affinity for the dopamine D2 receptor. In some embodiments, the patient has a history of extrapyramidal adverse events from previous antipsychotic therapy. In some embodiments, the patient is susceptible to extrapyramidal adverse events from antipsychotic drugs with direct affinity for the dopamine D2 receptor.

[0092] In some embodiments, the patient is not warned about extrapyramidal adverse events.

[0093] In some embodiments, the extrapyramidal adverse event is considered akathisia, restlessness, joint stiffness, musculoskeletal stiffness, nuchal rigidity, postural tremor, or tremor.

[0094] In some embodiments, the methods of the present disclosure minimize QT prolongation. In some embodiments, the methods are substantially devoid of QT prolongation. In some embodiments, the risk of QT prolongation in the patient is about the same as or similar to placebo. In some embodiments, the methods result in QT prolongation in 5% or less of patients. In some embodiments, the methods result in QT prolongation in 1% or less of patients. In some embodiments, the methods are substantially devoid of QT prolongation over a 29-day treatment period. In some embodiments, the methods result in QT prolongation in no greater proportion of patients than placebo.

[0095] In some embodiments, the patient is at increased risk of QT prolongation due to administration of an antipsychotic. In some embodiments, the patient has a history of QT prolongation due to previous antipsychotic therapy. In some embodiments, the patient is susceptible to QT prolongation due to antipsychotics with direct affinity for dopamine D2 receptors. In some embodiments, the patient has hypokalemia, hepatitis C, HIV, electrocardiogram T wave abnormalities, is female, is elderly, or is taking a second active drug known to increase the risk of QT prolongation.

[0096] In some embodiments, the patient is not actively monitored for QT prolongation. In some embodiments, the patient is not warned about QT prolongation. In some embodiments, the patient is not concurrently treated for QT prolongation.

[0097] In some embodiments, QT prolongation is considered to be one or both of the following: A QTcF interval of greater than 450 milliseconds that was not present at baseline is present in said patient at any time point; and An increase in the QTcF interval of 30 milliseconds or more from baseline on at least one post-baseline measurement.

[0098] In some embodiments, QT prolongation is considered to be one or both of the following: If the patient is male, the patient has a QTcF interval of greater than 450 milliseconds at any time point that was not present at baseline, or if the patient is female, the patient has a QTcF interval of greater than 470 milliseconds at any time point that was not present at baseline; and An increase in the QTcF interval of 30 milliseconds or more from baseline on at least one post-baseline measurement.

[0099] In some embodiments, QT prolongation is considered to be one or both of the following: If the patient is male, the patient has a QTcF interval of greater than 450 milliseconds at any time point that was not present at baseline, or if the patient is female, the patient has a QTcF interval of greater than 470 milliseconds at any time point that was not present at baseline; and An increase in the QTcF interval of 60 milliseconds or more from baseline on at least one post-baseline measurement.

[0100] Prolongation of the QTc interval on the electrocardiogram (ECG) can lead to torsades de pointes, syncope, and may be associated with the development of ventricular arrhythmias that may result in ventricular fibrillation and sudden death. The mean QTc interval in healthy adults is approximately 400 milliseconds. A QTc interval of 500 milliseconds or greater is considered a substantial risk factor for torsades de pointes.

[0101] In some embodiments, the disclosed methods minimize hyperprolactinemia. In some embodiments, the methods are substantially free of hyperprolactinemia. In some embodiments, the risk of hyperprolactinemia in the patient is about the same as or similar to placebo. In some embodiments, the methods are free of the risk of clinically significant hyperprolactinemia. In some embodiments, the methods are substantially free of hyperprolactinemia during a 29-day treatment period. In some embodiments, the methods are substantially free of hyperprolactinemia during a 26-week treatment period. In some embodiments, the methods result in hyperprolactinemia in patients at a rate no greater than placebo.

[0102] In some embodiments, the patient is at increased risk of hyperprolactinemia due to administration of an antipsychotic drug with direct affinity for the dopamine D2 receptor. In some embodiments, the patient has a history of hyperprolactinemia due to previous antipsychotic therapy. In some embodiments, the patient is susceptible to hyperprolactinemia due to an antipsychotic drug with direct affinity for the dopamine D2 receptor.

[0103] In some embodiments, the patient is not actively monitored for hyperprolactinemia, in some embodiments, the patient is not warned about hyperprolactinemia, and in some embodiments, the patient is not concurrently treated for hyperprolactinemia.

[0104] Hyperprolactinemia refers to a significant increase in the concentration of prolactin and is known to occur during the administration of certain antipsychotic drugs.

[0105] In some embodiments, the metabolic effects of the method are the same as or similar to a placebo, e.g., the patient's total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride, and / or glucose levels are the same as or similar to a placebo. In some embodiments, the method does not result in clinically significant weight gain.

[0106] In some embodiments, the disclosed methods minimize orthostatic hypotension. In some embodiments, the methods are substantially devoid of orthostatic hypotension. In some embodiments, the risk of orthostatic hypotension in the patient is about the same as or similar to placebo. In some embodiments, the methods result in orthostatic hypotension in 5% or less of patients. In some embodiments, the methods result in orthostatic hypotension in 4.2% or less of patients. In some embodiments, the methods result in orthostatic hypotension in 5% or less of patients over a 29-day treatment period. In some embodiments, the methods result in orthostatic hypotension in no greater proportion of patients than placebo.

[0107] In some embodiments, the patient is at increased risk of orthostatic hypotension due to administration of an antipsychotic. In some embodiments, the patient has a history of orthostatic hypotension due to previous antipsychotic therapy. In some embodiments, the patient is susceptible to orthostatic hypotension due to antipsychotics that have direct affinity for dopamine D2 receptors.

[0108] In some embodiments, the patient is not actively monitored for orthostatic hypotension, in some embodiments, the patient is not warned about orthostatic hypotension, and in some embodiments, the patient is not concurrently treated for orthostatic hypotension.

[0109] In some embodiments, the disclosed methods minimize orthostatic tachycardia. In some embodiments, the methods are substantially devoid of orthostatic tachycardia. In some embodiments, the risk of orthostatic tachycardia in the patient is about the same as or similar to placebo. In some embodiments, the methods result in orthostatic tachycardia in 5% or less of patients. In some embodiments, the methods result in orthostatic tachycardia in 4.2% or less of patients. In some embodiments, the methods result in orthostatic tachycardia in 5% or less of patients over a 29-day treatment period. In some embodiments, the methods result in orthostatic tachycardia in a rate that is no more than 2% greater than placebo.

[0110] In some embodiments, the patient is at increased risk of orthostatic tachycardia due to administration of an antipsychotic. In some embodiments, the patient has a history of orthostatic tachycardia due to previous antipsychotic therapy. In some embodiments, the patient is susceptible to orthostatic tachycardia due to antipsychotics that have direct affinity for dopamine D2 receptors.

[0111] In some embodiments, the patient is not actively monitored for orthostatic tachycardia, in some embodiments, the patient is not warned for orthostatic tachycardia, and in some embodiments, the patient is not concurrently treated for orthostatic tachycardia.

[0112] Compound 1 is an antipsychotic with a non-D2 mechanism of action that exhibits broad efficacy in animal models of psychosis and depression. As described in the Examples below, Compound 1 demonstrates efficacy in the treatment of schizophrenia. Specifically, the efficacy measures of the Positive and Negative Symptom Scale (PANSS) total score, PANSS subscores (negative, positive, and overall psychopathology), Clinical Global Impression-Severity (CGI-S) score, Brief Negative Symptom Scale (BNSS) total score, and Montgomery-Asberg Depression Rating Scale (MADRS) total score each showed improvement (e.g., compared to placebo) in patients suffering from an acute exacerbation of schizophrenia treated with Compound 1.

[0113] Thus, in some embodiments, the methods of the present disclosure result in one or more of the following: · A reduction of at least 17.2 in the PANSS total score from baseline; · PANSS total score effect size of at least 0.45; · A decrease of at least 5.5 in the PANSS positive subscale score from baseline; · An effect size of PANSS positive subscale score of at least 0.32; · A decrease of at least 3.1 in the PANSS negative subscale score from baseline; · An effect size of PANSS negative subscale score of at least 0.37; · A reduction of at least 9 in the PANSS total psychopathology subscale score from baseline; · An effect size of the PANSS total psychopathology subscale score of at least 0.51; · A decrease of at least 1 in CGI-S score from baseline; · An effect size of CGI-S score of at least 0.52; · A reduction of at least 7.1 in BNSS total score from baseline; · An effect size of BNSS total score of at least 0.48; A reduction in the MADRS total score of at least 3.3 from baseline; and / or · An effect size of MADRS total score of at least 0.32.

[0114] In some embodiments, the methods described herein further comprise treating the symptoms of insomnia, anxiety, or headache in the patient. In some embodiments, the risk of insomnia, anxiety, headache, or any combination thereof in the patient is less than placebo. In some embodiments, the methods minimize insomnia, anxiety, headache, or any combination thereof.

[0115] In some embodiments, the symptom is insomnia. In some embodiments, the symptom is anxiety. In some embodiments, the symptom is headache. In some embodiments, the methods described herein further comprise treating dizziness in the patient. In some embodiments, the risks of insomnia, anxiety, headache, schizophrenia, somnolence, agitation, nausea, diarrhea, and dyspepsia, individually or as a group, are not clinically significant (i.e., less than, the same as, about the same as, or similar to placebo).

[0116] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., once daily) for a 4-week treatment period. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., once daily) for a 29-day treatment period. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., once daily) for one month or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years; chronically, continuously). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in the evening or at night (e.g., once daily in the evening or at night). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered around bedtime (e.g., once daily at bedtime). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in the evening or around nighttime at bedtime (e.g., once daily in the evening or at nighttime at bedtime). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at approximately the same time every day (e.g., at approximately the same time every evening or nighttime at bedtime). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a daily dose (e.g., daily escalating dose, daily therapeutic dose) of about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 25 mg to about 100 mg, about 25 mg, about 50 mg, about 75 mg, or about 100 mg.

[0117] In some embodiments, administering Compound 1 or a pharmaceutically acceptable salt thereof comprises a titration period and a treatment period. In some instances, a first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered during the titration period, followed by a therapeutic dose of Compound 1 or a pharmaceutically acceptable salt thereof during the treatment period. In some instances, a second dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered after the first dose during the titration period and before the therapeutic dose administered during the treatment period. The first dose may be less than the therapeutic dose. In some instances, the first dose is 50 mg per day, and the second dose, if administered, is 75 mg / day, with the therapeutic dose being 50 mg per day, 75 mg per day, or 100 mg per day. In some embodiments, the titration period is 3 days, followed by a treatment period (e.g., beginning on the 4th day, for example, until the 29th day, and continuing for 6 months or more, for example, 1 year). In some embodiments, the titration period is 7 days, followed by a treatment period (e.g., beginning on day 8 and continuing for 6 months or more, such as 1 year, for example, until day 29). In some embodiments of a 7-day titration period, 50 mg / day of Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1-3, and 75 mg / day of Compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 4-7.

[0118] In some embodiments, the therapeutic dose may be gradually reduced (e.g., from a 100 mg dose to a 75 mg dose, from a 75 mg dose to a 50 mg dose, from a 50 mg dose to a 25 mg dose). In some examples, a 75 mg dose may be reduced to a 50 mg dose. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as a variable dose from about 25 mg per day to about 100 mg per day (e.g., about 25 mg per day, about 50 mg per day, about 75 mg per day, or about 100 mg per day).

[0119] In some embodiments, a method for treating schizophrenia in a patient is provided, comprising administering to the patient Compound 1, or a pharmaceutically acceptable salt thereof, at a first dose daily for 1 to 3 days, followed by administering to the patient Compound 1, or a pharmaceutically acceptable salt thereof, at a therapeutic dose daily, wherein the first dose is less than the therapeutic dose. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a first dose daily on days 1-3, and Compound 1, or a pharmaceutically acceptable salt thereof, at a therapeutic dose daily on days 3 and thereafter (e.g., on days 4-29). In some embodiments, the first dose is 50 mg and the therapeutic dose is 75 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally (e.g., once daily). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in the evening or at night (e.g., once daily in the evening or at night). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered around bedtime (e.g., once daily at bedtime). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in the evening or around bedtime at night (e.g., once daily in the evening or at bedtime at night). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at approximately the same time every day (e.g., at approximately the same time every evening or night around bedtime).

[0120] In some embodiments, a method for treating schizophrenia in a patient is provided, comprising administering 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily for a 29-day treatment period. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily for a period of 6 months or more (e.g., 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, or 5 years). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in the evening or at night (e.g., once daily in the evening or at night). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered around bedtime (e.g., once daily at bedtime). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in the evening or at night around bedtime (e.g., once daily in the evening or at night around bedtime). In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at approximately the same time every day (e.g., at approximately the same time every evening or night around bedtime).

[0121] In some embodiments, there is provided a method of treating schizophrenia in a patient, the method comprising: administering or having administered to said patient 75 mg of Compound 1, or a pharmaceutically acceptable salt thereof, per day for the duration of treatment; Determining or having determined whether said patient experienced any adverse events during the treatment period; If the patient experiences an adverse event during the treatment period, the dosage may be reduced or has been reduced to 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, daily. A method is provided, characterized in that

[0122] In some embodiments, the method further comprises monitoring the patient during the treatment period for adverse events.

[0123] In some embodiments, a method for treating schizophrenia in a patient is provided, the method comprising orally administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount achieves a maximum plasma concentration of Compound 1, or a pharmaceutically acceptable salt thereof, in the patient 1 to 4 hours after a single dose and 2 to 4 hours after multiple doses, wherein the therapeutically effective amount is 50 mg or 75 mg per day.

[0124] In some embodiments, a method for treating schizophrenia in a patient is provided, the method comprising orally administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and achieving a steady-state plasma concentration of Compound 1, or a pharmaceutically acceptable salt thereof, in the patient within 7 days, wherein the therapeutically effective amount is 50 mg or 75 mg per day.

[0125] In some embodiments, a method for treating symptoms of insomnia, anxiety, or headache in a patient with schizophrenia is provided, comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the symptom is insomnia. In some embodiments, the symptom is anxiety. In some embodiments, the symptom is headache.

[0126] In some embodiments, a method is provided for treating insomnia, anxiety, or headache associated with schizophrenia in a patient, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, a method for treating schizophrenia in a patient is provided, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the patient experiences a lower incidence of insomnia, anxiety, or headache, or any combination thereof, than placebo.

[0128] In some embodiments, a method is provided for reducing a PANSS total score in a patient suffering from schizophrenia, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, resulting in (i) a reduction in the PANSS total score from baseline of at least 17.2 or (ii) an effect size of the PANSS total score of at least 0.45.

[0129] In some embodiments, a method is provided for reducing a CGI-S score in a patient suffering from schizophrenia, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, resulting in (i) a decrease in a CGI-S score of at least 1 from baseline or (ii) an effect size of a CGI-S score of at least 0.52.

[0130] In some embodiments, a method is provided for reducing a BNSS total score in a patient suffering from schizophrenia, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, resulting in (i) a reduction in a BNSS total score from baseline of at least 7.1 or (ii) an effect size of a BNSS total score of at least 0.48.

[0131] In some embodiments, a method is provided for reducing a MADRS total score in a patient suffering from schizophrenia, the method comprising administering to the patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, resulting in (i) a reduction in a MADRS total score from baseline of at least 3.3 or (ii) an effect size of a MADRS total score of at least 0.32.

[0132] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered as part of a pharmaceutical composition. The pharmaceutical compositions of the present disclosure may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, sublingually, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0133] In some embodiments, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the composition of the present disclosure may be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.

[0134] In some embodiments, the pharmaceutically acceptable compositions of the present disclosure may be orally administered in any orally acceptable dosage form, such as capsules, tablets, aqueous suspensions or solutions.

[0135] In some embodiments, the pharmaceutical compositions of the present disclosure comprise one or more pharmaceutically acceptable excipients, such as one or more binders, fillers, buffers, stabilizers, surfactants, wetting agents, lubricants, diluents, disintegrants, viscosity-enhancing or viscosity-decreasing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, taste-masking agents, flavoring agents, flavorings, diluents, glazing agents, polymer matrix systems, plasticizers, and other known excipients that enhance the presentation of a drug or aid in the manufacture of a drug or pharmaceutical product comprising a composition of the present disclosure. Examples of carriers and additives well known to those skilled in the art are described in detail, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

[0136] In some embodiments, non-limiting examples of additives include corn starch, potato starch, or other starches, gelatin, natural and synthetic gums, such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., Nos. 2208, 2906, 2910), hydroxypropyl cellulose, titanium dioxide, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, silicic acid, sorbitol, starch, alginate, and the like. Perfumed starch, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins, other celluloses, gums, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel (AEROSIL 200, WR, Baltimore, MD) Grace Co.), coagulated aerosol of synthetic silica (sold by Degussa Co., Plano, Texas), CAB-O-SIL (a calcined silicon dioxide product sold by Cabot Co., Boston, Massachusetts), colorants, and mixtures thereof.

[0137] In some embodiments, the pharmaceutical composition is formulated with one or more pharmaceutically acceptable excipients according to known and established practices. Thus, in some embodiments, the composition is formulated as a liquid, powder, elixir, injectable solution, or suspension.

[0138] In some embodiments, oral dosage forms may be provided as tablets, caplets, or capsules, wherein the pharmacologically active ingredient is mixed with an inert solid diluent.

[0139] In some embodiments, the oral dosage form is a solid oral dosage form. In some embodiments, the solid oral dosage form comprises a tablet, and in some embodiments, the solid oral dosage form comprises a capsule. Tablets may also include granulating and disintegrating agents, and may be coated or uncoated.

[0140] In some embodiments, the topical formulation may be provided as, for example, a topical solution, lotion, cream, ointment, gel, foam, patch, powder, solid, sponge, tape, vapor, paste, or tincture.

[0141] In some embodiments, an appropriate daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, will be the amount of compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on factors described herein or understood by those skilled in the art. Generally, oral, intravenous, and subcutaneous doses of Compound 1, or a pharmaceutically acceptable salt thereof, for a patient will range from about 0.005 mg per kilogram of body weight to about 5 mg per kilogram of body weight per day. In some embodiments, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 0.125 mg per kilogram of body weight to about 2.5 mg per kilogram of body weight per day. In some embodiments, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 0.25 mg per kilogram of body weight to about 2.5 mg per kilogram of body weight per day. In some embodiments, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 0.125 mg per kilogram of body weight to about 1.125 mg per kilogram of body weight per day. In some embodiments, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 10 mg to about 300 mg per day. In another embodiment, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 20 mg to about 250 mg per day. In another embodiment, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 100 mg to about 300 mg per day. In another embodiment, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 10 mg to about 100 mg per day. In another embodiment, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 50 mg to about 75 mg per day. In another embodiment, the oral dose of Compound 1, or a pharmaceutically acceptable salt thereof, will range from about 50 mg to about 200 mg per day. Each of the dose ranges listed above may be formulated as single or multiple unit dose formulations.

[0142] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at about 50 mg or about 75 mg per day.

[0143] In some embodiments, the method achieves a maximum plasma concentration of Compound 1, or a pharmaceutically acceptable salt thereof, in the patient 1 to 4 hours after a single oral dose and 2 to 4 hours after multiple oral doses. In some embodiments, the method achieves a maximum plasma concentration of Compound 1, or a pharmaceutically acceptable salt thereof, in the patient 1 to 4 hours after a single oral dose. In some embodiments, the method achieves a maximum plasma concentration of Compound 1, or a pharmaceutically acceptable salt thereof, in the patient 2 to 4 hours after multiple oral doses.

[0144] In some embodiments, the method achieves a steady-state plasma concentration of Compound 1, or a pharmaceutically acceptable salt thereof, in the patient within seven days.

[0145] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily for a treatment period of 29 days.

[0146] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be used in combination with one or more second active agents that treat, prevent, and / or manage the diseases and disorders described herein.

