Methods of treating neurological diseases and disorders

Abstract

To provide methods of treating neurological or psychiatric diseases or disorders, such as schizophrenia.SOLUTION: A method of treating a neurological or psychiatric disease or disorder without causing a clinically significant risk of adverse events comprises administering, to a patient in need of treatment, a therapeutically effective amount of a compound 1 of the formula in the figure or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 776,247, filed April 5, 2019, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present disclosure relates to methods of treating neurological and psychiatric disorders. [Background technology]

[0003] D2 dopamine receptors are the primary target of typical and atypical antipsychotics. Wang et al. Nature 555, 269-273 (2018).However, many of the drugs that target D2 dopamine receptors 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, it has been challenging to develop non-D2 antipsychotic therapies that are both safe and effective. Girgis et al., J. Psychiatric Res. (2018), https: / / doi.org / 10.1016 / j.jpsychires.2018.07.006. In particular, a comprehensive review of the literature on experimental treatments for schizophrenia, which included 250 studies published between 1970 and 2017 using glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormonal, dopaminergic, metabolic, vitamin / naturopathic, histaminergic, infectious / inflammatory, and other miscellaneous mechanisms to treat schizophrenia, led Girgis to state that "despite several promising [non-D2] targets, such as allosteric modulation of NMDA and α7 nicotinic receptors, we cannot confidently claim that any of the mechanistically novel experimental treatments featured in this review are reliably effective in treating schizophrenia and are ready for clinical use." Therefore, there is a need for therapeutic agents that are effective in treating neurological and psychiatric diseases and disorders (eg, schizophrenia) and that have low incidence of adverse events.

[0004] As disclosed herein, Compound 1 has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) as a novel agent for the treatment of people with schizophrenia. Breakthrough Therapy Designation is intended to expedite the development and review of medicines for serious diseases or life-threatening conditions when preliminary clinical evidence indicates that a drug offers substantial improvement over existing therapies in one or more clinically significant endpoints. Compound 1 received Breakthrough Therapy Designation from the FDA based on pivotal Phase 2 data from the clinical trial disclosed herein. Summary of the Invention

[0005] The present specification relates to methods of 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, comprising: [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0007] In some embodiments, there is provided a method of treating a neurological or psychiatric disease or disorder in a patient, comprising: [ka] The method for minimizing adverse events in patients is provided, comprising administering to said patient a therapeutically effective amount of ribavirin or its pharmacologic acceptable salt.In some embodiments, the method minimizes the adverse events associated with antipsychotics that have affinity for dopamine D2 receptor.

[0008] In some embodiments, provided herein is a method for treating neurological or psychiatric disease or disorder in a patient, comprising administering to said patient a therapeutically effective amount of compound 1 or its pharma-ceutically acceptable salt, and does not substantially cause adverse events.In some embodiments, the risk of adverse events in a patient is almost the same or similar to that of placebo.

[0009] In some embodiments, a method for treating a neurological or psychiatric disease or disorder in a patient is provided, comprising administering to the patient a therapeutically effective amount of an antipsychotic drug that does not have direct affinity for the dopamine D2 receptor, the antipsychotic drug being selected from compound 1 or a pharma- ceutically acceptable salt thereof, and the method does not substantially cause the adverse events of antipsychotic drugs that have affinity for the dopamine D2 receptor.

[0010] In some embodiments, a method for 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 that does not have direct affinity for the dopamine D2 receptor, the antipsychotic being compound 1 or a pharma- ceutically acceptable salt thereof, minimizing adverse events associated with an antipsychotic that has affinity for the dopamine D2 receptor.

[0011] In some embodiments, provided herein is a method for treating neurological or psychiatric disease or disorder in a patient without exposing the patient to clinically significant risk, comprising administering compound 1 or its pharmaceutically acceptable salt to the patient, wherein the risk of adverse events is related to the antipsychotic drug with affinity for dopamine D2 receptor.In some embodiments, the disease or disorder is schizophrenia.

[0012] In some embodiments, a method of administering an antipsychotic to a patient in need thereof without incurring the risk of clinically significant adverse events is provided, comprising administering Compound 1 or a pharma- ceutically acceptable salt thereof to the patient, wherein the patient does not experience clinically significant adverse events.

[0013] In some embodiments, provide a method for treating the patient with neurological or psychiatric disease or disorder without causing the risk of clinically significant adverse events, by administering the therapeutically effective amount of compound 1 or its pharmacologic acceptable salt to the patient.In some embodiments, the patient has schizophrenia.

[0014] In some embodiments, adverse event refers to one or more of the following: cardiovascular adverse events (e.g., atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, 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.

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

[0016] In some embodiments, a method of treating a neurological or psychiatric disease or disorder in a patient is provided, comprising administering to the patient a therapeutically effective amount of an antipsychotic that does not have direct affinity for the dopamine D2 receptor, the method substantially not causing adverse events in the patient associated with antipsychotics that have affinity for dopamine D2.

[0017] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is crystalline Form A of Compound 1 hydrochloride. [Brief description 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.

[0019] [Diagram 2] FIG. 2 shows the MMRM analysis of the change from baseline in PANSS positive subscale scores from the study of Example 1.

[0020] [Diagram 3] FIG. 3 shows the MMRM analysis of the change from baseline in PANSS negative subscale scores from the study of Example 1.

[0021] [Figure 4] FIG. 4 shows the MMRM analysis of the change from baseline in PANSS general psychopathology subscale scores from the study of Example 1.

[0022] [Diagram 5] FIG. 5 shows MRM analysis of the change from baseline in CGI-S scores from the study of Example 1.

[0023] [Figure 6] FIG. 6 shows the MMRM analysis of the change from baseline in BNSS total score for the study of Example 1.

[0024] [Figure 7] FIG. 7 shows the MMRM analysis of the change from baseline in MADRS total score for the study of Example 1.

[0025] [Figure 8]FIG. 8 shows the median change from baseline to week 4 in prolactin levels from the study of Example 1.

[0026] [Figure 9] FIG. 9 shows the PANSS total scores observed during the double-blind treatment (Example 1) and the open-label extension study (Example 2).

[0027] [Figure 10] FIG. 10 shows the PANSS positive subscores observed during the double-blind treatment (Example 1) and the open-label extension study (Example 2).

[0028] [Figure 11] FIG. 11 shows the PANSS negative subscores observed during the double-blind treatment (Example 1) and the open-label extension study (Example 2).

[0029] [Figure 12] FIG. 12 shows the PANSS general psychopathology subscores observed during the double-blind treatment (Example 1) and the open-label extension study (Example 2).

[0030] [Figure 13] FIG. 13 shows the CGI-S scores observed during the double-blind treatment (Example 1) and the open-label extension study (Example 2).

[0031] [Figure 14] FIG. 14 shows the BNSS total scores observed during the double-blind treatment (Example 1) and the open-label extension study (Example 2).

[0032] [Figure 15] FIG. 15 shows the MADRS total scores observed during the double-blind treatment (Example 1) and the open-label extension study (Example 2).

[0033] [Figure 16] FIG. 16 shows the change from open-label baseline in prolactin levels at 26 weeks.

[0034] [Figure 17] FIG. 17 shows the change from open-label baseline in (A) body weight and (B) body mass index (BMI) at 26 weeks.

[0035] [Figure 18] FIG. 18 shows changes from open-label baseline in lipids at week 26: (A) total cholesterol (total), (B) triglycerides (total), (C) HDL (total), and (D) LDL (total).

[0036] [Figure 19] FIG. 19 shows blood glucose measurements at week 26: (A) glucose (total) and (B) HbA1c change from open-label baseline.

[0037] [Figure 20] FIG. 20 shows (A) the time to all-cause discontinuation in the study of Example 2 and (B) comparative data with other agents.

[0038] [Figure 21] FIG. 21 shows the XRPD of crystalline form A of Compound 1 hydrochloride measured in transmission mode. [Figure 22] FIG. 22 shows the XRPD of crystalline form A of Compound 1 hydrochloride measured in reflectance mode.

[0039] [Figure 23] FIG. 23 is a DSC thermogram of the A-type crystals of Compound 1 hydrochloride.

[0040] Detailed Description All publications cited herein are hereby incorporated by reference in their entirety.

[0041] 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:

[0042] 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.

[0043] Unless otherwise specified, the word "includes" (or any variations thereof, e.g., "include", "including") 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.

[0044] As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying, or inhibiting the progression of a disease or disorder or one or more symptoms thereof, including, but not limited to, a therapeutic effect. In some embodiments, treatment is administered after the development of one or more symptoms, e.g., an acute worsening of symptoms. In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered before symptoms develop (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after the symptoms have subsided, e.g., to prevent or delay their recurrence.

[0045] Therapeutic benefits include eradication and / or amelioration of the underlying disorder under treatment. Also included are eradication and / or amelioration of one or more symptoms associated with the underlying disorder, such that improvement is observed in the subject, even though the subject is still afflicted with the underlying disorder. In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disorder (e.g., reducing one or more symptoms of the disorder and / or reducing the severity of the disorder), (b) slowing or preventing the development of one or more symptoms associated with the disorder (e.g., stabilizing the disorder and / or slowing the deterioration or progression of the disorder), and / or (c) alleviating the disorder (e.g., causing regression of clinical symptoms, ameliorating the disorder, slowing the progression of the disorder, and / or improving quality of life).

[0046] As used herein, "administering" or "administration" of Compound 1, or a pharma- ceutically acceptable salt thereof, includes delivering Compound 1, or a pharma- ceutically acceptable salt thereof, or a prodrug or other pharma- ceutically acceptable derivative thereof, to a subject, e.g., using any suitable formulation or route of administration described herein.

[0047] The term "therapeutically effective amount" or "effective amount" as used herein means an amount effective to elicit a desired biological or medical response, and includes an amount of a compound sufficient to treat such a disorder when administered to a subject for treating such a disorder. The effective amount varies depending on the disorder and its severity, as well as the age, weight, etc., of the subject to be treated. An effective amount may be administered in one or more doses (e.g., a single dose or multiple doses may be required to achieve a desired treatment endpoint). An effective amount may be considered to be given in an effective amount when it achieves or achieves a desired or beneficial result in conjunction with one or more other substances. The appropriate dosage of a co-administered compound may be reduced due to the combined, additive, or synergistic effects of the compounds.

[0048] As used herein, "delaying" the development of a disorder means to postpone, slow, retard, stabilize, and / or prolong the development of the disorder. The length of the delay will vary depending on the history of the disease and the individual under treatment.

[0049] As used herein, "prevention" or "prevention" refers to a regimen that protects against the onset of a disorder, such that the clinical symptoms of the disorder do not develop. Thus, "prevention" refers to administering a therapy to a subject before symptoms of the disease become detectable in the subject (e.g., administering a therapy when no detectable symptoms of the disorder are present). The subject may be an individual at risk of developing a disorder.

[0050] As used herein, an "at risk" individual refers to an individual who is at risk of developing the disorder being treated, which may be indicated, for example, by one or more risk factors, which are measurable parameters that correlate with development of the disorder and are known in the art.

[0051] As used herein, a "subject" or "patient" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult or elderly adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats and / or dogs; birds, including commercially relevant birds such as chickens, ducks, geese, quail and / or turkeys.

[0052] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0053] The term "pharmaceutically acceptable salt" as used herein means a salt that is suitable for use in contact with the tissues of humans or lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al., describe soluble salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of Compound 1 include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include 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 pharma- ceutically 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, hexaphosphate, and the like. Counterions include sanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, 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. For preparing pharmaceutical formulations, pharma- ceutically acceptable counterions are preferred, although other anions are well tolerated as synthetic intermediates. Thus, X may be a pharma- ceutically undesirable anion, such as iodide, oxalate, trifluoromethanesulfonate, and the like, when such salts are chemical intermediates.

[0054] As used herein, the term "pharmaceutical acceptable excipient" includes, but is not limited to, any binder, filler, adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, emulsifier, anti-caking agent, flavoring agent, desiccant, plasticizer, disintegrant, lubricant, polymer matrix system, and abrasive approved by the U.S. Food and Drug Administration for use in humans or veterinary medicine.

[0055] As used herein, a "clinically significant" risk of an adverse event means a risk that is statistically significantly greater than that of a placebo. If the risk of an adverse event or a particular adverse event is lower, the same, or nearly the same as that of a placebo, then the risk is not clinically significant.

[0056] As used herein, the "clinically significant" risk of adverse events means that the risk of the same adverse events in antipsychotics with affinity for dopamine D2 receptors is lower, but not necessarily statistically significant.If the risk of adverse events or a particular adverse event is lower than that of antipsychotics with affinity for dopamine D2 receptors, the risk is not clinically significant.In some embodiments, the risk of clinically significant adverse events can be determined by those skilled in the art of treating and / or prescribing antipsychotics to patients in need.In some embodiments, the risk of clinically significant adverse events can be determined by comparative calculations across the entire patient population.

[0057] As used herein, a method that "does not substantially cause" adverse events means a method in which the incidence of adverse events is lower than, the same as, or nearly the same as a placebo.

[0058] "Minimize" adverse events as used herein means that the incidence of adverse events in a patient population is statistically significantly reduced compared to the paradigm incidence of adverse events in a patient population treated with an antipsychotic drug that has affinity for D2 dopamine receptors.Such antipsychotic drugs (e.g., as defined herein) that have affinity for D2 dopamine receptors will have therapeutic affinity for D2 dopamine receptors, so that those skilled in the art can propose direct targeting of D2 dopamine receptors as the primary (alone or in combination with another receptor) mechanism of action.Accordingly, the corresponding risk of adverse events in a patient is reduced.In some embodiments, the incidence of adverse events refers to the frequency or percentage of a particular adverse event across a patient population.In some embodiments, the incidence of adverse events refers to the total number of adverse events experienced by an individual subject.

[0059] As used herein, "antipsychotics" are a class of drugs that are specifically used to treat, prevent or manage psychosis, for example in schizophrenia or bipolar disorder, and more broadly to treat a variety of neurological and psychiatric disorders. The first generation of 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 are known as "non-5B9A antipsychotics" and 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 the D2 dopamine receptor.

[0060] "Adverse events associated with antipsychotics having affinity for dopamine D2 receptors" are understood by those skilled in the art as adverse events that are paradigms of D2 antipsychotic therapy. In some embodiments, adverse events associated with antipsychotics having affinity for dopamine D2 receptors are any one or more of the class effects of antipsychotics. In some embodiments, adverse events associated with antipsychotics having affinity for dopamine D2 receptors are any one or more of the class effects of typical antipsychotics. In some embodiments, adverse events associated with antipsychotics having affinity for dopamine D2 receptors are any one or more of the class effects of atypical antipsychotics. In some embodiments, adverse events associated with antipsychotics having affinity for dopamine D2 receptors are any one or more of the class effects of atypical antipsychotics. In some embodiments, adverse events associated with antipsychotics having 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, 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.

[0061] Various embodiments are described herein. Those skilled in the art who review this specification will easily recognize that the various embodiments can be combined in any variation. For example, the embodiments herein include treatment of various disorders, patient populations, administration of various dosage forms at various dosage amounts, minimization of various adverse events, improvement of various efficacy measurements, etc. Any combination of the various embodiments is within the scope of this specification.

