CN117580576A

CN117580576A - Use of LUVADAXISTAT for treating cognitive impairment

Info

Publication number: CN117580576A
Application number: CN202280032006.XA
Authority: CN
Inventors: 纳加·文卡特沙·穆尔西·帕特希·贾甘纳塔姆; 布莱恩·哈里尔; 尼古拉斯·德马蒂尼斯; 爱德华多·杜纳耶夫奇; 帕特里西奥·奥唐纳尔; 托马斯·A·梅斯克; 萨吉特·辛格·布拉尔; 毛拉·L·富瑞; 葛婷婷; 贾斯卡兰·B·辛格
Original assignee: Takeda Pharmaceutical Co Ltd; Neurocrine Biosciences Inc
Current assignee: Takeda Pharmaceutical Co Ltd; Neurocrine Biosciences Inc
Priority date: 2021-03-01
Filing date: 2022-02-28
Publication date: 2024-02-20

Abstract

Disclosed are methods of treating at least one cognitive symptom, such as at least one cognitive symptom associated with schizophrenia, comprising administering at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereofIs a compound of (a). Also disclosed are methods of increasing D-serine levels, synaptic plasticity and/or long term potentiation comprising administering at least one compound selected from the group consisting of compound (I) and a pharmaceutically acceptable salt thereof.

Description

Use of LUVADAXISTAT for treating cognitive impairment

The present application claims U.S. provisional application No. 63/200,327 filed on day 1, 3, 2021; U.S. provisional application No. 63/229,945 filed on 8.2021; U.S. provisional application No. 63/264,747 filed on 1/12/2021; priority of U.S. provisional application No. 63/265,628 filed on 12 months 17 of 2021, the respective contents of which are incorporated herein by reference in their entirety.

Disclosed herein are methods of treating cognitive impairment in a patient in need thereof. Also disclosed are methods of treating at least one cognitive symptom (e.g., at least one cognitive symptom associated with schizophrenia) in a patient in need thereof, as well as methods of increasing synaptic plasticity and/or long-term potentiation in a patient in need thereof.

Schizophrenia is a severe mental disorder that affects approximately 1% of the population, with a lifetime prevalence estimated at 5.6 to 11.9 per 1000. Schizophrenia is characterized by psychosis, cognitive impairment and/or social and motivational deficits. For example, schizophrenia may be characterized by positive symptoms (e.g., hallucinations or delusions), negative symptoms (e.g., anorgasmia, hypovolemia, emotional dullness, spontaneous speech decline, and social withdrawal), and/or Cognitive Impairment (CIAS) associated with schizophrenia. Cognitive symptoms of schizophrenia affect a wide range of areas including, but not limited to, attention, working memory, and/or executive function. While positive symptoms of schizophrenia tend to recur and alleviate, in today's environment, negative and cognitive symptoms of schizophrenia are often chronic and affect social functions in those suffering from them, reflecting the limited current knowledge of the symptomatic progression and available treatments.

Although negative symptoms and cognitive symptoms are highly predictive of quality of life and functional recovery, there is no approved treatment for cognitive impairment associated with schizophrenia. Thus, there is a need for new treatments for cognitive impairment, including those associated with schizophrenia.

D-amino acid oxidase (DAAO) is a peroxisome enzyme that degrades neutral D-amino acids, such as D-serine, which is an N-methyl-D-aspartate (NMDA) receptor co-agonist. Along with glutamate, D-serine mediates NMDA receptor transmission, synaptic plasticity and other physiological functions. Furthermore, D-serine is an endogenous ligand for the delta (δ) 2 glutamate receptor (glurδ2), which has been implicated in synaptic plasticity and long-term inhibition.

Thus, DAAO inhibitors are useful in treating cognitive impairment, including treating cognitive symptoms associated with schizophrenia and other psychotic disorders (e.g., psychotic disorders) and neurological disorders.

Compound (I) is a DAAO inhibitor having the structure:

see PCT publication No. WO 2013/027000, incorporated herein by reference, e.g., example 36. Compound (I) is also known as luvadaxistat, TAK-831 and NBI-1065844.

Disclosed herein are methods for treating cognitive impairment associated with schizophrenia in a patient in need thereof, the methods comprising administering to the patient from 1mg to 500mg (e.g., 1mg to 100 mg) of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily, wherein at least one cognitive symptom/cognitive domain associated with schizophrenia in the patient is treated by the administration.

Also disclosed herein is at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof for use in a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof, the method comprising administering to the patient from 1mg to 500mg (e.g., from 1mg to 100 mg) of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof per each time, wherein at least one cognitive symptom associated with schizophrenia in the patient is treated by the administration.

Also disclosed herein is the use of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof, the method comprising administering to the patient from 1mg to 500mg (e.g., from 1mg to 100 mg) of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof per day, wherein at least one cognitive symptom associated with schizophrenia in the patient is treated by the administration.

In some embodiments, the method comprises:

administering to the patient 1mg to 500mg (e.g., 1mg to 100mg, 10mg to 50mg, 20mg to 50mg, 25mg to 50mg, 20mg or 50mg, 20mg, 50 mg) of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily for 6 to 8 days;

Determining or having determined whether said 6 to 8 days of administration improves at least one biomarker selected from the group consisting of blink conditional reflex (EBC) response of said patient, mismatching negative wave (MMN) amplitude of said patient, and Auditory Steady State Response (ASSR) gamma band power of said patient; and

continuing to administer to the patient 1mg to 500mg (e.g., 1mg to 100mg;20mg to 50mg;20mg or 50mg;20mg;50 mg) of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof per each time if the 6 to 8 days of administration improves at least one biomarker.

In some embodiments, the at least one cognitive symptom associated with schizophrenia is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function. In some embodiments, the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

In some embodiments, the administering improves the patient's blink conditioned reflex (EBC) response. In some embodiments, the administering improves the patient's mismatching negative wave (MMN) amplitude. In some embodiments, the administering improves Auditory Steady State Response (ASSR) gamma band power of the patient.

In some embodiments, the administration increases D-serine levels in the patient.

In some embodiments, the administration improves performance on cognitive measurements of the patient. In some embodiments, the administration improves performance on cognitive domain measurements in the patient. In some embodiments, the administration improves the overall score on cognitive measures of the patient.

In some embodiments, the administration improves the patient's BACS synthesis score relative to a concise set of assessment of cognitive function (BACS) score measured on the patient prior to the administration. In some embodiments, the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administration. In some embodiments, the administration improves the patient's CPT-IP test relative to the patient's performance on a continuous operation test-same pair (CPT-IP) test prior to the administration. In some embodiments, the administration improves the patient's performance on the BVMT-R test relative to the patient's performance on a simple visual space memory test-revised (BVMT-R) test prior to the administration. In some embodiments, the administration improves the patient's performance on MSCEIT relative to the patient's performance on Mayer-saloviy-caroso mental quiz (MSCEIT) prior to the administration. In some embodiments, the administering improves the patient's performance on a Virtual Reality Function Capability Assessment Tool (VRFCAT) relative to the patient's performance on the VRFCAT prior to the administering. In some embodiments, the administration improves the patient' S CGI-S score relative to a clinical overall impression-severity scale (CGI-S) score measured on the patient prior to the administration.

In some embodiments, the patient has at least one stable negative symptom associated with schizophrenia prior to the administration. In some embodiments, the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the administration. In some embodiments, the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact. In some embodiments, the stability of the at least one stable negative symptom associated with schizophrenia is assessed/measured using the positive and negative symptom scale (PANSS). In some embodiments, the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

In some embodiments, the patient does not exhibit any depression or extrapyramidal symptoms prior to the administration. In some embodiments, the patient is administered a stable antipsychotic drug therapy at a dose of risperidone equivalent of 2-6mg prior to the administration.

In some embodiments, any negative symptoms associated with schizophrenia in the patient after the administration are not statistically significantly improved.

In some embodiments, the administration does not treat at least one negative symptom associated with schizophrenia. In some embodiments, the at least one negative symptom associated with schizophrenia is measured according to the positive and negative symptom scale (PANSS).

In some embodiments, the at least one compound is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient. In some embodiments, the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of pleasure, loss of motivation, and reduced social interest.

In some embodiments, the at least one additional therapeutic agent is a hypnotic. In some embodiments, the at least one additional therapeutic agent is selected from the group consisting of aripiprazole, olanzapine, risperidone, and quetiapine fumarate.

In some embodiments, the at least one compound is administered to the patient for more than 14 weeks. In some embodiments, the at least one compound is administered to the patient for more than 20 weeks.

In some embodiments, 20mg to 50mg of the at least one compound is administered to the patient once daily. In some embodiments, 20mg of the at least one compound is administered to the patient once daily. In some embodiments, 50mg of the at least one compound is administered to the patient per each time.

In some embodiments, 20mg of the at least one compound is administered to the patient once daily, followed by 50mg of the at least one compound to the patient once daily. In some embodiments, 20mg of the at least one compound is administered to the patient once daily for 14 weeks, followed by 50mg of the at least one compound administered to the patient once daily. In some embodiments, 20mg of the at least one compound is administered to the patient once daily for 14 weeks, and then 50mg of the at least one compound is administered to the patient once daily for 54 weeks.

In some embodiments, the at least one compound is administered orally. In some embodiments, the at least one compound is administered in the form of at least one tablet. In some embodiments, the at least one compound is administered in the form of at least one film coated tablet. In some embodiments, the at least one compound is administered in the form of two film coated tablets.

In some embodiments, the at least one compound is administered in the morning. In some embodiments, the at least one compound is administered with water or milk.

In some embodiments, the patient does not consume juice within 1 hour prior to administration or 1 hour after administration.

In some embodiments, the patient is diagnosed with schizophrenia at least one year prior to the administration. In some embodiments, the patient is diagnosed with schizophrenia as defined by the manual for diagnosis and statistics of mental disorders (DSM-5). In some embodiments, the patient is diagnosed with schizophrenia as defined by MINI version 7.0.2.

In some embodiments, the patient is in a stable regime of a psychotropic drug. In some embodiments, the patient is in a psychotropic regimen, wherein the psychotropic dose is not increased at least 2 months prior to the administration. In some embodiments, the patient is in a psychotropic regimen, wherein the psychotropic dose is reduced by no more than 25% at least 2 months prior to administration.