[0147] Some embodiments of the present disclosure include methods for treating neurological and psychiatric diseases and disorders, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. Some embodiments include methods for preventing or managing neurological and psychiatric diseases and disorders, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, that prevents or manages the disease.

[0148] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (hereinafter "DSM-5"), published in 2013 by the American Psychiatric Association and subsequently revised, provides a standard diagnostic system upon which those skilled in the art rely to diagnose a variety of diseases and disorders.

[0149] As used herein, the term "mood disorder" includes depression, major depression, major depressive disorder, minor depression, major depression without psychotic symptoms, major depression with psychotic symptoms, melancholia (formerly endogenous depression), atypical depression, dysthymic disorder, manic depression, bipolar disorder, bipolar depression, bipolar I disorder, bipolar II disorder, bipolar III disorder, cyclothymic disorder, and chronic hypomania.

[0150] Mental disorders are brain conditions characterized by identifiable symptoms that cause abnormalities in cognition, emotion, mood, or most integral aspects of behavior. These disorders can vary in symptom severity, duration, and functional impairment. Mental disorders afflict millions of people worldwide, causing significant human suffering and economic burden through lost productivity. Mood disorders are a type of mental illness and are often defined as a heterogeneous, usually relapsing group of disorders, such as unipolar (depressive) and bipolar (manic-depressive) disorders, characterized by pervasive mood disorders, psychomotor dysfunction, and autonomic symptoms. Suicide, the most serious complication in patients with mood disorders, is the cause of death in 15 to 25% of untreated patients with mood disorders, and unrecognized or inadequately treated depression contributes to 50 to 70% of all completed suicides.

[0151] In some embodiments, the neurological disorder is: depression (e.g., major depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive impairment; fibromyalgia; pain (e.g., neuropathic pain); sleep-related disorders, such as sleep disorders caused by psychiatric illness (e.g., sleep apnea, insomnia, narcolepsy, cataplexy); chronic fatigue syndrome; attention deficit disorder (ADD); attention deficit hyperactivity disorder (ADHD); restless legs syndrome; schizophrenia; anxiety (e.g., generalized anxiety disorder, social anxiety disorder, panic disorder); obsessive-compulsive disorder; post-traumatic stress disorder; seasonal affective disorder (SAD); premenstrual dysphoria; postmenopausal vasomotor symptoms (e.g., hot flashes, night sweats); neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis); mania; dysthymic disorder; cyclothymic disorder; obesity; and substance abuse or dependence (e.g., cocaine addiction, nicotine addiction). In another embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is useful for the treatment, prevention, and / or management of two or more co-occurring diseases / disorders, such as, for example, psychosis and depression.

[0152] Neurological disorders also include brain dysfunction such as, but not limited to, senile dementia, Alzheimer's dementia, cognition, memory impairment, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, attention deficit, speech disorder, Lennox syndrome, autism, and hyperactivity syndrome.

[0153] In some embodiments, the disease or disorder treated by the methods of the present disclosure comprises one or more of mood disorders, bipolar disorder (BPD), bipolar depression, sleep disorders, REM behavior disorders, psychotic disorders, Alzheimer's disease with agitation and / or psychosis, psychotic symptoms associated with Parkinson's disease, schizophrenia, attenuated psychotic syndrome, schizophrenia prodrome, and schizoaffective disorder.

[0154] In some embodiments, the neurological or psychiatric disease or disorder is one or more of mood disorder, bipolar disorder (BPD), bipolar depression, sleep disorder, REM behavior disorder, psychotic disorder, Alzheimer's disease with agitation and / or psychosis, psychotic symptoms associated with Parkinson's disease, schizophrenia, attenuated psychotic syndrome, schizophrenia prodrome, and schizoaffective disorder.

[0155] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia (paranoid, disorganized, catatonic, or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excited psychosis, psychotic disorder with generalized symptoms, substance-induced or drug-induced (e.g., phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other psychostimulants, and cocaine) psychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizophrenic psychosis, a "schizophrenia spectrum" disorder, such as schizoid or schizotypal personality disorder, or the positive, negative, and cognitive symptoms of both schizophrenia and other psychoses; acute stress disorder. anxiety disorders such as anxiety disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to generalized symptoms; substance-related disorders and addictive behaviors (such as substance-induced delirium, persistent dementia, persistent amnestic disorder, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances such as alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); and psychiatric disorders (such as major depression, manic-depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), such as Alzheimer's disease accompanied by agitation and / or psychosis.

[0156] In some embodiments, the neurological or psychiatric disease or disorder is selected from depressive disorders such as, but not limited to, unipolar depression, seasonal depression, postpartum depression, atypical depression, catatonic depression, geriatric depression, endogenous depression, melancholic depression, perinatal depression, occasional depression, chronic depression, bipolar depression, major depressive disorder (MDD), major depressive disorder with mixed features (MDD-MF), treatment-resistant depression (TRD), and dysthymia, which are associated with depressed mood (sadness), poor concentration, insomnia, fatigue, appetite disorders, excessive guilt and suicidal ideation, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), generalized mood disorders, and substance-induced mood disorders.

[0157] In some embodiments, the neurological or psychiatric disease or disorder is selected from bipolar disorders, including but not limited to bipolar depression, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, bipolar disorder and related disorders due to another medical illness, other specified bipolar disorder and related disorders, and bipolar disorder and related disorders not otherwise specified.

[0158] In some embodiments, the neurological or psychiatric disease or disorder is selected from eating disorders, including, but not limited to, obesity, bulimia nervosa, pica, and compulsive eating disorders.

[0159] In some embodiments, the neurological or psychiatric disease or disorder is selected from a sleep disorder such as, but not limited to, insomnia, disturbed sleep, jet lag, hypersomnia, cataplexy, sleep apnea, obstructive sleep apnea, REM sleep behavior disorder, restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, delayed sleep phase disorder, sleepwalking, night terrors, nocturnal enuresis, REM sleep behavior disorder, shift work sleep disorder, excessive daytime sleepiness, non-24-hour sleep-wake disorder, sleep paralysis, and narcolepsy.

[0160] In some embodiments, the neurological or psychiatric disease or disorder is bipolar disorder.Bipolar disorder (including both bipolar I and bipolar II) is a serious mental disorder with a prevalence of approximately 2% of the population, affecting both men and women equally.It is a relapsing-remitting disorder characterized by cycling between elevated moods (i.e., mania) and depressed moods, which distinguishes it from other disorders such as major depressive disorder and schizophrenia.

[0161] Bipolar I is defined by the occurrence of full-blown manic episodes, although most people experience severe depression. Manic symptoms include elevated or irritable mood, hyperactivity, grandiosity, decreased need for sleep, racing thoughts, and, in some cases, psychosis. Depressive episodes are characterized by anhedonia, sad mood, hopelessness, low self-esteem, poor concentration, and lethargy. Bipolar II is defined by the occurrence of major depressive episodes and hypomanic (milder manic) episodes, although patients spend a significant amount of time depressed. Other related disorders include cyclothymic disorder.

[0162] In bipolar II disorder, depressive episodes alternate with hypomania (relatively mild, nonpsychotic periods, usually less than a week in duration). During hypomanic periods, mood brightens, sleepiness decreases, and psychomotor activity accelerates beyond the patient's usual levels. Often, the switch is triggered by circadian factors (e.g., going to bed depressed and waking early in the morning hypomanic). Hypersomnia and hypereating are characteristic and may recur seasonally (e.g., in the fall or winter); insomnia and loss of appetite occur during depressive phases. For some individuals, hypomanic periods are adaptive because they are accompanied by high energy, self-confidence, and above-normal social functioning. Many patients who experience pleasant mood elevations, usually at the end of the depression, do not report them unless specifically questioned.

[0163] Patients with a major depressive episode and a family history of bipolar disorder (informally called bipolar III) often exhibit slight hypomanic tendencies; their temperament is described as elevated (i.e., driven, ambitious, and achievement-oriented).

[0164] In cyclothymic disorder, relatively mild hypomanic and minor depressive episodes occur irregularly, each lasting 2 to 3 days. Cyclothymic disorder is generally a precursor to bipolar II disorder. However, it can also occur as extreme irritability without the exacerbation of major mood disturbances. In such cases, short periods of retarded depression accompanied by low self-confidence and increased sleep alternate with periods of increased elation or enthusiasm and sleep deprivation. In other forms, mild depressive features predominate; the ease with which elation or irritability is induced by antidepressants indicates a bipolar tendency. In chronic hypomania, a clinically uncommon form, periods of elation predominate, and sleep duration habitually decreases to less than 6 hours. Individuals with this form are constantly overly cheerful, self-confident, overly active, overly scheduled, not thinking ahead, overly preoccupied, and intrusive; they rush about and talk to others with restless impulses.

[0165] Thus, in some embodiments, the neurological or psychiatric disease or disorder is one or more of bipolar I disorder, bipolar II disorder, cyclothymic disorder, other specified bipolar disorder and related disorders, or unspecified bipolar disorder and related disorders, as well as bipolar I disorder or bipolar II disorder with anxiety distress specifier, with mixed features, rapid cycling, with melancholic features, with atypical features, with mood-concordant psychotic features, with mood-incongruent psychotic features, with catatonia, perinatal onset, and / or seasonal type. A recent paper by Hu et al. [Prim Care Companion CNS Disord. 2014;16(2):PCC.13r01599] highlights that bipolar disorder is commonly encountered in primary care settings but is often misdiagnosed or undiagnosed. DSM-5 attempts to capture the majority of patients with mixed symptoms that do not constitute a syndrome by including a mixture of specifiers.

[0166] In some embodiments, the neurological or psychiatric disease or disorder is depressive disorder.Depressive disorder includes but is not limited to unipolar depression, seasonal depression, postpartum depression, atypical depression, catatonic depression, geriatric depression, endogenous depression, melancholic depression, perinatal depression, occasional depression, chronic depression, bipolar depression, major depressive disorder (MDD), major depressive disorder with mixed features (MDD-MF), treatment-resistant depression (TRD) and dysthymia, which is associated with depressed mood (sadness), poor concentration, insomnia, fatigue, appetite disorder, excessive guilt and suicidal ideation, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), generalized mood disorder and substance-induced mood disorder.

[0167] Depression is an affective disorder whose etiology cannot be explained by any single cause or theory. Unfortunately, treatment options are limited for depressed patients who experience a suboptimal clinical response to antidepressant treatment. Approximately thirty percent (30%) of patients who initiate antidepressant treatment experience a suboptimal or delayed clinical response to the first-line antidepressants typically used to treat depression.

[0168] Typically, when a patient shows a suboptimal or delayed clinical response after several weeks of treatment with an antidepressant, the clinician's first resort is to increase the antidepressant dosage. If the patient's response remains unsatisfactory after increasing the dosage, the most common approaches many clinicians will pursue are: a) switching to a different antidepressant; or b) adding a second antidepressant; or c) attempting augmentation therapy by administering agents such as lithium carbonate, thyroid hormone (triiodothyronine), psychostimulants, modafinil, atypical antipsychotics, buspirone, or pindolol.

[0169] In its fully syndromic manifestation, clinical depression manifests as major depressive disorder, with an episodic course and variable degrees of residual symptoms between episodes. Mood is commonly gloomy, irritable, and / or anxious. Patients may frown, have downturned mouths, slumped posture, poor eye contact, and short, curt (or absent) speech, appearing miserable. The morbid mood may be accompanied by preoccupation with guilt, self-deprecating thoughts, poor concentration, indecisiveness, decreased interest in daily activities, social withdrawal, feelings of helplessness, despair, and recurrent thoughts of death and suicide. Sleep disturbances are common. In some cases, the morbid mood is so profound that tears dry up; patients report an inability to experience normal emotions—such as grief, joy, and contentment—and a sense that the world has become colorless, lifeless, and dead.

[0170] Melancholia (formerly endogenous depression) is characterized by marked psychomotor retardation (of thought and activity) or psychomotor agitation (e.g., restlessness, hand clasping, compulsive conversation), weight loss, irrational feelings of guilt, and loss of the ability to experience pleasure. Mood and activity vary daily and are lowest in the morning. Most patients with melancholia complain of difficulty falling asleep, frequent awakenings, and difficulty falling asleep in the middle of the night or early morning. Sexual desire is often diminished or absent. Amenorrhea may occur. Eating disorders and weight loss may lead to wasting and secondary electrolyte imbalances.

[0171] In atypical depression, atypical vegetative symptoms dominate the clinical presentation; these include anxiety-like symptoms, evening worsening, early insomnia, hypersomnia that often extends into the daytime, and hyperphagia accompanied by weight gain. Unlike melancholic patients, atypical depressed patients exhibit a brightening mood in response to potentially positive events, but often experience a numbing depression at minor misfortunes. Atypical depressive disorder and bipolar II disorder overlap considerably.

[0172] In dysthymic disorder, depressive symptoms typically develop insidiously in childhood or adolescence and run an intermittent or mild course over years or decades; they are exacerbated by major depressive episodes (double depression). In pure dysthymia, depressive symptoms occur at subthreshold levels and overlap significantly with symptoms of depressive temperament: consistently gloomy, pessimistic, humorless, or unable to enjoy; passive and lethargic; withdrawn; skeptical, critical, or complaining; self-critical, self-blaming, and self-deprecating; and preoccupied with deficiencies, failures, and negative events.

[0173] A thorough evaluation of many people with depression reveals bipolar features, and as many as one in five patients with a depressive disorder also experience frank hypomania or mania. Most conversions from unipolar to bipolar disorder occur within five years of the onset of depressive symptoms. Predictors of conversion include early onset of depression (before age 25), postpartum depression, a high frequency of depressive episodes, rapid mood improvement with physical therapy (e.g., antidepressants, phototherapy, sleep deprivation, electroconvulsive therapy), and a family history of mood disorders spanning three consecutive generations.

[0174] Between episodes, patients with bipolar disorder exhibit depressed mood and occasional energetic activity; impairments in developmental and social functioning are more prevalent in bipolar depression than in unipolar disorder. Compared to unipolar disorder, depressive episodes are shorter (3 to 6 months), occur at a younger age, have a more abrupt onset, and have shorter cycles (the time between the onset of one episode and the next). Cycling is particularly pronounced in the rapid-cycling form of bipolar disorder (usually defined as four or more episodes per year). Furthermore, depressive episodes in bipolar disorder are a difficult-to-treat component of BPD. For example, psychiatrists indicate that approximately 25% of all patients with bipolar disorder are refractory to manic episodes, while approximately 70% are refractory to depressive episodes.

[0175] Thus, in some embodiments, the neurological or psychiatric disease or disorder is one or more of bipolar depression, major depressive disorder (MDD), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder (PMDD), major depressive disorder with mixed features (MDD-MF), depressive disorder due to another medical illness, other specified depressive disorder, depressive disorder not otherwise specified, or treatment-resistant depression (TRD), and MDD with anxiety distress specifier, with mixed features, with melancholic features, with atypical features, with mood-concordant psychotic features, with mood-incongruent psychotic features, with catatonia, perinatal onset, and / or seasonal affective disorder.

[0176] It should be understood that TRD is a term used in psychiatry to describe cases of major depressive disorder (MDD) that have not responded adequately to adequate treatment with at least two antidepressants.

[0177] In some embodiments, the depressive disorder is accompanied by acute suicidal tendencies or suicidal ideation. The U.S. Food and Drug Administration has adopted a "black box" label warning indicating that antidepressants may increase the risk of suicidal ideation and behavior in some children, adolescents, and young adults (age 24 and under) with a depressive disorder, such as MDD. In some embodiments, the compositions and methods of the present disclosure do not increase the risk of suicidal ideation and / or behavior in children, adolescents, and / or young adults with a depressive disorder, such as MDD. In some embodiments, the present disclosure provides drugs and treatment methods for treating one or more symptoms of a depressive disorder (e.g., MDD) in children, adolescents, and / or young adults that do not increase the risk of suicidal ideation and / or behavior.

[0178] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. Schizophrenia is a disorder of unknown cause, usually first presenting in early adulthood, characterized by characteristics such as psychotic symptoms, gradual progression and development, and / or impaired social behavior and occupational performance. Characteristic psychotic symptoms include disturbances in thought content (e.g., multiple, fragmented, disjointed, implausible, or simply delusional thoughts, or persecutory ideation) and intellectual impairment (e.g., loss of associations, imaginative leaps, scattered thoughts to the point of incomprehension), as well as disturbances in perception (e.g., hallucinations), emotion (e.g., superficial affect or helplessness), self-awareness, will, impulse, and / or interpersonal relationships, and psychomotor disorders (e.g., catatonia). Other symptoms are also associated with this disorder. Schizophrenia is classified into several subgroups: paranoid, characterized by delusions and hallucinations without thought disorder, disorganized behavior, and flattened affect; disorganized, also known as "disorganized schizophrenia," in which thought disorder and flattened affect coexist; catatonic, in which prominent psychomotor disturbances are evident and symptoms include catatonic stupor and waxy limbicness; and undifferentiated, in which psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic are not met. Schizophrenia symptoms typically manifest in three broad categories: positive, negative, and cognitive. Positive symptoms are those that represent an "excess" of normal experiences, such as hallucinations and delusions. Negative symptoms are those in which patients suffer from a lack of normal experiences, such as anhedonia and a lack of social interaction. Cognitive symptoms relate to cognitive impairment in patients with schizophrenia, such as a lack of sustained attention and poor decision-making.

[0179] Thus, in some embodiments, the neurological or psychiatric disease or disorder is one or more of schizotypal (personality) disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizophrenia, schizoaffective disorder, substance / medication-induced psychotic disorder, psychotic disorder due to another medical illness, other specified schizophrenia spectrum and other psychotic disorders, schizophrenia spectrum not otherwise specified, and other psychotic disorders.

[0180] It should be understood that schizoaffective disorder encompasses diseases that include aspects of both schizophrenia and mood disorders such as major depressive disorder and bipolar disorder.

[0181] In some embodiments, the neurological or psychiatric disease or disorder is anxiety disorder.Anxiety disorder is characterized by fear, worry and anxiety, which is usually generalized and unfocused as an overreaction to a situation.Anxiety disorders differ in the type of situation or object that induces fear, anxiety or avoidance behavior, and the associated cognitive ideation.Anxiety differs from fear in that anxiety is an emotional response to a perceived future threat, while fear is related to a perceived or real imminent threat.Anxiety also differs in the content of associated thoughts or beliefs. Examples of anxiety disorders include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack specific term, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, anxiety disorder due to another medical illness, illness anxiety disorder, social (pragmatic) communication disorder, other specified anxiety disorder, and anxiety disorder not otherwise specified; as well as stressor-related disorders such as reactive attachment disorder, disinhibited interpersonal interaction disorder, post-traumatic stress disorder (PTSD), acute stress disorder, and adjustment disorder.

[0182] In some embodiments, the neurological or psychiatric disease or disorder is a sleep disorder, including sleep disorders caused by a mental condition, including, but not limited to, insomnia, disturbed sleep, jet lag, hypersomnia, cataplexy, sleep-related disorders (e.g., sleep apnea, insomnia, narcolepsy, cataplexy), obstructive sleep apnea, REM sleep behavior disorder, restless legs syndrome, periodic limb movement disorder, circadian rhythm sleep disorder, delayed sleep phase disorder, sleepwalking, night terrors, nocturnal enuresis, REM sleep behavior disorder, shift work sleep disorder, excessive daytime sleepiness, non-24-hour sleep-wake disorder, sleep paralysis, and narcolepsy.