[0062] Compound 1, or a pharma- ceutically acceptable salt thereof, described herein for use in the methods herein has the following structure: [ka] For purposes of this specification, unless otherwise indicated or required by context, the term "Compound 1" may also be defined as [ka] Also included are pharma- ceutically acceptable salts of the formula:

[0063] 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 appreciate that there are many different ways to name compounds. Thus, compound 1 can 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 a pharmaceutically acceptable salt thereof. For example, Compound 1 or a pharma- ceutically acceptable salt thereof has been identified as SEP-0363856 or SEP-856 and has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) as a novel substance for the treatment of people with schizophrenia. Breakthrough Therapy Designation is intended to expedite the development and review of drugs for severe or life-threatening conditions where there is preliminary clinical evidence that a substantial improvement can be demonstrated compared to available therapies in one or more clinically significant endpoints. Compound 1 or a pharma-ceutically acceptable salt thereof received Breakthrough Therapy Designation from the FDA based on pivotal Phase 2 data from clinical trials disclosed herein. Compound 1 or a pharma-ceutically acceptable salt thereof is an antipsychotic with a non-direct D2 mechanism of action and exhibits broad efficacy in animal models of psychosis and depression. Molecular targets involved in the antipsychotic and antidepressant efficacy of Compound 1 or a pharma-ceutically acceptable salt thereof include trace amine associated receptor-1 (TAAR1) and 5HT 1AIt is understood that the agonist activity at both receptors is a major factor in the pathogenesis of rheumatoid arthritis. For example, as disclosed in Dedic et al. The Journal of Pharmacology and Experimental Therapeutics 371, 1-14 (2019), compound 1 was tested against a panel of known molecular targets (ion channels, G protein-coupled receptors (GPCRs) and enzymes) and compound 1 was found to have an agonistic effect at 10 μM and α 2A , α 2B , D2, 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2A , 5-HT 2B , 5-HT 2C The results showed that compound 1 inhibited specific binding at the human TAAR1 receptor (EC 50 was 0.14 ± 0.062 μM, and the maximum effective rate (E max ) = 101.3% ± 1.3%) and 5-HT 1A Receptor (EC 50 = 2.3 μM, range 0.1 to 3 μM, E max =74.7% ± 19.6%). In functional assays of the D2 receptor, compound 1 exhibited weak partial agonism, with an EC 50 The value was 10.44 ± 4 μM (cAMP, E max = 23.9% ± 7.6%) and 8 μM (β-arrestin recruitment, E max = 27.1%). Without being bound to a particular mechanism of action, compound 1 is theorized to also act as a presynaptic dopamine modulator.

[0064] Compound 1 can be used in the methods described herein as a free base or in the form of a pharma- ceutically acceptable salt. In some embodiments, the hydrochloride (HCl) salt of Compound 1 is used in the methods described herein.

[0065] Compound 1, or a pharma- ceutically acceptable salt thereof, can be obtained by the preparation methods described in PCT Patent Publication WO2011 / 069063 (U.S. Patent 8,710,245, issued April 29, 2014) or PCT Patent Publication WO2019 / 161238, the entire contents of which are incorporated herein by reference, or methods similar thereto.

[0066] Compound 1 or its pharmaceutically acceptable salt may be in amorphous form or crystalline amorphous form.In some embodiments, the crystalline form of compound 1 or its pharmaceutically acceptable salt is used in the methods described herein.In some embodiments, the A-type crystal of compound 1 HCl salt is used in the methods described herein.

[0067] In some embodiments, the crystalline form A of Compound 1 HCl salt is characterized by a powder X-ray diffraction pattern comprising peaks at 9.6±0.2°, 14.9±0.2°, 20.5±0.2° and 25.1±0.2° 2θ, in some embodiments, further comprising peaks at 20.2±0.2° and 20.8±0.2°, in some embodiments, further comprising peaks at 20.2±0.2°, 20.8±0.2° and one or more prominent peaks at 17.9±0.2°, 24.8±0.2° and 27.1±0.2°. An example of a method for preparing crystalline form A of Compound 1 HCl salt is provided in Example 2.

[0068] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is substantially enantiomerically pure. In some examples, a composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof comprises Compound 1 at about or greater than 90%, 95%, 97%, 99%, 99.5%, 99.7% or 99.9% of the total amount of Compound 1 and its (R)-enantiomer in the composition. In some embodiments, substantially enantiomerically pure Form A crystals of Compound 1 HCl salt are used in the methods described herein.

[0069] Also provided herein are pharmaceutical compositions and dosage forms comprising Compound 1 or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable excipients. The compositions and dosage forms provided herein may further comprise one or more additional active ingredients. Compound 1 or a pharma- ceutically acceptable salt thereof may be administered as part of a pharmaceutical composition described herein.

[0070] Selecting the right drug for treating a neurological or psychiatric disease or disorder requires finding a drug that causes little or no adverse events to 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 among available antipsychotics to treat patients without the risk of clinically significant adverse events. For example, this is important for patients at risk for QT prolongation, since QT prolongation is a serious adverse event that can lead to death. As disclosed herein, Compound 1, unlike some antipsychotics with affinity for dopamine D2 receptors, does not cause a risk of clinically significant QT prolongation, allowing for safer administration to patients at increased risk for QT prolongation. The risk of QT prolongation in patients who have not been previously treated with neurological or psychiatric drugs may be unknown. However, in some embodiments provided herein, Compound 1 can be administered without a clinically significant risk of QT prolongation. Other adverse events, such as cardiovascular events, may take longer 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 greatly reduce adverse events.

[0071] The present specification relates to methods of treating neurological and psychiatric diseases and disorders, such as schizophrenia.

[0072] In some embodiments, provided herein is a method of treating a patient having a neurological or psychiatric disease or disorder, comprising administering to the patient compound 1: [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0073] In some embodiments, provided herein is a method of treating a neurological or psychiatric disease or disorder in a patient, comprising administering to the patient compound 1: [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0074] In some embodiments, the present application provides a method for treating neurological or psychiatric disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of compound 1 or its pharma-ceutically acceptable salt, and does not substantially cause adverse events.In some embodiments, the method causes the risk of adverse events in the patient to be almost the same or similar to that of placebo.

[0075] In some embodiments, the present specification provides a method for treating a neurological or psychiatric disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an antipsychotic drug that does not have direct affinity for dopamine D2 receptors, selected from compound 1 or a pharma- ceutically acceptable salt thereof, which does not substantially cause the adverse events of antipsychotic drugs that have affinity for dopamine D2 receptors.

[0076] In some embodiments, the present disclosure provides a method for minimizing adverse events in patients who need to treat neurological or psychiatric disease or disorder, comprising administering to said patient a therapeutically effective amount of the antipsychotic of compound 1 or its pharma- ceutically acceptable salt, which does not have direct affinity to dopamine D2 receptor.In some embodiments, the method reduces the incidence of adverse events, etc., compared with the treatment with the antipsychotic of affinity to dopamine D2 receptor.

[0077] In some embodiments, provided herein is a method for treating a neurological or psychiatric disease or disorder in a patient without exposing the patient to a clinically significant risk of an adverse event, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, wherein the risk of an adverse event is associated with an antipsychotic drug having affinity for the dopamine D2 receptor.

[0078] In some embodiments, the method of administering antipsychotics to the patient in need thereof, who has not experienced clinically significant adverse events, without causing clinically significant risk of adverse events is provided, comprising administering to the patient a therapeutically effective amount of compound 1 or its pharma- ceutically acceptable salt.In some embodiments, the method treats neurological or psychiatric disease or disorder (e.g., schizophrenia) in the patient.

[0079] In some embodiments, provided herein is a method of treating a neurological or psychiatric disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an antipsychotic that has no direct affinity for the dopamine D2 receptor, wherein the adverse events in the patient are substantially free of adverse events associated with antipsychotics that have affinity for dopamine D2.

[0080] In some embodiments, the present disclosure provides the use of compound 1 or its pharmaceutically acceptable salt in the treatment of neurological or psychiatric disease or disorder generally described herein, for example, to minimize adverse events.The present disclosure also provides the use of compound 1 or its pharmaceutically acceptable salt in the manufacture of medicament for the treatment of neurological or psychiatric disease or disorder generally described herein, for example, to minimize adverse events.The present disclosure also provides the use of compound 1 or its pharmaceutically acceptable salt in the manufacture of medicament for the treatment of neurological or psychiatric disease or disorder generally described herein, for example, to minimize adverse events.

[0081] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered daily for a treatment period of 29 days. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered daily for a treatment period of 26 weeks or 30 weeks.

[0082] In some embodiments, adverse event refers to one or more of the following: cardiovascular adverse events (atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, 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.

[0083] In some embodiments, the methods herein are useful for treating a neurological or psychiatric disease or disorder in a patient. In some instances, the methods result in an improvement in one or more of the Positive and Negative Symptom Scale (PANSS) total score, the PANSS subscores (negative, positive, general psychopathology), the Clinical Global Impressions-Severity (CGI-S) score, the Brief Negative Symptom Scale (BNSS) total score, and the Montgomery-Asberg Depression Rating Scale (MADRS) total score.

[0084] In some embodiments, the method results in one or more of the following: a reduction from baseline in PANSS total score, e.g., a reduction from baseline in PANSS total score of at least 1, 2, 3, 4, 5, 7, 10, 15, or 17 (e.g., at least 17.2), or a reduction from baseline in PANSS total score of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%; or an effect size of at least 0.1, 0.2, 0.3, or 0.4 (e.g., at least 0.45) in PANSS total score; or a statistically significant improvement in 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 decrease from baseline in the PANSS negative subscale score, e.g., a decrease from baseline in the PANSS negative subscale score 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 decrease from baseline in the PANSS negative subscale score of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15% or 20%, or an effect size in the PANSS negative subscale score of at least 0.1, 0.2, 0.3 or 0.35 (e.g., at least 0.37); a decrease from baseline in the PANSS Positivity subscale score, e.g., a decrease from baseline in the PANSS Positivity subscale score of at least 1, 2, 3, 4, or 5 (e.g., at least 5.5), or a decrease from baseline in the PANSS Positivity subscale score of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%, or an effect size in the PANSS Positivity subscale score of at least 0.1, 0.2, or 0.3 (e.g., at least 0.32); a decrease from baseline in the PANSS general psychopathology subscale score, e.g., a decrease from baseline in the PANSS general psychopathology subscale score of at least 1, 2, 3, 4, 5, 7, or 9 (e.g., at least 9), or a decrease from baseline in the PANSS general psychopathology subscale score of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%, or an effect size for the PANSS general 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 from baseline in CGI-S score, e.g., a decrease from baseline in CGI-S score of at least 0.2, 0.4, 0.6, 0.8, or 1 (e.g., at least 1), or a decrease from baseline in CGI-S score of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%, or an effect size in CGI-S score of at least 0.1, 0.2, 0.3, 0.4, or 0.5 (e.g., at least 0.52); a decrease from baseline in the BNSS total score, e.g., a decrease from baseline in the BNSS total score of at least 1, 2, 3, 4, 5, 6, or 7 (e.g., at least 7.1), or a decrease from baseline in the BNSS total score of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, or 20%, or an effect size for the 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 decrease from baseline in MADRS total score, e.g., a decrease from baseline in MADRS total score of at least 0.5, 1, 1.5, 2, 2.5 or 3 (e.g., at least 3.3), or a decrease from baseline in MADRS total score of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15% or 20%, or an effect size for MADRS total score of at least 0.1, 0.2 or 0.3 (e.g., at least 0.32).

[0085] In some embodiments, the reduction in PANSS (total score or subscore), CGI-S, BNSS or MADRS score is measured after a 29 day treatment period.

[0086] In some embodiments, the score reduction is measured after 30 weeks of treatment.In some embodiments, the method herein causes: (i) PANSS total score after 30 weeks of treatment at least about 30 reduction from baseline; (ii) PANSS positive subscale score after 30 weeks of treatment at least about 10 reduction from baseline; (iii) PANSS negative subscale score after 30 weeks of treatment at least about 5 reduction from baseline; (iv) PANSS general psychopathology subscale score after 30 weeks of treatment at least about 15 reduction from baseline; (v) CGI-S score after 30 weeks of treatment at least about 1.5 reduction from baseline; (vi) BNSS total score after 30 weeks of treatment at least about 10 reduction from baseline; and / or (vii) MADRS total score after 30 weeks of treatment at least about 5 reduction from baseline.

[0087] In some embodiments, the method herein provides a reduction in the number of adverse events that lead to discontinuation, for example, during a 29-day, 26-week or 30-week treatment period.For example, in some embodiments, the method provides less than 50%, less than 40% or less than 35% of patients that discontinue treatment due to adverse events over a 26-week or 30-week treatment period.

[0088] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia.In some embodiments, the patient has acute exacerbation of schizophrenia.In some embodiments, the treatment of schizophrenia comprises ameliorating symptoms of schizophrenia.In some embodiments, the treatment of schizophrenia comprises treating negative symptoms of schizophrenia.

[0089] In some embodiments, the neurological or psychiatric disease or disorder is Parkinson's disease psychosis.

[0090] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia spectrum disorder, negative symptoms of schizophrenia, attenuated psychotic syndrome, prodromal schizophrenia, delusional disorder, psychosis, psychotic disorder, confusion, Tourette's syndrome, post-traumatic stress disorder, behavioral disorder, affective disorder, depression, bipolar disorder, major depressive disorder, dysthymia, mania (manic disorder), seasonal affective disorder, obsessive-compulsive disorder, narcolepsy, REM behavior disorder, substance abuse or dependence, Lesch-Nyhan disease, Wilson's disease, autism, Alzheimer's disease agitation, and psychosis or Huntington's chorea.

[0091] In some embodiments, the neurological or psychiatric disease or disorder is selected from schizophrenia, attenuated psychotic syndrome, prodromal schizophrenia, schizoid personality disorder, and schizotypal personality disorder.

[0092] In some embodiments, the neurological or psychiatric disease or disorder is Alzheimer's disease agitation and psychosis. In some embodiments, the patient has dementia. In some embodiments, the neurological or psychiatric disease or disorder is dementia-related psychosis.

[0093] In some embodiments, the psychosis is selected from organic psychosis, drug-induced psychosis, Parkinson's disease psychosis, and excitative psychosis.

[0094] In some embodiments, the neurological or psychiatric disease or disorder is a bipolar disorder selected from bipolar disorder and bipolar depression.

[0095] 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 that is a typical antipsychotic or an atypical antipsychotic. In some embodiments, the patient does not respond adequately to an antipsychotic that is a typical antipsychotic (e.g., chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, pericyazine, promazine, thioridazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, zuclopenthixol) or an atypical antipsychotic (e.g., aripiprazole, asenapine maleate, clozapine, iloperidone, lurasidone, olanzapine, olanzapine / fluoxetine, paliperidone, quetiapine, risperidone, ziprasidone).

[0096] In some embodiments, the patient is elderly.

[0097] In some embodiments, treating a neurological or psychiatric disease or disorder includes amelioration of symptoms of the neurological or psychiatric disease or disorder.

[0098] In some embodiments, the patient is characterized by one or more of the following: The patient is an adult; Patients have been diagnosed with schizophrenia for at least 6 months; The patient has experienced an acute exacerbation of psychotic symptoms for at least 2 months; The patient had not been hospitalized more than twice in the past for the treatment of an acute exacerbation of schizophrenia; Patients had a baseline PANSS total score of at least 80; The patient's baseline PANSS score was at least 4 in two or more of the following categories: delusions, conceptual disorganization, hallucinatory behavior, and unusual thought content; and Patients had a baseline CGI-S score of at least 4.