In some embodiments, the patient has stable symptomatology for at least 3 months prior to the administering.

In some embodiments, the patient is diagnosed with schizophrenia after 12 years of age. In some embodiments, the patient has not received a lifetime diagnosis of schizoaffective disorder, a lifetime diagnosis of bipolar disorder, or a lifetime diagnosis of obsessive compulsive disorder. In some embodiments, the patient does not have depression prior to administration. In some embodiments, the patient does not have depression as measured by the calori schizophrenia score depression scale (CDSS) prior to administration.

Also disclosed herein is a method of treating at least one cognitive symptom associated with schizophrenia in a patient, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptom projects P1, P3, P4, P5, P6), the method comprising administering to the patient 1mg to 500mg (e.g., 1mg to 100 mg) of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily, wherein at least one cognitive symptom associated with schizophrenia in the patient is treated by the administration.

Also disclosed herein is at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof for use in a method of treating at least one cognitive symptom associated with schizophrenia in a patient, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (P1 (delusions), P3 (hallucinogenic behaviors), P4 (excitement), P5 (exaggeration) and/or P6 (suspicion) <5 grade), the method comprising administering 1mg to 500mg (e.g., 1mg to 100 mg) of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof to the patient once daily.

Also disclosed herein is the use of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in a method of treating at least one cognitive symptom associated with schizophrenia in a patient having no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1, P3, P4, P5, P6 <5 grade), the method comprising administering to the patient 1mg to 500mg (e.g., 1mg to 100 mg) of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily.

In some embodiments, the method comprises:

Continuing to administer to the patient at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof, once daily, if the 6 to 8 days administration improves at least one biomarker, from 1mg to 500mg (e.g., from 1mg to 100mg, 10mg to 50mg, 20mg to 50mg, 25mg to 50mg, 20mg or 50mg, 20mg, 50 mg).

In some embodiments, the administration does not treat at least one negative symptom associated with schizophrenia.

In some embodiments, the patient does not exhibit any depression or extrapyramidal symptoms prior to the administration. In some embodiments, the patient is administered a stable antipsychotic drug therapy at a daily dose of risperidone equivalent of 2-6mg prior to the administration.

In some embodiments, 20mg to 50mg of the at least one compound is administered to the patient once daily. In some embodiments, 20mg of the at least one compound is administered to the patient once daily. In some embodiments, 50mg of the at least one compound is administered to the patient once daily.

In some embodiments, 20mg of the at least one compound is administered to the patient once per day, followed by 50mg of the at least one compound administered to the patient once daily. In some embodiments, 20mg of the at least one compound is administered to the patient once daily for 14 weeks, followed by 50mg of the at least one compound per minute to the patient. In some embodiments, 20mg of the at least one compound is administered to the patient once per day for 14 weeks, and then 50mg of the at least one compound is administered to the patient once daily for 54 weeks.

In some embodiments, the at least one compound is administered in combination with at least one additional active agent. In some embodiments, the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient. In some embodiments, the at least one additional active agent treats a behavioral problem associated with at least one negative symptom of schizophrenia in the patient. In some embodiments, the severity of the at least one symptom is measured according to the positive and negative symptom scale (PANSS).

In some embodiments, the at least one negative symptom associated with schizophrenia is a motor deficit syndrome. In some embodiments, the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of pleasure, flat emotion, loss of motivation, reduced energy, social withdrawal, and reduced interest in social contact.

Also disclosed herein is a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof, comprising administering to the patient 1mg to 500mug of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof per minute, wherein at least one cognitive symptom/cognitive domain associated with schizophrenia in the patient is treated by the administration. In some embodiments, the at least one cognitive symptom/cognitive domain associated with schizophrenia is expressed by a broad range of cognitive dysfunction. In some embodiments, the at least one cognitive symptom/domain associated with schizophrenia is poor information processing, impaired ability to focus on targets, abnormalities in working memory and learning, or any combination thereof.

Also disclosed herein is at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof for use in a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof, the method comprising administering to the patient from 50mg to 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof per each time, wherein at least one cognitive symptom/cognitive domain associated with schizophrenia in the patient is treated by the administration.

Also disclosed herein is the use of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof, the method comprising administering to the patient from 50mg to 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof once daily, wherein at least one cognitive symptom/domain associated with schizophrenia in the patient is treated by said administration.

In some embodiments, the method comprises:

administering to the patient 50 to 500mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily for 6 to 8 days;

if the 6 to 8 days of administration improves at least one biomarker, continuing to administer to the patient 50 to 500mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily.

In some embodiments, the patient has at least one stable negative symptom associated with schizophrenia prior to the administration. In some embodiments, the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the administration. In some embodiments, the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact. In some embodiments, the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a PANSS assessment. In some embodiments, the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

In some embodiments, 50mg of the at least one compound is administered to the patient once daily. In some embodiments, 125mg of the at least one compound is administered to the patient once daily. In some embodiments, 500mg of the at least one compound is administered to the patient once per patient. In some embodiments, less than 500mg of the at least one compound is administered to the patient once daily.

In some embodiments, the at least one compound is administered in the form of at least one film coated tablet. In some embodiments, the at least one compound is administered in the form of two film coated tablets.

Also disclosed herein is a method of treating at least one cognitive symptom associated with schizophrenia in a patient, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptom projects P1, P3, P4, P5, P6), comprising administering to the patient 1mg to 500mg once daily of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof, wherein at least one cognitive symptom associated with schizophrenia in the patient is treated by the administration.

Also disclosed herein is at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof for use in a method for treating at least one cognitive symptom associated with schizophrenia in a patient, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1, P3, P4, P5, P6 <5 grade), the method comprising administering to the patient 50mg to 500mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily.

Also disclosed herein is the use of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in a method of treating at least one cognitive symptom associated with schizophrenia in a patient having no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1, P3, P4, P5, P6 <5 grade), the method comprising administering to the patient 50mg to 500mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily.

In some embodiments, the method comprises:

Also disclosed herein are methods of treating cognitive impairment in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof, wherein the patient exhibits at least one cognitive symptom prior to the administration.

Also disclosed herein is a method for treating cognitive impairment in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound selected from compound (I) and a pharmaceutically acceptable salt thereof, wherein the patient exhibits at least one cognitive symptom prior to the administration.

Also disclosed herein is the use of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in a method of treating cognitive impairment in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof, wherein the patient exhibits at least one cognitive symptom prior to the administration.

In some embodiments, the method comprises:

administering to said patient a therapeutically effective amount of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof, once per each time, for 6 to 8 days;

continuing to administer a therapeutically effective amount of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof once daily to said patient if said 6 to 8 day administration improves at least one biomarker.

In some embodiments, the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function. In some embodiments, the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

In some embodiments, the administering treats the at least one cognitive symptom.

In some embodiments, the at least one cognitive symptom is associated with a psychotic disorder. In some embodiments, the psychotic disorder is selected from psychosis, schizophreniform disorder, schizoaffective disorder, and schizophreniform disorder unrelated to aggression. In some embodiments, the psychotic disorder is a schizophreniform disorder, schizoaffective disorder, and schizophrenic disorder unrelated to aggression. In some embodiments, the psychotic disorder is schizophrenia unrelated to aggression.

In some embodiments, the patient has dementia. In some embodiments, the patient has a mood disorder.

In some embodiments, the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium. In some embodiments, the patient has a disease selected from the group consisting of: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

In some embodiments, 1mg to 100mg of the at least one compound is administered to the patient per each time. In some embodiments, 20mg to 50mg of the at least one compound is administered to the patient per each time. In some embodiments, 20mug of the at least one compound is administered to the patient per each time. In some embodiments, 50mg of the at least one compound is administered to the patient once daily. In some embodiments, 20mg or 50mg of the at least one compound is administered to the patient once daily.

In some embodiments, 50mg to 500mg of the at least one compound is administered to the patient once daily. In some embodiments, 125mg of the at least one compound is administered to the patient once daily. In some embodiments, 500mg of the at least one compound is administered to the patient once daily. In some embodiments, less than 500mg of the at least one compound is administered to the patient once daily.

Also disclosed herein are methods of increasing D-serine levels in a patient in need thereof, comprising administering to the patient less than 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof once daily.

Also disclosed herein is at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof for use in a method of increasing D-serine levels in a patient in need thereof, the method comprising administering less than 500mg of the at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof per each time to the patient.

Also disclosed herein is the use of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in a method of increasing D-serine levels in a patient in need thereof, the method comprising administering to the patient less than 500mg of the at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof once daily.

In some embodiments, 20mg of the at least one compound is administered to the patient once daily. In some embodiments, 50mug of the at least one compound is administered to the patient once daily. In some embodiments, 125mg of the at least one compound is administered to the patient once per patient.

In some embodiments, 1mg to 100mg of the at least one compound is administered to the patient per each time. In some embodiments, 20mg to 50mg of the at least one compound is administered to the patient per each time.

In some embodiments, 20mg or 50mg of the at least one compound is administered to the patient once daily.

In some embodiments, 20mg of the at least one compound is administered to the patient once per day, followed by 50mg of the at least one compound per time to the patient. In some embodiments, 20mug of the at least one compound is administered to the patient once daily for 14 weeks, followed by 50mg of the at least one compound per day to the patient. In some embodiments, 20mg of the at least one compound is administered to the patient once daily for 14 weeks, and then 50mg of the at least one compound is administered to the patient once daily for 54 weeks.

In some embodiments, the patient exhibits at least one cognitive symptom prior to administration.

In some embodiments, the at least one compound is administered in combination with at least one additional active agent. In some embodiments, the at least one additional therapeutic agent is a hypnotic. In some embodiments, the at least one additional therapeutic agent is selected from the group consisting of aripiprazole, olanzapine, risperidone, and quetiapine fumarate.

In some embodiments, the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

Also disclosed herein are methods of increasing long-term potentiation in a patient in need thereof, the method comprising administering to the patient less than 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof once daily.

Also disclosed herein is at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof for use in a method for increasing long-term potentiation in a patient in need thereof, the method comprising administering less than 500mg of the at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof to the patient once daily.