[0183] In some embodiments, the neurological or psychiatric disease or disorder is a social dysfunction disorder. In some embodiments, the social dysfunction is a neurodevelopmental disorder, obsessive-compulsive disorder, or disruptive-impulse-control-conduct disorder. In some embodiments, the social dysfunction is a language disorder, a speech disorder, a childhood-onset fluency disorder (stuttering), a social communication disorder, developmental coordination disorder, stereotypic movement disorder, a tic disorder, Tourette's disorder, a persistent (chronic) motor or vocal tic disorder, a provisional tic disorder, another tic disorder, a tic disorder not otherwise specified, obsessive-compulsive disorder, or an impulse control disorder. In some embodiments, the social dysfunction is a language disorder, a speech disorder, a childhood-onset fluency disorder (stuttering), a social communication disorder, developmental coordination disorder, stereotypic movement disorder, a tic disorder, Tourette's disorder, a persistent (chronic) motor or vocal tic disorder, a provisional tic disorder, another tic disorder, or a tic disorder not otherwise specified. In some embodiments, the social impairment is a language disorder, a speech disorder, a childhood-onset fluency disorder (stuttering), or a social communication disorder. In some embodiments, the social impairment is a language disorder, a childhood-onset fluency disorder (stuttering), a social communication disorder, developmental coordination disorder, stereotypy disorder, persistent (chronic) motor or vocal tic disorder, provisional tic disorder, other specified tic disorder, or tic disorder not otherwise specified.

[0184] Combination therapy In some embodiments, the compounds disclosed herein provide methods for treating the neurological and / or psychiatric diseases or disorders described herein, comprising administering a compound disclosed herein in combination with one or more pharmaceutical agents. Suitable pharmaceutical agents that may be used in combination with the compounds of the invention include anti-Parkinson's agents, anti-Alzheimer's agents, antidepressants, antipsychotics, anti-ischemic agents, CNS depressants, anticholinergic agents, nootropics, anti-epileptic agents, attention-enhancing (e.g., anti-ADD / ADHD) agents, sleep-promoting agents, wake-promoting agents, and analgesics.

[0185] Suitable anti-Parkinson's medications include dopamine replacement therapy (e.g., L-DOPA, carbidopa, COMT inhibitors such as entacapone or tolcapone), dopamine agonists (e.g., D1 agonists, D2 agonists, mixed D1 / D2 agonists, bromocriptine, pergolide, cabergoline, ropinirole, pramipexole, piribedil, or apomorphine in combination with domperidone), histamine H2 antagonists, monoamine oxidase inhibitors (e.g., selegiline, rasagiline, safinamide, and tranylcypromine), pimavanserin (a non-dopamine atypical antipsychotic that inhibits serotonin 5-HT 2A Certain atypical antipsychotics, such as benzodiazepines (inverse agonists of the benzodiazepine receptor), and amantadine.

[0186] In some embodiments, the compounds of the invention may be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (as its hydrochloride or lactate salt as appropriate) and trihexyphenidyl (benzhexyl) hydrochloride, COMT inhibitors such as entacapone or tolcapone, MAO A / B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergics, NMDA receptor antagonists, serotonin receptor antagonists, and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide, and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, such as alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Lisuride and pramipexole are typically used in their non-salt form.

[0187] Suitable anti-Alzheimer's drugs include beta-secretase inhibitors, gamma-secretase inhibitors, cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, HMG-CoA reductase inhibitors, NSAIDs such as ibuprofen, vitamin E, and anti-amyloid antibodies. In some embodiments, the anti-Alzheimer's drug is memantine.

[0188] Suitable antidepressants and anxiolytics include norepinephrine reuptake inhibitors (such as tertiary amine tricyclic antidepressants and secondary amine tricyclic antidepressants), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), serotonin-noradrenaline reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, alpha-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, particularly 5-HT1A partial agonists, and corticotropin-releasing factor (CRF) antagonists.

[0189] Specific suitable antidepressants and anti-anxiety drugs include amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, citalopram, escitalopram, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide; venlafaxine; desvenlafaxine, duloxetine Antidepressants and anti-anxiety drugs include tianeptine, aprepitant, bupropion, vilazodone, mirtazapine, lithium, nefazodone, trazodone, and viloxazine, alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam, buspirone, flesinoxan, gepirone, and ipsapirone, reboxetine, vortioxetine, clorazepate, and ketamine, and pharmaceutically acceptable salts thereof. In some embodiments, the suitable antidepressant and anti-anxiety drug is tianeptine, or a pharmaceutically acceptable salt thereof.

[0190] Suitable antipsychotics and mood stabilizers include D2 antagonists, 5HT2A antagonists, atypical antipsychotics, lithium, and anticonvulsants.

[0191] Specific suitable antipsychotics and mood stabilizers include chlorpromazine, fluphenazine, haloperidol, amisulpride, perphenazine, thioridazine, trifluoperazine, aripiprazole, asenapine, clozapine, olanzapine, paliperidone, brexpiprazole, paliperidone, cariprazine, pimavanserin, iloperidone, lumateperone, MIN-101, quetiapine, risperidone, ziprasidone, lurasidone, flupenthixol, levomepromazine, pericyazine, perphenazine, pimozide, prochlorperazine, zuclopenthixol, olanzapine and fluoxetine, lithium, carbamazepine, lamotrigine, valproic acid, iloperidone, thiothixene, gabapentin, tiagabine, and pharmaceutically acceptable salts thereof.

[0192] Suitable antiepileptic drugs include levetiracetam, oxcarbazepine, clobazam, retigabine, zonisamide, felbamate, esclicarbazepine acetate, lacosamide, carbamazepine, tiagabine, methsuximide, progabide, valproic acid, lamotrigine, brivaracetam, rufinamide, topiramate, and perampanel.

[0193] Suitable alertness-enhancing medications include methylphenidate, atomoxetine, guanfacine, D-amphetamine, lisdexamfetamine, methylamphetamine, and clonidine.

[0194] Suitable sleep-promoting agents include ramelteon, triazolam, zopiclone, eszopiclone, zolpidem, temazepam, and trazodone.

[0195] Suitable wake-promoting agents include modafinil, D-amphetamine, caffeine, and armodafinil.

[0196] Suitable analgesics include dextromethorphan, tapentadol, buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, morphine, naloxegol, oxycodone, tramadol, gabapentil, difluprednate, pregabalin, acetyl salicyclic acid, bromfenac, diclofenac, diflunisal, indomethacin, ketorolac, meoxican, and naproxen.

[0197] In some embodiments, the compounds and compositions disclosed herein may be used in combination with other therapies, including psychotherapy, cognitive behavioral therapy, electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, and deep brain stimulation. [Example]

[0198] Example 1.1: 4-Week Clinical Trial

[0199] Compound 1 was evaluated in adult subjects with acute psychosis due to schizophrenia in a 4-week, randomized, double-blind, parallel-group, placebo-controlled, flexible-dose, multicenter study to investigate its efficacy and safety. Hospitalized patients (male and female) aged 18 to 40 years (inclusive) were eligible for enrollment if they met the inclusion criteria. Inclusion criteria included: 1. Subjects met DSM-5 criteria for schizophrenia as confirmed by clinical interview (referenced to DSM-5 and confirmed using SCID-CT) and had a disease duration of 6 months or more, whether treated or untreated. 2. Subjects had a CGI-S score of 4 or greater (moderate or greater) at screening and baseline (Day 1) 3. Subjects had a PANSS total score of 80 or greater at screening and baseline (Day 1) and a PANSS item score of 4 or greater on two or more of the following PANSS items: delusions, conceptual disorganization, hallucinations, and unnatural thought content. 4. (i) A significant deterioration in one or more areas of functioning, e.g., occupational, social, or personal care, i.e., hygiene; and (ii) at the time of screening, the subject was experiencing an acute exacerbation of psychotic symptoms (continuous for 2 months or less), as evidenced by hospitalization for acute exacerbation of psychosis or hospitalization for treatment of acute exacerbation of psychosis for 2 consecutive weeks or less immediately prior to screening. 5. The subject has been hospitalized no more than two times previously for treatment of an acute exacerbation of schizophrenia (not including the current hospitalization). 6. At baseline, the subject had a total score of less than 5 on the SAS

[0200] Patients were excluded from the study if they met any of the following exclusion criteria: 1. The subject answered "yes" to item 4 (active suicidal ideation, intention to carry out, no specific plan) or item 5 (suicidal ideation, specific plan and intention) of the C-SSRS assessment of suicidal ideation during the screening period (past month) and / or at baseline. 2. Subject has previously received Compound 1 treatment 3. Subject has a lifetime history or presence of symptoms consistent with a major psychiatric disorder other than schizophrenia as defined by DSM-5, including but not limited to alcohol use disorder (within the past 12 months), substance (other than nicotine or caffeine) use disorder within the past 12 months, major depressive disorder, bipolar depression, mania, schizoaffective disorder, obsessive-compulsive disorder, or post-traumatic stress disorder. 4. Subject is deemed by the investigator to be at significant risk of harm to self, others, or property. 5. The subject has attempted suicide within 3 months prior to screening 6. The subject was involuntarily hospitalized 7. The subject was receiving antipsychotic medication at screening with a total dose equivalent to 12.0 mg / day or more of haloperidol (unless the duration of such treatment was less than 2 weeks and the subject may still be eligible). 8. Subject has received electroconvulsive therapy (ECT) within 6 months prior to screening or is expected to require ECT during the study period 9. Subject is determined by the investigator to be resistant to antipsychotic treatment based on failure to respond to two or more commercially available antipsychotics administered at adequate doses for at least four weeks within the one-year period prior to screening. 10. Subject has a history of treatment with clozapine for refractory psychosis and / or has received treatment with clozapine (for any reason) within 4 months of screening 11. Subject was currently participating in, or had participated within 6 months prior to signing the informed consent, a study using an investigational or commercially available compound or device, or had participated in two or more studies within 24 months prior to signing the informed consent. 12. Subject received a depot antipsychotic unless the last injection occurred at least one treatment cycle or at least 30 days (whichever is longer) before the screening period.

[0201] To be eligible for randomization, patients met the following randomization criteria: 1. Subjects had a PANSS total score of 80 or greater at baseline (Day 1). 2. Subjects had a PANSS item score of 4 or greater on two or more of the following PANSS items at baseline: delusions, conceptual disorganization, hallucinations, and unnatural thought content. 3. Subject did not demonstrate a 20% or greater decrease (improvement) in the PANSS total score between screening and baseline visits, or the PANSS total score did not decrease below 80 at baseline 4. Subjects had a CGI-S score of 4 or greater at baseline 5. At baseline, the subject had a total score of less than 5 on the SAS 6. The subject did not answer "yes" to item 4 (active suicidal ideation, intention to carry it out, no specific plan) or item 5 (suicidal ideation, specific plan and intention) of the C-SSRS assessment of suicidal ideation at baseline (since the last visit) 7. Subject meets all other inclusion criteria and none of the exclusion criteria at baseline

[0202] Treatment with Compound 1 was administered orally as size 0, Swedish orange capsules (50 mg or 75 mg) once daily. Compound 1 was taken before bedtime each evening, either before or after meals. Patients received Compound 1 at 50 mg / day on days 1 through 3. On day 4, patients were permitted (but not required) to increase the dose to 75 mg / day. Thereafter, dose increases were performed at the investigator's discretion at regular weekly visits beginning at Visit 4 (Week 1) if necessary to optimize efficacy. Dose reductions for tolerability were permitted more frequently than weekly. Patients were given flexibility to increase the dose until Visit 6 (Week 3), but no dose adjustments were permitted thereafter. The treatment duration was 4 weeks.

[0203] The competing placebo treatment was a size 0, Swedish orange capsule, administered orally once daily. Placebo treatment was administered at the same time each evening before bedtime, either before or after meals. Subjects randomized to placebo received the placebo throughout the study.

[0204] Both Compound 1 and placebo were provided in blister packs with identical packaging, labeling, weight, appearance, and dosing schedule.

[0205] Treatment with anticholinergics or propranolol was permitted for akathisia and movement disorders. Lorazepam, temazepam, and eszopiclone (or their equivalents) were permitted as needed for anxiety or insomnia, but not within 8 hours before any study assessment. The primary efficacy endpoint was the change from baseline to week 4 in the Positive and Negative Symptom Scale (PANSS) total score. Prespecified secondary efficacy endpoints included change from baseline to week 4 in the Clinical Global Impression-Severity (CGI-S) score, PANSS subscale scores, Brief Negative Symptom Scale (BNSS) total score, and Montgomery-Asberg Depression Rating Scale (MADRS) total score; PANSS response (defined as a ≥20% improvement in the PANSS total score); and change from baseline in the Uncorrelated PANSS Score Matrix (UPSM)-transformed PANSS factor severity score. The UPSM-transformed PANSS factors assess drug effects on clinical symptom domains of schizophrenia with greater specificity by correcting for correlated improvements across individual PANSS items. Mixed model for repeated measures (MMRM) analysis was used to analyze changes from baseline in primary and secondary efficacy measures.

[0206] Study design The study consisted of three periods: (1) screening / washout (up to 14 days), (2) treatment (4 weeks, inpatient), and (3) follow-up visit (7 days after the last study drug dose for subjects who discontinued the study before Visit 7 (Week 4) or completed the study but did not participate in the open-label extension study (described in Example 1.2)). During the screening / washout period, patients were assessed for eligibility for a period of up to 14 days, during which time all psychotropic medications were tapered in a manner consistent with package inserts and conventional medical practice. Subjects remained hospitalized during the screening / washout period.

[0207] During the double-blind phase, patients remained hospitalized until week 4, at which point they were eligible for discharge. At baseline (Day 1), subjects who successfully washed out of prior medication and met the randomization criteria were randomly assigned in a 1:1 ratio to one of two treatment groups: Compound 1 (50 mg / day or 75 mg / day, flexibly administered for 4 weeks) or placebo (4 weeks). Study medication administration began the evening of the baseline visit. Treatment, as described above, continued once daily in the evening for the remainder of the study.

[0208] Subjects who completed the double-blind treatment phase were eligible to participate in a separate, open-label, 26-week extension study. Subjects who discontinued the study early or completed the study but did not participate in the 6-month extension study were required to complete a follow-up visit 7 days (± 2 days) after their last dose of study drug or placebo.

[0209] safety Safety assessments included monitoring for adverse and serious adverse events, vital signs and weight assessments, clinical laboratory tests (e.g., fasting lipid and fasting glucose levels), and 12-lead electrocardiograms. Extrapyramidal symptoms were assessed using the Simpson-Angus Rating Scale (SAS; a 10-item scale ranging from 0 to 40, with higher scores indicating more severe extrapyramidal symptoms), the Barnes Rating Scale for Drug-Induced Akathisia (BARS; a global clinical assessment score ranging from 0 to 5, with higher scores indicating more severe akathisia), and the Abnormal Involuntary Movements Scale (AIMS; a global score ranging from 0 to 44, with higher scores indicating more frequent and severe abnormal involuntary movements). Suicidality was assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI; a global score ranging from 0 to 21, with higher scores indicating poorer sleep quality).

[0210] statistical analysis methodEfficacy analyses were performed in a modified intention-to-treat population, which included all patients who underwent randomization, received at least one of Compound 1 or placebo, and had a baseline efficacy assessment and at least one post-baseline assessment based on the PANSS or CGI-S scale. However, all patients met these criteria, and the modified intention-to-treat population was the same as the intention-to-treat population. The safety population included all patients who underwent randomization and received at least one of Compound 1 or placebo. No interim analyses or open-label data monitoring were performed in this study.

[0211] The primary efficacy endpoint was assessed using a repeated measures mixed model; effect sizes were calculated as the absolute value of the difference between the Compound 1 and placebo groups in the change in score from baseline at week 4 divided by the pooled standard deviation of the between-group difference in change in score. To assess the robustness of the repeated measures mixed model analysis of the primary endpoint and the potential impact of missing data due to early discontinuation, tipping-point analysis and pattern mixture modeling with placebo-based multiple imputation were performed as sensitivity analyses.

[0212] Secondary efficacy endpoints were also assessed using mixed models for repeated measures, except for the UPSM-transformed PANSS factors, which were assessed using a prespecified analysis of covariance model to assess domain-specific change in patients completing the 4-week study. Because no multiple comparison adjustment was made, no inferences can be drawn regarding the secondary efficacy endpoints. These results are presented as point estimates with only unadjusted 95% confidence intervals. PANSS responses were assessed with logistic regression models using the PANSS total score at baseline as a covariate.

[0213] Safety data (including adverse events, laboratory values, clinical assessment results, and C-SSRS scores) were analyzed using descriptive statistics. Changes in SAS, BARS, and AIMS scores from baseline were assessed using mixed models for repeated measures. Post-baseline PSQI assessments were performed only once; therefore, these data were evaluated using analysis of covariance.

[0214] result In this randomized, placebo-controlled, 4-week study, Compound 1, at a flexible dose of 50 or 75 mg / day, demonstrated statistically significant and clinically important symptom improvements in patients with schizophrenia experiencing an acute exacerbation. Compound 1 demonstrated robust, broad-spectrum activity, including positive, negative, depressive, and general psychopathology symptoms. Improvement in negative symptoms was particularly significant, demonstrating an effect size of 0.48 on the Brief Negative Symptom Scale. The tolerability and safety profile of Compound 1 appeared similar to placebo in this 4-week study.

[0215] patientA total of 295 patients were screened, of whom 245 were randomized, received at least one of Compound 1 or placebo, and underwent at least one post-baseline efficacy assessment. The 4-week study was completed by 78.3% of patients in the Compound 1 group and 79.2% of patients in the placebo group. Reasons for discontinuation in the Compound 1 group included: 26 patients discontinued treatment, 5 did not demonstrate efficacy, 10 experienced adverse events, 9 withdrew consent, and 2 discontinued for other reasons. Reasons for discontinuation in the placebo group included: 26 patients discontinued treatment, 4 did not demonstrate efficacy, 8 experienced adverse events, and 14 withdrew consent. The proportion of patients in the Compound 1 group receiving a dose of 75 mg per day was 67.2% at week 1, 70.0% at week 2, and 72.5% at week 3. The dose of Compound 1 was reduced from 75 mg to 50 mg per day in four patients. The mean (±SD) duration of Compound 1 or placebo treatment was 24.3 ± 7.6 days in the Compound 1 group and 25.4 ± 6.4 days in the placebo group. Concomitant medication use included anticholinergics (one patient in the placebo group), antipsychotics (one patient in the placebo group), anxiolytics (32 patients in the Compound 1 group and 30 patients in the placebo group), and hypnotics and sedatives (10 patients in the Compound 1 group and 15 patients in the placebo group). Clinical and demographic characteristics between patients at baseline were similar in the two study groups. The mean age was 30.3 years, 81.6% were Caucasian, 63.7% were male, and the mean time since onset of schizophrenia was 5 years. The mean PANSS total score at baseline was 101.4 in the Compound 1 group and 99.7 in the placebo group.

[0216] Baseline characteristics Baseline patient characteristics are shown in Table 1.

[0217] [Table 1] [Table 2]

[0218] Effectiveness The least-squares mean change from baseline in the PANSS total score at week 4 was -17.2 points in the Compound 1 group and -9.7 points in the placebo group (least-squares mean difference, -7.5 points; 95% confidence interval [CI], -11.9 to -3.0; P = 0.001). The least-squares mean between-group differences in the change from baseline in the CGI-S scale score and the PANSS positive, negative, and global psychopathology subscale scores at week 4 were -0.5 points (95% CI, -0.7 to -0.2), -1.7 points (95% CI, -3.1 to -0.3), -1.5 points (95% CI, -2.6 to -0.4), and -4.3 points (95% CI, -6.6 to -2.0), respectively. The least-squares mean between-group differences in the change from baseline in BNSS and MADRS total scores at week 4 were -4.3 points (95% CI, -6.8 to -1.8) and -1.8 points (95% CI, -3.2 to -0.3), respectively. PANSS responses were observed in 64.6% of patients in the Compound 1 group and 44.0% of patients in the placebo group at week 4 (odds ratio, 2.6; 95% CI, 1.4 to 4.9). Because there was no preplanned adjustment for multiple comparisons for the secondary endpoints, confidence intervals are not adjusted for multiple comparisons, and no inferences can be drawn from the secondary endpoint data. Planned sensitivity analyses were in the same direction as the results of the primary efficacy analysis. Analysis of study arm by country showed no significant interaction effects at week 4.