[0099] In some embodiments, adverse event refers to one or more of the following: cardiovascular adverse events (e.g., atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, 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.

[0100] The D2 dopamine receptor is the primary target of both typical and atypical antipsychotics. Wang et al. Nature 555, 269-273 (2018). Unfortunately, many drugs that target the D2 dopamine receptor cause severe and potentially life-threatening side effects due to promiscuous activities on related receptors. Wang et al. NATURE 555, 269-273 (2018).Currently available antipsychotics 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, 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.

[0101] In some embodiments, the adverse event associated with the antipsychotic is any one or more of the adverse events with class effect defined by the EBGM ranking using FAERS. In some embodiments, the adverse event associated with the antipsychotic is any one or more of the following: hyperprolactinemia, abnormal blood prolactin levels, increased blood prolactin levels, galactorrhea, cogwheel rigidity, obesity, metabolic syndrome, akathisia, oromandibular dystonia, Parkinson's disease, sialorrhea, gaze onset, obsessive-compulsive disorder, muscular rigidity, type 2 diabetes, diabetes mellitus, overweight, Parkinsonian gait, tongue spasm, tardive dyskinesia, bradykinesia, TIC, psychomotor retardation, extrapyramidal disorder, enuresis, glucose tolerance impaired), excessive salivation, dystonia, diabetes, restlessness, torticollis, poor fasting glucose, self-inflicted dermatopathy, elevated body mass index, hyperactivity, hepatitis virus, dyskinesia, elevated blood triglycerides, QT prolonged, sleep disorders, orthostatic hypertension, teeth grinding, increased appetite, excessive eye blinking, chronic pancreatitis, weight gain, dyslipidemia, restless legs syndrome, tongue biting or stiff neck.

[0102] 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, Parkinson's disease, sialorrhea, gaze onset, obsessive-compulsive disorder, muscle rigidity, type 2 diabetes, diabetes, overweight, Parkinsonian gait, tongue spasm, tardive dyskinesia, bradykinesia, Tic, psychomotor retardation, extrapyramidal disorder, urinary incontinence, impaired glucose tolerance, The drug does not significantly increase the risk of any one or more of the following adverse events: hypertension, hypersalivation, dystonia, diabetes, restlessness, torticollis, poor fasting glucose, self-injury dermatopathy, elevated body mass index, hyperactivity, hepatitis virus, dyskinesia, elevated blood triglycerides, electrocardiogram QT prolonged, dyssomnia, sleep disorders, orthostatic hypertension, teeth grinding, increased appetite, excessive eye blinking, chronic pancreatitis, weight gain, dyslipidemia, restless legs syndrome, tongue biting, or stiff neck.

[0103] Compound 1 or its pharmaceutically acceptable salts have no direct affinity to D2 dopamine receptors. As described herein (e.g., in the following examples), compound 1 or its pharmaceutically acceptable salts, when administered to patients, do 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 herein (e.g., in Examples 1 and 2), compound 1 has strong efficacy and an adverse event profile similar to placebo. In particular, the incidence of cardiovascular adverse events (including QT prolongation, orthostatic hypotension, orthostatic tachycardia), extrapyramidal adverse events, hyperprolactinemia, insomnia, anxiety and headache experienced by patients is not clinically significant (i.e., lower than placebo, the same as placebo, almost the same as or similar to placebo).

[0104] In some embodiments, the method herein minimizes cardiovascular adverse events. In some embodiments, the method does not substantially cause cardiovascular adverse events. In some embodiments, the risk of cardiovascular adverse events in patients is almost the same or similar to placebo. In some embodiments, the method causes cardiovascular events in less than 5% or the same patients. In some embodiments, the method causes cardiovascular adverse events in less than 4.2% or the same patients. In some embodiments, the method causes cardiovascular adverse events in less than 5% or the same patients (e.g., less than 4.2% or the same) during a 29-day treatment period. In some embodiments, the method causes cardiovascular adverse events in less than 6% or the same patients (e.g., less than 5.8% or the same) during a 26-week treatment period. In some embodiments, the method causes cardiovascular adverse events in patients at a percentage not more than 1% higher than placebo.

[0105] In some embodiments, the patient is at increased risk of cardiovascular adverse events due to antipsychotics that have direct affinity to dopamine D2 receptors.In some embodiments, the patient has a history of cardiovascular disease.In some embodiments, the patient has a history of cardiovascular adverse events due to previous antipsychotic therapy.In some embodiments, the patient is susceptible to cardiovascular adverse events due to antipsychotics that have direct affinity to dopamine D2 receptors.

[0106] In some embodiments, the patient is not actively monitored for cardiovascular adverse events during treatment. In some embodiments, the patient is not monitored by electrocardiography monitoring during treatment. In some embodiments, the patient is not warned about cardiovascular adverse events. In some embodiments, the patient is not simultaneously treated for cardiovascular adverse events.

[0107] In some embodiments, the cardiovascular adverse event is characterized by atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hypotension, or hot flashes. In some embodiments, the cardiovascular adverse event is characterized by atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension, or orthostatic tachycardia.

[0108] In some embodiments, the method herein minimizes extrapyramidal adverse events. In some embodiments, the present invention does not substantially cause extrapyramidal adverse events. In some embodiments, the risk of extrapyramidal adverse events in patients is almost the same or similar to placebo. In some embodiments, the method causes extrapyramidal adverse events in less than 5% or the same number of patients. In some embodiments, the method causes extrapyramidal adverse events in less than 3.3% or the same number of patients. In some embodiments, the method causes extrapyramidal adverse events in less than 5% or the same number of patients during a 29-day treatment period. In some embodiments, the method causes extrapyramidal adverse events in less than 5% or the same number of patients (e.g., less than 3.2% or the same number of patients) during a 26-week treatment period. In some embodiments, the method causes extrapyramidal adverse events in patients at a percentage lower than placebo.

[0109] In some embodiments, the patient is at increased risk of extrapyramidal adverse events caused by antipsychotics with direct affinity to dopamine D2 receptor.In some embodiments, the patient has a history of extrapyramidal adverse events caused by previous antipsychotic therapy.In some embodiments, the patient is susceptible to extrapyramidal adverse events caused by antipsychotics with direct affinity to dopamine D2 receptor.

[0110] In some embodiments, the patient is not warned about extrapyramidal adverse events.

[0111] In some embodiments, the extrapyramidal adverse event is characterized by akathisia, restlessness, joint stiffness, musculoskeletal stiffness, neck stiffness, postural tremor or tremor.

[0112] In some embodiments, the method herein minimizes QT prolongation. In some embodiments, the method does not substantially cause QT prolongation. In some embodiments, the risk of QT prolongation in patients is about the same or similar to placebo. In some embodiments, the method causes QT prolongation in less than 5% or the same number of patients. In some embodiments, the method causes QT prolongation in less than 1% or the same number of patients. In some embodiments, the method does not substantially cause QT prolongation during the 29-day treatment period. In some embodiments, the method causes QT prolongation in patients at a percentage lower than placebo.

[0113] In some embodiments, the patient is at increased risk of QT prolongation due to administration of antipsychotics.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 that have direct affinity for dopamine D2 receptors.In some embodiments, the patient has hypokalemia, hepatitis C, HIV, T wave abnormalities on electrocardiogram, is female, is elderly, or takes a second active substance that is known to increase the risk of QT prolongation.

[0114] 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 receiving treatment for QT prolongation.

[0115] In some embodiments, the QT prolongation is characterized by one or both of the following: The patient has a QTcF interval greater than 450 msec at any time that was not present at baseline; and An increase from baseline in QTcF interval of greater than or equal to 30 msec in at least one post-baseline measurement.

[0116] In some embodiments, the QT prolongation is characterized by one or both of the following: A QTcF interval in the patient that was absent at baseline and exceeds 450 msec at any time if the patient is male, or that was absent at baseline and exceeds 470 msec at any time if the patient is female; and An increase from baseline in QTcF interval of greater than or equal to 30 msec in at least one post-baseline measurement.

[0117] In some embodiments, the QT prolongation is characterized by one or both of the following: A QTcF interval in the patient that was absent at baseline and exceeds 450 msec at any time if the patient is male, or that was absent at baseline and exceeds 470 msec at any time if the patient is female; and An increase from baseline in QTcF interval of greater than or equal to 60 msec in at least one post-baseline measurement.

[0118] Prolongation of the QTc interval on the electrocardiogram (ECG) may be associated with the development of ventricular tachycardia (torsade de pointes), a ventricular arrhythmia that can cause syncope and progress to ventricular fibrillation and sudden death. The average QTc interval in healthy adults is approximately 400 msec. A QTc interval of 500 msec or greater is considered a substantial risk factor for ventricular tachycardia.

[0119] In some embodiments, the methods herein minimize hyperprolactinemia. In some embodiments, the methods do not substantially cause hyperprolactinemia. In some embodiments, the risk of hyperprolactinemia in patients is about the same or similar to placebo. In some embodiments, the methods do not have a clinically significant risk of hyperprolactinemia. In some embodiments, the methods do not substantially cause hyperprolactinemia during the 29 day treatment period. In some embodiments, the methods do not substantially cause hyperprolactinemia during the 26 week treatment period. In some embodiments, the present invention results in a percentage of hyperprolactinemia occurring in patients that is lower than placebo.

[0120] In some embodiments, the patient is at increased risk of hyperprolactinemia caused by the administration of antipsychotics with direct affinity to dopamine D2 receptor.In some embodiments, the patient has a history of hyperprolactinemia caused by previous antipsychotic therapy.In some embodiments, the patient is susceptible to hyperprolactinemia caused by antipsychotics with direct affinity to dopamine D2 receptor.

[0121] In some embodiments, the patient is not actively monitored for hyperprolactinemia. In some embodiments, the patient is not warned about hyperprolactinemia. In some embodiments, the patient is not concurrently receiving treatment for hyperprolactinemia.

[0122] Hyperprolactinemia means significantly elevated levels of prolactin and is known to occur during the administration of certain antipsychotic medications.

[0123] In some embodiments, the metabolic effects of the present invention are the same or similar to a placebo, eg, total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride, and / or glucose levels in a patient are the same or similar to a placebo.

[0124] In some embodiments, the method herein minimizes orthostatic hypotension. In some embodiments, the present invention does not substantially cause orthostatic hypotension. In some embodiments, the risk of orthostatic hypotension in patients is almost the same or similar to placebo. In some embodiments, the method causes orthostatic hypotension in less than 5% or the same patients. In some embodiments, the method causes orthostatic hypotension in less than 4.2% or the same patients. In some embodiments, the method causes orthostatic hypotension in less than 5% or the same patients during the 29-day treatment period. In some embodiments, the method causes orthostatic hypotension in patients at a percentage lower than placebo.

[0125] In some embodiments, the patient is at increased risk of orthostatic hypotension caused by antipsychotic drug administration.In some embodiments, the patient has a history of orthostatic hypotension caused by previous antipsychotic therapy.In some embodiments, the patient is susceptible to orthostatic hypotension caused by antipsychotic drug with direct affinity to dopamine D2 receptor.

[0126] In some embodiments, the patient is not actively monitored for orthostatic hypotension. In some embodiments, the patient is not warned about orthostatic hypotension. In some embodiments, the patient is not concurrently treated for orthostatic hypotension.

[0127] In some embodiments, the method herein minimizes orthostatic tachycardia. In some embodiments, the method does not substantially cause orthostatic tachycardia. In some embodiments, the risk of orthostatic tachycardia in patients is about the same or similar to placebo. In some embodiments, the method causes orthostatic tachycardia in less than 5% or the same number of patients. In some embodiments, the method causes orthostatic tachycardia in less than 4.2% or the same number of patients. In some embodiments, the method causes orthostatic tachycardia in less than 5% or the same number of patients during the 29-day treatment period. In some embodiments, the method causes orthostatic tachycardia in patients at a percentage not more than 2% higher than placebo.

[0128] In some embodiments, the patient is at increased risk of orthostatic tachycardia caused by antipsychotic drug administration.In some embodiments, the patient has a history of orthostatic tachycardia caused by previous antipsychotic therapy.In some embodiments, the patient is susceptible to orthostatic tachycardia caused by antipsychotic drug with direct affinity to dopamine D2 receptor.

[0129] In some embodiments, the patient is not actively monitored for orthostatic tachycardia. In some embodiments, the patient is not warned about orthostatic tachycardia. In some embodiments, the patient is not concurrently receiving treatment for orthostatic tachycardia.

[0130] Compound 1 is an antipsychotic with a non-D2 mechanism of action that shows broad efficacy in animal models of psychosis and depression. As described in the Examples below, Compound 1 shows efficacy in treating schizophrenia. Specifically, in patients with acute exacerbations of schizophrenia administered Compound 1, efficacy measures of Positive and Negative Symptom Scale (PANSS) total score, PANSS subscores (negative, positive, general psychopathology), Clinical Global Impressions-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).

[0131] Thus, in some embodiments, the method provides one or more of the following results: · A decrease in PANSS total score of at least 17.2 from baseline; ·PANSS total effect size of at least 0.45; · A decrease in PANSS positive subscale score of at least 5.5 from baseline; ·PANSS positive subscale score effect size of at least 0.32; · A decrease in PANSS negative subscale score of at least 3.1 from baseline; · an effect size of at least 0.37 for PANSS negative subscale scores; · A decrease in PANSS general psychopathology subscale score of at least 9 from baseline; · an effect size of at least 0.51 for the PANSS general psychopathology subscale score; · A decrease in CGI-S score of at least 1 from baseline; · an effect size of at least 0.52 on CGI-S scores; · A decrease in BNSS total score of at least 7.1 from baseline; · Effect size for BNSS total score of at least 0.48; A decrease in MADRS total score of at least 3.3 from baseline; and / or · An effect size for the MADRS total score of at least 0.32.

[0132] In some embodiments, the method herein further comprises 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 lower than placebo.In some embodiments, the method herein minimizes insomnia, anxiety, headache, or any combination thereof.

[0133] 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 a patient. In some embodiments, the risk of insomnia, anxiety, headache, schizophrenia, somnolence, agitation, nausea, diarrhea and dyspepsia, individually or as a group, is not clinically significant (i.e., lower than placebo, the same or nearly the same as placebo).

[0134] In some embodiments, the administration of Compound 1 or a pharma- ceutically acceptable salt thereof includes a titration period and a treatment period. In some examples, the first dose of Compound 1 or a pharma- ceutically acceptable salt thereof is administered during the titration period, followed by a therapeutic dose of Compound 1 or a pharma- ceutically acceptable salt thereof during the treatment period. The titration dose is less than the therapeutic dose. In some examples, the titration dose is 50 mg per day, and the therapeutic dose is 75 mg per day. In some embodiments, the titration period is 3 days, followed by a treatment period (e.g., beginning on day 4 and continuing until day 29). In some embodiments, 50 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered on days 1 to 3, and 75 mg of Compound 1 or a pharma- ceutically acceptable salt thereof is administered on days 4 to 29.

[0135] In some embodiments, the therapeutic dose can be tapered to a reduced dose.In some examples, the dose of 75mg can be reduced to a dose of 50mg.In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered at a variable dose of 50mg per day or 75mg per day.