Also disclosed herein is the use of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof in the preparation of a medicament for use in a method of increasing long-term potentiation in a patient in need thereof, the method comprising administering less than 500mg of the at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof to the patient once per each.

In some embodiments, 20mg of the at least one compound is administered to the patient once daily. In some embodiments, 50mg of the at least one compound is administered to the patient once daily. In some embodiments, 125mg of the at least one compound is administered to the patient once daily.

In some embodiments, 1mg to 100mg of the at least one compound is administered to the patient once daily. In some embodiments, 20mg to 50mg of the at least one compound is administered to the patient once daily.

In some embodiments, 20rmg of the at least one compound is administered to the patient once per day, followed by 50mg of the at least one compound per day to the patient. In some embodiments, 20mug of the at least one compound is administered to the patient once daily for 14 weeks, followed by 50mg of the at least one compound per day to the patient. In some embodiments, 20mg of the at least one compound is administered to the patient once per each for 14 weeks, and then 50mg of the at least one compound is administered to the patient once per each for 54 weeks.

Also disclosed herein are methods of increasing synaptic plasticity in a patient in need thereof, comprising administering to the patient less than 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof per each time.

Also disclosed herein is at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof for use in a method of increasing synaptic plasticity in a patient in need thereof, the method comprising administering less than 500mg of the at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof per each time to the patient.

Also disclosed herein is the use of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in a method of increasing synaptic plasticity in a patient in need thereof, the method comprising administering less than 500mg of the at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof per each time to the patient.

In some embodiments, 20mg of the at least one compound is administered to the patient once daily. In some embodiments, 50mg of the at least one compound is administered to the patient once daily. In some embodiments, 125mg of the at least one compound is administered to the patient once per patient.

In some embodiments, 20mg or 50mg of the at least one compound is administered to the patient once per each.

In some embodiments, 20mg of the at least one compound is administered to the patient once daily, followed by 50rmg of the at least one compound per each time to the patient. In some embodiments, 20mg of the at least one compound is administered to the patient once daily for 14 weeks, followed by 50rmg of the at least one compound administered to the patient once daily. In some embodiments, 20mg of the at least one compound is administered to the patient once daily for 14 weeks, and then 50mg of the at least one compound is administered to the patient once daily for 54 weeks.

In some embodiments, the patient does not consume juice within 1 hour before or after administration.

In some embodiments, the administration increases the long-term potentiation of the patient.

It is to be understood that references herein to a method of treatment (e.g., a method of treating cognitive impairment) using at least one compound selected from the group consisting of compound (I) and a pharmaceutically acceptable salt are also to be construed as references to: -at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts for use in a method of treating, for example, cognitive impairment; and/or

-use of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of, for example, cognitive impairment.

Non-limiting example embodiment 1:

without limitation, some embodiments of the present disclosure include:

1. a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof, comprising administering to the patient from 50mg to 500mg once daily of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

wherein at least one cognitive symptom associated with schizophrenia in said patient is treated by said administering.

2. The method of treating cognitive impairment associated with schizophrenia according to embodiment 1, wherein the at least one cognitive symptom associated with schizophrenia is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency and impaired executive function.

3. The method of treating cognitive impairment associated with schizophrenia according to embodiment 1 or 2, wherein the administration improves the patient's cognitive function conciseness kit assessment (BACS) score of synthesis relative to the BACS score of synthesis measured on the patient prior to the administration.

4. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 3, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function and impaired social cognition.

5. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 4, wherein the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administration.

6. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 5, wherein the patient has at least one stable negative symptom associated with schizophrenia prior to the administration.

7. The method of treating cognitive impairment associated with schizophrenia according to embodiment 6, wherein the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social interaction.

8. The method of treating cognitive impairment associated with schizophrenia according to embodiment 6, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using PANSS.

9. The method of treating cognitive impairment associated with schizophrenia according to embodiment 6 or 7, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

10. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 6 to 9, wherein the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the administration.

11. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 5, wherein any negative symptoms associated with schizophrenia in the patient are not statistically significantly improved following the administration.

12. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 11, wherein the at least one compound is administered in combination with at least one additional active agent.

13. The method of treating cognitive impairment associated with schizophrenia according to embodiment 12, wherein the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient.

14. The method of treating cognitive impairment associated with schizophrenia according to embodiment 13, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

15. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 14, wherein the at least one compound is administered to the patient for more than 14 weeks.

16. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 15, wherein the at least one compound is administered to the patient for more than 20 weeks.

17. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 16, wherein 50mg of the at least one compound is administered to the patient once daily.

18. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 16, wherein 125mg of the at least one compound is administered once daily to the patient.

19. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 16, wherein 500mg of the at least one compound is administered to the patient once per patient.

20. A method of treating cognitive impairment in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound selected from the group consisting of compound (I):

wherein the patient exhibits at least one cognitive symptom prior to the administration.

21. The method of treating cognitive impairment according to embodiment 20, wherein the at least one cognitive symptom is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

22. The method of treating cognitive impairment according to embodiment 20 or 21, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution, impaired working memory, impaired processing speed, impaired language function and impaired social cognition.

23. The method of treating cognitive impairment according to any one of embodiments 20 to 22, wherein the administering treats the at least one cognitive symptom.

24. The method of treating cognitive impairment according to any one of embodiments 20 to 23 wherein the at least one cognitive symptom is associated with a psychotic disorder.

25. The method of treating cognitive impairment according to embodiment 24, wherein the psychotic disorder is selected from the group consisting of psychosis, schizophreniform disorder, schizoaffective disorder, and schizophreniform unrelated to aggression.

26. The method of treating cognitive impairment according to embodiment 24 or 25, wherein the psychotic disorder is a schizophreniform disorder, a schizoaffective disorder, and schizophrenic disorder unrelated to aggression.

27. The method of treating cognitive impairment according to any one of embodiments 24 to 26, wherein the psychotic disorder is schizophrenia unrelated to aggression.

28. The method of treating cognitive impairment according to any one of embodiments 20 to 23 wherein the at least one cognitive symptom is associated with: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

29. The method of treating cognitive impairment according to any one of embodiments 20 to 23 wherein the at least one cognitive symptom is associated with: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

30. The method of treating cognitive impairment according to any one of embodiments 20 to 29, wherein 50mg to 500mg of the at least one compound is administered to the patient per each time.

31. The method of treating cognitive impairment according to any one of embodiments 20 to 30, wherein the at least one compound is administered in combination with at least one additional active agent.

32. The method of treating cognitive impairment of embodiment 31, wherein the patient suffers from schizophrenia and the at least one additional active agent treats at least one negative symptom in the patient.

33. The method of treating cognitive impairment according to embodiment 32, wherein the at least one negative symptom is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

34. The method of treating cognitive impairment according to any one of embodiments 20 to 33, wherein the patient has at least one stable negative symptom selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact prior to the administering.

35. The method of treating cognitive impairment according to any one of embodiments 1 to 34 wherein the at least one compound is administered in the form of at least one film-coated tablet.

36. A method of treating at least one cognitive symptom associated with schizophrenia in a patient, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptom projects P1, P3, P4, P5, P6), comprising administering to the patient 50mg to 500mg once daily of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof:

37. The method of treating at least one cognitive symptom associated with schizophrenia according to embodiment 36, wherein the administration improves the patient's cognitive function conciseness kit assessment (BACS) score of synthesis relative to a BACS score of synthesis measured on the patient prior to the administration.

38. The method of treating at least one cognitive symptom associated with schizophrenia according to embodiment 36 or 37, wherein the administering improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administering.

39. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of embodiments 36-38, wherein any negative symptom associated with schizophrenia in the patient is not statistically significantly improved following the administration.

40. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of embodiments 36-39, wherein the administering does not treat at least one negative symptom associated with schizophrenia.

41. The method of treating at least one cognitive symptom associated with schizophrenia according to embodiment 40, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

42. The method of treating cognitive impairment associated with schizophrenia according to any one of embodiments 1 to 19, wherein the administration does not treat at least one negative symptom associated with schizophrenia.

43. The method of treating at least one cognitive symptom associated with schizophrenia according to embodiment 42, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

44. A pharmaceutical composition for use in treating cognitive impairment associated with schizophrenia in a patient in need thereof, wherein:

the pharmaceutical composition comprises 50mg to 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

the pharmaceutical composition is administered once daily; and

at least one cognitive symptom associated with schizophrenia in a patient is treated by said use.

45. The pharmaceutical composition for the use according to embodiment 44, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

46. The pharmaceutical composition for use according to embodiment 44 or 45, wherein the use improves the patient's cognitive function conciseness kit assessment (BACS) score of synthesis relative to the BACS score of synthesis measured on the patient prior to the use.

47. The pharmaceutical composition for the use according to any one of embodiments 44 to 46, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function and impaired social cognition.

48. The pharmaceutical composition for the use according to any one of embodiments 44-47, wherein the use improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the SCoRS interviewer score measured on the patient prior to the use.

49. The pharmaceutical composition for the use according to any one of embodiments 44 to 48, wherein the patient has at least one stable negative symptom associated with schizophrenia prior to the use.

50. The pharmaceutical composition for the use according to embodiment 49, wherein the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

51. The pharmaceutical composition for the use according to embodiment 49, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using PANSS.

52. The pharmaceutical composition for use according to embodiment 49 or 50, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

53. The pharmaceutical composition for the use according to any one of embodiments 49 to 52, wherein the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the use.

54. The pharmaceutical composition for the use according to any one of embodiments 44 to 48, wherein any negative symptoms associated with schizophrenia in the patient after the use are not statistically significantly improved.

55. The pharmaceutical composition for the use according to any one of embodiments 44 to 54, wherein the pharmaceutical composition is for use in combination with at least one additional active agent.

56. The pharmaceutical composition for the use according to embodiment 55, wherein the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient.

57. The pharmaceutical composition for the use according to embodiment 56, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

58. The pharmaceutical composition for the use according to any one of embodiments 44 to 57, wherein the pharmaceutical composition is for the use for more than 14 weeks.

59. The pharmaceutical composition for the use according to any one of embodiments 44 to 58, wherein the pharmaceutical composition is for the use for more than 20 weeks.