[0219] safety Patients were monitored for adverse events. An adverse event is a harmful medical occurrence that began with or after the first dose of study medication. The incidence of adverse events in the treatment group was very low. Across all types of adverse events, the incidence in the treatment group was similar to placebo. For certain adverse events, the incidence in the treatment group was lower than placebo. The incidence of adverse events compared favorably with commercially available antipsychotics, such as atypical antipsychotics that have affinity for D2 dopamine receptors.

[0220] Adverse events are summarized in Tables 2–6. Serious adverse events occurred in seven patients (5.8%) in the compound 1 group and two patients (1.6%) in the placebo group. The incidence of insomnia was 3.3% in the compound 1 group and 10.4% in the placebo group, with concomitant sleep medications used in 8.3% and 12.0% of patients, respectively. Treatment with compound 1 improved sleep quality compared with placebo treatment, with the least-squares mean (±SE) change from baseline in PSQI global score at week 4 being −2.5 ± 0.4 points in the compound 1 group and −1.7 ± 0.4 points in the placebo group.

[0221] The incidence of extrapyramidal symptoms (akathisia, restlessness, musculoskeletal or joint stiffness, tremor, and neck stiffness) was 3.3% in the Compound 1 group and 3.2% in the placebo group. At week 4, the least-squares mean changes from baseline in the SAS, BARS, and AIMS scores, used to determine the effect on movement disorders, were -0.01 ± 0.01 points, 0.0 ± 0.06 points, and 0.0 ± 0.01 points, respectively, in the Compound 1 group and 0.01 ± 0.01 points, 0.1 ± 0.05 points, and 0.0 ± 0.01 points, respectively, in the placebo group. Concomitant medications to treat extrapyramidal symptoms were prescribed to one patient in the Compound 1 group (lorazepam for restlessness) and one patient in the placebo group (trihexyphenidyl for hand tremor and restlessness).

[0222] The two serious adverse events in the Compound 1 group were a worsening of schizophrenia and acute cardiovascular failure in a 37-year-old woman, resulting in sudden death 7 days after she first took a 50 mg dose of Compound 1. The patient had a history of essential hypertension, and autopsy revealed coronary artery disease and pulmonary embolism. There were four serious events in the placebo group (three patients had worsening schizophrenia and one patient attempted suicide). According to C-SSRS scores, there were no suicidal thoughts or behaviors among patients in the Compound 1 group and two instances of suicidal tendencies among patients in the placebo group.

[0223] Differences in vital signs (e.g., orthostatic hypotension or tachycardia), weight, body mass index, and laboratory values ​​(e.g., prolactin and fasting metabolic rate) between the Compound 1 and placebo groups were also tracked. There were no clinically significant electrocardiogram abnormalities after baseline, and no patient in the Compound 1 or placebo group had a prolongation of the corrected QT interval (QTcF) calculated using the Fridericia formula of greater than 450 milliseconds or an increase in the QTcF interval of greater than 60 milliseconds. In the placebo group, the change from baseline in weight at week 4 was 0.1 ± 2.3 kg, and the change from baseline in body mass index at week 4 was 0.0 ± 0.8. In the Compound 1 group, the change from baseline in weight at week 4 was 0.3 ± 1.9 kg, and the change from baseline in body mass index at week 4 was 0.1 ± 0.6. In the placebo group, the median change in prolactin levels (male / female) from baseline at week 4 was -0.036 / -0.101 nmol / liter. In the Compound 1 group, the median change in prolactin levels (male / female) from baseline at week 4 was -0.037 / -0.175 nmol / liter.

[0224] Figure 1 shows the change in patients' PANSS total scores from baseline over the 4-week study. The treatment group had a least squares mean change from baseline at week 4 of -17.2 compared to -9.7 for placebo, corresponding to an effect size of 0.45.

[0225] Figure 2 shows the change in patients' PANSS positive subscale scores from baseline over the 4-week study. The treatment group had a least squares mean change from baseline at week 4 of -5.5 compared to -3.9 for placebo, corresponding to an effect size of 0.32.

[0226] Figure 3 shows the change in patients' PANSS negative subscale scores from baseline over the 4-week study. The treatment group had a least squares mean change from baseline at week 4 of -3.1 compared to -1.6 for placebo, corresponding to an effect size of 0.37.

[0227] Figure 4 shows the change in patients' PANSS Global Psychopathology subscale scores from baseline over the 4-week study. The treatment group had a least squares mean change from baseline at week 4 of -9.0 compared to -4.7 for placebo, corresponding to an effect size of 0.51.

[0228] Figure 5 shows the change in patients' CGI-S scores from baseline over the 4-week study. The treatment group had a least squares mean change from baseline at week 4 of -1.0 compared to -0.5 for placebo, corresponding to an effect size of 0.52.

[0229] Figure 6 shows the change in patients' BNSS total scores from baseline over the 4-week study. The treatment group had a least squares mean change from baseline at week 4 of -7.1 compared to -2.7 for placebo, corresponding to an effect size of 0.48.

[0230] Figure 7 shows the change in patients' MADRS total scores from baseline over the course of the 4-week study. The treatment group had a least squares mean change from baseline at week 4 of -3.3 compared to -1.6 for placebo, corresponding to an effect size of 0.32.

[0231] Table 2 shows the incidence of common adverse events occurring in 2% or more of patients in either the treatment group or placebo. The incidence of headache, insomnia, acute exacerbation of schizophrenia, and anxiety was each lower in the treatment group than in the placebo group.

[0232] [Table 3]

[0233] The incidence of extrapyramidal adverse events is shown in Table 3. The incidence of extrapyramidal adverse events in the treatment groups was similar to that in the placebo group.

[0234] [Table 4]

[0235] Table 4 shows the incidence of cardiovascular adverse events. The incidence of cardiovascular adverse events in the treatment group was similar to that of placebo. The combined incidence of cardiovascular adverse events in the treatment group was 4.2% compared with 4.0% for placebo.

[0236] [Table 5]

[0237] Table 5 shows the incidence of serious adverse events. The incidence of serious adverse events in the treatment groups was lower than in the placebo group.

[0238] [Table 6]

[0239] Table 6 shows the incidence of adverse events leading to study discontinuation. The incidence of such adverse events was similar between treatment groups and placebo.

[0240] [Table 7]

[0241] Figure 8 shows the median change in prolactin levels from baseline at week 4. Treatment groups experienced an average decrease in prolactin. Table 7 shows the change in prolactin from baseline at week 4. Compound 1 had no clinically significant effect on prolactin.

[0242] [Table 8]

[0243] Table 8 shows the incidence of orthostatic hypotension and orthostatic tachycardia. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mmHg or more or a decrease in diastolic blood pressure of 10 mmHg or more after the subject has been standing for at least 2 to 4 minutes, compared to the systolic and diastolic blood pressure measured in the supine position, respectively. Orthostatic tachycardia is defined as an increase in heart rate of 20 beats per minute (bpm) or more and a heart rate higher than 100 bpm after the subject has been standing for at least 2 to 4 minutes, compared to the heart rate measured in the supine position. The incidence of orthostatic hypotension and orthostatic tachycardia in the treatment group was similar to placebo, and the incidence of orthostatic hypotension in the treatment group was lower than placebo.

[0244] [Table 9]

[0245] Table 9 shows the incidence of QT prolongation as determined by the QTcF interval. Patient data were collected by electrocardiogram (ECG). The number and percentage of subjects whose QTc values ​​fell into the following categories were identified. The same criteria apply to both QTcF and QTcB: A QTc value greater than 450 msec not present at baseline and present at any time after baseline (including unscheduled visits) A QTc value greater than 480 msec not present at baseline and present at any time after baseline (including unscheduled visits) A QTc value greater than 500 msec not present at baseline and present at any time after baseline (including unscheduled visits) An increase in QTc value of 30 msec or more from baseline in at least one post-baseline measurement (including unscheduled visits) AND an increase in QTc value of less than 60 msec from baseline in all post-baseline measurements (including unscheduled visits) A QTc increase of 60 msec or more from baseline on at least one post-baseline measurement (including unscheduled visits) There were no incidences of QT prolongation in both the treatment and placebo groups.

[0246] [Table 10]

[0247] Table 10 shows extrapyramidal symptoms as determined by the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary Movement Scale (AIMS), and the Simpson-Angus Rating Scale (SAS).

[0248] [Table 11]

[0249] Thus, various methods of the present disclosure result in a low incidence of adverse events, e.g., an incidence of adverse events that is less than, the same as, about the same as, or similar to a placebo, in contrast to many typical and atypical antipsychotics that have affinity for the dopamine D2 receptor and result in a higher incidence of adverse events.

[0250] ConsiderationIn this 4-week, flexible-dose study involving patients with acute exacerbations of schizophrenia, Compound 1, a drug that does not bind to dopamine D2 receptors, resulted in greater reductions from baseline in PANSS total scores at week 4 (primary efficacy endpoint) compared with placebo. Treatment with Compound 1 was associated with changes in severity scores on secondary efficacy measures (e.g., the CGI-S scale and the PANSS positive, negative, and global psychopathology subscales) at week 4 that were in the same direction as scores in the primary efficacy analysis. Treatment with Compound 1 was also associated with changes in severity scores for negative symptoms of schizophrenia (as measured by both the BNSS total score and the UPSM-transformed PANSS negative symptom factor score) at week 4 that were in the same direction as scores in the primary efficacy analysis. It has previously been shown that changes in UPSM-transformed PANSS negative symptom factor scores (apathy or lack of motivation and emotion) correlate poorly with changes in UPSM-transformed PANSS positive symptom factor scores, a finding suggesting that the specific effect on negative symptoms measured by the UPSM negative symptom factor. Reductions in PANSS total scores were observed during an additional 26-week extension study of open-label treatment with Compound 1 (see Example 1.2).

[0251] The proportion of patients who discontinued Compound 1 or placebo was similar between the two groups (21.7% vs. 20.8%, respectively), similar to or lower than the proportion of patients who dropped out in previous short-term trials of first- and second-generation antipsychotics. However, the design of these previous trials does not allow direct comparison with our study. The incidence of adverse events was generally similar between the Compound 1 and placebo groups, with differences in each event of 2.5% or less. The Compound 1 and placebo groups were similar with respect to the proportion of patients reporting extrapyramidal symptoms (3.3% vs. 3.2%), the proportion using medications for extrapyramidal symptoms, and movement disorder scale findings. Furthermore, prolactin levels were minimally affected in the Compound 1 group. These results are consistent with Compound 1 not binding to D2 receptors. Short-term treatment with Compound 1 resulted in a mean weight gain of 0.3 kg, decreases in total and LDL cholesterol levels, and no changes in other metabolic laboratory parameters. No clinically significant electrocardiogram abnormalities (e.g., QTcF interval prolongation) were observed after baseline.

[0252] In conclusion, in this 4-week study involving patients with acute exacerbation of schizophrenia, TAAR1 and 5-HT 1A Compound 1, a drug that exhibits agonist activity at the receptor, produced a greater reduction in PANSS total score compared to placebo.

[0253] Example 1.2: 26-Week Extension Study

[0254] A 26-week open-label safety and tolerability extension study was conducted on subjects with schizophrenia who completed the treatment period of Example 1.1. Patients who met the inclusion criteria were immediately transferred from the Example 1.1 study to the extension study (in this study, the assessment at Visit 7 (Day 29) of Example 1.1 served as the baseline assessment). If deemed appropriate by the investigator, subjects were hospitalized for the first week of the study. During the treatment period, patients were seen once a week for the first four weeks, then once every four weeks until Week 26. Between visits (between Weeks 1 and 2, and at Weeks 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25), members of the clinical research staff telephoned patients to monitor clinical symptoms and adverse events. Subjects who discontinued or completed the study early were required to complete a follow-up visit 7 days (± 2 days) after the last dose of study medication.

[0255] A total of 156 patients (80.8% of those who completed the 4-week study) were enrolled in the 26-week open-label extension study and treated with Compound 1. Among the 77 patients who were initially randomized to treatment with Compound 1 in the double-blind Example 1.1 study and then continued treatment in the open-label extension, the mean (±SD) change in PANSS total score from extension study baseline at week 26 was -17.1 ± 12.4 points. Among the 79 patients who were initially randomized to treatment with placebo and then switched to open-label Compound 1, the mean change in PANSS total score from extension study baseline at week 26 was -27.9 ± 16.4 points. Adverse events related to extrapyramidal symptoms that occurred among the 156 patients included parkinsonism (2 patients), dyskinesia (1 patient), tremor (1 patient), and restlessness (1 patient).

[0256] Patients received Compound 1 orally at 50 mg / day once daily (referred to as "Compound 1" in the table) during Days 1–3 of the extension study. Starting on Day 4, variable doses from 25 to 75 mg / day were permitted if deemed clinically necessary by the investigator (for safety, tolerability, or efficacy reasons). On Day 4, subjects were permitted (but not required) to increase the dose to 75 mg / day for efficacy reasons. Subsequent dose increases were made at the investigator's discretion at routine visits if needed to optimize efficacy. The Day 4 dose change occurred at an unscheduled visit. Thereafter, dose escalations occurred at weekly intervals, by one dose level, up to a maximum dose of 75 mg / day. Dose reductions for tolerability were permitted at any time during the study. Doses of 25, 50, and 75 mg / day were permitted during Weeks 2–26 of the study.

[0257] Treatment with Compound 1 consisted of size 0 Swedish orange capsules (25, 50, or 75 mg / day) administered orally once daily. The study drug was taken at approximately the same time each evening before bedtime, either before or after meals.

[0258] Safety and tolerability were monitored throughout the study by collecting physical examination results, ECG, vital signs, AEs, clinical laboratory parameters, C-SSRS, weight, and BMI. Efficacy was assessed using the PANSS total and subscale scores, as well as CGI-S, BNSS, and MADRS scores. Subjects provided information about subjective drug effects via a questionnaire.

[0259] To be eligible for participation, patients met all of the following inclusion criteria: 1. Subjects completed the 4-week study of Example 1.1. 2. Subjects were not taking any medications other than the study drug for the purpose of controlling the symptoms of schizophrenia during the study period of Example 1.1.

[0260] Patients did not meet any of the following exclusion criteria: 1. The subject responded "yes" to item 4 (active suicidal ideation, with intent to carry it out, no specific plan) or item 5 (active suicidal ideation, with specific plan and intent) of the C-SSRS assessment of "Suicidal Ideation" at Visit 7 of the study in Example 1.1. 2. The subject had a clinically significant abnormality (e.g., physical exam, vital signs, ECG, or laboratory tests) at Visit 7 of the study in Example 1.1 that the investigator, in consultation with the clinical observer, deemed inappropriate for admission to the study. 3. The subject had a positive urine drug screen (UDS) test or a positive breath alcohol test at Visit 7 of the study in Example 1.1. 4. The subject was pregnant or lactating. 5. The subject was deemed by the investigator to be at high risk of non-compliance. 6. The subject is otherwise deemed unsuitable by the investigator to participate in this study.

[0261] The primary endpoints of the study were the incidence of overall AEs, SAEs, and AEs leading to discontinuation. Secondary endpoints were: · Laboratory tests (hematology, blood chemistry, urinalysis, glucose and lipid panel, prolactin, glycosylated hemoglobin (HbA1c)) absolute values ​​and changes from double-blind (DB) baseline in Example 1.1; Clinical assessments (vital signs, weight, BMI, blood pressure [supine and upright], heart rate [supine and upright], 12-lead ECG) absolute values ​​and changes from DB baseline in Example 1.1; · Frequency and severity of suicidal ideation and behavior using the C-SSRS; Relapse rate and time to relapse during the 26-week open-label period in patients who showed a clinical response to 4 weeks of treatment according to Example 1.1 (relapse was defined as the occurrence of any of the following): ○ 30% or greater increase in PANSS total score from clinical response and CGI-S score of 3 or greater; o rehospitalization due to worsening psychiatric illness; ○ Development of suicidal or homicidal thoughts and / or risk of harming self or others; Changes from DB baseline (see Table 1) in Example 1.1 in PANSS total score, PANSS subscale scores (positive, negative, and overall psychopathology), CGI-S score, BNSS total score, and MADRS total score; and The proportion of patients who achieved a response (defined as a ≥ 20% improvement from baseline in PANSS total score, calculated using (1) the DB baseline of the Example 1.1 study in subjects assigned to double-blind Compound 1, and (2) the OL baseline of this study in subjects assigned to double-blind placebo in the Example 1.1 study).

[0262] result :

[0263] One hundred and five subjects (66.9%) completed the 26-week study, and 52 subjects (33.1%) discontinued due to adverse events (18 subjects; 11.5%), subject withdrawal (16 subjects; 10.2%), other (9 subjects; 5.7%), lack of efficacy (8 subjects; 5.1%), or noncompliance (1 subject; 0.6%).

[0264] Efficacy measures were recorded over a 26-week extension study.

[0265] FIG. 9 shows the PANSS total score during the extension study, with the PANSS total score data from the study in Example 1.1 shown for reference.

[0266] FIG. 10 shows the PANSS positive subscale scores during the extension study, with the PANSS positive subscale score data for the study in Example 1.1 shown for reference.

[0267] FIG. 11 shows the PANSS negative subscale scores during the extension study, with the PANSS negative subscale score data for the study in Example 1.1 shown for reference.

[0268] FIG. 12 shows the PANSS Global Psychopathology subscale score data for the study in Example 1.1 shown for reference, with the PANSS Global Psychopathology subscale scores during the extension study.

[0269] FIG. 13 shows the CGI-S scores during the extension study, with the CGI-S score data from the study in Example 1.1 shown for reference.

[0270] Figure 14 shows the BNSS total score during the extension study period, with the BNSS total score data from the study in Example 1.1 shown for reference.

[0271] Figure 15 shows the MADRS total score during the extension study, with the MADRS total score data from the study in Example 1.1 shown for reference.

[0272] Adverse events were monitored and recorded during the extension study. The incidence of adverse events remained low for both (i) subjects who previously received placebo and received active treatment for the first time during the extension study, and (ii) subjects who continued to receive active treatment from the study in Example 1.1 into the extension study. Tables 11-16 show adverse events experienced during the extension study.

[0273] [Table 12]

[0274] [Table 13]

[0275] [Table 14]

[0276] The change in prolactin levels from baseline at week 26 is shown in FIG.

[0277] [Table 15]

[0278] [Table 16]

[0279] [Table 17]

[0280] Figure 20A shows the time to all-cause discontinuation in the extension study, and Figure 20B shows the time to discontinuation for several other drugs (olanzapine, risperidone, ziprasidone, perphenazine, and quetiapine).

[0281] Additional clinical measurements were taken during the study. The change in weight and BMI from open-label baseline (i.e., at the start of the extension study) at week 26 is shown in Figures 17A and B. The change in lipid measurements (total cholesterol, triglycerides, HDL, LDL) from open-label baseline is shown in Figures 18A-D. The change in glycemic index (glucose, HbA1c) from open-label baseline is shown in Figures 19A and B.

[0282] Functional improvement was also measured by the UPSA-B score, an assessment of daily living skills. Compound 1 improved subjects' UPSA-B total scores from an average of about 76 to an average of about 84 (effect size of 0.66) over 26 weeks.

[0283] Overall, the extension study demonstrated a high completion rate; sustained improvement in schizophrenia symptoms (i.e., improved efficacy scores); very low incidence of EPS-related, prolactin-related, and cardiovascular-related adverse events; and modest changes in weight, lipid, and glycemic indexes.