[0136] In some embodiments, provided herein is a method of treating schizophrenia in a patient, comprising administering to the patient Compound 1 or a pharmaceutically acceptable salt thereof daily for 1-3 days at an initial dose, followed by administering to the patient Compound 1 or a pharmaceutically acceptable salt thereof daily at a therapeutic dose, where the initial dose is sub-therapeutic. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered daily at an initial dose on days 1-3, and Compound 1 or a pharmaceutically acceptable salt thereof is administered daily at a therapeutic dose on days 4-29. In some embodiments, the initial 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 a day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0137] In some embodiments, the present disclosure provides a method for treating schizophrenia in a patient, comprising administering 50 mg of compound 1 or a pharmaceutically acceptable salt to the patient per day.In some embodiments, compound 1 or a pharmaceutically acceptable salt is administered once a day.In some embodiments, compound 1 or a pharmaceutically acceptable salt is administered every day for a treatment period of 29 days.In some embodiments, compound 1 or a pharmaceutically acceptable salt is administered orally.

[0138] In some embodiments, provided herein is a method of treating schizophrenia in a patient, comprising: the patient is receiving or has been receiving 75 mg orally daily of Compound 1 or a pharma- ceutically acceptable salt thereof during the treatment period; Determined or determined whether the patient experienced any adverse events during treatment; and If the patient experiences an adverse event during treatment, the dose of Compound 1 or a pharma- ceutically acceptable salt thereof may be reduced or decreased to 50 mg daily; A method including the same is provided.

[0139] In some embodiments, the methods further comprise monitoring the patient for adverse events during the treatment period.

[0140] In some embodiments, provided herein is a method of treating schizophrenia in a patient, comprising administering a therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, of 50 mg per day or 75 mg per day to achieve a maximum plasma concentration of Compound 1, or a pharma-ceutically acceptable salt thereof, in the patient 1-4 hours after a single dose or 2-4 hours after multiple doses.

[0141] In some embodiments, provided herein is a method of treating schizophrenia in a patient, comprising orally administering a therapeutically effective amount of Compound 1, or a pharma- ceutical acceptable salt thereof, of 50 mg per day or 75 mg per day to achieve a steady-state plasma concentration of Compound 1, or a pharma-ceutical acceptable salt thereof, in the patient within 7 days.

[0142] In some embodiments, the present disclosure provides a method for treating insomnia, anxiety or headache symptoms in patients with schizophrenia, comprising administering to said patient a therapeutically effective amount of compound 1 or its pharma- ceutically acceptable salt.In some embodiments, the symptom is insomnia.In some embodiments, the symptom is anxiety.In some embodiments, the symptom is headache.

[0143] In some embodiments, provided herein is a method for treating insomnia, anxiety, or headache associated with schizophrenia in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0144] In some embodiments, provided herein is a method of treating schizophrenia in a patient, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, wherein the patient experiences a lower incidence of insomnia, anxiety or headache, or any combination thereof, than placebo.

[0145] In some embodiments, provided herein is a method of reducing the PANSS total score in a patient suffering from schizophrenia, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, resulting in: (i) a reduction in the PANSS total score of at least 17.2 from baseline; or (ii) an effect size for the PANSS total score of at least 0.45.

[0146] In some embodiments, provided herein is a method for reducing a CGI-S score in a patient suffering from schizophrenia, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, resulting in (i) a CGI-S score reduction of at least 1 from baseline, or (ii) an effect size for the CGI-S score of at least 0.52.

[0147] In some embodiments, provided herein is a method for reducing a BNSS total score in a patient suffering from schizophrenia, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, resulting in (i) a reduction in a BNSS total score of at least 7.1 from baseline, or (ii) an effect size for the BNSS total score of at least 0.48.

[0148] In some embodiments, provided herein is a method for reducing MADRS total score in a patient suffering from schizophrenia, comprising administering to the patient a therapeutically effective amount of Compound 1 or a pharma- ceutically acceptable salt thereof, resulting in (i) a reduction in MADRS total score of at least 3.3 from baseline, or (ii) an effect size for MADRS total score of at least 0.32.

[0149] In some embodiments, compound 1 or its pharmaceutically acceptable salt may be administered as part of pharmaceutical composition.The pharmaceutical composition herein can be administered orally, parenterally, by inhalation, topically, rectally, nasally, bucally, sublingually, vaginally, or via implanted reservoir.The term "parenteral" used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0150] In some embodiments, the composition is administered orally, intraperitoneally or intravenously.The sterile injectable form of the composition of the present invention may be an aqueous or oily suspension.These suspensions can be formulated by the method known in the art using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution of 1,3-butanediol.

[0151] In some embodiments, the pharma- ceutically acceptable compositions herein may be orally administered in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions.

[0152] In some embodiments, the pharmaceutical compositions herein comprise one or more pharma- ceutical acceptable excipients, including one or more binders, bulking agents, buffers, stabilizers, surfactants, wetting agents, lubricants, diluents, disintegrants, viscosity enhancing or reducing agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, flavoring agents, fragrances, flavoring agents, diluents, abrasives, polymer matrix systems, plasticizers, and other excipients that provide an elegant presentation of the drug or are useful in the manufacture of a medicament or pharmaceutical product comprising the compositions herein. Examples of carriers and excipients are well known to those skilled in the art and 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.

[0153] In some embodiments, non-limiting examples of excipients 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 carboxymethylcellulose, sodium carboxymethylcellulose), 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, pregelatinized 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 Examples of suitable additives include, but are not limited to, cellulose acetate, cellulose esters ...

[0154] In some embodiments, the pharmaceutical composition is formulated with one or more pharma- ceutical acceptable excipients according to known and established practices. Thus, in some embodiments, the composition is formulated, for example, as a liquid, powder, elixir, injectable solution, or suspension.

[0155] In some embodiments, formulations for oral use may be provided as tablets, caplets or capsules in which the pharmacologically active ingredient is mixed with an inert solid diluent.

[0156] In some embodiments, the oral dosage form is a solid oral dosage form. In some embodiments, the solid oral dosage form is a tablet, and in some embodiments, the solid oral dosage form is a capsule. Tablets include granulating agents and disintegrating agents, and may be coated or uncoated.

[0157] In some embodiments, formulations for topical use may be provided as, for example, a topical solution, lotion, cream, ointment, gel, foam, patch, powder, solid, sponge, tape, vapor, paste, or tincture.

[0158] In some embodiments, a suitable daily dose of Compound 1 or a pharma- ceutically acceptable salt thereof is the amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective amount generally depends on the factors described herein or understood by one of ordinary skill in the art. In general, the oral, intravenous, or subcutaneous dose of Compound 1 or a pharma- ceutically acceptable salt thereof to a patient ranges from about 0.005 mg per kg of body weight to about 5 mg per kg of body weight per day. In some embodiments, the oral dose of Compound 1 or a pharma- ceutically acceptable salt thereof ranges from about 0.125 mg per kg of body weight to about 2.5 mg per kg of body weight per day. In some embodiments, the oral dose of Compound 1 or a pharma- ceutically acceptable salt thereof ranges from about 0.25 mg per kg of body weight to about 2.5 mg per kg of body weight per day. In some embodiments, the oral dose of Compound 1 or a pharma- ceutically acceptable salt thereof ranges from about 0.125 mg per kg of body weight to about 1.125 mg per kg of body weight per day. In some embodiments, the oral dose of compound 1 or a pharma- ceutically acceptable salt thereof is in the range of about 10 mg to about 300 mg per day. In another embodiment, the oral dose of compound 1 or a pharma- ceutically acceptable salt thereof is in the range of about 20 mg to about 250 mg per day. In another embodiment, the oral dose of compound 1 or a pharma- ceutically acceptable salt thereof is in the range of about 100 mg to about 300 mg per day. In another embodiment, the oral dose of compound 1 or a pharma- ceutically acceptable salt thereof is in the range of about 10 mg to about 100 mg per day. In another embodiment, the oral dose of compound 1 or a pharma- ceutically acceptable salt thereof is in the range of about 50 mg to about 75 mg per day. In another embodiment, the oral dose of compound 1 or a pharma- ceutically acceptable salt thereof is in the range of about 50 mg to about 200 mg per day. Each of the above dosage ranges can be formulated as a single or multiple unit preparation.

[0159] In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered orally.In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered daily.In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered at about 50mg or about 75mg per day.

[0160] In some embodiments, the methods of the invention achieve a maximum plasma concentration of Compound 1 or a pharma- ceutically acceptable salt thereof in a patient 1-4 hours after a single oral dose and 2-4 hours after multiple oral doses. In some embodiments, the methods of the invention achieve a maximum plasma concentration of Compound 1 or a pharma- ceutically acceptable salt thereof in a patient 1-4 hours after a single oral dose. In some embodiments, the methods of the invention achieve a maximum plasma concentration of Compound 1 or a pharma- ceutically acceptable salt thereof in a patient 2-4 hours after multiple oral doses.

[0161] In some embodiments, the methods of the invention achieve a steady state plasma concentration of Compound 1, or a pharma- ceutically acceptable salt thereof, in a patient within seven days.

[0162] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered daily during a 29-day treatment period.

[0163] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, may be used in combination with one or more second active agents to treat, prevent, and / or manage the diseases and disorders described herein.

[0164] Some embodiments herein include a method of 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 a method of 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, to prevent or manage the disease.

[0165] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published by the American Psychiatric Association in 2013, provides a standard diagnostic system that practitioners rely on when diagnosing a variety of illnesses and disorders.

[0166] The term "mood disorder" as used herein includes depression, major depression, major depressive disorder, minor depression, major depression without psychosis, major depression with psychosis, 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.

[0167] Mental disorders are brain pathologies characterized by identifiable symptoms that result in abnormalities in the most integrative aspects of cognition, emotion, mood, or behavior. These disorders may differ in severity of symptoms, duration, and functional impairment. Mental illnesses afflict millions of people worldwide, resulting in significant human suffering and economic burden through lost productivity. Mood disorders are a type of mental illness and are defined as a heterogeneous, typically relapsing group of disorders, including unipolar (depressive) and bipolar (manic depression), characterized by pervasive mood disturbances, psychomotor dysfunction, and autonomic symptoms. Suicide, the most serious complication of patients with mood disorders, is responsible for death in 15-25% of untreated patients with mood disorders, and unrecognized or inadequately treated depression is responsible for 50-70% of completed suicides.

[0168] In some embodiments, the neurological disorder is depression (e.g., major depressive disorder or dysthymia); bipolar disorder, seasonal affective disorder; cognitive disorders; fibromyalgia; pain (e.g., neuropathic pain); sleep-related disorders (e.g., sleep apnea, insomnia, narcolepsy, cataplexy) (including sleep disorders caused by psychopsychiatric conditions); 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 dependency (e.g., cocaine addiction, nicotine addiction). In another embodiment, Compound 1, or a pharma- ceutically acceptable salt thereof, is useful for treating, preventing, and / or managing two or more co-occurring conditions / disorders, such as psychosis and depression.

[0169] Neurological disorders also include, but are not limited to, cerebral dysfunction such as senile dementia, Alzheimer's dementia, cognition, memory loss, amnesia / amnesic syndrome, epilepsy, impaired consciousness, coma, impaired attention, speech disorder, Lennox syndrome, autism, and hyperkinetic syndrome.

[0170] In some embodiments, the disease or disorder treated by the methods herein is These include one or more of the following: mood disorders, bipolar disorder (BPD), bipolar depression, sleep disorders, REM behavioral disorders, psychotic disorders, Alzheimer's disease with agitation and / or psychosis, Parkinson's disease psychosis, schizophrenia, attenuated psychotic syndrome, prodromal schizophrenia, and schizoaffective disorder.

[0171] 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, Parkinson's disease psychosis, schizophrenia, attenuated psychotic syndrome, prodromal schizophrenia, and schizoaffective disorder.

[0172] In some embodiments, the neurological or psychiatric disease or disorder is psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophrenia disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychoaffective disorder, aggression, confusion, Parkinson's psychosis, excited psychosis, psychotic disorder due to a common medical condition, substance-induced or drug-induced (e.g., phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other psychostimulants, and cocaine) psychotic disorder, psychosis associated with an affective disorder, brief reactive psychosis, schizophrenic psychosis, "schizophrenia-spectrum" disorders such as schizotypal or schizotypal personality disorder, or illnesses related to psychosis including both the positive and negative symptoms and cognitive symptoms of schizophrenia and other psychoses (major depression, manic-depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome); anxiety disorders including acute stress 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 phobia; substance-related disorders and addictive behaviors (including substance-induced mental confusion, persistent dementia, persistent amnesic disorder, psychotic disorder or anxiety disorder; tolerance, dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); and Alzheimer's disease with agitation and / or psychosis.

[0173] In some embodiments, the neurological or psychiatric disease or disorder is selected from depressive disorders including, but not limited to, unipolar depression, seasonal depression, postpartum depression, atypical depression, catatonic depression, geriatric depression, endogenous depression, melancholic depression, perinatal depression, situational 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 thoughts of suicide, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to general health conditions and substance-induced mood disorders.

[0174] In some embodiments, the neurological or psychiatric disease or disorder is selected from bipolar disorder, including but not limited to bipolar depression, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar and related disorders, bipolar and related disorders due to another medical condition, other specified bipolar and related disorders, and bipolar and related disorders not otherwise specified.

[0175] 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.

[0176] In some embodiments, the neurological or psychiatric disease or disorder is selected from sleep disorders including, 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, rapid eye movement sleep behavior disorder, shift work sleep disorder, excessive daytime sleepiness, non-24-hour sleep-wake disorder, awakening episodes, and narcolepsy.

[0177] 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 illness with a prevalence of about 2% of the population, affecting both men and women.It is a relapsing-remitting state characterized by cycling between elevated (i.e., manic) and depressed moods, and is distinct from other disorders such as major depressive disorder and schizophrenia.

[0178] Bipolar I is defined by the occurrence of full manic episodes, although most people experience significant depression. Manic symptoms include elation, irritability, hyperactivity, grandiosity, decreased need for sleep, racing thoughts, and occasionally psychosis. Depressive episodes are characterized by anhedonia, sad mood, hopelessness, low self-esteem, diminished concentration, and lethargy. Bipolar II is defined by the occurrence of major depressive episodes and hypomanic (less severe manic) episodes, although patients spend significantly more time in a depressed state. Other related conditions include cyclothymic disorder.

[0179] In bipolar II disorder, depressive episodes alternate with hypomania (relatively mild, nonpsychotic periods, usually less than a week long). During hypomanic periods, mood brightens, the need for sleep decreases, and psychomotor activity accelerates beyond the patient's usual level. Often, this switch is triggered by circadian factors (e.g., going to bed in a depressed mood and waking up early in the morning in a hypomanic state). Hypersomnia and overeating are characteristic and may recur seasonally (e.g., in autumn and winter), while insomnia and anorexia occur during the depressive phase. For some, hypomanic periods are adaptive, as they are associated with high energy, self-confidence, and paranormal social functioning. Many patients usually experience a pleasant elevation in mood at the end of the depression, but do not report it unless specifically asked.

[0180] Patients with major depressive episodes and a family history of bipolar disorder (informally referred to as bipolar III) often exhibit subtle hypomanic tendencies; such a temperament is described as hyperthymic (i.e., driven, ambitious and achievement-oriented).