60. The pharmaceutical composition for the use according to any one of embodiments 44 to 59, wherein the pharmaceutical composition comprises 50mg of the at least one compound.

61. The pharmaceutical composition for the use according to any one of embodiments 44 to 59, wherein the pharmaceutical composition comprises 125mg of the at least one compound.

62. The pharmaceutical composition for the use according to any one of embodiments 44 to 59, wherein the pharmaceutical composition comprises 500mg of the at least one compound.

63. The pharmaceutical composition for the use according to any one of embodiments 44 to 62, wherein the use does not treat a negative symptom associated with schizophrenia.

64. The pharmaceutical composition for the use according to embodiment 63, wherein the at least one negative symptom associated with schizophrenia prior to the administration is selected from the group consisting of absence of hedonia, loss of motivation, and reduced interest in social contact.

65. A pharmaceutical composition for use in treating cognitive impairment in a patient in need thereof, wherein:

The pharmaceutical composition comprises a therapeutically effective amount of at least one compound selected from the group consisting of compound (I):

and is also provided with

The patient exhibits at least one cognitive symptom prior to use.

66. The pharmaceutical composition for the use according to embodiment 65, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

67. The pharmaceutical composition for the use according to embodiment 65 or 66, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

68. The pharmaceutical composition for the use according to any one of embodiments 65 to 67, wherein the use treats the at least one cognitive symptom.

69. The pharmaceutical composition for the use according to any one of embodiments 65 to 68, wherein the at least one cognitive symptom is associated with a psychotic disorder.

70. The pharmaceutical composition for the use according to embodiment 69, wherein the psychotic disorder is selected from psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder unrelated to aggression.

71. The pharmaceutical composition for the use according to embodiment 69 or 70, wherein the psychotic disorder is a schizophreniform disorder, schizoaffective disorder, and schizophrenic disorder unrelated to aggression.

72. The pharmaceutical composition for the use according to any one of embodiments 69 to 71, wherein the psychotic disorder is schizophrenia unrelated to aggression.

73. The pharmaceutical composition for the use according to any one of embodiments 65 to 68, wherein the at least one cognitive symptom is associated with: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

74. The pharmaceutical composition for the use according to any one of embodiments 65 to 68, wherein the at least one cognitive symptom is associated with: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

75. The pharmaceutical composition for the use according to any one of embodiments 65 to 74, wherein:

the pharmaceutical composition comprises 50mg to 500mg of the at least one compound;

the pharmaceutical composition is used once every day.

76. The pharmaceutical composition for the use according to any one of embodiments 65 to 75, wherein the pharmaceutical composition is for use in combination with at least one additional active agent.

77. The pharmaceutical composition for use according to embodiment 76, wherein the patient has schizophrenia and the at least one additional active agent treats at least one negative symptom in the patient.

78. The pharmaceutical composition for the use according to embodiment 77, wherein the at least one negative symptom is selected from the group consisting of absence of hedonia, loss of motivation, and reduced interest in social contact.

79. The pharmaceutical composition for the use according to any one of embodiments 65 to 78, wherein the patient has at least one stable negative symptom prior to the use, the negative symptom selected from the group consisting of lack of pleasure, loss of motivation, and reduced interest in social contact.

80. The pharmaceutical composition for the use according to any one of embodiments 44 to 79, wherein the pharmaceutical composition is in the form of at least one film coated tablet.

81. A pharmaceutical composition for use in treating at least one cognitive symptom associated with schizophrenia in a patient, wherein:

the medicine composition is used once every time;

the patient had no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptoms item P1, P3, P4, P5, P6); and

82. The pharmaceutical composition for use according to embodiment 81, wherein the use improves the patient's cognitive function concise set of assessment (BACS) score of synthesis relative to the BACS score of synthesis measured on the patient prior to the use.

83. The pharmaceutical composition for the use according to embodiment 81 or 82, wherein the use improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the use.

84. The pharmaceutical composition for the use according to any one of embodiments 81 to 83, wherein any negative symptoms associated with schizophrenia in the patient after the use are not statistically significantly improved.

85. The pharmaceutical composition for the use according to any one of embodiments 81 to 84, wherein the use does not treat at least one negative symptom associated with schizophrenia.

86. The pharmaceutical composition for the use according to embodiment 85, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

87. A pharmaceutical composition comprising 50mg to 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

use in the manufacture of a medicament for treating cognitive impairment associated with schizophrenia in a patient in need thereof, wherein:

the pharmaceutical composition is administered once daily; and

88. The use according to embodiment 87, wherein the at least one cognitive symptom associated with schizophrenia is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

89. The use of embodiment 87 or 88, wherein the use improves the patient's BACS synthesis score relative to a concise set of assessment of cognitive function (BACS) score of schizophrenia measured on the patient prior to the use.

90. The use according to any one of embodiments 87-89, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

91. The use of any of embodiments 87-90, wherein the use improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the use.

92. The use of any one of embodiments 87 to 91, wherein the patient has at least one stable negative symptom associated with schizophrenia prior to the use.

93. The use of embodiment 92, wherein the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

94. The use of embodiment 92, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using PANSS.

95. The use according to embodiments 92 or 93, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

96. The use according to any one of embodiments 87 to 95, wherein the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the use.

97. The use of any one of embodiments 87-91, wherein any negative symptoms associated with schizophrenia in the patient after the use are not statistically significantly improved.

98. The use according to any one of embodiments 87 to 97, wherein the pharmaceutical composition is for use in combination with at least one additional active agent.

99. The use of embodiment 98, wherein the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient.

100. The use according to embodiment 99, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

101. The use according to any one of embodiments 87 to 100, wherein the pharmaceutical composition is for the use for more than 14 weeks.

102. The use according to any one of embodiments 87 to 101, wherein the pharmaceutical composition is for the use for more than 20 weeks.

103. The use according to any one of embodiments 87 to 102, wherein the pharmaceutical composition comprises 50mg of the at least one compound.

104. The use of any one of embodiments 87 to 102, wherein the pharmaceutical composition comprises 125mg of the at least one compound.

105. The use of any one of embodiments 87 to 102, wherein the pharmaceutical composition comprises 500mg of the at least one compound.

106. The use according to any one of embodiments 87 to 105, wherein the use does not treat a negative symptom associated with schizophrenia.

107. The use according to embodiment 106, wherein the at least one negative symptom associated with schizophrenia prior to the administration is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

108. Use of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof, for treating cognitive impairment in a patient in need thereof:

Wherein the patient exhibits at least one cognitive symptom prior to the use.

109. The use according to embodiment 108, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

110. The use according to embodiments 108 or 109, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

111. The use according to any one of embodiments 108 to 110, wherein the use treats the at least one cognitive symptom.

112. The use according to any one of embodiments 108 to 111, wherein the at least one cognitive symptom is associated with a psychotic disorder.

113. The use according to embodiment 112, wherein the psychotic disorder is selected from psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder unrelated to aggression.

114. The use according to embodiment 112 or 113, wherein the psychotic disorder is a schizophreniform disorder, schizoaffective disorder, and schizophrenic disorder independent of aggression.

115. The use according to any one of embodiments 112 to 114, wherein the psychotic disorder is schizophrenia unrelated to aggression.

116. The use according to any one of embodiments 108 to 111, wherein the at least one cognitive symptom is associated with: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

117. The use according to any one of embodiments 108 to 111, wherein the at least one cognitive symptom is associated with: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

118. The use according to any one of embodiments 108 to 117, wherein:

the pharmaceutical composition is administered once daily.

119. The use according to any one of embodiments 108 to 118, wherein the pharmaceutical composition is for use in combination with at least one additional active agent.

120. The use of embodiment 119, wherein the patient has schizophrenia and the at least one additional active agent treats at least one negative symptom in the patient.

121. The use according to embodiment 120, wherein the at least one negative symptom is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social interaction.

122. The use according to any one of embodiments 108 to 121, wherein the patient has at least one stable negative symptom prior to the use, the negative symptom selected from the group consisting of lack of pleasure, loss of motivation, and reduced interest in social contact.

123. The use according to any one of embodiments 87 to 122, wherein the pharmaceutical composition is in the form of at least one film coated tablet.

124. A pharmaceutical composition comprising 50mg to 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

use in treating at least one cognitive symptom associated with schizophrenia in a patient, wherein:

the pharmaceutical composition is administered once daily;

125. The use of embodiment 124, wherein the use improves the patient's cognitive function conciseness kit assessment (BACS) score of synthesis relative to a BACS score of synthesis measured on the patient prior to the use.

126. The use according to embodiments 124 or 125, wherein the use improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the SCoRS interviewer score measured on the patient prior to the use.

127. The use of any one of embodiments 124-126, wherein any negative symptoms associated with schizophrenia in the patient after the use are not statistically significantly improved.

128. The use according to any one of embodiments 124-127, wherein the use does not treat at least one negative symptom associated with schizophrenia.

129. The use according to embodiment 128, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

130. A method of increasing D-serine levels, long term potentiation and/or synaptic plasticity in a patient in need thereof, the method comprising administering to the patient less than 500mg once daily of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

131. the method of embodiment 130, wherein 50mg of the at least one compound is administered to the patient once daily.

132. The method of embodiment 130 or 131, wherein the method increases D-serine levels in the patient.

133. The method of any one of embodiments 130-132, wherein the method increases long-term potentiation in the patient.

134. The method of any one of embodiments 130-133, wherein the method increases synaptic plasticity in the patient.

135. The method according to any one of embodiments 130-134, wherein the patient exhibits at least one cognitive symptom prior to the administering.

136. The method according to embodiment 135, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

137. The method according to embodiment 135, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

138. The method of any of embodiments 130-137, wherein the administering improves at least one biomarker selected from the group consisting of blink conditional reflection (EBC) response of the patient, mismatching negative wave (MMN) amplitude of the patient, and Auditory Steady State Response (ASSR) gamma band power of the patient.

139. The method according to any one of embodiments 130 to 138, wherein the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

140. The method according to any one of embodiments 130 to 138, wherein the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

141. The method according to any one of embodiments 130-138, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1, P3, P4, P5, P6 <5 grade).