[0284] Example 1.3: 6-Week Clinical Trial (Psychiatric Symptoms Associated with Parkinson's Disease)

[0285] Compound 1 was evaluated in adults aged 55 years or older with a clinical diagnosis of Parkinson's disease-associated psychosis. The efficacy, safety, and tolerability of Compound 1 in subjects with Parkinson's disease-associated psychosis were investigated in a multicenter, randomized, parallel-group, placebo-controlled study. Eligible patients met established National Institute of Neurological Disorders and Stroke / National Institute of Mental Health (NINDS / NIMH) diagnostic criteria for Parkinson's disease-associated psychosis, had idiopathic Parkinson's disease consistent with UK Brain Bank criteria, had idiopathic Parkinson's disease for at least one year, had psychotic symptoms that developed after the diagnosis of Parkinson's disease for at least one month, occurred at least weekly in the month prior to screening, and were severe enough to require treatment with an antipsychotic. Patients were required to have clinically significant Parkinson's disease-associated psychosis at screening (Visit 1) and baseline (Visit 3), as measured by a combined score of 6 or greater or an individual score of 4 or greater on the Neuropsychiatric Inventory (NPI) Item A (delusions) and / or Item B (hallucinations). Patients had been receiving dopamine therapy and other treatments for Parkinson's disease motor symptoms for at least one month prior to screening and throughout the study period. Patients had to have a Mini-Mental State Examination (MMSE) score greater than 16 out of 30, and a caregiver was required at the time of the examination.

[0286] According to the diagnostic criteria, patients were excluded if their psychosis was atypical or secondary to medication or other neurodegenerative disorders, if dementia was diagnosed concurrently with or before PD, or if dementia was associated with other toxic or metabolic disorders, if motor symptoms began less than one year before the onset of dementia, or if symptoms were consistent with dementia with Lewy bodies. Patients were excluded if they failed to respond to two or more adequate doses of antipsychotic medication within one year of screening. Other exclusion criteria included a stroke or other uncontrolled neurological disease less than six months before baseline, suicidal ideation at screening or baseline, or any clinically significant medical or chronic condition that would limit the patient's ability to participate in the study. Patients were excluded if they underwent surgical treatment for PD.

[0287] Standard protocol approval and patient consent

[0288] Patients provided written informed consent in accordance with the Declaration of Helsinki. Participating centers received institutional review board approval. Caregivers also consented to patients' participation in the study and to the collection of caregiver data related to assessment of patients' neuropsychiatric status (measured by the NPI).

[0289] Study design

[0290] This study evaluated the efficacy, safety, and tolerability of double-blind Compound 1 at variable doses of 25, 50, or 75 mg / day. The study consisted of a screening / washout period (up to 14 days prior to double-blind treatment) and a double-blind treatment period (6 weeks). During the screening period, any antipsychotic or centrally acting anticholinergic medication was tapered or discontinued. Prior antipsychotic treatment was discontinued at least 5 half-lives before the NPI and MMSE screening assessments.

[0291] The study included an additional 12-week open-label phase after completion of the double-blind phase to provide long-term safety and tolerability information.

[0292] At baseline (Day 1), patients who successfully completed the screening / washout phase were randomly assigned 2:1 to Compound 1 or placebo. Double-blind study medication was taken in the clinic at baseline and on the day of the patient's dose increase. Subsequent doses, beginning the following day, were taken at bedtime. Patients randomized to Compound 1 were administered 25 mg / day for 1 week (Days 1 through 7). If there were no safety or tolerability issues, patients were increased to 50 mg / day in Week 2 and 75 mg / day in Week 3. Patients still receiving 25 mg / day were increased to 50 mg / day in Week 3 unless there were safety and tolerability concerns. Dose increases were not permitted after Week 5. Dose reductions to 50 mg / day or 25 mg / day were permitted at any time by one dose level for safety and tolerability reasons. Patients who completed the double-blind treatment phase could continue into the open-label extension.

[0293] Assessments were conducted at screening, baseline, and weekly visits (see Table 1.3.1 for rating scale score ranges).

[0294] [Table 18] [Table 19] [Table 20]

[0295] The primary outcome was the change from baseline to week 6 (day 43) in the SAPS-PD total score. The SAPS-PD includes seven items assessing individual symptoms, a global hallucinations item, and a global delusions item. The SAPS-PD was assessed by trained, calibrated, centrally administered, blinded raters. Other secondary efficacy endpoints at week 6 included the proportion of patients achieving a 30% or greater, 50% or greater, and 100% or greater reduction in the SAPS-PD total score; the change from baseline in the SAPS-PD hallucinations and delusions subscale scores; the change from baseline in the Clinical Global Impression-Severity (CGI-S) score; the NPI illusions and delusions score; the Sleep in Parkinson's Disease (SCOPA-DS and SCOPA-NS) scales for daytime sleepiness and nighttime sleepiness; and the MMSE score. To evaluate the effect of treatment with Compound 1 on Parkinson's disease motor symptoms, changes in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III motor score from baseline to week 6 were included. Safety assessments included adverse events (AEs), serious AEs, AEs leading to discontinuation, electrocardiogram (ECG), vital signs, clinical laboratory assessments, and suicidal ideation as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS). Patients were evaluated for orthostatic hypotension based on predefined criteria. Orthostatic hypotension was defined as a decrease of ≥20 mmHg in systolic blood pressure or ≥10 mmHg in diastolic blood pressure.

[0296] statistical analysis method

[0297] The sample size was determined to investigate the efficacy, safety, and tolerability of compound 1 (25, 50, or 75 mg / day) administered at variable doses for 6 weeks. A sample size of 36 patients was determined to detect a treatment effect size of approximately 0.5 for compound 1 vs. placebo in the change from baseline in the SAPS-PD total score at week 6. This was estimated using an independent, two-group t-test with a two-sided significance level of 0.05. Approximately 36 patients were randomly assigned to compound 1 or placebo in a 2:1 ratio. The safety population included all patients who underwent randomization and received at least one dose of study drug during the double-blind treatment period. The modified intention-to-treat (mITT) population was defined as all patients who underwent randomization, received at least one dose of study drug, and had a baseline SAPS-PD, NPI, or CGI-S total score and at least one post-baseline total score during the double-blind treatment period. The mITT population was the primary population for efficacy analyses. For selected efficacy measures, including primary and secondary endpoints, changes from baseline were assessed using a mixed model for repeated measures (MMRM) approach, including factors for treatment, visit (as categorical variables), and the interaction between treatment and visit, with baseline score included as a covariate.

[0298] result

[0299] patient

[0300] Eighty patients were screened, and 25 were randomly assigned to receive Compound 1 and 14 to receive placebo. Of the randomized patients, 60.0% completed double-blind treatment with Compound 1 and 78.6% with placebo. The most common reasons for discontinuation were AEs in the Compound 1 group (5 / 10 patients) and study withdrawal in the placebo group (2 / 3 patients). Seventeen (43.6%) patients were taking antipsychotics or centrally acting anticholinergics before screening and washout: 17.9% were taking pimavanserin, 15.4% were taking quetiapine, and 2.6% were taking risperidone. One patient randomly assigned to Compound 1 was not included in the mITT efficacy analysis. Table 1.3.1 shows the baseline demographic and clinical characteristics of the mITT population. The mean (range) time since PD onset was 9.0 (2.4-20.7) years. Overall, baseline SAPS-PD, NPI, MMSE, and CGI-S scores indicate that the patient population had a preponderance of hallucinations compared with delusions at baseline. Significant cognitive impairment (MMSE ≤ 24) was present in 36.8% of patients at baseline. There were no significant differences on these measures between treatment groups at baseline.

[0301] The mean (range) duration of treatment was 32.1 (2-43) days for Compound 1 and 37.4 (9-45) days for placebo. All patients received 25 mg for 1 week. In the Compound 1 treatment group, 50.0% increased the dose to 75 mg by week 3, and more than half (59.1%) received 75 mg by week 5. Dose rates were similar for patients receiving matched placebo.

[0302] Effectiveness

[0303] Treatment with Compound 1 resulted in improvement in psychotic symptoms as measured by the SAPS-PD total score after 6 weeks. The least squares (LS) mean standard error (SE) change from baseline at week 6 was -2.5 (1.62) and -1.4 (2.0) for Compound 1 and placebo, respectively, indicating no statistically significant difference (p = not significant [ns]). Reductions in SAPS-PD total score were observed as early as week 1 in all patients receiving 25 mg of Compound 1 and were consistent through week 6. SAPS-PD responders were defined as patients who demonstrated a 30% or greater, 50% or greater, and 100% or greater improvement (reduction) in the SAPS-PD total score from baseline, respectively. At week 6, both a 30% or greater response and a 50% or greater response were achieved in 37.5% of patients in the Compound 1 group and 27.3% in the placebo group. Resolution of psychotic symptoms (ie, 100% response) occurred in 25.0% of patients in the Compound 1 group and in none of the placebo group at week 6.

[0304] Treatment with Compound 1 resulted in improvement in hallucinations as measured by the SAPS-PD hallucination score after 6 weeks of treatment. The LS mean (SE) change from baseline in the SAPS-PD hallucination subscale score at week 6 was -3.6 (1.07) and -1.9 (1.35; p = ns) for Compound 1 vs. placebo, respectively. A decrease in the SAPS-PD total score was seen in Compound 1 patients as early as week 1 and remained consistent through week 6. Conversely, no improvement was seen in the SAPS-PD delusion subscale score, and the SAPS-PD delusion subscale score at week 6 showed a mild worsening in the Compound 1 group.

[0305] Studies have shown that cognitive impairment can affect the treatment of patients with PDP. To evaluate the efficacy of Compound 1 in patients with Parkinson's disease and cognitive impairment, exploratory analyses were conducted in patients with an MMSE score of 24 or less (a sign of cognitive impairment) and in patients with an MMSE score of greater than 24. Treatment with Compound 1 in patients with a baseline MMSE score of 24 or less resulted in an improvement in the SAPS-PD total score at week 6. The LS mean (SE) change in SAPS-PD total score from baseline at week 6 was -5.2 (2.81) and -2.1 (3.00; p=ns) for Compound 1 and placebo, respectively. A decrease in SAPS-PD total score was observed at week 1 and continued throughout the 6-week treatment period. For patients with an MMSE score greater than 24, no consistent decrease in SAPS-PD total score was observed throughout the 6-week treatment period. The LS mean (SE) change from baseline at week 6 was -1.3 (2.03) for Compound 1 and -0.4 (2.94) for placebo. Treatment with Compound 1 did not affect MMSE scores. The LS mean (SE) change from baseline in MMSE scores at week 6 was -0.8 (0.48) and 0.3 (0.55) for Compound 1 and placebo, respectively (p=ns).

[0306] There were no significant differences between the Compound 1 and placebo groups in the change from baseline in CGI-S scores at week 6; the LS mean (SE) changes from baseline at week 6 were -0.4 (0.33) and -0.7 (0.39) for Compound 1 and placebo, respectively (p = ns). NPI total scores and NPI hallucinations + delusions scores did not differ between Compound 1 and placebo. The Compound 1 group showed improvement in the NPI hallucinations subscale scores at week 6. The LS mean (SE) changes from baseline in NPI hallucinations subscale scores at week 6 were -2.5 (0.77) and -0.8 (0.97; p = ns) for Compound 1 and placebo, respectively. At week 6, there was a significant improvement (p=0.022) in the change from baseline in LS mean (SE) SCOPA-DS scores for patients receiving Compound 1 (-1.8 [0.74]) versus placebo (0.9 [0.80]). Conversely, there was no improvement in the change from baseline in SCOPA-NS scores at week 6. The LS mean (SE) SCOPA-NS scores at week 6 were -0.1 (0.73) and 0.2 (0.79; p=ns) for Compound 1 and placebo, respectively.

[0307] safety

[0308] To assess whether treatment with Compound 1 affected motor symptoms of PD, UPDRS Part III scores were measured at baseline and at post-baseline visits. The mean (SD) baseline UPDRS Part III scores were 33.4 (10.28) and 35.9 (13.12) for the Compound 1 and placebo groups, respectively. No consistent changes were observed in the LS mean (SE) change in UPDRS Part III scores from baseline through week 6 for the Compound 1 and placebo groups.

[0309] Overall, 18 (72.0%) patients in the Compound 1 group experienced 65 AEs, and 12 (85.7%) patients in the placebo group experienced 32 AEs. Two patients in the Compound 1 group experienced serious AEs: hip fracture and mental status changes, respectively; neither event was considered related to treatment, and both resolved. Five patients in the Compound 1 group each experienced an AE that led to discontinuation. No deaths were reported.

[0310] AEs are shown in Table 1.3.2 by dose at the time of event onset. [Table 21]

[0311] The most common AEs (≥10%) for Compound 1 vs. placebo included hallucinations (24% vs. 14%), confusion (20% vs. 14%), dizziness (16% vs. 7%), nausea (12% vs. 7%), falls (12% vs. 21%), and fatigue (8% vs. 14%). Overall, the incidence of psychiatric AEs was higher in the 50 mg and 75 mg Compound 1 dose groups compared with the 25 mg dose group. The incidence of confusion was highest in patients receiving Compound 1 at 75 mg.

[0312] Overall, the incidence of orthostatic hypotension in patients before and after dosing was similar in the placebo and Compound 1 groups. There were no clinically significant changes in ECG parameters, clinical laboratory values, or C-SSRS over the study period. This study suggests that improvement in Parkinson's disease-associated psychiatric symptoms with Compound 1 occurred without deterioration in motor function, as indicated by no worsening in UPDRS Part III scores.

[0313] Example 2: Class-effect adverse events across antipsychotics

[0314] The antipsychotic class of pharmaceutical compounds is characterized, in part, by specific adverse event risks associated with its use to treat schizophrenia, bipolar disorder, and depression patient populations. The Medical Device Regulatory Association (MedDRA) is an internationally used terminology for medical conditions, medications, and medical devices, including adverse events. Using MedDRA terminology standardization (preferred terms), a preferred terminology for antipsychotic-related adverse events was established based on reports to the FDA Real-World Adverse Event Reporting Database (FAERS). Specifically, FAERS is used to identify preferred terms related to 11 most recently FDA-approved antipsychotic medications (aripiprazole, asenapine, brexpiprazole, cariprazine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone). Preferred terms cover a variety of healthcare systems and organ manifestations. A total of over 9,500 adverse event records were generated using data from the second quarter of 2018 deployed on the Empirica Signal server.

[0315] The preferred terms for adverse events in the 11 antipsychotic drug pool were ranked by relative risk using the calculated empirical Bayesian geometric mean (EBGM). Preferred terms corresponding to individual symptoms of schizophrenia and / or bipolar disorder, such as those corresponding to individual items on psychotic symptom rating scales (e.g., PANSS, MADRS) used in clinical trials for schizophrenia or bipolar disorder, were selected and noted as disease-related and not analyzed as drug side effects. A higher EBGM value for a drug corresponds to a greater statistical association between the preferred term / adverse event and that drug compared with all other drugs and all other preferred terms / adverse events. Here, a ranking by EBGM value was created, listing preferred terms / adverse events that describe the effects of antipsychotics as a class (calculated for the 11 antipsychotic drug pool as a whole). Therefore, compounds that cause adverse events associated with top-ranked preferred terms (e.g., preferred terms with EGGM values ​​above a threshold) in a clinically relevant portion of the treated patient population can be considered to have an adverse event profile similar to that of antipsychotics.

[0316] As an example, preferred terms associated with a pool of 11 antipsychotic drugs are shown below in Table 17. Compounds that exhibit adverse events corresponding to these exemplary preferred terms in a clinically relevant portion of the patient population can be considered to have an adverse event profile similar to the antipsychotic class.

[0317] [Table 22] [Table 23]

[0318] The clinical trial data for Example 1.1 (4-week study) were searched using over 9,500 preferred terms for adverse events across 11 antipsychotic drug pools. The ranking of preferred terms for Compound 1 by EBGM is shown in Table 18. Compound 1 exhibited clinically insignificant incidences of adverse events associated with current antipsychotic drug classes (e.g., hyperprolactinemia, abnormal blood prolactin levels, increased blood prolactin levels, galactorrhea, cogwheel rigidity, obesity, metabolic syndrome, etc.), as defined by preferred terms with the highest relative risk in real-world adverse event reporting databases (e.g., class-related adverse events). Additionally, preferred terms observed in subjects receiving placebo as a comparator for Compound 1 also exhibited similar adverse event incidence rates. Therefore, Compound 1 does not exhibit an adverse event profile consistent with an antipsychotic drug class effect.

[0319] [Table 24]

[0320] Example 3: Pharmacokinetics

[0321] The pharmacokinetics (PK), safety, and tolerability of Compound 1 were evaluated in healthy adult male subjects and in adult male and female patients with schizophrenia at single ascending doses (5 mg to 125 mg and 25 mg to 150 mg), and in adult male and female patients with schizophrenia at multiple ascending doses (10, 25, 50, 75, and 100 mg, once daily). Blood samples were collected from 0 to 144 hours post-dose for PK analysis. Safety assessments included adverse events, vital signs, clinical tests, physical and neurological examinations, C-SSRS, 12-lead ECG, and safety EEG.

[0322] Healthy adult male subjects, single ascending dose

[0323] The safety, tolerability, and maximum tolerated dose (MTD) of a single oral dose of Compound 1 were studied in 39 healthy adult male subjects. Subjects were required to be aged 18-50 years (inclusive), with a BMI of 16-32 kg / m² (inclusive), not diagnosed with schizophrenia, and not taking concomitant CNS-active medications or CYP2D6 inhibitors.

[0324] Compound 1 was administered to subjects as a single dose at concentrations of 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, and 125 mg. There were 6 subjects in each group except the 125 mg group (9 subjects received this dose) and 13 placebo subjects. There were no deaths or treatment-emergent clinically significant laboratory changes in this study. The results of plasma PK parameters are shown in Table 19 below.

[0325] [Table 25]

[0326] Adult male and female subjects with schizophrenia, single ascending dose

[0327] A study was conducted to evaluate the safety, tolerability, and MTD of a single oral dose of Compound 1 in male and female subjects with schizophrenia. Subjects were required to be male or female, aged 18 to 55 years (inclusive), with a BMI between 19.5 kg / m² and 37 kg / m² (inclusive). In addition, subjects were required to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; Text Revision (DSM-IV-TR) criteria for a primary diagnosis of schizophrenia and not be taking concomitant CNS-active medications or CYP2D6 inhibitors.

[0328] Compound 1 was administered to subjects as a single dose at concentrations of 25 mg, 50 mg, 100 mg, and 150 mg. There were 9 subjects in each group and 12 placebo subjects. There were no deaths or treatment-emergent clinically significant laboratory changes in this study. The results of plasma PK parameters are shown in Table 20 below.

[0329] [Table 26]

[0330] Study Design: Adult male and female subjects with schizophrenia, multiple ascending doses; Two-part clinical study: multiple dose and 28-day open-label

[0331] The study was conducted in two parts: a multiple-dose study and a 28-day open-label study. Compound 1 was evaluated in adult male and female subjects diagnosed with schizophrenia to investigate its safety, tolerability, and pharmacokinetics in the treatment of schizophrenia. The study had two separate parts, enrolling different patient cohorts but utilizing the same study inclusion criteria. Part A was a multicenter, randomized, single-blind, placebo-controlled, ascending multiple-dose oral study, while Part B was a single-center, non-randomized, open-label study evaluating the safety, tolerability, and pharmacokinetics of treatment with Compound 1 at a 75 mg / day dose over 28 days. Efficacy evaluations were conducted during the open-label treatment period in Part B.

[0332] Study inclusion criteria:Male and female subjects were eligible for enrollment if they were aged 18 to 55 years (inclusive) and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; Text Revision (DSM-IV-TR) criteria for a primary diagnosis of schizophrenia. Subjects had a body mass index (BMI) between 19.5 and 37 kg / m. 2 (inclusive); clinically stable for the past 6 months; CGI-S score ≤4; PANSS total score ≤80 (scores ≤4 [moderate or worse] on the following PANSS items: hostility [P7], uncooperativeness [G8]). Subjects were required to remain drug-free throughout the study period, i.e., not use antipsychotics, antidepressants, or mood stabilizers, or prescription or over-the-counter medications (e.g., vitamins and nutritional supplements). Permitted medications included over-the-counter pain relievers (e.g., acetaminophen), hydrocortisone cream, female contraceptives, and medications for stable conditions (e.g., hypertension or hypercholesterolemia); limited use of lorazepam and zolpidem was permitted during the washout and treatment periods.