[0181] In cyclothymic disorder, the patient experiences an irregular course of less severe hypomanic and minor depressive periods, each lasting several days. Cyclothymic disorder is generally a precursor to bipolar II disorder. However, it may also occur as extreme irritability without being complicated by a major mood disorder. In such cases, short cycles of delayed depression with low self-confidence and increased sleep alternate with increased elation or enthusiasm and reduced sleep. In another form, low-grade depressiveness predominates, and the bipolar tendency is indicated mainly by how easily elation or irritability is induced by antidepressants. In chronic hypomania, a rarely seen clinical form, periods of elation predominate and sleep is habitually reduced to less than six hours. This type of person is always overly cheerful, self-confident, energetic, organized, thoughtless, overly involved, busybody, and has a restless urge to talk down to people.

[0182] 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 and related disorders, or bipolar and related disorders not otherwise specified, and bipolar I disorder or bipolar II disorder with specifiers of anxious distress, mixed features, rapid cycling, melancholic features, atypical features, mood-congruent psychotic features, mood-incongruent psychotic features, catatonia, perinatal onset, and / or seasonal pattern. A recent article 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 includes mixed specifiers to capture the majority of patients with subsyndromal mixed symptoms.

[0183] 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, situational 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 melancholic mood (sadness), poor concentration, insomnia, fatigue, appetite disorder, excessive guilt and thoughts of suicide, premenstrual tension (PMS) and premenstrual dysphoric disorder (PDD), mood disorder due to general health condition and substance-induced mood disorder.

[0184] Depression is an affective disorder whose etiology cannot be explained by a single cause or theory. Unfortunately, treatment options for depressed patients who have a suboptimal clinical response to antidepressant treatment are limited. Approximately 30% of patients who initiate antidepressant treatment have a suboptimal or delayed clinical response to the first-line antidepressants commonly used to treat depression.

[0185] Typically, when a patient has a suboptimal or delayed clinical response after several weeks of treatment with an antidepressant, the clinician's first approach is to increase the dose of the antidepressant. If the patient's response is still inadequate after increasing the dose, the most common approach taken by many clinicians is to a) change to a different antidepressant, b) add a second antidepressant, or c) attempt augmentation therapy by administering agents such as lithium carbonate, thyroid hormone (triiodothyronine), psychostimulants, modafinil, atypical antipsychotics, buspirone, or pindolol.

[0186] Clinical depression, in its full symptomatological expression, appears as major depressive disorder, with varying degrees of residual symptoms over the course of and between episodes. Mood is typically melancholic, irritable, and / or anxious. Patients may appear miserable, with furrowed brows, downturned corners of the mouth, slumped posture, poor eye contact, and monosyllabic (or absent) speech. Morbid mood may be accompanied by preoccupation with guilt, self-negating thoughts, poor concentration, indecisiveness, decreased interest in usual activities, social withdrawal, feelings of helplessness, hopelessness, and recurrent thoughts of death or suicide. Sleep disturbances are common. Some individuals complain that their morbid mood is so deep that tears dry up, they are unable to experience normal emotions such as sadness, joy, and pleasure, and the world feels colorless, lifeless, and dead.

[0187] Melancholia (formerly endogenous depression) is characterized by marked psychomotor (thought and activity) slowing or agitation (e.g., restlessness, hand clenching, mental strain of speech), weight loss, irrational feelings of guilt, and loss of ability to experience pleasure. Many patients with the melancholic type complain of difficulty falling asleep, multiple awakenings, and insomnia during the night or early morning. Libido is often diminished or absent. Amenorrhea may occur. Eating disorders and weight loss may result in emaciation and secondary disturbances in electrolyte balance.

[0188] In atypical depression, the clinical symptoms are dominated by anti-vegetative features, including anxiety-phobic symptoms, evening worsening, early insomnia, hypersomnia that often extends into the daytime, and hyperphagia with weight gain. Unlike melancholia, atypical depressives are often uplifted by positive events, but minor adversities often cause them to crash into a paralyzing depression. There is considerable overlap between atypical depression and bipolar II disorder.

[0189] In dysthymic disorder, depressive symptoms typically begin insidiously in childhood or adolescence and run an intermittent or low-intensity course over years or decades, sometimes exacerbated by major depressive episodes (double depression). In pure dysthymia, depressive symptoms occur at subthreshold levels and overlap considerably with the symptoms of depressive temperament: habitually gloomy, pessimistic, humorless, or incapable of joy; passive and lethargic; withdrawn, skeptical, critical, or complaining; self-critical, self-reflective, and self-loathing; and a preoccupation with imperfections, failures, and negative events.

[0190] Many depressed patients have bipolar features when thoroughly evaluated, and one in five patients with a depressive disorder also experience frank hypomania or mania. Switching from unipolar to bipolar disorder most often occurs within five years of the onset of depressive symptoms. Predictors of switching include early onset of depression (before age 25), postpartum depression, frequent depressive episodes, mood quickly improving with physical treatments (e.g., antidepressants, phototherapy, sleep deprivation, electroconvulsive therapy), and a family history of mood disorders in three consecutive generations.

[0191] Patients with bipolar disorder show depressive moodiness and sometimes high-energy activity between episodes, and impairments in development and social functioning in bipolar depression are more common than in unipolar disorder. Bipolar disorder has shorter depressive episodes (3-6 months), younger age of onset, more abrupt onset of episodes, and shorter cycles (time between the onset of one episode and the onset of the next episode) than unipolar disorder. The cycles are especially accentuated in the rapid cycling form of bipolar disorder (usually defined as ≥4 episodes / year). Also, depressive episodes in bipolar disorder are the more difficult part of BPD to treat. For example, psychiatrists have shown that about 25% of all bipolar disorder patients are refractory during manic episodes, whereas about 70% are refractory during depressive episodes.

[0192] 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 health condition, other specified depressive disorder, depressive disorder not otherwise specified, or treatment-resistant depression (TRD), and MDD with specifiers of anxious distress, mixed features, melancholic features, atypical features, mood-concordant psychotic features, mood-incongruent psychotic features, catatonia, perinatal onset, and / or seasonal pattern, and seasonal affective disorder.

[0193] It should be understood that TRD is a term used in clinical psychiatry to describe cases of major depressive disorder (MDD) that have not responded adequately to an adequate course of at least two antidepressants.

[0194] In some embodiments, the depressive disorder is associated with acute suicidal tendencies or suicidal ideation.The United States 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 (up to age 24) with depressive disorder, such as MDD.In some embodiments, the compositions and methods herein do not increase the risk of suicidal ideation and / or behavior in children, adolescents and / or young adults with depressive disorder, such as MDD.In some embodiments, the present invention provides a medicament and method for treating one or more symptoms of depressive disorder (e.g., MDD) in children, adolescents and / or young adults without increasing the risk of suicidal ideation and / or behavior.

[0195] In some embodiments, the neurological or psychiatric disease or disorder is schizophrenia. Schizophrenia is a disorder of unknown etiology that usually first appears in early adulthood and is characterized by psychotic symptoms, gradual progression and development, and / or impaired social behavior and professional skills. Characteristic psychotic symptoms are disturbances in thought content (e.g., multiple, fragmented, incoherent, implausible or simply delusional content, or paranoid thoughts) and mental disorders (e.g., loss of associations, imaginative leaps, thought scattering to the point of incomprehensibility), as well as disturbances in perception (e.g., hallucinations), emotions (e.g., superficial or inadequate emotions), self-awareness, intentions, impulses and / or interpersonal relationships, and psychotic disorders (e.g., catatonia). Other symptoms are also associated with this disorder. Schizophrenia is divided into subgroups: paranoid type, characterized by delusions and hallucinations, but without thought disorder, disorganized behavior, and flattened affect; disorganized type, also called "hypertrophic schizophrenia", in which both thought disorder and flattened affect are present; catatonic type, in which prominent psychomotor disturbances are evident and symptoms include catatonic stupor and lameness; and undifferentiated type, in which psychotic symptoms are present but do not meet the criteria for paranoid, disorganized, or catatonic types. Schizophrenia symptoms usually appear in three broad categories: positive, negative, and cognitive symptoms. Positive symptoms are symptoms that represent an "excess" of normal experiences, such as hallucinations and delusions. Negative symptoms are symptoms in which the patient suffers from a lack of normal experiences, such as anhedonia and lack of social interaction. Cognitive symptoms are related to cognitive impairment in schizophrenia, such as lack of sustained attention and poor decision-making.

[0196] Thus, in some embodiments, the neurological or psychiatric disease or disorder is one or more of schizotypal (personality) disorder, delusional disorder, brief psychotic disorder, schizophrenia disorder, schizophrenia, schizoaffective disorder, substance / medication-induced psychotic disorder, psychotic disorder due to another health condition, other specified schizophrenia spectrum and other psychotic disorder, schizophrenia spectrum and other psychotic disorder not otherwise specified.

[0197] Schizoaffective disorder should be understood to include conditions which include aspects of both schizophrenia and a mood disorder, such as major depressive disorder or bipolar disorder.

[0198] In some embodiments, the neurological or psychiatric disease or disorder is anxiety disorder. Anxiety disorders are characterized by fear, worry and concern, and are 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 ideas. The difference between anxiety and fear is that anxiety is an emotional response to a perceived future threat, while fear is related to a perceived or current threat. Also, the content of the associated thoughts and beliefs is different. Examples of anxiety disorders include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack specifier, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, anxiety disorder due to another health condition, illness anxiety disorder, social (pragmatic) communication disorder, other specified anxiety disorder, and anxiety disorder not otherwise specified, as well as tension-related disorders, including reactive attachment disorder, disinhibited social interaction disorder, post-traumatic stress disorder (PTSD), acute stress disorder, and adjustment disorder.

[0199] In some embodiments, the neurological or psychiatric disease or disorder is a sleep disorder, including sleep disorders caused by a psychiatric condition, including, but not limited to, insomnia, sleep disturbance, 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, awakening episodes, and narcolepsy.

[0200] In some embodiments, the neurological or psychiatric disease or disorder is social dysfunction.In some embodiments, the social dysfunction is neurodevelopmental disorder, obsessive-compulsive disorder or disruptive, impulse control and conduct disorder.In some embodiments, the social dysfunction is speech disorder, speech speech disorder, childhood onset fluency (stuttering), social communication disorder, developmental coordination disorder, stereotypic movement disorder, tic disorder, Tourette's disorder, persistent (chronic) movement disorder or vocal tic disorder, provisional tic disorder, another specific tic disorder, tic disorder not otherwise specified, obsessive-compulsive disorder or impulse control disorder.In some embodiments, the social dysfunction is speech disorder, speech speech disorder, childhood onset fluency (stuttering), social communication disorder, developmental coordination disorder, stereotypic movement disorder, tic disorder, Tourette's disorder, persistent (chronic) movement disorder or vocal tic disorder, provisional tic disorder, another specific tic disorder or tic disorder not otherwise specified. In some embodiments, the social dysfunction is a speech disorder, a speech speech disorder, a childhood-onset fluency (stuttering) or a social communication disorder. In some embodiments, the social dysfunction is a speech disorder, a childhood-onset fluency (stuttering), a social communication disorder, developmental coordination disorder, a stereotypic movement disorder, a persistent (chronic) movement disorder or a vocal tic disorder, a provisional tic disorder, other specified tic disorder or a tic disorder not otherwise specified. EXAMPLES

[0201] Example 1: 4-week clinical trial

[0202] Compound 1 was evaluated in human patients during a 4-week randomized placebo-controlled trial to study its efficacy and safety in the treatment of schizophrenia. Inpatients aged 18 to 40 years who met DSM-5 criteria for schizophrenia and were experiencing an acute exacerbation of psychotic symptoms (PANSS total score ≥ 80; conceptual disorganization, abnormal thought content score ≥ 4 on two or more items) were eligible. Patients were randomized, double-blind, to receive 4 weeks of flexible-dose treatment with Compound 1 hydrochloride orally administered once daily (50 mg or 75 mg doses). The primary efficacy endpoint was the change from baseline to week 4 in the Positive and Negative Symptom Scale (PANSS) total score. Secondary efficacy endpoints included change from baseline to week 4 in Clinical Global Impression-Severity (CGI-S) score, PANSS subscale scores, Brief Negative Symptoms Scale (BNSS) total score, and Montgomery-Asberg Depression Rating Scale (MADRS) total score. Changes from baseline in primary and secondary efficacy measures were analyzed using Mixed Model for Repeated Measurement (MMRM) analyses.

[0203] Research design: Patients first underwent a screening / washout period of up to 14 days. Patients were randomly assigned to a placebo or treatment group. The treatment group received Compound 1 at 50 mg / day for 3 days, followed by variable doses of Compound 1 at 50 mg / day or 75 mg / day on days 4-29. The placebo group received placebo for 29 days.

[0204] Main entry criteria: Men and women aged 18-40 Time since first diagnosis of schizophrenia ≥ 6 months -Time since current psychotic exacerbation ≤2 months Prior hospitalizations for treatment of acute exacerbations of schizophrenia ≤2 Screening and baseline PANSS total score ≥ 80 and PANSS item scores ≥ 4 for two or more of the following: delusions (P1), conceptual disorganization (P2), hallucinatory behavior (P3), and abnormal thought content (G9) Screening and baseline CGI-S score ≥ 4

[0205] Study Endpoints: Primary Endpoint: Change from baseline in PANSS total score at week 4 Secondary Endpoints: Change from baseline in CGI-S score at week 4 Change from baseline in PANSS subscale scores at week 4 Change from baseline in BNSS total score at week 4 Change from baseline in MADRS total score at week 4 Incidence of adverse events (AEs), serious adverse events (SAEs), and adverse events leading to study discontinuation

[0206] Statistical analysis methods Mixed-effects models with repeated measures (MMRM) were used. Changes from baseline in PANSS total score were analyzed using MMRM models with fixed effects for treatment, visit (day 4, weeks 1-4), with interaction between treatment and visit, baseline PANSS total score, and pooled center as categorical variables. Centers were pooled by country. An unstructured covariance matrix was used to model within-subject correlations. MMRM was also used for the analysis of secondary endpoints.

[0207] Baseline characteristics: Baseline subject characteristics are shown in Table 1.

[0208] [Table 1]

[0209] resultIn this randomized, placebo-controlled, 4-week study, Compound 1, at variable doses of 50 mg or 75 mg / day, demonstrated statistically significant and clinically meaningful symptom improvement in schizophrenia patients experiencing an acute exacerbation. Compound 1 demonstrated potent and broad activity across a range of positive, negative, depressive and general psychopathology symptoms. Improvement in negative symptoms was particularly notable, with an effect size of 0.48 on the Brief Negative Symptom Scale. The tolerability and safety profile of Compound 1 appeared to be similar to placebo in this 4-week study.

[0210] Efficacy:

[0211] Figure 1 shows the change from baseline in patients' PANSS total scores over the 4-week study. The least squares mean change from baseline at week 4 was -9.7 for placebo vs. -17.2 for treatment, corresponding to an effect size of 0.45.

[0212] Figure 2 shows the change from baseline in patients' PANSS positive subscale scores over the 4-week study. The least squares mean change from baseline at week 4 was -5.5 for the treatment group compared with -3.9 for placebo, corresponding to an effect size of 0.32.

[0213] Figure 3 shows the change from baseline in patients' PANSS negative subscale scores over the 4-week study. The least squares mean change from baseline at week 4 was -3.1 for the treatment group compared with -1.6 for placebo, corresponding to an effect size of 0.37.

[0214] Figure 4 shows the change from baseline in patients' PANSS general psychopathology subscale scores over the 4-week study. The least squares mean change from baseline at week 4 was -9.0 for the treatment group compared with -4.7 for placebo, corresponding to an effect size of 0.51.