142. A pharmaceutical composition for use in increasing D-serine levels, long term potentiation and/or synaptic plasticity in a patient in need thereof, wherein:

the pharmaceutical composition comprises less than 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

and the pharmaceutical composition is used once per day.

143. The pharmaceutical composition for the use according to embodiment 142, wherein the pharmaceutical composition comprises 50mg of the at least one compound.

144. The pharmaceutical composition for use according to embodiment 142 or 143, wherein the use increases D-serine levels in the patient.

145. The pharmaceutical composition for use according to any one of embodiments 142-144, wherein the use increases long-term potentiation in the patient.

146. The pharmaceutical composition for use according to any one of embodiments 142-145, wherein the use increases synaptic plasticity in the patient.

147. The pharmaceutical composition for the use according to any one of embodiments 142-146, wherein the patient exhibits at least one cognitive symptom prior to the use.

148. The pharmaceutical composition for the use according to embodiment 147, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

149. The pharmaceutical composition for the use according to embodiment 147, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

150. The pharmaceutical composition for use according to any one of embodiments 142-149, wherein the use improves at least one biomarker selected from the group consisting of: the blink conditional reflection (EBC) response of the patient, the mismatching negative wave (MMN) amplitude of the patient, and the Auditory Steady State Response (ASSR) gamma band power of the patient.

151. The pharmaceutical composition for use according to any one of embodiments 142-150, wherein the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

152. The pharmaceutical composition for use according to any one of embodiments 142-150, wherein the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

153. The pharmaceutical composition for the use according to any one of embodiments 142-150, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptoms item P1, P3, P4, P5, P6).

154. Use of a pharmaceutical composition comprising less than 500mg of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for increasing D-serine levels, long term potentiation and/or synaptic plasticity in a patient in need thereof:

wherein the pharmaceutical composition is for every single use.

155. The use of embodiment 154, wherein the pharmaceutical composition comprises 50mg of the at least one compound.

156. The use of embodiment 154 or 155, wherein said use increases D-serine levels in said patient.

157. The use of any one of embodiments 154 to 156, wherein the use increases long term potentiation in the patient.

158. The use of any one of embodiments 154 to 157, wherein the use increases synaptic plasticity in the patient.

159. The use according to any one of embodiments 154-158, wherein the patient exhibits at least one cognitive symptom prior to the use.

160. The use of embodiment 159, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

161. The use of embodiment 159, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

162. The use of any one of embodiments 154 to 161, wherein the use improves at least one biomarker selected from the group consisting of: the blink conditional reflection (EBC) response of the patient, the mismatching negative wave (MMN) amplitude of the patient, and the Auditory Steady State Response (ASSR) gamma band power of the patient.

163. The use according to any one of embodiments 154 to 162, wherein the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

164. The use according to any one of embodiments 154 to 162, wherein the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

165. The use according to any one of embodiments 154 to 162, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1, P3, P4, P5, P6 <5 grade).

Non-limiting example embodiment 2:

without limitation, some embodiments/clauses of the present disclosure include:

2. A method of treating cognitive impairment associated with schizophrenia according to clause 1, wherein the method comprises:

3. The method of treating cognitive impairment associated with schizophrenia according to clause 1 or 2, wherein the at least one cognitive symptom associated with schizophrenia is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency and impaired executive function.

4. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-3, wherein the administration improves the patient's BACS synthesis score relative to a concise set of assessment of cognitive function (BACS) score measured on the patient prior to the administration.

5. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-4, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

6. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-5, wherein the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administration.

7. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-6, wherein the patient has at least one stable negative symptom associated with schizophrenia prior to the administration.

8. The method of treating cognitive impairment associated with schizophrenia according to clause 7, wherein the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

9. The method of treating cognitive impairment associated with schizophrenia according to clause 7, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using PANSS.

10. The method of treating cognitive impairment associated with schizophrenia according to clause 7 or 8, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

11. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 7-10, wherein the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the administration.

12. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-6, wherein any negative symptoms associated with schizophrenia in the patient are not statistically significantly improved following the administration.

13. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-12, wherein the at least one compound is administered in combination with at least one additional active agent.

14. The method of treating cognitive impairment associated with schizophrenia according to clause 13, wherein the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient.

15. The method of treating cognitive impairment associated with schizophrenia according to clause 14, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

16. The method of treating cognitive impairment associated with schizophrenia according to clause 13, wherein the at least one additional therapeutic agent is selected from the group consisting of aripiprazole, olanzapine, risperidone and quetiapine fumarate.

17. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-16, wherein the at least one compound is administered to the patient for more than 14 weeks.

18. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-17, wherein the at least one compound is administered to the patient for more than 20 weeks.

19. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-18, wherein 50mg of the at least one compound is administered to the patient once per each.

20. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-19, wherein 125mg of the at least one compound is administered to the patient once daily.

21. The method of treating cognitive impairment associated with schizophrenia according to any one of clauses 1-20, wherein the administration does not treat at least one negative symptom associated with schizophrenia.

22. The method of treating cognitive impairment associated with schizophrenia according to clause 21, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

23. A method of treating cognitive impairment in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound selected from the group consisting of compound (I):

24. A method of treating cognitive impairment according to clause 23, wherein the method comprises:

administering to the patient a therapeutically effective amount of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily for 6 to 8 days;

25. The method of treating cognitive impairment according to clause 23 or 24, wherein the at least one cognitive symptom is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

26. The method of treating cognitive impairment according to any one of clauses 23 to 25, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

27. The method of treating cognitive impairment according to any one of clauses 23-26, wherein the administering treats the at least one cognitive symptom.

28. The method of treating cognitive impairment according to any one of clauses 23 to 27, wherein the at least one cognitive symptom is associated with a psychotic disorder.

29. The method of treating cognitive impairment according to clause 28, wherein the psychotic disorder is selected from psychosis, schizophreniform disorder, schizoaffective disorder, and schizophreniform disorder unrelated to aggression.

30. The method of treating cognitive impairment according to clause 28 or 29, wherein the psychotic disorder is a schizophreniform disorder, a schizoaffective disorder, and schizophrenic disorder unrelated to aggression.

31. The method of treating cognitive impairment according to any one of clauses 28 to 30, wherein the psychotic disorder is schizophrenia unrelated to aggression.

32. The method of treating cognitive impairment according to any one of clauses 23-28, wherein the at least one cognitive symptom is associated with: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

33. The method of treating cognitive impairment according to any one of clauses 23-28, wherein the at least one cognitive symptom is associated with: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

34. The method of treating cognitive impairment of any one of clauses 23-33, wherein 50mg of the at least one compound is administered to the patient per each time.

35. The method of treating cognitive impairment according to any one of clauses 23-34, wherein the at least one compound is administered in combination with at least one additional active agent.

36. The method of treating cognitive impairment of clause 35, wherein the patient has schizophrenia and the at least one additional active agent treats at least one negative symptom in the patient.

37. The method of treating cognitive impairment according to clause 36, wherein the at least one negative symptom is selected from the group consisting of lack of pleasure, loss of motivation, and reduced interest in social contact.

38. The method of treating cognitive impairment according to any one of clauses 23-37, wherein the patient has at least one stable negative symptom selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact prior to the administering.

39. The method of treating cognitive impairment according to any one of clauses 1 to 38, wherein the at least one compound is administered in the form of at least one film-coated tablet.

40. A method of treating at least one cognitive symptom associated with schizophrenia in a patient, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptom projects P1, P3, P4, P5, P6), comprising administering to the patient 50mg to 500mg once daily of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof:

41. A method of treating at least one cognitive symptom associated with schizophrenia according to clause 40, wherein the method comprises:

42. The method of treating at least one cognitive symptom associated with schizophrenia according to clause 40 or 41, wherein the administration improves the patient's cognitive function conciseness kit assessment (BACS) score of synthesis relative to the BACS score of synthesis measured on the patient prior to the administration.

43. The method of treating at least one cognitive symptom associated with schizophrenia according to any of clauses 40-42, wherein the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administration.

44. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of clauses 40-43, wherein any negative symptom associated with schizophrenia in the patient is not statistically significantly improved following the administration.

45. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of clauses 40-44, wherein the administering does not treat at least one negative symptom associated with schizophrenia.

46. The method of treating at least one cognitive symptom associated with schizophrenia according to clause 45, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

47. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of clauses 40-46, wherein 50mg of the at least one compound is administered to the patient once daily.

48. A method of increasing D-serine levels, long term potentiation and/or synaptic plasticity in a patient in need thereof, the method comprising administering to the patient less than 500mg once daily of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

49. the method of clause 48, wherein 50mg of the at least one compound is administered to the patient once daily.

50. The method of clause 48 or 49, wherein the method increases D-serine levels in the patient.

51. The method of any one of clauses 48 to 50, wherein the method increases long term potentiation in the patient.

52. The method of any one of clauses 48 to 51, wherein the method increases synaptic plasticity in the patient.

53. The method of any one of clauses 48 to 52, wherein the patient exhibits at least one cognitive symptom prior to the administering.

54. The method of clause 53, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

55. The method of clause 53, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

56. The method of any of clauses 48-55, wherein the administering improves at least one biomarker selected from the group consisting of blink conditional reflection (EBC) response of the patient, mismatching negative wave (MMN) amplitude of the patient, and Auditory Steady State Response (ASSR) gamma band power of the patient.

57. The method of any one of clauses 48 to 56, wherein the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

58. The method of any one of clauses 48 to 56, wherein the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

59. The method of any one of clauses 48 to 56, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1, P3, P4, P5, P6 <5 grade).

Non-limiting example embodiment 3:

without limitation, some embodiments/features of the present disclosure include:

1. a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof, comprising administering to the patient from 1mg to 500mg once daily of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

2. A method of treating cognitive impairment associated with schizophrenia according to feature 1, wherein the method comprises:

administering to the patient 1mg to 500mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof once daily for 6 to 8 days;

Continuing to administer 1mg to 500mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof to the patient once daily if the 6 to 8 day administration improves at least one biomarker.

3. The method of treating cognitive impairment associated with schizophrenia according to feature 1 or 2, wherein the at least one cognitive symptom associated with schizophrenia is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency and impaired executive function.

4. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 3, wherein the administration improves the patient's BACS synthesis score relative to a concise set of assessment of cognitive function (BACS) score measured on the patient prior to the administration.

5. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 4, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function and impaired social cognition.

6. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 5, wherein the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administration.

7. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 6, wherein the administration improves at least one metric selected from the group consisting of:

the patient's performance on a continuous operation test-the same pair (CPT-IP) test relative to the CPT-IP test prior to the administration;

the patient's performance on the simple visual space memory test-revision (BVMT-R) test relative to the patient's performance on the BVMT-R test prior to the administration;

the patient's performance on Mayer-saloviy-caroso mood quiz (MSCEIT) relative to the patient's performance on MSCEIT prior to the administration;

-the patient's performance on a Virtual Reality Functional Capability Assessment Tool (VRFCAT) relative to the patient's performance on VRFCAT prior to the administration; and

the patient' S clinical global impression-severity scale (CGI-S) score relative to the CGI-S score measured on the patient prior to the administration.

8. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 7, wherein the patient has at least one stable negative symptom associated with schizophrenia prior to the administration.

9. The method of treating cognitive impairment associated with schizophrenia according to feature 8, wherein the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

10. The method of treating cognitive impairment associated with schizophrenia according to feature 8, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using PANSS.

11. The method of treating cognitive impairment associated with schizophrenia according to feature 8 or 9, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

12. The method of treating cognitive impairment associated with schizophrenia according to any one of features 8 to 11, wherein the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the administration.

13. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 7, wherein any negative symptoms associated with schizophrenia in the patient after the administration are not statistically significantly improved.

14. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 13, wherein the at least one compound is administered in combination with at least one additional active agent.

15. The method of treating cognitive impairment associated with schizophrenia according to feature 14, wherein the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient.

16. The method of treating cognitive impairment associated with schizophrenia according to feature 15, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

17. The method of treating cognitive impairment associated with schizophrenia according to feature 14, wherein the at least one additional therapeutic agent is selected from the group consisting of aripiprazole, olanzapine, risperidone and quetiapine fumarate.

18. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 17, wherein the at least one compound is administered to the patient for more than 14 weeks.

19. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 18, wherein the at least one compound is administered to the patient for more than 20 weeks.

20. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 19, wherein 1mg to 100mg of the at least one compound is administered to the patient once daily.

21. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 19, wherein 20mg or 50mg of the at least one compound is administered to the patient once daily.

22. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 19, wherein 20mg of the at least one compound is administered to the patient per one time.

23. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 19, wherein 50mg of the at least one compound is administered to the patient once daily.

24. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 23, wherein the administration does not treat at least one negative symptom associated with schizophrenia.

25. The method of treating cognitive impairment associated with schizophrenia according to feature 24, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

26. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 25, wherein the patient is in a stable regime of a psychotropic drug.

27. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 26, wherein the patient is diagnosed with schizophrenia at least one year prior to the administration.

28. The method of treating cognitive impairment associated with schizophrenia according to any one of features 1 to 27, wherein the patient has stable symptomatology for at least 3 months prior to the administration.

29. A method of treating cognitive impairment in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound selected from the group consisting of compound (I):

30. A method of treating cognitive impairment according to feature 29, wherein the method comprises:

31. The method of treating cognitive impairment according to either feature 29 or 30, wherein the at least one cognitive symptom is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

32. The method of treating cognitive impairment according to any one of features 29-31 wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution, impaired working memory, impaired processing speed, impaired language function and impaired social cognition.

33. The method of treating cognitive impairment according to any one of features 29-32 wherein the administering treats the at least one cognitive symptom.

34. The method of treating cognitive impairment according to any one of features 29-33 wherein the at least one cognitive symptom is associated with a psychotic disorder.

35. The method of treating cognitive impairment according to feature 34, wherein the psychotic disorder is selected from the group consisting of psychosis, schizophreniform disorder, schizoaffective disorder, and schizophreniform unrelated to aggression.

36. The method of treating cognitive impairment according to either feature 34 or 35, wherein the psychotic disorder is a schizophreniform disorder, a schizoaffective disorder, or a schizophrenic disorder unrelated to aggression.

37. The method of treating cognitive impairment according to any one of features 34 to 36 wherein the psychotic disorder is schizophrenia unrelated to aggression.

38. The method of treating cognitive impairment according to any one of features 29-34 wherein the at least one cognitive symptom is associated with: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

39. The method of treating cognitive impairment according to any one of features 29-34 wherein the at least one cognitive symptom is associated with: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

40. The method of treating cognitive impairment according to any one of features 29-39, wherein 50mg of the at least one compound is administered to the patient once daily.

41. The method of treating cognitive impairment according to any one of features 29-39, wherein 20mg of the at least one compound is administered to the patient once daily.

42. The method of treating cognitive impairment according to any one of features 29-41, wherein the at least one compound is administered in combination with at least one additional active agent.

43. The method of treating cognitive impairment of claim 42, wherein the patient suffers from schizophrenia and the at least one additional active agent treats at least one negative symptom in the patient.

44. The method of treating cognitive impairment of feature 43, wherein the at least one negative symptom is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social interaction.

45. The method of treating cognitive impairment of any one of claims 29 to 44, wherein the patient prior to the administration has at least one stable negative symptom selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social interaction.

46. The method of treating cognitive impairment of any one of features 1 to 45, wherein the at least one compound is administered in the form of at least one film-coated tablet.

47. The method of treating cognitive impairment of any one of features 1 to 46, wherein the at least one compound is administered with water or milk.

48. A method of treating at least one cognitive symptom associated with schizophrenia in a patient, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptom projects P1, P3, P4, P5, P6), comprising administering to the patient 1mg to 500mg once daily of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof:

49. A method of treating at least one cognitive symptom associated with schizophrenia according to feature 48, wherein the method comprises:

50. The method of treating at least one cognitive symptom associated with schizophrenia according to feature 48 or 49, wherein the administration improves the patient's cognitive function conciseness kit assessment (BACS) score of synthesis relative to BACS score measured on the patient prior to the administration.

51. A method of treating at least one cognitive symptom associated with schizophrenia according to any of features 48-50, wherein the administration improves the patient's cognitive performance rating scale (SCoRS) interview score relative to the patient's SCoRS interview score measured prior to the administration.

52. A method of treating at least one cognitive symptom associated with schizophrenia according to any one of features 48-51, wherein the administration improves at least one metric selected from the group consisting of:

53. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of features 48-52, wherein any negative symptom associated with schizophrenia in the patient is not statistically significantly improved following the administration.

54. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of features 48-53, wherein the administering does not treat at least one negative symptom associated with schizophrenia.

55. The method of treating at least one cognitive symptom associated with schizophrenia according to feature 54, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

56. A method of treating at least one cognitive symptom associated with schizophrenia according to any one of features 48-55, wherein 50mg of the at least one compound is administered to the patient once per day.

57. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of features 48-55, wherein the patient is administered 20mg of the at least one compound once daily.

58. A method of increasing D-serine levels, long term potentiation and/or synaptic plasticity in a patient in need thereof, the method comprising administering to the patient less than 500mg once daily of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

59. The method of feature 58, wherein 50mg of the at least one compound is administered to the patient once daily.

60. The method of feature 58, wherein 20mg of the at least one compound is administered to the patient per each time.

61. The method of any one of features 58-60, wherein the method increases D-serine levels in the patient.

62. The method of any one of features 58-61, wherein the method increases long-term potentiation in the patient.

63. The method of any one of features 58-62, wherein the method increases synaptic plasticity in the patient.

64. The method according to any one of features 58-63, wherein the patient exhibits at least one cognitive symptom prior to the administering.

65. The method according to feature 64, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

66. The method according to feature 64, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

67. The method of any of features 58-66, wherein the administering improves at least one biomarker selected from the group consisting of blink conditional reflection (EBC) response of the patient, mismatching negative wave (MMN) amplitude of the patient, and Auditory Steady State Response (ASSR) gamma band power of the patient.

68. The method of any one of features 58 to 67, wherein the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

69. The method of any one of features 58 to 67, wherein the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

70. The method according to any one of features 58 to 67, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1, P3, P4, P5, P6 <5 grade).

71. Compound (I) or a pharmaceutically acceptable salt thereof for use in a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof:

the method comprising administering to the patient 1mg to 500mg of the compound (I) or a pharmaceutically acceptable salt thereof once daily,

72. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 71, wherein the method comprises:

administering 1mg to 500mg of the compound (I) or a pharmaceutically acceptable salt thereof to the patient once daily for 6 to 8 days;

continuing to administer 1mg to 500mg of the compound (I) or a pharmaceutically acceptable salt thereof to the patient once daily if the 6 to 8 day administration improves at least one biomarker.

73. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 71 or 72, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency and impaired executive function.

74. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 73, wherein the administration improves the patient's BACS synthesis score relative to a clear set of cognitive function assessment (BACS) score of schizophrenia measured on the patient prior to the administration.

75. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 74, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function and impaired social cognition.

76. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 75, wherein the administration improves the patient's SCoRS interviewer score relative to a cognitive function rating scale (SCoRS) interviewer score measured on the patient prior to the administration.

77. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 76, wherein the administration improves at least one metric selected from the group consisting of:

78. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 77, wherein the patient has at least one stable negative symptom associated with schizophrenia prior to the administration.

79. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 78, wherein the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

80. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 78, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using PANSS.

81. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 78 or 79, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

82. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 78 to 81, wherein the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the administration.

83. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 77, wherein any negative symptoms associated with schizophrenia in the patient after said administration are not statistically significantly improved.

84. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 83, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional active agent.

85. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 84, wherein the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient.

86. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 85, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

87. The compound (I) or a pharmaceutically acceptable salt thereof for the use according to feature 84, wherein the at least one additional therapeutic agent is selected from aripiprazole, olanzapine, risperidone and quetiapine fumarate.

88. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71-87, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient for more than 14 weeks.

89. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71-88, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient for more than 20 weeks.

90. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 89, wherein 1mg to 100mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

91. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 89, wherein 20mg or 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

92. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 89, wherein 20mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient per unit.

93. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71-89, wherein 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

94. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 93, wherein the administration does not treat at least one negative symptom associated with schizophrenia.

95. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 94, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social interaction.

96. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 95, wherein the patient is in a psychotropic stabilization regimen.

97. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 96, wherein the patient is diagnosed with schizophrenia at least one year prior to the administration.

98. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 97, wherein the patient has stable symptomology for at least 3 months prior to the administration.

99. A compound (I) or a pharmaceutically acceptable salt thereof for use in a method of treating cognitive impairment in a patient in need thereof:

The method comprising administering to the patient a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof,

100. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 99, wherein the method comprises:

administering to the patient a therapeutically effective amount of at least one compound selected from the group consisting of the compound (I) or a pharmaceutically acceptable salt thereof once daily for 6 to 8 days;

continuing to administer a therapeutically effective amount of the compound (I) or a pharmaceutically acceptable salt thereof once daily to the patient if the 6 to 8 day administration improves at least one biomarker.

101. The compound (I) or a pharmaceutically acceptable salt thereof for the use according to feature 99 or 100, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing rate, impaired speech fluency and impaired executive function.

102. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 101, wherein the at least one cognitive symptom is selected from impaired attention, memory, reasoning, problem solving, impaired working memory, processing speed, impaired language function and impaired social cognition.

103. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 102, wherein the administration treats the at least one cognitive symptom.

104. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 103, wherein the at least one cognitive symptom is associated with a psychotic disorder.

105. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 104, wherein the psychotic disorder is selected from psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder independent of aggression.

106. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 104 or 105, wherein the psychotic disorder is schizophreniform disorder, schizoaffective disorder, and schizophreniform disorder unrelated to aggression.

107. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 104 to 106, wherein the psychotic disorder is schizophrenia unrelated to aggression.

108. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 104, wherein the at least one cognitive symptom is associated with: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

109. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 104, wherein the at least one cognitive symptom is associated with: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

110. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 109, wherein 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient per unit.

111. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 109, wherein 20mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient per unit.

112. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 111, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional active agent.

113. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 112, wherein the patient has schizophrenia and the at least one additional active agent treats at least one negative symptom in the patient.

114. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 113, wherein the at least one negative symptom is selected from the group consisting of absence of hedonia, loss of motivation, and reduced interest in social contact.

115. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 99 to 114, wherein the patient has at least one stable negative symptom prior to the administration selected from the group consisting of absence of hedonia, loss of motivation, and reduced interest in social networking.

116. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 115, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in the form of at least one film coated tablet.

117. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 71 to 116, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered with water or milk.

118. A compound (I) or a pharmaceutically acceptable salt thereof for use in a method of treating at least one cognitive symptom associated with schizophrenia in a patient:

wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptoms items P1, P3, P4, P5, P6),

the method comprises administering 1mg to 500mg of the compound (I) or a pharmaceutically acceptable salt thereof to the patient once daily.

119. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 118, wherein the method comprises:

120. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 118 or 119, wherein the administration improves the patient's BACS synthesis score relative to a concise set of assessment of cognitive function (BACS) score of schizophrenia measured on the patient prior to the administration.

121. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 118 to 120, wherein the administration improves the patient's SCoRS interviewer score relative to a cognitive function rating scale (SCoRS) interviewer score measured on the patient prior to the administration.

122. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 118 to 121, wherein the administration improves at least one metric selected from the group consisting of:

the patient' S clinical global impression-severity scale (CGI-S) score relative to the CG-S score measured on the patient prior to the administration.

123. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 118 to 122, wherein any negative symptoms associated with schizophrenia in the patient after the administration are not statistically significantly improved.

124. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 118 to 123, wherein the administration does not treat at least one negative symptom associated with schizophrenia.

125. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 124, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

126. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 118 to 125, wherein 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

127. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 118 to 125, wherein 20mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

128. Compound (I) or a pharmaceutically acceptable salt thereof for use in a method of increasing D-serine levels, long term potentiation and/or synaptic plasticity in a patient in need thereof:

the method comprises administering less than 500mg of the compound (I) or a pharmaceutically acceptable salt thereof to the patient once daily.

129. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 128, wherein 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

130. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 128, wherein 20mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

131. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 128-130, wherein the method increases D-serine levels in the patient.

132. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 128-131, wherein the method increases long-term potentiation in the patient.

133. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 128-132, wherein the method increases synaptic plasticity in the patient.

134. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 128-133, wherein the patient exhibits at least one cognitive symptom prior to the administration.

135. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 134, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

136. The compound (I) or a pharmaceutically acceptable salt thereof for use according to feature 134, wherein the at least one cognitive symptom is selected from impaired attention, memory, reasoning, resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

137. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 128-136, wherein the administration improves at least one biomarker selected from the group consisting of blink conditional reflectance (EBC) response of the patient, mismatching negative wave (MMN) amplitude of the patient, and Auditory Steady State Response (ASSR) gamma band power of the patient.

138. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 128-137, wherein the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

139. The compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 128-137, wherein the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

140. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of features 128 to 137, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptoms item P1, P3, P4, P5, P6).

141. Use of compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating cognitive impairment associated with schizophrenia in a patient in need thereof:

wherein the method comprises administering to the patient 1mg to 500mg of the compound (I) or a pharmaceutically acceptable salt thereof once daily,

142. The use of feature 141, wherein the method comprises:

143. The use according to feature 141 or 142, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

144. The use of any one of features 141-143, wherein the administration improves the patient's BACS synthesis score relative to a concise set of cognitive function assessment (BACS) score of schizophrenia measured on the patient prior to the administration.

145. The use according to any one of features 141-144, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

146. The use of any of features 141-145, wherein the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the SCoRS interviewer score measured on the patient prior to the administration.

147. The use of any one of features 141-146, wherein the administration improves at least one metric selected from the group consisting of:

the patient's performance on Mayer-saloviy-caroso mood quiz (MSCEIT) relative to the patient's performance on msce|t prior to the administration;

148. The use of any one of features 141-147, wherein the patient has at least one stable negative symptom associated with schizophrenia prior to the administration.

149. The use according to feature 148, wherein the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

150. The use according to feature 148, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using PANSS.

151. The use according to feature 148 or 149, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

152. The use according to any one of features 148-151, wherein the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the administration.

153. The use of any one of features 141-147, wherein any negative symptoms associated with schizophrenia in the patient after the administration are not statistically significantly improved.

154. The use of any one of features 141-153, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional active agent.

155. The use according to feature 154, wherein the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient.

156. The use according to feature 155, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

157. The use according to feature 154, wherein the at least one additional therapeutic agent is selected from aripiprazole, olanzapine, risperidone, and quetiapine fumarate.

158. The use of any one of features 141-157, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient for more than 14 weeks.

159. The use of any one of features 141-158, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient for more than 20 weeks.

160. The use according to any one of features 141 to 159, wherein 1mg to 100mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient per minute.

161. The use of any one of features 141-159, wherein 20mg or 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

162. The use according to any one of features 141-159, wherein 20mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient per unit.

163. The use of any one of features 141-159, wherein 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

164. The use of any one of features 141-163, wherein the administration does not treat at least one negative symptom associated with schizophrenia.

165. The use according to feature 164, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

166. The use of any one of features 141-165, wherein the patient is in a psychotropic stabilization regimen.

167. The use of any one of features 141-166, wherein the patient is diagnosed with schizophrenia at least one year prior to the administration.

168. The use of any one of features 141-167, wherein the patient has stable symptomatology for at least 3 months prior to the administering.

169. Use of compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating cognitive impairment in a patient in need thereof:

Comprising administering to said patient a therapeutically effective amount of said compound (I) or a pharmaceutically acceptable salt thereof,

170. The use according to feature 169, wherein the method comprises:

administering a therapeutically effective amount of the compound (I) or a pharmaceutically acceptable salt thereof once daily to the patient for 6 to 8 days;

171. The use according to feature 169 or 170, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

172. The use according to any one of features 169-171, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

173. The use according to any one of features 169-172, wherein the administration treats the at least one cognitive symptom.

174. The use according to any one of features 169-173, wherein the at least one cognitive symptom is associated with a psychotic disorder.

175. The use according to feature 174, wherein the psychotic disorder is selected from psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder unrelated to aggression.

176. The use according to feature 174 or 175, wherein the psychotic disorder is a schizophreniform disorder, schizoaffective disorder, and schizophrenic disorder not associated with aggression.

177. The use according to any one of the features 174 to 176, wherein the psychotic disorder is schizophrenia unrelated to aggression.

178. The use according to any one of features 169-174, wherein the at least one cognitive symptom is associated with: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

179. The use according to any one of features 169-174, wherein the at least one cognitive symptom is associated with: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

180. The use according to any one of the features 169 to 179, wherein 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient per unit.

181. The use according to any one of the features 169 to 179, wherein 20mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered once daily to the patient.

182. The use according to any one of features 169 to 181, wherein said compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional active agent.

183. The use according to feature 182, wherein the patient has schizophrenia and the at least one additional active agent treats at least one negative symptom in the patient.

184. The use according to claim 183, wherein said at least one negative symptom is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social interaction.

185. The use according to any one of the features 169-184, wherein the patient has at least one stable negative symptom selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact prior to the administration.

186. The use according to any one of features 141 to 185, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in the form of at least one film coated tablet.

187. The use of any one of features 141-186, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered with water or milk.

188. Use of compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating at least one cognitive symptom associated with schizophrenia in a patient:

189. The use of feature 188, wherein the method comprises:

190. The use according to feature 188 or 189, wherein the administration improves the patient's cognitive function conciseness kit scale (BACS) score of synthesis relative to the BACS score of synthesis measured on the patient prior to the administration.

191. The use according to any one of features 188-190, wherein the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administration.

192. The use according to any one of features 188-191, wherein the administration improves at least one metric selected from the group consisting of:

193. The use of any one of claims 188-192, wherein any negative symptoms associated with schizophrenia in the patient after the administration are not statistically significantly improved.

194. The use according to any one of features 188-193, wherein the administration does not treat at least one negative symptom associated with schizophrenia.