[0333] Study Design: Multiple Dose (Part A) Sixty subjects were randomized into five ascending dose cohorts (N=12) and assigned to the following Compound 1 dose groups: 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg (administered orally once daily under fasting conditions). Within each cohort, subjects were randomized in a 3:1 ratio to receive either Compound 1 (N=9) or matching placebo (N=3) for 7 days.

[0334] Of the 60 randomized subjects, 71.7% were male, the mean age was 41.8 years (range 24-55), 85.0% were African American, and the mean PANSS total score was 59.4. All but one subject completed the study according to protocol; this subject discontinued the study due to an SAE for psychotic disorder (determined to be unrelated to the study medication).

[0335] Table 21 shows the pharmacokinetic parameters following (A) a single oral dose of increasing concentrations of Compound 1 on day 1 and (B) multiple doses of Compound 1 on day 7.

[0336] [Table 27]

[0337] In the dose range of 10 to 100 mg / day, Compound 1 max The AUC 0-24 The mean V of Compound 1 on day 7 was approximately dose-proportional (β = 1.30 [95% CI: 1.10-1.50]). ss / F and mean CL ss / F did not appear to change significantly with increasing dose.

[0338] Study Design: 28-day open-label dosing (Part B) :

[0339] In an open-label study, adult patients (N=16) diagnosed with schizophrenia were hospitalized and completed washout from their previous antipsychotic medication. After successful washout, subjects received Compound 1 (75 mg / day) for 28 days. Patients remained hospitalized for the first 2 weeks of medication and were outpatients for the remaining 2 weeks of medication. Safety assessments included adverse event rates, clinical laboratory measures, and movement disorder scales (BARS, AIMS, and M-SAS). The effects of Compound 1 on the Positive and Negative Symptoms (PANSS) scale and Clinical Global Impression-Severity Scale (CGI-S) were also assessed.

[0340] A total of 14 subjects completed the 28-day open-label study. Two subjects discontinued the study after 2 weeks due to multiple minor adverse events. Of the 16 randomized subjects, 50% were male, the mean age was 31.8 years (range 23-40), 75.0% were African American, and the mean PANSS total score was 73.3.

[0341] No exacerbation of schizophrenia symptoms was observed in any subject. There were no treatment-emergent clinically significant laboratory changes (effects on ECG parameters (e.g., QTcB and QTcF intervals); neurological examination; or movement disorders as measured by the Barnes Akathisia Rating Scale, the Abnormal Involuntary Movements Scale, or the Modified Simpson-Angus Rating Scale) or any deaths in either Part A or Part B of the study.

[0342] Pharmacokinetic parameters after multiple doses of Compound 1 at 75 mg / day (Part B, Day 13) were as follows: max (CV%), 316ng / mL (17.5%); max (median), 4.0 hours; AUC 0-24 , 3487 h·ng / mL. Visual inspection of the mean trough plasma concentrations of Compound 1 indicated that steady state was achieved by day 7.

[0343] Furthermore, treatment with Compound 1 demonstrated improvements in efficacy measures (PANSS total score, CGI-S) compared to baseline. Moreover, ad hoc subgroup analyses showed significantly greater reductions in PANSS total score from baseline at the end of the 28-day treatment period in subjects with fewer hospitalizations per year compared to subjects with more hospitalizations per year.

[0344] In summary, no safety issues were observed with multiple oral doses of Compound 1 at doses ranging from 10 to 100 mg / d for 7 days or at 75 mg / d for 28 days. There were no treatment-emergent, clinically significant changes in vital signs, physical examination, laboratory values, or ECG parameters (e.g., QTcF interval). No subjects developed treatment-emergent suicidal ideation or behavior. Treatment with Compound 1 at 75 mg / d for 28 days was associated with improvements in PANSS total scores, with improvements greater in patients with higher baseline PANSS total scores, younger patients, and fewer hospitalizations. The results of this study demonstrated an acceptable safety and tolerability profile of Compound 1 (75 mg / day) for up to 28 days in patients with schizophrenia.

[0345] Pharmacokinetic (pk) metrics measured from plasma samples across various populations (e.g., clinical studies) can be pooled to model population pharmacokinetic profiles. For example, pk measurements across nine various populations (e.g., clinical studies) were pooled to obtain the modeled population pk profiles shown in Table 22.

[0346] [Table 28]

[0347] Example 4: Preparation of crystalline form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (“(S)-TPMA”) HCl (i.e., crystalline form A of the HCl salt of Compound 1) and its formulation

[0348] Scheme 1: Preparation of 4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflate [ka]

[0349] 77 g of 3-thiopheneethanol (compound A) was added to a solution of 69 g of N-methylaminoacetaldehyde dimethyl acetal in 595 ml (508 g) of 2-methyltetrahydrofuran (THF). After stirring for 5 minutes, 99 g (58.2 ml) of trifluoromethanesulfonic acid was added. Note that trifluoromethanesulfonic acid is a highly toxic substance. The reaction was heated to reflux (80 ± 2 °C) for 1 hour. The reaction was then distilled at atmospheric pressure to remove the by-product methanol, and the reaction volume was reduced to the target volume of 460 ml over 4-8 hours. The reaction was considered complete when HPLC analysis of the sample showed that compound 1B remained at 1.0% or less (HPLC peak area % of the peaks of compounds A, B, and C of interest).

[0350] If the amount of compound B was 1% or greater, an appropriate amount of 2-methyl THF was added, and distillation continued until the target volume was reached. If the target volume was reached before completion of the reaction (approximately 4 hours), 300 ml of 2-methyl THF was added to the reaction mixture to continue distillation. After completion of the reaction, the reaction mixture was cooled to approximately 40-50°C and concentrated by vacuum distillation to a target volume of 325 ml. 218 g (325 ml) of toluene was then added over approximately 15 minutes, and the resulting slurry was stirred at 50±2°C for 1 hour, then linearly cooled to 20±2°C over 1 hour and 45 minutes with stirring. The slurry was filtered, and the product cake was washed with a mixture of 2-methyl THF and toluene (1:1 v / v). The wet cake was dried under vacuum at 40±5°C to a constant weight, yielding racemic TPMA triflate (compound C) as an off-white solid. The yield was approximately 79%.

[0351] Scheme 2: Preparation of (S)-(-)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R) mandelate [ka]

[0352] To a suspension of 555.3 g of TPMA triflate (compound 1C) in 1668 ml of methyl tert-butyl ether (MTBE) was added 1076 g of 1.77 N aqueous KOH. After stirring for 10 minutes, the pH was checked, and if it was below 13, small amounts of 1.77 N KOH were added to bring the pH above 13. The aqueous and organic layers were set aside, separated, and collected separately. The MTBE (upper) organic layer was retained for further processing. The aqueous (lower) layer was extracted twice with MTBE (835 ml once, 150 ml twice), and the organic (MBTE) layer was collected each time. The MTBE layers were combined and washed with 20% aqueous NaCl (492.9 g), stirred, and the phases were allowed to settle for 10 minutes. The aqueous layer was removed, and the remaining MTBE organic layer was distilled at atmospheric pressure to reduce the reaction volume to a target value of 1.9 L. Upon completion, the solution was cooled to approximately 45°C and concentrated by vacuum distillation to a target volume of 890 ml, maintaining the temperature at 35-45°C. The water content after vacuum distillation was found to be approximately 0.37% by weight. It was then filtered and washed with 204 ml of MTBE to remove insoluble material, and the solution (filtrate) was transferred to a clean reactor. The solvent was switched by adding 2512 ml of acetonitrile and vacuum distilling at 35-45°C to a target volume of 800 ml. The reactor was then washed with 150 ml of acetonitrile, which was added to the solution. The resulting solution was a solution of TPMA free base (Compound D) in acetonitrile. If necessary, acetonitrile was then added to the TPMA free base (Compound D) in acetonitrile to achieve a concentration of approximately 33% Compound D by weight.

[0353] A solution of 250.3 g of (R)-mandelic acid in 1828 ml of acetone was warmed to 48±2°C. Next, a solution of TPMA free base in acetonitrile (302.1 g of Compound D in 917.7 g of acetonitrile) was added while maintaining the reaction temperature below 51°C. After stirring for approximately 10 minutes at 48±2°C, the solution was cooled to 45±2°C and seeded with 1.5 g of (S)-TPMA (R)-mandelate crystals. The solution was stirred for approximately 30 minutes at 45±2°C and linearly cooled to 21±2°C over 90 minutes. After holding at 45±2°C for approximately 30 minutes, the solution was linearly cooled to 10±2°C over 45 minutes. The reaction slurry was then stirred for 60 minutes at 10±2°C, filtered, and the product cake was washed with a mixture of acetone / CHCN (2.3:1 wt / wt). The wet cake was dried under vacuum at 40±2° C. to a constant weight to give crude (S)-TPMA (R)-mandelate (Compound E) as a white crystalline solid in approximately 41% yield.

[0354] Scheme 3: Recrystallization of (S)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R) mandelate [ka]

[0355] A slurry of crude (S)-TPMA (R)-mandelate (Compound E) (200.1 g) from Scheme 2 in 4205 ml of acetone was warmed to approximately 56°C (the boiling point of acetone) and stirred until a clear solution was obtained. After the solution was cooled to 47±2°C over approximately 20 minutes, (S)-TPMA (R)-mandelate seed crystals were added. The solution was stirred at 47±2°C for approximately 30 minutes and then linearly cooled to 21±2°C over 90 minutes. After holding at 21±2°C for approximately 30 minutes, the slurry was linearly cooled to 10±2°C over 45 minutes, then stirred at 10±2°C for 1 hour, filtered, and the product cake was washed with acetone (two times with 401 ml each). The wet cake was dried under vacuum at approximately 40±2°C to constant weight, yielding (S)-TPMA (R)-mandelate (purified Compound E) as a white crystalline solid. The yield was about 77%.

[0356] Scheme 4: Formation of (S)-(-)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride in crystalline form A [ka]

[0357] Scheme 4 of this example provides the reactive crystallization of (S)-(−)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine HCl ((S)-TPMA HCl) as crystalline form A. (S)-TPMA HCl crystallizes in two different forms (polymorphs): block-like crystals (form A) and needle-like crystals (form B). Based on the single crystal X-ray diffraction studies described herein, Form A has a monoclinic crystal system, while Form B has an orthorhombic crystal system.

[0358] To a suspension of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)-mandelate salt (Compound E) (100 g) of Scheme 3 in 305 ml of MTBE was added 172.5 ml of 10% aqueous KOH solution. After stirring for 10 minutes at 20±2°C, the aqueous and organic layers were separated. The organic MTBE (upper) layer was set aside for further processing. If the pH of the aqueous layer was less than 13, a small amount of 19% KOH solution was added to raise the pH to 13. The aqueous (lower) layer was back-extracted twice with MTBE (first with 208 ml of MTBE and then with 155 ml of MTBE), each time setting the organic layer aside for further processing. The set aside organic layers were combined, and the combined organic layers were azeotropically distilled to remove water and distilled at atmospheric pressure to a target of 140 ml. The solution was filtered to remove insoluble materials (e.g., salts precipitated by water removal), and the filtrate was transferred to a clean reactor. 775 ml of isopropanol was added (bringing the total volume of the solution to approximately 1030 ml), and the solvent was switched by vacuum distillation at <45 °C to obtain a 10%–15% solution of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine in isopropanol.

[0359] In various embodiments, the amount of isopropanol added is selected to achieve a weight percent concentration of the free base (Compound F) of 6-7%. The reaction mixture was cooled to 20±2°C, filtered, the filter was washed with 78 ml of isopropanol, and the filtrate was transferred to a clean reactor. Next, 201.6 g of a 6% HCl (w / w) solution in isopropanol was added to the reactor over 45 minutes at approximately 20±2°C. It should be understood that in various embodiments, the target amount of HCl is approximately 10% excess relative to the molar equivalent of the free base (Compound F). The HCl was added as follows: the first 10% was added over 15 minutes, then 30% was added over 15 minutes, and then the remaining amount was added over 15 minutes. A swept-blade impeller was used in a 5 L-scale reactor at 160 to 270 rpm with a treatment volume of approximately 740 ml to obtain appropriate particle size and particle distribution without any apparent agglomeration. The resulting slurry was warmed linearly to 40±2°C over 20 minutes and held at 40±2°C for approximately 30 minutes. It was then cooled linearly to 20±2°C over 20 minutes. After stirring at 20±2°C for approximately 30 minutes, the slurry was filtered and the product cake was washed with isopropanol (86 ml once, 92 ml twice). The cake was dried under vacuum at approximately 40±2°C to a constant weight to give (S)-(-)-TPMA hydrochloride (Compound G) as a white crystalline solid. The yield was approximately 84%.

[0360] In Step 4b of Scheme 4, slow addition, i.e., a low rate of supersaturation generation, favors the formation of the desired blocky (S)-(−)-TPMA HCl crystals (Form A) while reducing the formation of undesired needle-like crystals (Form B), and higher temperatures favor the formation of blocky Form A crystals over Form B.

[0361] (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride (Compound G) obtained in Example 4 1 The H NMR spectrum has the following characteristics: 1H NMR (300 MHz, DMSO-d6); δ (ppm): 2.53 (s, 3 H, -CH3); 2.5-2.8 (m, ,2 H, -CH2-); 3.15-3.37 (2dd, 2 H, CH2-NH); 3.77 and 4.13 (2ddd, 2 H, CH2-O); 5.19 (dd, 1 H, O-CH-C=); 6.95 (d, J = 5 Hz, 1 H, HC=); 7.49 (dd, J = 5 Hz, 1 H, HC=); 9.12 (br, 2 H, NH2 + )

[0362] Figures 21 and 22 show XRPD patterns of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride Form A. Figure 21 is the XRPD measured in transmission, and Figure 22 is the XRPD measured in reflection. Figure 23 is the DSC thermogram of crystalline form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride.

[0363] Formulation and Manufacturing

[0364] Formulations comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient are disclosed, for example, in PCT Patent Publication No. WO2019 / 161238, the entire contents of which are incorporated herein by reference or by analogy thereto.

[0365] In some embodiments, pharmaceutical compositions are provided comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, pharmaceutical compositions substantially similar to the formulations set forth in Tables 23 and 24 are provided. [Table 29] [Table 30]

[0366] Example 5: Preclinical Abuse Liability Assessment of Compound 1

[0367] Compound 1 is a unique non-D2, non-5-HT 2A It is a psychotropic drug with a mechanism of action (MOA) that has shown broad efficacy across multiple animal models of schizophrenia. The molecular targets involved in the antipsychotic efficacy of Compound 1 have not been fully elucidated, but they are thought to be trace amine associated receptor-1 (TAAR1) and 5HT 1A This includes receptor agonism. Based on its unique MOA and profile in animal models, Compound 1 is a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders. See, for example, Koblan et al. The New England Journal of Medicine 382(16), 1497-1506 (2020); Dedic et al. The Journal of Pharmacology and Experimental Therapeutics 371, 1-14 (2019). Given Compound 1's central nervous system activity, a series of nonclinical studies were conducted on Compound 1 to evaluate its potential risk of abuse. The U.S. Food and Drug Administration (FDA) provided a guidance document for assessing the abuse potential of drugs: "Assessment of Abuse Potential of Drugs. Guidance for Industry. January 2017," which is incorporated herein in its entirety. A series of abuse-relevant animal behavioral studies (self-administration and drug discrimination) were conducted in male and female rats to assess whether Compound 1 produces behavioral changes suggestive of abuse potential in humans. Further studies were conducted to examine the potential of Compound 1 to prevent reinstatement of cocaine-seeking behavior in male rats.

[0368] Experimentally naive rats were housed individually in plastic cages with bedding. The animal room was maintained under a 12 / 12-hour light / dark cycle with constant ambient temperature and relative humidity. Animals were acclimated to the laboratory conditions before the start of the experiment and had free access to water. Except for the training of female rats in the MDMA drug discrimination experiment, access to food was restricted to facilitate the training and maintenance of operant behavior. Experiments were conducted in operant chambers (MED Associates, Inc., St. Albans, Vermont, USA) located in sound-attenuated and ventilated cubicles. Each chamber was equipped with a stimulus light and a lever near a food container connected to the food dispenser. Chambers for reinstatement studies were also equipped with a Sonalert® tone generator.

[0369] Self-administration studies: After successful completion of operant training and recovery from intravenous (iv) catheterization surgery, self-administration training sessions were conducted (0.5 mg / kg / cocaine infusion under an FR10 schedule, 0.07 mg / kg / amphetamine infusion under an FR5 schedule, or 0.015 mg / kg / heroin infusion under an FR3 schedule). After training drug responding stabilized, saline was substituted until self-administration ceased. Increasing iv doses of Compound 1, selected based on evaluation of Compound 1's effects on operant behavior, were substituted for the training drug for at least five consecutive test sessions. Intermittent retests with the training drug (0.25 mg / kg / cocaine infusion, 0.07 mg / kg / amphetamine infusion, 0.015 mg / kg / heroin infusion) were conducted to ensure maintenance of self-administration behavior. The average number of infusions over the last three sessions of stable responding (average of 10 sessions if stable responding was not observed) was calculated for each animal.

[0370] Figures 24A, 24B, and 24C show that Compound 1 was not self-administered by rats trained to self-administer cocaine, amphetamine, or heroin, respectively. In the self-administration (cocaine substitution) test, the mean (±SEM) number of infusions for male SD rats (n=10) was 1.9±0.4, 1.5±0.3, and 1.0±0.3 per session at Compound 1 dose levels of 0.1, 0.3, and 1 mg / kg / infusion, respectively. The mean number of infusions at each Compound 1 dose level was significantly lower than the mean of the preceding cocaine session (range 32.7±2.1 to 33.4±2.7; p<0.001, Tukey's multiple comparison test) and was not significantly different from vehicle (2.2±0.5) or saline (3.1±0.3) controls.

[0371] In the self-administration (amphetamine substitution) test, the mean (±SEM) number of infusions per session for male SD rats (n=12) was 2.5±0.3, 2.4±0.6, and 1.8±0.3 at Compound 1 dose levels of 0.1, 0.3, and 1 mg / kg / infusion, respectively. The mean number of infusions at each Compound 1 dose level was significantly lower than the mean of the preceding amphetamine session (range 18.5±0.5 to 19.4±0.6; p<0.001, Tukey's multiple comparison test) and was not significantly different from vehicle (3.5±0.6) or saline (3.4±0.4) controls.

[0372] In the self-administration (heroin substitution) test, the mean (±SEM) number of infusions in male SD rats (n = 8-9 per session) was 8.0 ± 2.5, 5.4 ± 0.9, 6.4 ± 1.4, and 4.4 ± 0.5 at Compound 1 dose levels of 0.01, 0.03, 0.1, and 0.3 mg / kg / injection, respectively. The statistically corrected mean number of infusions at each Compound 1 dose level was significantly lower than the mean for heroin acquisition sessions (19.0 ± 0.4; p < 0.001, Dunnett's test) and not significantly different from the mean for saline extinction sessions (4.8 ± 0.2).

[0373] Drug discrimination: After successful completion of operant training, separate groups of rats were trained to discriminate between training drug (0.6 mg / kg amphetamine ip or 1.25 mg / kg 3,4-methylenedioxymethamphetamine (MDMA) ip) and saline in a two-choice lever-press test using food reinforcement (amphetamine FR10, MDMA FR5). Training drug was administered 15 min before the session. Once each animal achieved the discrimination training criterion, Compound 1 or a dose of buspirone was administered orally before the test session. The percentage of total responses and response rate on the training drug-matched lever were calculated for each rat.

[0374] Figures 25A and 25B show that Compound 1 did not generalize to amphetamine cues in rats. Mean (±SEM) amphetamine-paired lever responses of 3.5% (±2.0%), 11.2% (±5.8%), and 13.7% (±6.6%) were observed at Compound 1 doses of 3, 10, and 30 mg / kg, respectively, in male SD rats (n=10). Mean (±SEM) response rates (responses / s) were unaffected by Compound 1 doses of 3 or 10 mg / kg (0.77±0.12 or 0.69±0.10 vs. 0.91±0.13 responses / s (vehicle), respectively, p>0.05). At 30 mg / kg, Compound 1 significantly reduced response rates (0.42±0.05, *p<0.001, Tukey's multiple comparison test).