[0215] Figure 5 shows the change from baseline in patients' CGI-S scores over the 4-week study. The least squares mean change from baseline at week 4 was -1.0 for the treatment group compared with -0.5 for the placebo, which corresponds to an effect size of 0.52.

[0216] Figure 6 shows the change from baseline in patients' BNSS total scores over the 4-week study. The least squares mean change from baseline at week 4 was -7.1 for the treatment group compared with -2.7 for placebo, which corresponds to an effect size of 0.48.

[0217] Figure 7 shows the change from baseline in patients' MADRS total scores over the 4-week study. The least squares mean change from baseline at week 4 was -1.6 for placebo vs. -3.3 for treatment, corresponding to an effect size of 0.32.

[0218] Adverse Events:

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

[0220] The incidence of common adverse events occurring in 2% or more of patients in either the treatment or placebo groups is summarized in Table 2. The incidence of headache, insomnia, acute exacerbation of schizophrenia, and anxiety was each lower in the treatment groups than in the placebo group.

[0221] [Table 2]

[0222] The incidence of extrapyramidal adverse events is summarized in Table 3. The incidence of extrapyramidal adverse events in the treatment groups was nearly identical to that of placebo.

[0223] [Table 3]

[0224] The incidence of cardiovascular adverse events is summarized in Table 4. The incidence of cardiovascular adverse events was similar in the treatment groups to placebo. The overall incidence of cardiovascular adverse events was 4.2% in the treatment group compared with 4.0% in the placebo group.

[0225] [Table 4]

[0226] The incidence of serious adverse events is summarized in Table 5. The incidence of serious adverse events in the treatment groups was lower than in the placebo group.

[0227] [Table 5]

[0228] The incidence of adverse events leading to study discontinuation is summarized in Table 6. The incidence of such adverse events was similar between the treatment and placebo groups.

[0229] [Table 6]

[0230] Figure 8 shows the median change from baseline in prolactin levels at week 4. Treatment groups experienced a mean decrease in prolactin. The change in prolactin from baseline at week 4 is summarized in Table 7. Compound 1 had no clinically significant effect on prolactin.

[0231] [Table 7]

[0232] The incidence rates of orthostatic hypotension and orthostatic tachycardia are summarized in Table 8. Orthostatic tachycardia 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, respectively, after a subject has been standing for at least 2-4 minutes, compared to systolic and diastolic blood pressure measured in the supine position. Orthostatic tachycardia is defined as an increase in heart rate of 20 beats per minute (bpm) or more, and a heart rate of more than 100 bpm, after a subject has been standing for at least 2-4 minutes, compared to 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.

[0233] [Table 8]

[0234] The incidence of QT prolongation measured by QTcF interval is summarized in Table 9. Patient data were collected via electrocardiogram (ECG). The number and percentage of subjects with QTc values ​​falling into the following categories were identified. The same criteria were applied for both QTcF and QTcB: Not present at baseline and greater than 450 msec at any time after baseline (including unscheduled visits) Not present at baseline and greater than 480 msec at any time point after baseline (including unscheduled visits) Not present at baseline and greater than 500 msec at any time after baseline (including unscheduled visits) An increase of ≥30 msec from baseline in at least one post-baseline measurement (including unscheduled visits) and an increase of <60 msec from baseline in all post-baseline measurements (including unscheduled visits) Increase of ≥60 msec from baseline in at least one post-baseline measurement (including unscheduled visits) There was no incidence of QT prolongation in both treatment and placebo groups.

[0235] [Table 9]

[0236] Table 10 summarizes the extrapyramidal symptoms measured by the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary Movement Scale (AIMS) and the Simpson-Anga Scale (SAS).

[0237] [Table 10]

[0238] Therefore, the various methods herein have a low incidence of adverse events, for example, lower than placebo, the same as placebo, or almost the same as placebo, or similar adverse events.This is in contrast to many typical and atypical antipsychotics that have affinity for dopamine D2 receptors and have a higher incidence of adverse events.

[0239] Example 2: 26-Week Extension Study

[0240] Schizophrenia subjects who completed the treatment phase of Example 1 were subjected to a 26-week open-label extension study. Patients who met the entry criteria were immediately transferred from the Example 1 study to the extension study. A total of 157 patients participated in the extension study. Patients were administered Compound 1 hydrochloride (referred to as "Compound 1" in the table) orally once daily at 50 mg / day on days 1-3 of the extension study, followed by variable doses of 25 mg / day, 50 mg / day, or 75 mg / day for the remaining 26 weeks.

[0241] Safety and tolerability were monitored throughout the study by collecting physical examination results, electrocardiograms, vital signs, AEs, clinical laboratory parameters, C-SSRS, weight, and BMI. Efficacy was assessed using PANSS total and subscale scores, as well as CGI-S, BNSS, and MADRS scores. Subjects provided information on subjective drug effects via questionnaires.

[0242] The primary endpoints were the incidence of overall AEs, SAEs, and AEs leading to discontinuation. Secondary endpoints included: · Absolute values ​​and changes from baseline in the laboratory tests in Example 1 (hematology, serum chemistry, urinalysis, glucose and lipid panel, prolactin, glycosylated hemoglobin (HbA1c)); - absolute values ​​and changes from DB baseline in clinical assessments of Example 1 (vital signs, weight, BMI, blood pressure [supine vs. standing], heart rate [supine vs. standing], 12-lead ECG); and Changes from DB baseline in Example 1 PANSS total score, PANSS subscale scores (positive, negative, and general psychopathology), CGI-S score, BNSS total score, and MADRS total score (see Table 1) were included.

[0243] result:

[0244] One hundred and five subjects (66.9%) completed the 26-week study, with 52 subjects (33.1%) discontinuing due to adverse events (18; 11.5%), subject withdrawal (16; 10.2%), other (9; 5.7%), lack of efficacy (8; 5.1%), or noncompliance (1; 0.6%).

[0245] Efficacy assessments were recorded over the course of the 26-week extension study.

[0246] FIG. 9 shows the PANSS total scores during the extension study, with the PANSS total score data from the study of Example 1 provided for reference.

[0247] FIG. 10 shows the PANSS Positive Subscale scores during the expansion study, with the PANSS Positive Subscale score data from the study in Example 1 provided for reference.

[0248] FIG. 11 shows the PANSS Negative subscale scores during the expansion study, with the PANSS Negative subscale score data from the study in Example 1 provided for reference.

[0249] FIG. 12 shows the PANSS General Psychopathology subscale scores during the expansion study, with the PANSS General Psychopathology subscale score data from the Example 1 study provided for reference.

[0250] FIG. 13 shows the CGI-S scores during the expansion study, with the CGI-S score data from the study of Example 1 provided for reference.

[0251] FIG. 14 shows the BNSS total scores during the expansion study, with the BNSS total score data from the study in Example 1 provided for reference.

[0252] FIG. 15 shows the MADRS total scores during the expansion study, with the MADRS total score data from the study in Example 1 provided for reference.

[0253] Adverse events were monitored and recorded during the extension study. The incidence of adverse events remained low in both (i) subjects who had previously received placebo and were first treated with active treatment during the extension study, and (ii) subjects who continued to receive active treatment from the study of Example 1 to the extension study. Tables 11-16 show the adverse events experienced during the extension study.

[0254] [Table 11]

[0255] [Table 12]

[0256] [Table 13]

[0257] The change from baseline in prolactin levels at week 26 is shown in FIG.

[0258] [Table 14]

[0259] [Table 15]

[0260] [Table 16]

[0261] Figure 20A shows the time to all causes of discontinuation in the expansion study, and Figure 20B shows the time to discontinuation for several other drugs, including olanzapine, risperidone, ziprasidone, perphenazine, and quetiapine.

[0262] Additional laboratory tests were performed during the study. Changes from open-label baseline (i.e., at the start of the expansion study) in weight and BMI at week 26 are shown in Figures 17A and B. Changes from open-label baseline in lipid measures (total cholesterol, triglycerides, HDL, LDL) are shown in Figures 18A-D. Changes from open-label baseline in blood glucose measures (glucose, HbA1c) are shown in Figure 19A,B.

[0263] Functional improvement was also measured by the UPSA-B score, a performance-based assessment of skills. Compound 1 improved subjects' UPSA-B total score from an average of about 76 to an average of about 84 over the 26-week period (effect size 0.66).

[0264] Overall, the expansion study demonstrated a high success rate, sustained improvement in schizophrenia symptoms (i.e., improved efficacy scores), very low rates of EPS-related, prolactin-related, and cardiovascular-related adverse events, and minimal changes in weight, lipid, and glucose measures.

[0265] Example 3: Class-effect adverse events across antipsychotics

[0266] Pharmaceutical compounds in the antipsychotic class are characterized, in part, by specific adverse event risks associated with their use in the treatment of schizophrenia, bipolar disorder and depression patient populations. The Medical Dictionary for Drug Regulatory Affairs (MedDRA) is a set of internationally used terms related to health conditions, medicines and medical devices, including adverse events. Using standardization of MedDRA terms (preferred terms), we created a list of preferred terms for adverse events related to the antipsychotic class based on reports to the FDA's Real-World Adverse Event Reporting Database (FAERS). In particular, we used FAERS to identify preferred terms related to 11 recently FDA-approved antipsychotics (aripiprazole, asenapine, brexpiprazole, cariprazine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone). The preferred terms cover symptoms in different health systems and organs. A total of more than 9,500 adverse event records were generated using data from the second quarter of 2018 deployed on the Empirica signal server.

[0267] The adverse event priority terms for the pool of 11 antipsychotics were ranked by relative risk using the calculated empirical Bayesian geometric mean (EBGM). Prioritized terms corresponding to individual symptoms of schizophrenia and / or bipolar disorder, such as those corresponding to individual items of psychiatric symptom rating scales (e.g., PANSS, MADRS) used in clinical trials for schizophrenia or bipolar disorder, were selected and flagged as disease-related and not analyzed as medication side effects. The higher the EBGM value of a drug, the higher the statistical association between the priority term / adverse event and that drug compared to all other drugs and all other priority terms / adverse events. Here, a rank order by EBGM value is created and priority terms / adverse events that describe the effect of antipsychotics (calculated as the overall pool of 11 antipsychotics) are listed. Thus, compounds that cause adverse events with priority terms in the high rankings (e.g., priority terms with EGBM values ​​above a threshold) in a clinically significant portion of the treated patient population can be considered to have an adverse event profile similar to the class of antipsychotics.

[0268] As an example, preferred terms associated with a pool of 11 antipsychotic drugs are shown below in Table 17. Compounds that exhibit a clinically significant portion of the patient population with adverse events matching these example preferred terms can be considered to have an adverse event profile similar to the antipsychotic class.

[0269] [Table 17-1] [Table 17-2]

[0270] More than 9,500 preferred terms for adverse events across a pool of 11 antipsychotics were used to query the clinical trial data for Example 1 (a 4-week study). The EBGM ranking of preferred terms for Compound 1 is shown in Table 18. Compound 1 demonstrated a clinically insignificant incidence of adverse events associated with the current antipsychotic class (e.g., hyperprolactinemia, abnormal blood prolactin levels, elevated blood prolactin levels, galactorrhea, cogwheel rigidity, obesity, metabolic syndrome) as defined by preferred terms with the greatest relative risk in real-world adverse event reporting databases (e.g., class-related adverse events). Additionally, preferred terms observed in subjects receiving Compound 1 and placebo as a comparison showed similar incidence of adverse events. Thus, Compound 1 does not demonstrate an adverse event profile matching the class effect of antipsychotics.

[0271] [Table 18]

[0272] Example 4: Pharmacokinetics

[0273] The pharmacokinetics (PK), safety and tolerability of compound 1 were evaluated in healthy adult male subjects and adult male and female patients with schizophrenia at single ascending doses (5 mg to 125 mg and 25 mg to 150 mg), respectively, and in adult male and female patients with schizophrenia at multiple ascending doses (10 mg, 25 mg, 50 mg, 75 mg, and 100 mg once daily). Blood samples were collected from 0 to 144 hours post-dose and subjected to PK analysis. Safety evaluations included adverse events, vital signs, clinical laboratory tests, physical and neurological examinations, C-SSRS, 12-lead electrocardiogram, and safety electroencephalogram.

[0274] Healthy adult male subjects, single ascending dose

[0275] The safety, tolerability, and maximum tolerated dose (MTD) of a single oral dose of compound 1 was studied in 39 normal healthy adult male subjects. Subjects were healthy men aged 18-50 years (inclusive), with a BMI of 16-32 kg / m2 (inclusive), without a diagnosis of schizophrenia, and without concomitant use of CNS-active medications or CYP2D6 inhibitors.

[0276] Compound 1 was administered to subjects in single doses at concentrations of 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, and 125 mg. There were 6 subjects in each group, except for the 125 mg group, in which 9 subjects received that dose, and 13 placebo subjects. There were no deaths or treatment-emergent clinically significant changes in laboratory parameters in this study. The results of plasma PK parameters are shown in Table 19 below.

[0277] [Table 19]

[0278] Single ascending dose study in adult males and females with schizophrenia

[0279] 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. The subjects were male or female, aged 18 to 55 years (inclusive), with a BMI of 19.5 kg / m 2 ~37kg / m 2 In addition, subjects were required to meet the primary diagnostic criteria for schizophrenia in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; Text Revision (DSM-IV-TR) and not to be taking any CNS-active medications or CYP2D6 inhibitors.

[0280] Compound 1 was administered as a single dose to subjects 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 clinically significant treatment-emerged changes in laboratory parameters in this study. The results of plasma PK parameters are shown in Table 20 below.

[0281] [Table 20]

[0282] Study design: Adult male and female subjects with schizophrenia, multiple ascending doses; 2-part clinical trial: multiple doses and 28-day open label

[0283] The study consisted of two parts: a multiple-dose study and a 28-day open-label study. Compound 1 was evaluated in human adult male and female subjects diagnosed with schizophrenia to test its safety, tolerability, and pharmacokinetics in the treatment of schizophrenia. The study was divided into two parts, enrolling separate cohorts of patients but using the same study entry criteria. Part A was a multicenter, randomized, single-blind, placebo-controlled, ascending multiple-dose oral study, and Part B was a single-center, non-randomized, open-label study to evaluate the safety, tolerability, and pharmacokinetics of Compound 1 at a dose of 75 mg / day for 28 days. Efficacy evaluations were performed during the open-label treatment period in Part B.

[0284] Study participation criteria Male and female subjects aged 18 to 55 years were eligible to participate if they met the primary diagnostic criteria for schizophrenia in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; Text Revision (DSM-IV-TR). 2Subjects were required to be (including); clinically stable for the past 6 months; CGI-S score ≤ 4; and PANSS total score ≤ 80 (PANSS subscales of hostility [P7] and uncooperativeness [G8] ≤ 4 [moderate or higher]). Subjects were required to be drug-free during the study period, including not using prescription or over-the-counter medications, including antipsychotics, antidepressants, or mood stabilizers, or vitamins or dietary supplements. Permitted medications included over-the-counter pain relievers, such as acetaminophen, hydrocortisone cream, hydrocortisone cream, female contraceptives, medications for stable conditions (e.g., hypertension, hypercholesterolemia, etc.), with limited use of lorazepam and zolpidem permitted during washout and treatment periods.

[0285] Study Design: Multiple Dose (Part A): Sixty subjects were randomized into five ascending dose cohorts (N=12) and assigned to the following doses of Compound 1: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg (administered orally once daily on an empty stomach). Within each cohort, subjects were randomized 3:1 to receive either Compound 1 (N=9) or matching placebo (N=3) for 7 days.

[0286] Of the 60 randomly assigned subjects, 71.7% were male, 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 per protocol; this subject discontinued the study due to an SAE for psychotic disorder (determined to be unrelated to study medication).

[0287] Table 21 shows the pharmacokinetic parameters of Compound 1 following (A) a single oral dose of ascending concentrations on day 1, and (B) multiple doses on day 7.

[0288] [Table 21]

[0289] In the dose range of 10 to 100 mg / day, Compound 1 max dose-proportional (β=1.17 [95% CI: 0.98-1.37]), AUC 0-24 The mean V on day 7 for compound 1 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 substantially with increasing dose.

[0290] Study Design: 28-day open-label treatment (Part B) :

[0291] In an open-label study, adult patients (N=16) diagnosed with schizophrenia were admitted to the clinic and completed washout of their previous antipsychotic medication. After successful washout, subjects were administered Compound 1 (75 mg / day) for 28 days. Patients remained in the clinic for the first 2 weeks of treatment and were administered as outpatients for the remaining 2 weeks. Safety evaluations included incidence of adverse events, clinical laboratory measurements and movement disorder scales (BARS, AIMS and M-SAS). The effect of Compound 1 on the Positive and Negative Syndrome (PANSS) scale and Clinical Global Impressions Scale-Severity (CGI-S) were also evaluated.

[0292] 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 years), 75.0% were African American, and the mean PANSS total score was 73.3.

[0293] No worsening of schizophrenia symptoms was observed in any subject. No treatment-emergent clinically significant changes in laboratory parameters, electrocardiogram parameters including QTcB and QTcF intervals, neurological examination, or effects on movement disorders measured by the Barnes akathisia scale, the abnormal involuntary movement scale, or the Simpson-Anga scale were observed in either Part A or Part B of the study, and there were no deaths.

[0294] Pharmacokinetic parameters following multiple doses of Compound 1 at 75 mg / day (Part B, Day 13) were as follows: max (CV%), 316ng / mL (17.5%), t max (median), 4.0 hours, AUC 0-24 , 3487 h·ng / mL. The mean trough plasma concentration of compound 1 was visually determined to have reached steady state by day 7.

[0295] Treatment with Compound 1 also improved efficacy measures (PANSS total score, CGI-S) compared to baseline. Furthermore, ad hoc subgroup analyses showed that the reduction from baseline in PANSS total score at the end of the 28-day treatment period was significantly greater in subjects with fewer annual hospitalizations due to illness compared to those with more frequent hospitalizations.

[0296] In summary, no safety issues were observed following multiple oral administration of compound 1 at doses ranging from 10 to 100 mg / day for 7 days or at 75 mg / day for 28 days. No treatment-induced clinically significant changes occurred in vital signs, physical examination, laboratory parameters, or electrocardiogram parameters, including QTcF interval. Additionally, no subjects developed suicidal ideation or behavior under treatment. Treatment with compound 1 at 75 mg / day for 28 days was associated with improvements in PANSS total scores, with greater improvements in patients with higher baseline PANSS total scores, younger patients, and fewer hospitalizations. The results of this study demonstrate an acceptable safety and tolerability profile of compound 1 (75 mg / day) in patients with schizophrenia up to 28 days.

[0297] Example 5: Preparation of Form A Crystals of (S)-(4,5-Dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine ("(S)-TPMA") HCl (i.e., Form A Crystals of Compound 1 Hydrochloride)

[0298] Scheme 1: Preparation of 4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflate [ka]

[0299] 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. It should be noted that trifluoromethanesulfonic acid is a highly hazardous substance. The reaction was heated to reflux (80 ± 2 °C) for 1 h. The by-product methanol was subsequently removed by distillation at atmospheric pressure, reducing the reaction volume to the target volume of 460 ml over 4-8 h. The reaction was deemed complete if compound 1B remained at or below 1.0% (HPLC peak area % of peaks of interest, compounds A, B and C).

[0300] If the amount of compound B was 1% or more, an appropriate amount of 2-methyl THF was added and distillation was continued to the target amount. If the target amount was reached before the end of the reaction (about 4 hours), 300 ml of 2-methyl THF was added and distillation was continued. After the reaction was completed, the reaction was cooled to about 40-50 °C and concentrated to the target amount of 325 ml by vacuum distillation. Subsequently, 218 g (325 ml) of toluene was added over about 15 minutes, and the formed reaction suspension was stirred at 50 ± 2 °C for 1 hour, and then cooled linearly to 20 ± 2 °C over 1 hour 45 minutes with stirring. The suspension was filtered and the product cake was washed with a mixture of 2-methyl THF and toluene (1:1 volume / volume). The wet cake was dried to constant weight under vacuum at 40 ± 5 °C to obtain racemic TPMA triflate (compound C) as an off-white solid in about 79% yield.

[0301] Scheme 2: Preparation of (S)-(-)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R) mandelate [ka]

[0302] 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 min, the pH was checked and if it was less than 13, small amounts of 1.77 N KOH were added until the pH was 13 or higher. The aqueous and organic layers were allowed to settle, separate, and collected separately. The MTBE (top) organic layer was retained for further processing. The aqueous (bottom) layer was extracted twice with MTBE (first with 835 ml and second with 150 ml), and the organic (MBTE) layer was collected each time. The MTBE layers (organic layers) were combined and washed with 20% aqueous NaCl (492.9 g) with stirring, and the phases were allowed to settle for 10 min. The aqueous layer was removed and the remaining MTBE organic layer was distilled at atmospheric pressure to reduce the reaction volume to the target level of 1.9 L. Upon completion, the process stream was cooled to approximately 45°C and concentrated by vacuum distillation to a target volume of 890 ml while maintaining the temperature at 35-45°C. The water content after vacuum distillation was found to be approximately 0.37 wt%. Filtration was then performed using a wash of 204 ml MTBE to remove insoluble material and the process stream (filtrate) was transferred to a clean reactor. 2512 mL of acetonitrile was added and a solvent switch was performed by vacuum distillation at 35-45°C until a target volume of 800 mL was reached, at which point the reactor was washed with 150 ml of acetonitrile and added to the process stream. The resulting process stream, a solution of TPMA free base (compound D) in acetonitrile. Acetonitrile was then added to the solution of TPMA free base (compound D) in acetonitrile as needed to achieve approximately 33 wt% of compound D.

[0303] A solution of 250.3 g of (R)-mandelic acid A in 1828 ml of acetone was warmed to 48±2° C. A solution of TPMA free base in acetonitrile (917.7 g of a solution of 302.1 g of compound D in acetonitrile) was then added at a rate to maintain the reaction temperature below 51° C. After stirring for 10 minutes at 48±2° C., the process stream was cooled to 45±2° C. and 1.5 g of (S)-TPMA(R)-mandelate seed crystals were charged. The process stream was stirred for 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 process stream was linearly cooled to 10±2° C. over 45 minutes. The reaction suspension was then stirred for 60 minutes at 10±2° C., filtered and the product cake was washed with an acetone / CH3CN mixture (2.3:1 wt / wt). The wet cake was dried under vacuum at 40±2° C. to constant weight to give crude (S)-TPMA(R)-mandelate (compound E) as a white crystalline solid in approximately 41% yield.

[0304] Scheme 3: Recrystallization of (S)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R) mandelate [ka]

[0305] A suspension of crude (S)-TPMA(R)-Mandelate (compound E) from scheme 2 (200.1 g) in 4205 ml of acetone was warmed to about 56° C. (the boiling point of acetone) and stirred until a clear solution was obtained. The solution was cooled to 47±2° C. over about 20 minutes, after which (S)-TPMA(R)-Mandelate seed crystals were added. The process stream was stirred at 47±2° C. for about 30 minutes and linearly cooled to 21±2° C. over 90 minutes. After about 30 minutes of holding at 21±2° C., the suspension was linearly cooled to 10±2° C. over 45 minutes, followed by stirring at 10±2° C. for 1 hour, filtering and washing the product cake with acetone (2 times with 401 ml each time). The wet cake was dried under vacuum at about 40±2° C. to constant weight to give (S)-TPMA(R)-mandelate (purified Compound E) as a white crystalline solid in about 77% yield.

[0306] Scheme 4: Formation of A-type crystals of (S)-(-)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride [ka]

[0307] Scheme 4 of this example reactively crystallizes (S)-(-)-4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine HCl, ((S)-TPMA HCl), as Form A crystals. Upon crystallization, (S)-TPMA HCl exhibits two distinct forms (polymorphs), the first being block-like crystals (Form A) and the second being needle-like crystals (Form B). According to single crystal X-ray diffraction studies described herein, Form A is monoclinic and Form B is orthorhombic.

[0308] To a suspension of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)-mandelate salt (compound E) from scheme 3 (100 g) in 305 ml MTBE, 172.5 ml of 10% aqueous KOH was added. After stirring for 10 min at 20±2° C., the aqueous and organic phases were separated. The organic MTBE (top) phase was saved and subjected to further processing. If the pH of the aqueous phase was below 13, a small amount of 19% aqueous KOH was added to raise the pH to 13. The aqueous (bottom) phase was back-extracted twice with MTBE (first with 208 ml MTBE and second with 155 ml MTBE), saving the organic phase and applying further processing each time. The saved organic layers were combined and the combined organic phase was azeotropically distilled to remove water and distilled at atmospheric pressure to a target volume of 140 ml. The process stream was then filtered to remove insoluble material (e.g., salts precipitated upon removal of water) and the filtrate was transferred to a clean reactor. 775 ml of isopropanol was added (bringing the total process stream volume to approximately 1030 ml) and solvent switching was performed by vacuum distillation at a temperature below 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.

[0309] In various embodiments, the amount of isopropanol was selected to adjust the weight percent concentration of the free base (compound F) to 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. Subsequently, 201.6 g of a 6% HCl (w / w) solution in isopropanol was added to the reactor over 45 minutes at about 20±2°C. It should be appreciated that in various embodiments, the target amount of HCl is about 10% excess relative to the molar equivalent of the free base (compound F). The first 10% of the hydrochloric acid was added over 15 minutes, the next 30% was added over 15 minutes, and the remaining amount was added over 15 minutes. A 5 L scale reactor with a 160 rpm to 270 rpm retreating curve impeller was used, with a process flow volume of about 740 ml, producing moderately sized particles and particle distribution, with no obvious agglomeration observed. The formed suspension was warmed linearly to 40±2° C. over 20 minutes and held at 40±2° C. for about 30 minutes. It was then cooled linearly to 20±2° C. over 20 minutes. After stirring at 20±2° C. for about 30 minutes, the suspension was filtered and the product cake was washed with isopropanol (first with 86 ml and second with 92 ml). The cake was dried to constant weight under vacuum at 40±2° C. to give (S)-(−)-TPMA hydrochloride (compound G) as a white crystalline solid in about 84% yield.

[0310] In step 4b of Scheme 4, slow addition, i.e., low rate of supersaturation, favors the formation of the desired block (S)-(-)-TPMA HCl crystals (Form A) while reducing the formation of undesirable needles (Form B), and high temperature favors the formation of block-like Form A crystals over Form B.

[0311] The (S)-(-)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride (Compound G) obtained in Example 2 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 + ).

[0312] Figures 21 and 22 show XRPD patterns of Form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride, where Figure 21 is the XRPD measured in transmission mode and Figure 22 is the XRPD measured in reflection mode. Figure 23 is the DSC thermogram of polymorph Form A of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine hydrochloride.

[0313] Various preferred embodiments [A]-[CB] of the present invention can be described in the following text.

[0314] [Embodiment A] A method of treating a neurological or psychiatric disease or disorder without causing a clinically significant risk of an adverse event in a patient in need of treatment who has not previously experienced a clinically significant risk of an adverse event, comprising administering to said patient compound 1: [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0315] [Embodiment B] A method for treating a neurological or psychiatric disease or disorder without causing a clinically significant risk of adverse events in a patient in need of treatment, comprising administering to a patient compound 1: [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0316] [Embodiment C] A method of treating a patient having a neurological or psychiatric disease or disorder without incurring a clinically significant risk of adverse events, comprising administering to the patient Compound 1: [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0317] [Embodiment D] A method of treating schizophrenia in a patient in need of treatment without causing a clinically significant risk of adverse events, comprising administering to said patient compound 1: [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0318] [Embodiment E] A method of treating a patient with schizophrenia without incurring a clinically significant risk of adverse events, comprising administering to a patient compound 1: [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0319] [Embodiment F] A method of treating a neurological or psychiatric disease or disorder in a patient, comprising administering to said patient Compound 1: [ka] 4. A method for minimizing adverse events associated with antipsychotics having affinity for dopamine D2 in a patient, comprising administering to the patient an antipsychotic having affinity for dopamine D2, or a pharma- ceutically acceptable salt thereof.

[0320] [Embodiment G] A method for treating a neurological or psychiatric disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an antipsychotic that has no direct affinity for the dopamine D2 receptor, the method substantially not causing adverse events in the patient that are associated with antipsychotics that have affinity for dopamine D2.

[0321] [Embodiment H] An antipsychotic drug that does not have direct affinity for the dopamine D2 receptor is compound 1. [ka] or a pharma- ceutically acceptable salt thereof.

[0322] [Embodiment I] A method of minimizing adverse events in a patient in need of treatment for a neurological or psychiatric disease or disorder, 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 selected from the group consisting of Compound 1: [ka] or a pharma- ceutically acceptable salt thereof, for minimizing adverse events associated with antipsychotic drugs having affinity for dopamine D2 receptors.

[0323] [Embodiment J] A method according to any one of the above embodiments [A] to [I] or any other embodiment of the present invention, wherein the neurological or psychiatric disease or disorder is schizophrenia.

[0324] [Embodiment K] The method according to embodiment [J] above or any other embodiment of the invention, further comprising treating negative symptoms of schizophrenia.

[0325] [Embodiment L] A method according to any one of the above embodiments [A]-[I] or a method according to other embodiments of the invention, wherein the neurological or psychiatric disease or disorder is schizophrenia spectrum disorder, negative symptoms of schizophrenia, attenuated psychotic syndrome, prodromal schizophrenia, delusional disorder, psychosis, psychotic disorder, mental confusion, 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 states, Lesch-Nyhan disease, Wilson's disease, autism, Alzheimer's agitation and psychosis, or Huntington's chorea.

[0326] [Embodiment M] A method according to any one of embodiments [A]-[J] or [L] above or any other embodiment of the invention, wherein the neurological or psychiatric disease or disorder is selected from schizophrenia, attenuated psychotic syndrome, prodromal schizophrenia, schizoid personality disorder and schizotypal personality disorder.

[0327] [Embodiment N] The method according to embodiment [L] above or any other embodiment of the invention, wherein the psychosis is selected from organic psychosis, drug-induced psychosis, Parkinson's disease psychosis and excited psychosis.

[0328] [Embodiment O] A method according to any one of the above embodiments [A]-[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.

[0329] [Embodiment P] A method according to any one of the above embodiments [A]-[O] or any other embodiment of the invention, wherein Compound 1 or a pharma- ceutically acceptable salt thereof comprises Compound 1 hydrochloride.

[0330] [Embodiment Q] A method according to any one of the above embodiments [A]-[P] or any other embodiment of the invention, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is orally administered.