[0375] Figures 26A and 26B show that Compound 1 partially generalized to ipMDMA cues in rats. In female Lister hooded rats (n = 6-7 / dose), Compound 1 did not generalize to MDMA cues at 3 or 10 mg / kg (19.8 ± 8.5% and 15.1 ± 8.1% generalization to MDMA, respectively). At 30 mg / kg, Compound 1 partially generalized to MDMA cues (43.0 ± 17.6% generalization). Neither Compound 1 dose produced an unacceptable suppression of lever pressing. In female Lister hooded rats (n = 6 / dose), buspirone did not generalize to MDMA cues at 0.3 or 1 mg / kg (6.6 ± 3.9% or 10.8 ± 7.9% generalization to MDMA, respectively). At the highest dose, buspirone partially generalized to the MDMA cue (37.2 ± 20.4% generalization). No buspirone dose produced an unacceptable suppression of lever pressing.

[0376] MDMA and 5-HT 2A Agonist hallucinogens generalize completely to the discriminative cues of MDMA. 1A This is due to the presence of buspirone (5-HT 40), an approved non-specific anti-anxiety drug. 1A Compound 1 (a partial agonist) partially generalized to the MDMA cues. Like buspirone, Compound 1 partially generalized to the MDMA cues. Like buspirone, Compound 1 partially generalized to the MDMA cues. The results suggest that Compound 1 has MDMA-like or 5-HT 2A Without wishing to be bound by any particular theory, the partial generalization seen with the highest dose of Compound 1 may be due to its 5-HT 1A This is most likely due to its agonistic properties.

[0377] Cocaine relapse:After recovery from the intravenous catheterization surgery, rats were trained under FR1 to self-administer cocaine (0.5 mg / kg / infusion), during which an infusion was delivered for each active lever press. During the infusion, a tone was emitted from the Sonalert®, a stimulus light flashed, and the room light was extinguished. After successful cocaine self-administration training, extinction sessions were conducted under either "prime" or "cued" conditions. During the "prime" extinction session, no cocaine infusions were administered. All other conditions during extinction were identical to those during self-administration. During the "cued" extinction session, the room light was brightened and the lever extended, but no infusions were administered, and no other stimulus changes occurred as scheduled. Compound 1 (1–10 mg / kg) or its vehicle was administered orally 60 min before the session, and conditions during reinstatement were identical to those during extinction, except that either (a) 17 mg / kg ip cocaine was administered 10 min before the session ("prime"), or (b) no self-administered cocaine infusion was administered, and a cue previously associated with the cocaine infusion was presented noncontingently for 6 s at the beginning of the reinstatement test session and with each right lever press ("cue"). The mean number of active lever presses during the reinstatement test session was calculated for each animal.

[0378] Figures 27A and 27B show that Compound 1 attenuated cue-induced reinstatement of responding in rats trained to self-administer cocaine (0.5 mg / kg / infusion). Compound 1 (10 mg / kg) significantly reduced cue-reinstated responding in male Long-Evans hooded rats (n = 11-12 / group). The mean (±SEM) number of active lever presses during the cue-induced reinstatement test session was 90.08 ± 17.86, 94.92 ± 16.83, 57.27 ± 9.36, and 45.36 ± 5.55 for vehicle, 1, 3, or 10 mg / kg Compound 1, respectively (*p < 0.05, uncorrected Fisher's LSD test). Compound 1 (1, 3, or 10 mg / kg) significantly reduced cocaine-primed reinstatement responding in male Long-Evans hooded rats (n = 11-12 / group). The mean (±SEM) number of active lever presses during the cocaine-primed reinstatement test session was 84.38 ± 14.65, 109.82 ± 22.16, 77.08 ± 19.70, and 70.17 ± 17.78 for vehicle, 1, 3, or 10 mg / kg Compound 1, respectively.

[0379] Rats trained to self-administer amphetamine or cocaine did not self-administer Compound 1. Similarly, Compound 1 did not positively reinforce rats trained to self-administer low doses of heroin. Based on the predictive validity of established self-administration procedures in rodents, these results suggest that Compound 1 does not exhibit reinforcing effects in humans. Across the behaviorally active dose range of 3 to 30 mg / kg, Compound 1 did not exhibit similar subjective qualities as amphetamine in rats trained with amphetamine cues in a drug discrimination procedure. 5-HT 1ACompound 1 and buspirone, unspecified anxiolytics with partial agonist activity, showed weak (<50%) partial generalization to MDMA-induced cues. Collectively, these results suggest that Compound 1 is unlikely to pose a risk for recreational abuse in humans. Furthermore, the results of the reinstatement study suggest the potential therapeutic utility of Compound 1 in the treatment of substance use disorders.

[0380] Physical dependence:

[0381] The potential for Compound 1 to produce withdrawal-induced physical dependence was evaluated. [Table 31]

[0382] During the baseline period (days -6 to 0), rats were orally dosed once daily (qd) with vehicle for habituation, and then twice daily (bid) with vehicle, Compound 1, or diazepam at a weight-based dose from days 1 to 46. Animals were not dosed during the withdrawal period. Morning dosing was staggered to allow individual observation of all animals each day. Baseline period: Vehicle 7 days (days -6 to 0) Drug administration period: 46 days (days 1 to 46) Withdrawal period: 7 days (days 47 to 53) End: 8th day (54th day) of drug withdrawal

[0383] Body weights were recorded before each dosing session on Days -6 through 46 and in the morning during the withdrawal period. Only body weights recorded before the morning dosing session were used for statistical analysis. Food and water intakes were measured once daily in the morning immediately prior to dosing on Days -6 through 46 and in the morning during the withdrawal period. Body temperature was measured once daily using a rectal probe immediately prior to dosing on Days -6 through 46 and immediately after weight measurements during the withdrawal period. A detailed observation checklist was used to record any physical or behavioral signs of pharmacological effect during the dosing period and of drug dependence during the withdrawal period. Rats were observed for 2 minutes on the platform of their open cages (in the animal room where they were housed throughout the study) 1 hour after the morning dose during baseline and the dosing period, and twice daily during Day 46 and the withdrawal period. For data interpretation, with respect to physical or behavioral signs, withdrawal was defined as beginning with the afternoon observation on Day 46 (because this observation occurred 5 hours after the last dose of diazepam or Compound 1). For all other endpoints, withdrawal begins on day 47.

[0384] Three groups of 13 rats (12 blood-collecting rats and 1 reserve) were administered vehicle or Compound 1 (3 and 10 mg / kg po, bid) on days 1 through 46 to reflect the dosing regimen of rats during the main period. Blood samples were collected at the following time points: pre-dose, 30 min, 1 h, 2 h, 4 h, 7 h, 7.5 h, 8 h, 9 h, 11 h, and 24 h, on days 1, 23, and 46 (n = 3 rats per time point). Dose-regimen analysis was performed.

[0385] resultRats in the vehicle-treated control group showed few behavioral and physical signs during the baseline, treatment, and withdrawal periods, with an overall low incidence (2–3 rats). During the baseline period, these signs were limited to rearing, increased locomotor activity (in response to finger snapping), and increased irritability in response to treatment or mild restraint. During the treatment period, rearing, attempts to escape from the cage, increased locomotor activity, increased locomotor activity, piloerection, and hair wetting were observed. Only rearing was observed at a moderate incidence (Days 4, 5, and 9; 4 rats). When vehicle treatment was abruptly terminated, only increased locomotor activity was observed, and the incidence was lower compared to the mornings of Days 42–46 of the treatment period. During the withdrawal period, behaviors were limited to attempts to escape from the cage, increased locomotor activity, increased locomotor activity, and hair wetting, with the exception of increased locomotor activity (Day 49; 4 rats), and the incidence was similarly low.

[0386] Compound 1 (3 mg / kg / day po, bid) did not affect body weight, food intake, water intake, or body temperature during the dosing period, or the daily changes during the withdrawal period, expressed daily, weekly, or overall. Cessation of Compound 1 (3 mg / kg po, bid) administration resulted in a rare but significant increase in daily food intake compared to vehicle on withdrawal day 4 (day 50). However, when the data were analyzed as the daily change in food intake throughout the withdrawal period, no significant change was observed (difference from the mean of days 42 to 46). A significant increase in daily water intake compared to vehicle was observed on withdrawal days 1 to 5 (days 47–51). This was reflected in a significant increase in the daily change in water intake on withdrawal days 4 and 5 (days 50 and 51) compared to dosing days 42–46. Withdrawal from Compound 1 (3 mg / kg po, bid) did not significantly affect body weight or body temperature. Compound 1 (3 mg / kg pobid) produced rearing behavior, increased body tone, increased locomotor activity, increased response to sound, piloerection, and hair wetting at low to moderate incidences. Increased locomotor activity and increased body tone were predominantly, but not exclusively, observed during the first 1 to 2 weeks of treatment, and increased response to sound was observed sporadically throughout the treatment period, while piloerection and hair wetting were observed throughout the treatment period. When treatment with Compound 1 (3 mg / kg pobid) was terminated, the only new behaviors observed were teeth-chattering (at a low incidence on Day 4 (afternoon)) and nose staining (also at a low incidence). Furthermore, increased hunched posture, increased locomotor activity, piloerection, and hair wetting were observed during the withdrawal period compared to the end of the treatment period (Days 42–46 morning). Compared to vehicle, there was an increased incidence of hunched posture, rearing behavior, increased reactivity to sound, piloerection, teeth chattering, wet fur, and muzzle staining, and a decreased incidence of cage escape attempts and increased locomotor activity during the withdrawal period.Compound 1 (10 mg / kg pobid) caused an initial weight loss over the first 4 days of the dosing period, which continued throughout most of the dosing period, resulting in a significant decrease in daily body weight compared to vehicle-treated controls, up to and including day 36. At the end of the dosing period, rat body weights were -2.6% lower than vehicle controls (p=0.088). Compound 1 (10 mg / kg pobid) caused a significant decrease in daily food intake during week 1 (days 2, 3, and 7) and sporadically thereafter (days 8, 11, 12, 13, 23, and 45) (range: week 1; -11.2% to -25.9%; weeks 2–6; -8.0% to -14.5%). This was reflected in a decrease in average weekly food intake during and throughout weeks 1–4. Compound 1 (10 mg / kg pobid) also produced a significant decrease in daily water intake (days 1, 9, 11, 13, 15, and 23). This effect was limited to weeks 1 and 2, as shown when the data were analyzed weekly or overall. No effect on body temperature was observed throughout the treatment period. After abrupt cessation of Compound 1 (10 mg / kg pobid), daily body weights on days 1 through 7 of withdrawal (days 47 through 53) were lower than vehicle, but not significantly different, and slowly returned to vehicle control levels. When body weight was expressed as the cumulative change in body weight (difference from day 46) over the 7-day withdrawal period, a progressive increase in cumulative body weight gain (from days 46 to 53) was observed (likely representing a reversal of the Compound 1-related body weight / weight gain reduction observed during the treatment period), reaching statistical significance on day 53. Daily food intake remained significantly low on day 1 of withdrawal (day 47) and increased above control levels on days 4 and 7 (days 50 and 53). When food intake was analyzed as the daily change in food intake during the withdrawal period (difference from the mean of days 42 through 46), significant decreases were observed on days 1 and 5 of withdrawal (days 47 and 51) and increases were observed on days 4 and 7 (days 50 and 53). However, the effect on day 51 is not considered representative of drug-related withdrawal symptoms, as a similar decrease was observed across all dose groups on this day.As a result, food intake is expected to decrease initially during the withdrawal period, followed by a gradual increase toward the end of the withdrawal period. This increase likely reflects a reversal of the Compound 1-associated decrease in food intake during the treatment period. When data were analyzed as the daily change in water intake (compared to the last 5 days of the treatment period), a significant increase in daily water intake was observed throughout the withdrawal period (days 47 to 53) and from days 47 to 53 (days 1 to 7 of withdrawal). A rare significant decrease in the daily change in body temperature was observed on day 3 of withdrawal (day 49) only when data were analyzed as the difference from the mean body temperature over the last 5 days of the treatment period (days 42 to 46). Daily body temperature remained unchanged compared to vehicle throughout the withdrawal period. Overt behavioral and physical signs were observed with low to high incidence throughout the treatment period and included hunched posture, piloerection, abdominal sagging, increased body tone, increased locomotor activity, increased response to sound, and moist fur. Five new behavioral and physical signs were observed at low incidence upon cessation of Compound 1 (10 mg / kg pobid): tremor (Day 48 PM; 2 rats), ptosis (Days 47 PM, 48 PM, and 49 PM; 2–3 rats), irregular breathing (Days 47 PM and 49 PM; 2 rats), teeth chattering (Days 47 PM, 49 PM, and 51 PM; 2 rats), and nose pigmentation (Days 46 PM, 47 PM, 48 PM, 49 PM–51 AM, and 53 AM / PM; 2–3 rats). Additionally, increased incidences of rearing, cage escape attempts, and increased locomotor activity were observed over the withdrawal period compared with the end of the treatment period (Days 42–46 AM). A decrease in the incidence of abdominal sagging, hunched posture, increased reactivity to sound, and piloerection was also observed compared to the end of the treatment period.A decrease in the incidence of abdominal sagging, hunched posture, rearing behavior, teeth chattering behavior, tremors, increased reactivity to sound, piloerection, increased body tone, ptosis, irregular breathing or increased breathing, increased locomotor activity, wet fur and muzzle staining, and cage escape attempts was observed over the withdrawal period compared to vehicle.

[0387] Diazepam was administered using an ascending dose regimen (0, 15, or 20 mg / kg po bid on days 1-5, 6-18, and 19-46). Compared with vehicle-treated controls, diazepam had no effect on daily body weight on days 1-18, but significantly elevated this parameter on days 19-46. This was reflected in significantly increased body weight gain throughout the treatment period. At the end of the treatment period, the body weight of diazepam-treated rats was 5.4% higher than that of vehicle-treated rats. This increase in body weight was associated with significant increases in food intake on most days from day 7 onward, mean daily food intake from weeks 2 through 5, and days 36-45, as well as overall daily food intake throughout the treatment period, but not water intake. Diazepam administration also caused an increase in daily body temperature throughout the treatment period, reaching statistical significance on days 2 to 4, 7, 12, 28 to 31, 33 to 35, 37, 38, 40, 41, and 44. This was reflected in significant increases in mean body temperature throughout weeks 1, 4, 5, and days 36 to 46, as well as throughout the treatment period. Upon withdrawal of diazepam, a decrease in daily weight loss or weight gain was observed, along with decreases in food consumption, water intake, and body temperature (compared to the treatment period); for food and water intake, the decreases were particularly pronounced on day 1 of withdrawal and attenuated over the treatment period. Obvious behavioral and physical signs were observed at low to high incidence during diazepam treatment and included ataxia / staggering, hunched posture, paw-lifting, behavioral inhibition, rearing, cage escape attempts, increased body tone, decreased body tone, increased locomotor activity, increased reactivity to sound, and wet fur. Behaviors with lower incidence also included jumping, decreased locomotor activity, exophthalmos, irregular breathing, decreased respiration, and purposeless chewing. The incidence of many behavioral and physical signs quickly returned to control levels upon withdrawal or significantly decreased during the withdrawal period. However, abdominal floppiness, increased respiration, and muzzle pigmentation were observed at low to moderate incidence and remained throughout the treatment period.Additionally, increased incidences of rearing behavior, increased body tone, increased reactivity to sound, piloerection, wet fur, and paw lifting were observed over the withdrawal period compared to the end of the treatment period (mornings on Days 42-46). Decreased incidences of ataxia / staggering, hunched posture, jumping, cage escape attempts, increased locomotor activity, decreased respiration, and purposeless chewing were also observed compared to the end of the treatment period. Increased incidences of abdominal sagging, hunched posture, paw lifting, rearing behavior, decreased locomotor activity, irregular or increased respiration, increased reactivity to sound, piloerection, increased body tone, wet fur, and muzzle staining were observed over the withdrawal period compared to vehicle. Furthermore, decreased incidences of increased locomotor activity and cage escape attempts were observed. All dose-regimen samples were within ±10% of the acceptance criteria. The maximum plasma concentrations (Cmax) on days 1, 23, and 46 were 534, 490, and 520 ng / ml, respectively, at 3 mg / kg pobid, and 1390, 1690, and 1940 ng / ml, respectively, at 10 mg / kg pobid. Compound 1 doses of 3 and 10 mg / kg pobid in this study achieved 1.14- to 1.23-fold and 3.23- to 4.50-fold greater drug exposures, respectively, compared to the clinically effective dose in humans (100 mg dose, Cmax = 431 ng / ml; Compound 1 Investigator's Brochure, Version 9.0).

[0388] conclusionThis study followed accepted criteria for determining the potential for inducing a physical dependence syndrome, including sufficient duration of administration, abrupt cessation of administration, and frequent monitoring for several days after cessation (CHMP / EMA, 2006; CDER / FDA, 2017). After 46 days of cessation, a typical pattern of diazepam withdrawal signs, such as anorexia and hypodipsia, was observed. Physical dependence was demonstrated by changes in the incidence or expression of many behavioral and physical signs after abrupt cessation of administration compared with vehicle. Cessation of Compound 1 (3 mg / kg pobid) on day 46 resulted in changes in the incidence of behavioral and physical signs suggestive of withdrawal (polydipsia, hunched posture, rearing behavior, increased reactivity to noise, piloerection, teeth chattering, wet fur, muzzle discoloration, and cage escape attempts). There was also evidence of withdrawal following cessation of treatment with Compound 1 (10 mg / kg pobid) as indicated by transient anorexia, polydipsia, and changes in the incidence of behavioral and physical signs suggestive of withdrawal (sagging abdomen, rearing behavior, increased locomotor activity, increased reactivity to sound, teeth chattering, tremors, ptosis, piloerection, hunched posture, wet fur, muzzle pigmentation, increased body tone, cage escape attempts, and irregular or increased breathing).

[0389] In summary, discontinuation of Compound 1 at either 3 or 10 mg / kg pobid after 46 days of administration resulted in a dose-dependent increase in several withdrawal signs indicative of physical dependence. However, the incidence and severity of physiological effects and physical signs during withdrawal from Compound 1 differed from those observed during withdrawal from diazepam (10 / 15 / 20 mg / kg pobid), indicating a distinctly milder withdrawal syndrome.