[0331] [Embodiment R] A method according to any one of the above embodiments [A] to [Q] or any other embodiment of the invention, in which Compound 1, or a pharma- ceutically acceptable salt thereof, is orally administered.

[0332] [Embodiment S] A method according to any one of the above embodiments [A] to [R] or any other embodiment of the invention, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered at about 50 mg or about 75 mg per day.

[0333] [Embodiment T] A method according to any one of the above embodiments [A]-[S] or any other embodiment of the invention, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered daily during a treatment period of 29 days.

[0334] [Embodiment U] A method according to any one of the above embodiments [A]-[S] or any other embodiment of the invention, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered daily during a treatment period of 26 weeks.

[0335] [Embodiment V] A method according to any one of the above embodiments [A] to [U] or other embodiments of the present invention, wherein the risk of an adverse event in the patient is approximately the same or similar to that of a placebo.

[0336] [Embodiment W] A method according to any one of the above embodiments [A] to [V] or any other embodiment of the present invention, which minimizes adverse cardiovascular events.

[0337] [Embodiment X] A method according to any one of the above embodiments [A]-[W] or any other embodiment of the present invention, in which cardiovascular events occur in less than or equal to 5% of patients.

[0338] [Embodiment Y] A method according to any one of the above embodiments [A] to [W] or any other embodiment of the present invention, wherein the patient is at increased risk of adverse cardiovascular events due to administration of an antipsychotic drug.

[0339] [Embodiment Z] The method according to embodiment [T] above or any other embodiment of the invention, wherein less than or equal to 5% of patients experience adverse cardiovascular events during a 29 day treatment period.

[0340] [Embodiment AA] The method according to embodiment [U] above or any other embodiment of the invention, wherein less than or equal to 6% of patients experience adverse cardiovascular events during a 26 week treatment period.

[0341] [Embodiment AB] A method according to any one of the above embodiments [A]-[V] or any other embodiment of the invention, in which the patient experiences adverse cardiovascular events at a rate approximately the same or similar to that of placebo.

[0342] [Embodiment AC] A method according to any one of embodiments [W] to [AB] above or other embodiments of the invention, wherein the cardiovascular adverse event is characterized by atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hypotension, hot flashes, QT prolongation, orthostatic hypotension or orthostatic tachycardia.

[0343] [Embodiment AD] A method according to any one of embodiments [A]-[V] above or any other embodiment of the invention, which minimizes extrapyramidal adverse events.

[0344] [Embodiment AE] A method according to any one of embodiments [A]-[V] or [AD] above or any other embodiment of the invention, in which extrapyramidal adverse events occur in less than or equal to 5% of patients.

[0345] [Embodiment AF] A method according to any one of embodiments [A]-[V] or [AD] above 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.

[0346] [Embodiment AG] A method according to any one of the above embodiments [AD]-[AF] or other embodiments of the invention, wherein the extrapyramidal adverse event is characterized by akathisia, restlessness, joint stiffness, musculoskeletal stiffness, neck stiffness, postural tremor or tremor.

[0347] [Embodiment AH] A method according to any one of the above embodiments [A]-[V] or any other embodiment of the invention, in which patients experience extrapyramidal adverse events at a percentage lower than or equal to placebo.

[0348] [Embodiment AI] A method according to any one of the above embodiments [A] to [V] or any other embodiment of the invention, which does not substantially cause QT prolongation.

[0349] [Embodiment AJ] A method according to any one of embodiments [A]-[V] or [AI] above or any other embodiment of the invention, wherein QT prolongation occurs in less than or equal to 5% of patients.

[0350] [Embodiment AK] A method according to any one of embodiments [A]-[V] or [AI] above or any other embodiment of the invention, wherein the patient is at increased risk of QT prolongation due to administration of an antipsychotic drug.

[0351] [Embodiment AL] A method according to embodiment [T] above or any other embodiment of the invention, which does not cause substantial QT prolongation during the 29 day treatment period.

[0352] [Embodiment AM] A method according to any one of the above embodiments [A]-[V] or any other embodiment of the invention, in which QT prolongation occurs in patients at a percentage lower than placebo.

[0353] [EMBODIMENT AN] The method according to any one of the above embodiments [AI]-[AM] or any other embodiment of the invention, wherein the QT prolongation is characterized by one or both of the following: The patient has a QTcF interval greater than 450 msec at any time that was not present at baseline; and An increase from baseline in QTcF interval of greater than or equal to 30 msec in at least one post-baseline measurement.

[0354] [Embodiment AO] A method according to any one of the above embodiments [A]-[V] or any other embodiment of the invention, which minimizes hyperprolactinemia in a patient.

[0355] [EMBODIMENT AP] A method according to any one of the above embodiments [A]-[V] or any other embodiment of the invention, in which hyperprolactinemia occurs in patients at a percentage lower than placebo.

[0356] [Embodiment AQ] A method according to any one of embodiments [A]-[V] above or any other embodiment of the invention, which minimizes orthostatic hypotension in a patient.

[0357] [EMBODIMENT AR] A method according to any one of the above embodiments [A]-[V] or [AQ] or any other embodiment of the invention, wherein orthostatic hypotension occurs in less than or equal to 5% of patients.

[0358] [Embodiment AS] A method according to any one of embodiments [A]-[V] or [AQ] above or any other embodiment of the invention, wherein the patient is at increased risk of orthostatic hypotension due to administration of an antipsychotic drug.

[0359] [Embodiment AT] A method according to any one of the above embodiments [A]-[V] or any other embodiment of the invention, in which orthostatic hypotension occurs in patients at a percentage lower than placebo.

[0360] [Embodiment AU] A method according to any one of embodiments [A]-[V] above or any other embodiment of the invention, for minimizing orthostatic tachycardia in a patient.

[0361] [Embodiment AV] A method according to any one of embodiments [A]-[V] or [AU] above or any other embodiment of the invention, in which orthostatic tachycardia occurs in less than or equal to 5% of patients.

[0362] [Embodiment AW] A method according to any one of embodiments [A] to [V] or [AU] above or any other embodiment of the invention, wherein the patient is at increased risk of orthostatic tachycardia due to administration of an antipsychotic drug.

[0363] [Embodiment AX] A method according to any one of the above embodiments [A]-[V] or any other embodiment of the invention, in which orthostatic tachycardia occurs in patients at a percentage approximately equal to or similar to that of placebo.

[0364] [Embodiment AY] A method according to any one of embodiments [A] to [AX] above or any other embodiment of the invention, resulting in: (i) a reduction in PANSS total score of at least 17.2 from baseline, or (ii) an effect size in PANSS total score of at least 0.45.

[0365] [EMBODIMENT AZ] The method according to embodiment [AY] above or any other embodiment of the invention, wherein the outcome is measured 29 days after treatment.

[0366] [Embodiment BA] A method according to any one of embodiments [AX] or [AY] above or any other embodiment of the invention, wherein the PANSS total score is reduced from baseline by at least about 30 after 30 days of treatment.

[0367] [Embodiment BB] A method according to any one of embodiments [A] to [BA] above or any other embodiment of the invention, resulting in: (i) a reduction in the PANSS Positive subscale score of at least 5.5 from baseline, or (ii) an effect size for the PANSS Positive subscale score of at least 0.32.

[0368] [Embodiment BC] The method according to embodiment [BB] above or any other embodiment of the invention, wherein the outcome is measured 29 days after treatment.

[0369] [Embodiment BD] A method according to any one of embodiments [BB] or [BC] above or any other embodiment of the invention, which results in a reduction in the PANSS positive subscale score of at least about 10 from baseline after 30 weeks of treatment.

[0370] [Embodiment BE] A method according to any one of embodiments [A] to [BD] above or any other embodiment of the invention, resulting in: (i) a decrease in the PANSS Negative subscale score of at least 3.1 from baseline, or (ii) an effect size for the PANSS Negative subscale score of at least 0.37.

[0371] [Embodiment BF] The method according to embodiment [BE] above or any other embodiment of the invention, wherein the outcome is measured 29 days after treatment.

[0372] [Embodiment BG] A method according to any one of embodiments [BE] or [BF] above or any other embodiment of the invention, which results in a reduction in the PANSS negative subscale score of at least about 5 from baseline after 30 weeks of treatment.

[0373] [Embodiment BH] A method according to any one of embodiments [A] to [BG] above or any other embodiment of the invention, resulting in: (i) a reduction in the PANSS General Psychopathology subscale score of at least 9 from baseline, or (ii) an effect size for the PANSS General Psychopathology subscale score of at least 0.51.

[0374] [Embodiment BI] The method according to embodiment [BH] above or any other embodiment of the invention, wherein the outcome is measured 29 days after treatment.

[0375] [Embodiment BJ] A method according to any one of embodiments [BH] or [BI] above or any other embodiment of the invention, resulting in a reduction in the PANSS general psychopathology subscale score of at least about 15 from baseline after 30 weeks of treatment.

[0376] [Embodiment BK] A method according to any one of embodiments [A] to [BJ] above or any other embodiment of the invention, resulting in: (i) a CGI-S score reduction of at least 1 from baseline, or (ii) an effect size for the CGI-S score of at least 0.52.

[0377] [Embodiment BL] The method according to embodiment [BK] above or any other embodiment of the invention, wherein the outcome is measured 29 days after treatment.

[0378] [Embodiment BM] A ​​method according to any one of embodiments [BK] or [BL] above 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.

[0379] [Embodiment BN] A method according to any one of embodiments [A] to [BM] above or any other embodiment of the invention, which results in: (i) a reduction in BNSS total score of at least 7.1 from baseline, or (ii) an effect size for BNSS total score of at least 0.48.

[0380] [EMBODIMENT BO] The method according to embodiment [BN] above or any other embodiment of the invention, wherein the outcome is measured 29 days after treatment.

[0381] [Embodiment BP] A method according to any one of embodiments [BN] or [BO] above or any other embodiment of the invention, which results in a reduction in BNSS total score from baseline of at least about 10 after 30 weeks of treatment.

[0382] [Embodiment BQ] A method according to any one of embodiments [A] to [BP] above or any other embodiment of the invention, which results in: (i) a reduction in MADRS total score of at least 3.3 from baseline, or (ii) an effect size for MADRS total score of at least 0.32.

[0383] [EMBODIMENT BR] The method according to embodiment [BQ] above or any other embodiment of the invention, wherein the outcome is measured 29 days after treatment.

[0384] [Embodiment BS] A method according to any one of embodiments [BQ] or [BR] above or any other embodiment of the invention, which results in a reduction in MADRS total score from baseline of at least about 5 after 30 weeks of treatment.

[0385] [Embodiment BT] A method according to any one of embodiments [A]-[V] above or any other embodiment of the invention, comprising treating symptoms of insomnia, anxiety or headache in a patient.

[0386] [Embodiment BU] A method according to any one of embodiments [A]-[V] above or any other embodiment of the invention, which minimizes insomnia, anxiety, headaches or any combination thereof in a patient.

[0387] [Embodiment BV] A method according to any one of embodiments [BT] or [BU] above or any other embodiment of the invention, wherein the risk of insomnia, anxiety, headache or any combination thereof in a patient is lower than placebo.

[0388] [Embodiment BW] A method according to any one of the above embodiments [A]-[BV] or any other embodiment of the invention, comprising administering to a patient an initial dose of Compound 1, or a pharma- ceutically acceptable salt thereof, daily for 1 to 3 days, followed by daily administration of a therapeutic amount of Compound 1, or a pharma- ceutically acceptable salt thereof, wherein the initial dose is sub-therapeutic, and the neurological or psychiatric disease or disorder is schizophrenia.

[0389] [Embodiment BX] A method according to any one of the above embodiments [A]-[BW] or any other embodiment of the invention, wherein Compound 1 or a pharma- ceutically acceptable salt thereof is administered daily at an initial dose on days 1-3, and Compound 1 or a pharma- ceutically acceptable salt thereof is administered daily at a therapeutic dose on days 4-29.

[0390] [EMBODIMENT BY] A method according to any one of the above embodiments [BW] or [BX] or any other embodiment of the invention, wherein the initial dose is 50 mg and the therapeutic dose is 75 mg.

[0391] [Embodiment BZ] A method of treating schizophrenia in a patient, comprising: During the treatment period, patients were administered Compound 1 [ka] or a pharma- ceutical acceptable salt thereof, 75 mg orally per day; Determined or determined whether the patient experienced any adverse events during treatment; and If the patient experiences an adverse event during treatment, reducing or decreasing Compound 1, or a pharma- ceutically acceptable salt thereof, to 50 mg per day. Including

[0392] [Embodiment CA] A method for treating symptoms of insomnia, anxiety or headache in a patient with schizophrenia, comprising administering to said patient compound 1. [ka] or a pharma- ceutically acceptable salt thereof to said patient.

[0393] [Embodiment CB] A method according to any one of the above embodiments [A] to [CA] or any other embodiment of the present invention, wherein Compound 1 or a pharma- ceutically acceptable salt thereof is Type A crystal of Compound 1 hydrochloride.

[0394] In addition to those described herein, various modifications of the present invention will become 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. Compound 1 for use in the treatment of a neurological or psychiatric disease or disorder to minimize the risk of a clinically significant adverse cardiovascular event in a patient in need of such treatment: 【Chemistry 1】 or a pharma- ceutical acceptable salt thereof, A pharmaceutical composition adapted for administration to a patient of a therapeutically effective amount of Compound 1 or a pharma- ceutical acceptable salt thereof, wherein the clinically significant cardiovascular adverse event is atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hot flashes, QT prolongation, or orthostatic tachycardia.

2. The pharmaceutical composition of claim 1, wherein the serious cardiovascular adverse event is QT prolongation.

3. Compound 1 for use in treating a patient with a neurological or psychiatric disease or disorder to minimize cardiovascular adverse events commonly known to be associated with antipsychotics having affinity for dopamine D2: 【Chemistry 2】 or a pharma- ceutical acceptable salt thereof, A pharmaceutical composition adapted for administration to a patient of a therapeutically effective amount of Compound 1 or a pharma- ceutical acceptable salt thereof, wherein the cardiovascular adverse event is atrial tachycardia, bradycardia, cardiovascular insufficiency, palpitations, orthostatic tachycardia syndrome, elevated blood pressure, hypertension, hot flashes, QT prolongation, or orthostatic tachycardia.

4. The pharmaceutical composition of claim 3, wherein the serious cardiovascular adverse event is QT prolongation.

5. 4. The pharmaceutical composition of claim 1 or 3, wherein the neurological or psychiatric disease or disorder is schizophrenia.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the neurological or psychiatric disease or disorder is schizophrenia spectrum disorder, negative symptoms of schizophrenia, attenuated psychotic syndrome, prodromal schizophrenia, delusional disorder, psychosis, psychotic disorder, mental confusion, 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, Alzheimer's disease agitation and psychosis, or Huntington's chorea.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the neurological or psychiatric disease or disorder is selected from schizophrenia, attenuated psychotic syndrome, prodromal schizophrenia, schizoid personality disorder and schizophrenic personality disorder.

8. 8. The pharmaceutical composition of claim 7, wherein the psychosis is selected from organic psychosis, drug-induced psychosis, Parkinson's disease psychosis and agitated psychosis.

9. 9. The pharmaceutical composition of any of claims 1 to 8, wherein compound 1 or a pharma- ceutically acceptable salt thereof comprises an HCl salt of compound 1.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, which, upon use, results in cardiovascular adverse events in patients at rates approximately the same or similar to those of a placebo.

Images