[0390] Various preferred embodiments [A] to [CB] of the present invention are set out below: [Embodiment A] 1. A method for treating a neurological or psychiatric disease or disorder in a patient in need of treatment that does not pose a risk of clinically significant adverse events, said method comprising administering to said patient a therapeutically effective amount of Compound 1. [ka] or a pharmaceutically acceptable salt thereof, wherein the patient experiences no clinically significant adverse events. [Embodiment B] 1. A method for treating a neurological or psychiatric disease or disorder in a patient in need of treatment that does not pose a risk of clinically significant adverse events, said method comprising administering to said patient a therapeutically effective amount of Compound 1. [ka] or a pharmaceutically acceptable salt thereof. [Embodiment C] 1. A method for treating a patient having a neurological or psychiatric disease or disorder that does not pose a risk of clinically significant adverse events, said method comprising administering to said patient a therapeutically effective amount of Compound 1. [ka] or a pharmaceutically acceptable salt thereof. [Embodiment D] 1. A method for treating schizophrenia in a patient in need thereof, which method does not pose a risk of clinically significant adverse events, said method comprising administering to said patient a therapeutically effective amount of Compound 1. [ka] or a pharmaceutically acceptable salt thereof. [Embodiment E] 1. A method for treating a patient with schizophrenia that does not pose a risk of clinically significant adverse events, said method comprising administering to said patient a therapeutically effective amount of Compound 1. [ka] or a pharmaceutically acceptable salt thereof. [Embodiment F] 1. A method for treating a neurological or psychiatric disease or disorder in a patient, said method comprising administering to said patient a therapeutically effective amount of Compound 1 [ka] or a pharmaceutically acceptable salt thereof, thereby minimizing adverse events associated with antipsychotic drugs having affinity for dopamine D2 in said patient. [Embodiment G] 1. A method for treating a neurological or psychiatric disease or disorder in a patient, said method comprising administering to said patient a therapeutically effective amount of an antipsychotic drug that does not have direct affinity for dopamine D2 receptors, said method being substantially devoid of adverse events in said patient, said adverse events being associated with antipsychotic drugs that have affinity for dopamine D2. [Embodiment H] The antipsychotic drug having no direct affinity for the dopamine D2 receptor is Compound 1. [ka] or a pharmaceutically acceptable salt thereof. [Embodiment I] 1. A method of minimizing adverse events in a patient in need of treatment for a neurological or psychiatric disease or disorder, said method comprising administering to said patient a therapeutically effective amount of an antipsychotic drug that does not have direct affinity for dopamine D2 receptors, said antipsychotic drug being selected from the group consisting of Compound 1 and Compound 2. [ka] or a pharmaceutically acceptable salt thereof, wherein said method minimizes adverse events associated with antipsychotic drugs having affinity for dopamine D2 receptors. [Embodiment J] The method of any one of embodiments [A] to [I], or any other embodiment of the invention, wherein the neurological or psychiatric disease or disorder is schizophrenia. [Embodiment K] The method of embodiment [J] or any other embodiment of the invention, further comprising treating negative symptoms of schizophrenia. [Embodiment L] The neurological or psychiatric disease or disorder is schizophrenia, cognitive impairment associated with schizophrenia, schizophrenia spectrum disorder, negative symptoms of schizophrenia, attenuated psychotic syndrome, prodrome of schizophrenia, delusional disorder, psychosis, psychotic disorder, delirium, Tourette's syndrome, anxiety and related disorders such as generalized anxiety disorder (GAD) and post-traumatic stress disorder, behavioral disorder, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, bipolar depression, treatment-resistant depression (TRD), and major depressive disorder. A method according to any one of embodiments [A] to [I], or any other embodiment of the present invention, wherein the treatment is a mood disorder such as myelodysplastic syndromes (MDD); mania, seasonal affective disorder, obsessive-compulsive disorder, narcolepsy, rapid eye movement disorder (REM) behavior disorder, substance abuse or dependence, Lesch-Nyhan disease, Wilson's disease, autism spectrum disorder, dementia, dementia-related psychosis (DRP), Parkinson's disease (PDP), and agitation and psychosis of Alzheimer's disease, or Huntington's disease. [Embodiment M] The method of any one of embodiments [A] to [J] or [L], or any other embodiment of the invention, wherein the neurological or psychiatric disease or disorder is selected from schizophrenia, attenuated psychotic syndrome, schizophrenia prodrome, schizoid personality disorder, and schizotypal personality disorder. [Embodiment N] The method according to embodiment [L] or any other embodiment of the invention, wherein the psychosis is selected from organic psychosis, drug-induced psychosis, psychotic symptoms associated with Parkinson's disease, and excited psychosis. [Embodiment O] The method of any one of embodiments [A] to [N], or any other embodiment of the invention, wherein the patient has not responded adequately to an antipsychotic that is at least one typical antipsychotic or at least one atypical antipsychotic. [Embodiment P] The method of any one of embodiments [A] to [O], or any other embodiment of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, comprises the HCl salt of Compound 1. [Embodiment Q] The method of any one of embodiments [A] to [P], or any other embodiment of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally. [Embodiment R] The method according to any one of embodiments [A] to [Q], or other embodiments of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily in the evening or at night or around bedtime. [Embodiment S] The method according to any one of embodiments [A] to [R], or other embodiments of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered at about 50 mg or about 75 mg per day. [Embodiment T] The method of any one of embodiments [A] to [S], or any other embodiment of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily for a treatment period of 4 weeks. [Embodiment U] The method of any one of embodiments [A] to [S], or any other embodiment of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily for a treatment period of 26 weeks. [Embodiment V] The method of any one of embodiments [A] to [U], or other embodiments of the invention, wherein the risk of an adverse event in said patient is about the same as or similar to placebo. [Embodiment W] The method according to any one of embodiments [A] to [V], or any other embodiment of the present invention, which minimizes adverse cardiovascular events. [Embodiment X] The method of any one of embodiments [A] to [W], or any other embodiment of the invention, which results in cardiovascular events in 5% or less of patients. [Embodiment Y] The method of any one of embodiments [A] to [W], or any other embodiment of the invention, wherein the patient is at increased risk of adverse cardiovascular events due to administration of an antipsychotic drug. [Embodiment Z] The method of embodiment [T], or any other embodiment of the invention, resulting in cardiovascular adverse events in 5% or less of patients during a 29-day treatment period. [Embodiment AA] The method of embodiment [U], or any other embodiment of the invention, resulting in cardiovascular adverse events in 6% or less of patients during a 26-week treatment period. [Embodiment AB] The method of any one of embodiments [A] to [V], or other embodiments of the present invention, which results in adverse cardiovascular events in patients at rates approximately the same as or similar to placebo. [Embodiment AC] The method of any one of embodiments [W] to [AB], or other embodiments of the invention, wherein the cardiovascular adverse event is considered to be atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, postural orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension, or orthostatic tachycardia. [Embodiment AD] The method according to any one of embodiments [A] to [V], or any other embodiment of the invention, which minimizes extrapyramidal adverse events. [Embodiment AE] The method of any one of embodiments [A] to [V] or [AD], or any other embodiment of the invention, which results in extrapyramidal adverse events in 5% or less of patients. [Embodiment AF] The method of any one of embodiments [A] to [V] or [AD], or any other embodiment of the invention, wherein the patient is at increased risk of extrapyramidal adverse events due to administration of an antipsychotic drug. [Embodiment AG] The method of any one of embodiments [AD] to [AF], or other embodiments of the invention, wherein the extrapyramidal adverse event is considered to be akathisia, restlessness, joint stiffness, musculoskeletal stiffness, nuchal rigidity, postural tremor, or tremor. [Embodiment AH] The method of any one of embodiments [A] to [V], or any other embodiment of the invention, which results in extrapyramidal adverse events in patients at a rate no greater than placebo. [Embodiment AI] The method according to any one of embodiments [A] to [V], or any other embodiment of the invention, which is substantially devoid of QT prolongation. [Embodiment AJ] The method of any one of embodiments [A] to [V] or [AI], or any other embodiment of the invention, which results in QT prolongation in 5% or less of patients. [Embodiment AK] The method of any one of embodiments [A] to [V] or [AI], or any other embodiment of the invention, wherein the patient is at increased risk of QT prolongation due to administration of an antipsychotic drug. [Embodiment AL] The method of embodiment [T], or any other embodiment of the invention, wherein the method is substantially devoid of QT prolongation during a treatment period of 29 days. [Embodiment AM] The method of any one of embodiments [A] to [V], or any other embodiment of the invention, which results in QT prolongation in no greater proportion of patients than placebo. [Embodiment AN] QT prolongation is due to: A QTcF interval of greater than 450 milliseconds that was not present at baseline is present in said patient at any time point; and An increase in the QTcF interval of 30 milliseconds or more from baseline on at least one post-baseline measurement A method as described in any one of embodiments [AI] to [AM] or any other embodiment of the present invention, which is considered to be one or both of: [Embodiment AO] The method according to any one of embodiments [A] to [V], or any other embodiment of the invention, which minimizes hyperprolactinemia in said patient. [Embodiment AP] The method of any one of embodiments [A] to [V], or any other embodiment of the invention, which produces hyperprolactinemia in patients in a proportion not greater than placebo. [Embodiment AQ] The method of any one of embodiments [A] to [V], or any other embodiment of the invention, which minimizes orthostatic hypotension in said patient. [Embodiment AR] The method of any one of embodiments [A] to [V] or [AQ], or any other embodiment of the invention, which results in orthostatic hypotension in 5% or less of patients. [Embodiment AS] The method of any one of embodiments [A] to [V] or [AQ], or any other embodiment of the invention, wherein the patient has an increased risk of orthostatic hypotension due to administration of an antipsychotic drug. [Embodiment AT] The method of any one of embodiments [A] to [V], or any other embodiment of the invention, which results in orthostatic hypotension in patients at a rate no greater than placebo. [Embodiment AU] The method of any one of embodiments [A] to [V], or any other embodiment of the present invention, which minimizes orthostatic tachycardia in the patient. [Embodiment AV] A method according to any one of embodiments [A] to [V] or [AU], or any other embodiment of the invention, that results in orthostatic tachycardia in 5% or less of patients. [Embodiment AW] The method of any one of embodiments [A] to [V] or [AU], or any other embodiment of the invention, wherein the patient has an increased risk of orthostatic tachycardia due to administration of an antipsychotic drug. [Embodiment AX] A method according to any one of embodiments [A] to [V], or any other embodiment of the invention, which produces orthostatic tachycardia in patients at rates approximately the same as or similar to placebo. [Embodiment AY] A method according to any one of embodiments [A] to [AX], or any other embodiment of the invention, which results in (i) a reduction in the PANSS total score from baseline of at least 17.2 or (ii) an effect size of the PANSS total score of at least 0.45. [Embodiment AZ] The method according to embodiment [AY], or any other embodiment of the invention, wherein the results are measured after a treatment period of 29 days. [Embodiment BA] The method of any one of embodiments [AX] or [AY], or other embodiments of the invention, which results in a reduction of at least about 30 in the PANSS total score from baseline after 30 weeks of treatment. [Embodiment BB] A method according to any one of embodiments [A] to [BA], or any other embodiment of the invention, which results in (i) a reduction in the PANSS Positive subscale score of at least 5.5 from baseline or (ii) an effect size of the PANSS Positive subscale score of at least 0.32. [Embodiment BC] The method according to embodiment [BB] or any other embodiment of the invention, wherein the results are measured after a treatment period of 29 days. [Embodiment BD] The method of any one of embodiments [BB] or [BC], or other embodiments of the invention, resulting in a reduction of at least about 10 in PANSS positive subscale score from baseline after 30 weeks of treatment. [Embodiment BE] A method according to any one of embodiments [A] to [BD], or any other embodiment of the invention, which results in (i) a reduction in the PANSS Negative subscale score of at least 3.1 from baseline or (ii) an effect size of the PANSS Negative subscale score of at least 0.37. [Embodiment BF] The method according to embodiment [BE] or any other embodiment of the invention, wherein the results are measured after a treatment period of 29 days. [Embodiment BG] The method of any one of embodiments [BE] or [BF], or other embodiments of the invention, resulting in a reduction of at least about 5 in PANSS negative subscale score from baseline after 30 weeks of treatment. [Embodiment BH] The method of any one of embodiments [A] to [BG], or any other embodiment of the invention, resulting in (i) a reduction in the PANSS Global Psychopathology subscale score of at least 9 from baseline or (ii) an effect size of the PANSS Global Psychopathology subscale score of at least 0.51. [Embodiment BI] The method according to embodiment [BH] or any other embodiment of the invention, wherein the results are measured after a treatment period of 29 days. [Embodiment BJ] A method according to any one of embodiments [BH] or [BI], or any other embodiment of the invention, which results in a reduction of at least about 15 in the PANSS Global Psychopathology subscale score from baseline after 30 weeks of treatment. [Embodiment BK] A method according to any one of embodiments [A] to [BJ], or any other embodiment of the invention, which results in (i) a reduction in CGI-S score of at least 1 from baseline or (ii) an effect size of CGI-S score of at least 0.52. [Embodiment BL] The method according to embodiment [BK] or any other embodiment of the invention, wherein the results are measured after a treatment period of 29 days. [Embodiment BM] A method according to any one of embodiments [BK] or [BL], or any other embodiment of the invention, which results in a reduction in CGI-S score from baseline of at least about 1.5 after 30 weeks of treatment. [Embodiment BN] A method according to any one of embodiments [A] to [BM], or other embodiments of the invention, which results in (i) a reduction in BNSS total score from baseline of at least 7.1 or (ii) an effect size of BNSS total score of at least 0.48. [Embodiment BO] The method of embodiment [BN] or any other embodiment of the invention, wherein the results are measured after a treatment period of 29 days. [Embodiment BP] The method according to any one of embodiments [BN] or [BO], or other embodiments of the invention, which results in a reduction of at least about 10 in BNSS total score from baseline after 30 weeks of treatment. [Embodiment BQ] A method according to any one of embodiments [A] to [BP], or other embodiments of the invention, which results in (i) a reduction in the MADRS total score from baseline of at least 3.3 or (ii) an effect size of the MADRS total score of at least 0.32. [Embodiment BR] The method according to embodiment [BQ] or any other embodiment of the invention, wherein said results are measured after a treatment period of 29 days. [Embodiment BS] The method of any one of embodiments [BQ] or [BR], or other embodiments of the invention, which results in a reduction in MADRS total score from baseline of at least about 5 after 30 weeks of treatment. [Embodiment BT] The method of any one of embodiments [A] to [V], or any other embodiment of the invention, comprising treating insomnia, anxiety, or headache symptoms in said patient. [Embodiment BU] The method of any one of embodiments [A] to [V], or any other embodiment of the present invention, which minimizes insomnia, anxiety, headache, or any combination thereof in said patient. [Embodiment BV] The method according to any one of embodiments [BT] or [BU], or any other embodiment of the invention, wherein the risk of insomnia, anxiety, headache, or any combination thereof in said patient is less than placebo. [Embodiment BW] The method of any one of embodiments [A] to [BV], or any other embodiment of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is orally administered at a first dose daily for 1 to 3 days, followed by administering Compound 1, or a pharmaceutically acceptable salt thereof, at a therapeutic dose to the patient daily, wherein the first dose is less than the therapeutic dose, and the neurological or psychiatric disease or disorder is schizophrenia. [Embodiment BX] The method of any one of embodiments [A] to [BW], or any other embodiment of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily at said first dose on days 1 to 3, and Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily at said therapeutic dose on days 4 to 29. [Embodiment BY] The method according to any one of embodiments [BW] or [BX], or other embodiments of the invention, wherein the first dose is 50 mg and the therapeutic dose is 75 mg. [Embodiment BZ] 1. A method for treating schizophrenia in a patient, said method comprising: The patient received 75 mg of Compound 1 daily. [ka] or a pharmaceutically acceptable salt thereof is or has been administered orally for a period of treatment; Determining or having determined whether said patient experienced any adverse events during the treatment period; If the patient experiences an adverse event during the treatment period, the dosage may be reduced or has been reduced to 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, daily. A method characterized by: [Embodiment CA] 1. A method for treating symptoms of insomnia, anxiety, or headache in a patient with schizophrenia, said method comprising administering to said patient a therapeutically effective amount of Compound 1. [ka] or a pharmaceutically acceptable salt thereof. [Embodiment CB] The method according to any one of embodiments [A] to [CA], or any other embodiment of the invention, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is Compound 1 hydrochloride in crystalline form A. [Embodiment CC] The following sequence of steps: (c) dissolving 4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine free base in acetonitrile to obtain a 25% to 35% solution by weight, adding the solution to a 15 to 20% (weight to weight) solution of (R)-mandelic acid in acetone (40 to 55°C), cooling to 10 to 25°C, and filtering the (S)-(-)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)-mandelate; (d) reacting the (S)-(−)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R) mandelate with an excess of aqueous base to obtain (S)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine free base; and (e) dissolving the (S)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine free base in isopropyl alcohol to a concentration of 6-10% by weight, adding 6% HCl (w / w) in isopropanol at a rate selected to minimize supersaturation, holding the mixture at 35-45°C for 15 to 60 minutes, cooling to 15-25°C, and filtering the (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride crystalline form A; A method for preparing (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride crystalline form A, comprising: [Embodiment CD] The following sequence of steps: (a) reacting 3-thiopheneethanol with N-methylaminoacetaldehyde dimethyl acetal in the presence of trifluoromethanesulfonic acid to give 4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflate; and (b) reacting the 4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflate with an excess amount of aqueous base to obtain 4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine free base; The method according to embodiment [CC], or any other embodiment of the invention, wherein 4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine free base is prepared by [Embodiment CE] Compound 1 hydrochloride crystalline form A, prepared by the method described in embodiment [CC] or embodiment [CD], or in other embodiments of the present invention. [Embodiment CF] The method of any one of embodiments [A] to [CB], or any other embodiment of the invention, further characterized by administering Compound 1, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutical agents. [CG of the embodiment] The method of embodiment [CF], or any other embodiment of the invention, wherein the one or more pharmaceutical agents is an anti-Parkinson's agent, an anti-Alzheimer's agent, an antidepressant, an antipsychotic, an anti-ischemic agent, a CNS depressant, an anticholinergic agent, a nootropic agent, an anti-epileptic agent, an attention-enhancing (e.g., anti-ADD / ADHD) agent, a sleep-promoting agent, a wake-promoting agent, or an analgesic agent.

[0391] In addition to what is described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, and publications) is hereby incorporated by reference in its entirety.

Claims

1. A pharmaceutical composition for treating neurological or psychiatric disorders or conditions in patients without reducing sleep quality, wherein the pharmaceutical composition comprises compound 1 【Chemistry 1】 A pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof, in solid oral dosage form, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a therapeutically effective dose in the evening, at night, or around bedtime, wherein the patient is a human being.

2. A pharmaceutical composition for treating neurological or psychiatric disorders or conditions in patients, wherein the pharmaceutical composition comprises compound 1 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, comprising a solid oral dosage form, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a therapeutically effective dose in the evening, at night, or around bedtime, and 2.0 to 4.0 hours after single or multiple doses. ｍａｘ A pharmaceutical composition provided, wherein the patient is a human.

3. After multiple doses, C levels ranged from 7.97 to 31.5 ng / mL. ｔｒｏｕｇｈ The pharmaceutical composition according to claim 2, which provides the following.

4. A pharmaceutical composition for treating neurological or psychiatric disorders or conditions in patients, wherein the pharmaceutical composition comprises compound 1 【Transformation 3】 The present invention comprises a pharmaceutically acceptable salt thereof, is in solid oral dosage form, and is characterized in that compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient in a therapeutically effective dose in the evening, at night, or around bedtime, with a concentration of 7.97 to 31.5 ng / mL of C after multiple administrations. ｔｒｏｕｇｈ A pharmaceutical composition provided, wherein the patient is a human.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the hydrochloride salt of compound 1 is used to administer to the patient.

6. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that crystalline form A of the hydrochloride salt of compound 1 is used to administer to the patient.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the therapeutically effective dose is 50 to 100 mg.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the neurological or psychiatric disorder or disability is selected from schizophrenia, Parkinson's disease, Alzheimer's disease, and anxiety.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the neurological or psychiatric disorder or disability is schizophrenia.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the neurological or psychiatric disorder or disorder is anxiety.

11. The pharmaceutical composition according to any one of claims 1 to 8, wherein the neurological or psychiatric disorder or disorder is generalized anxiety disorder.

12. The pharmaceutical composition according to any one of claims 1 to 8, wherein the neurological or psychiatric disorder or disability is Parkinson's disease.

13. The pharmaceutical composition according to any one of claims 1 to 8, wherein the neurological or psychiatric disorder or disability is Alzheimer's disease.

14. A pharmaceutical composition according to any one of claims 1 to 13 for the continuous treatment of a neurological or psychiatric disorder or disability in the patient for six months or more, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is used in such a manner that it is administered in a therapeutically effective amount for six months or more.

15. After multiple doses, C levels ranged from 7.97 to 31.5 ng / mL. ｔｒｏｕｇｈ A pharmaceutical composition according to any one of claims 1, 2, and 5 to 14, which provides the following:

16. A 2.0 to 4.0 hour t after a single or multiple doses. ｍａｘ A pharmaceutical composition according to any one of claims 1 and 4 to 14, which provides the following:

17. The pharmaceutical composition according to any one of claims 1 to 6, wherein the solid oral dosage form is a tablet.

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