195. The use according to feature 194, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

196. The use according to any one of features 188 to 195, wherein 50mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

197. The use according to any one of features 188 to 195, wherein 20mg of the compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient per unit.

198. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in a method of increasing D-serine levels, long term potentiation and/or synaptic plasticity in a patient in need thereof:

199. The use of feature 198, wherein 50mg of compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

200. The use of feature 198, wherein 20mg of compound (I) or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

201. The use of any one of features 198-200, wherein the method increases D-serine levels in the patient.

202. The use of any one of features 198-201, wherein the method increases long-term potentiation in the patient.

203. The use of any one of features 198-202, wherein the method increases synaptic plasticity in the patient.

204. The use according to any one of features 198-203, wherein the patient exhibits at least one cognitive symptom prior to the administration.

205. The use according to feature 204, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

206. The use according to feature 204, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

207. The use of any of features 198-206, wherein the administration improves at least one biomarker selected from the group consisting of blink conditional reflection (EBC) response of the patient, mismatching negative wave (MMN) amplitude of the patient, and Auditory Steady State Response (ASSR) gamma band power of the patient.

208. The use of any one of features 198-207, wherein the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

209. The use of any one of features 198-207, wherein the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

210. The use according to any one of features 198 to 207, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1, P3, P4, P5, P6 <5 grade).

Brief description of the drawings

FIG. 1A is a graph depicting the effect of D-serine administration on short term potentiation in the hippocampus of rats compared to vehicle.

FIG. 1B is a graph depicting the effect of D-serine administration on long-term inhibition in the hippocampus of rats compared to vehicle.

FIG. 1C is a graph showing the change in enhancement and inhibition with D-serine administration compared to vehicle.

Figure 2 depicts the effect of compound (I) on mouse hippocampal synaptic plasticity after a single oral dose of compound (I).

Figure 3 depicts the effect of compound (I) on mouse hippocampal synaptic plasticity following a sub-chronic (14 day) oral dose of compound (I).

FIG. 4A is a graph depicting plasma D-serine levels following sub-chronic administration of compound (I) in a mouse model.

FIG. 4B is a graph depicting brain D-serine levels following sub-chronic administration of compound (I) in a mouse model.

Fig. 5 depicts the study design of the phase 2 INTERACT study of compound (I) as adjuvant therapy (clinical trial. Government identifier: NCT 03382639) in adults with schizophrenia with persistent negative symptoms.

Fig. 6 is a graph depicting the mean Least Squares (LS) change from baseline in patients participating in an intermittent study during a 12 week treatment period PANSS NSFS.

Figure 7 is a graph depicting the Least Squares (LS) mean change from baseline in BACS synthesis score over a 12 week treatment period for patients enrolled in the intermittent study.

Fig. 8 is a graph depicting the Least Squares (LS) mean change in SCoRS interviewer total score from baseline over a 12 week treatment period for patients participating in an intermittent study.

Fig. 9 depicts a study design (clinical trial. Government identifier: NCT 03359785) for phase 1 studies designed to evaluate the pharmacodynamic effects, safety, tolerability and pharmacokinetics of compound (I) in patients with schizophrenia in multiple oral doses.

Fig. 10 depicts blink condition reflex assessment (clinical trial. Government identifier: NCT 03359785) used in phase 1b studies evaluating multiple oral doses of compound (I) in patients with schizophrenia.

Fig. 11A and 11B are graphs depicting the mismatch negative (MMN) of baseline (pre-drug and pre-placebo).

Fig. 12A is a graph showing the least-squares mean change in blink condition reflection after 50mg treatment with placebo or compound (I) in patients with schizophrenia.

Fig. 12B is a graph showing the least-squares mean change in blink condition reflection following treatment with 500mg of placebo or compound (I) in patients with schizophrenia.

Fig. 13A is a graph showing the least squares mean change in MMN after 50mg treatment with placebo or compound (I) in patients with schizophrenia.

Fig. 13B is a graph showing the least squares mean change in MMN following treatment with 500mg of placebo or compound (I) in patients with schizophrenia.

Fig. 14A is a graph showing the least squares mean change in ASSR after 50mg treatment with placebo or compound (I) in patients with schizophrenia.

Fig. 14B is a graph showing the least squares mean change in ASSR after 500mg treatment with placebo or compound (I) in patients with schizophrenia.

Figure 15 summarizes the directionality of the pharmacodynamic endpoint changes observed in phase 1b studies evaluating multiple oral doses of compound (I) in patients with schizophrenia (clinical trial government identifier: NCT 03359785).

Fig. 16A and 16B are study design schematics of a planned phase 2B study for evaluating the safety and efficacy of compound (I) in improving cognitive performance in individuals with schizophrenia as compared to placebo.

Definition:

as used herein, unless otherwise indicated, "a" or "an" entity refers to one or more of the entities, e.g., "a compound" refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein.

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

As used herein, "administering" an API to a patient refers to any route by which the API is introduced or delivered to the patient (e.g., oral delivery). Administration includes self-administration and administration by another person.

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

As used herein, "effective amount," "effective dose," or "therapeutically effective amount" refers to the amount of a molecule that treats a patient suffering from a condition when administered in a single or multiple doses. The effective amount can be determined by the attending diagnostician by using known techniques and by observing results obtained in similar circumstances. In determining an effective amount, the attending diagnostician considers a number of factors, including, but not limited to: species of patient; its size, age and general health; the particular condition, disorder or disease involved; the extent or severity of involvement of the condition, disorder or disease, the response of the individual patient; the particular compound being administered; the mode of administration; bioavailability characteristics of the administered formulation; the selected dosing regimen; concomitant use of a drug; as well as other related situations.

As used herein, the amount expressed in terms of "mg of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof" is based on the total weight of the free base of compound (I) present in the form of the free base of compound (I) and/or one or more pharmaceutically acceptable salts thereof.

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

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

As used herein, the terms "patient" and "subject" are used interchangeably and refer to a mammal, such as a human.

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

As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic salt form of a compound of the present disclosure. Pharmaceutically acceptable salts of compound (I) of the present disclosure include those derived from suitable inorganic and organic acids and inorganic and organic bases. Pharmaceutically acceptable salts are well known in the art. Suitable pharmaceutically acceptable salts are, for example, those described in Berge, s.m., et al j.pharma.sci.66:1-19 (1977). Non-limiting examples of pharmaceutically acceptable salts disclosed in this article include: acetate salt; benzene sulfonate; a benzoate; bicarbonate; bitartrate; a bromide; calcium ethylenediamine tetraacetate; camphorsulfonate; a carbonate salt; a chloride; a citrate salt; dihydrochloride; ethylenediamine tetraacetic acid salt; ethanedisulfonate; etodolac; ethanesulfonate; a fumarate salt; glucoheptonate; gluconate; glutamic acid; p-hydroxyacetylaminobenzenearsenate; hexyl resorcinol salts; haibamin; a hydrobromide salt; a hydrochloride salt; hydroxy naphthalene formate; iodide; isethionate; lactate; lactobionate; malate; maleic acid salts; mandelate; methanesulfonic acid salt; methyl bromide; methyl nitrate; methyl sulfate; mucic acid salt; naphthalene sulfonate; nitrate salts; pamoate (pamoate); pantothenate; phosphate/hydrogen phosphate; polygalacturonate; salicylates; a stearate; basic acetate; succinate; a sulfate; tannate; tartrate; a teociate; triethyliodine; benzathine; chloroprocaine; choline; diethanolamine; ethylenediamine; meglumine; procaine; aluminum; calcium; lithium; magnesium; potassium; sodium; and zinc.

Non-limiting examples of pharmaceutically acceptable salts derived from suitable acids include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid; salts with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed using other methods used in the art, such as ion exchange. Other non-limiting examples of pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates,Bisulfate, borate, butyrate, camphoric acid, camphorsulfonic acid, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodinate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Non-limiting examples of pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N ⁺ (C _1-4 Alkyl group ₄ And (3) salt. The present disclosure also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other non-limiting examples of pharmaceutically acceptable salts include benzenesulfonate salts and glucosamine salts.

Further, herein "at least one compound selected from the group consisting of compound (I) and a pharmaceutically acceptable salt thereof" is used interchangeably with "at least one compound or salt selected from the group consisting of compound (I) and a pharmaceutically acceptable salt thereof" and "at least one entity selected from the group consisting of compound (I) and a pharmaceutically acceptable salt". Similarly, the term "at least one compound" may be used interchangeably herein with "at least one compound or salt" or "at least one entity".

As used herein, the term "reduce" means a negative change of at least 5%, including but not limited to a negative change of 5%, a negative change of 10%, a negative change of 25%, a negative change of 30%, a negative change of 50%, a negative change of 75%, or a negative change of 100%.

As used herein, the terms "treatment", "treatment" or "treatment" when used in connection with a disorder or condition include any effect that results in an improvement in the disorder or condition, such as a reduction, decrease, modulation, improvement or elimination. Improvement or alleviation of the severity of any symptom of a disorder or condition can be readily assessed according to standard methods and techniques known in the art. As non-limiting examples, in some embodiments, a cognitive test set (e.g., BACS, MCCB, cogState or Cambridge cognition) or measurement of functional capacity (e.g., SCoRS, UPSA, UPSA-B, CAI or VRFCAT) can be used to evaluate the effect of administration.

As used herein, "calgari schizophrenia depression scale" or "CDSS" is used to assess the symptoms of major depression in schizophrenic patients, and is specifically designed to assess co-morbid depression symptoms. See, for example, addington D, addington J, maticka-tyndalee. "Assessing depression in schizophrenia: the Calgary Depression scale. "Br.J.Psychiatry support.1993; (22): cdss consists of 9 items: depression mood, forfeitude, self-detraction, criminal implication, pathological criminal cachexia, morning depression, early awakening, suicide and observed depression manifestations. Rating each item using a 0 to 3 point scale (0-3); the CDSS score may be 0 to 27. Items on CDSS are all typical depressive symptoms and do not appear to overlap with negative symptoms of schizophrenia. The CDSS will be performed by a researcher or other qualified field personnel.

If one, more than one, or all of the group members are present in, applied to, or otherwise associated with a given product or method, then the claims or descriptions including "or" and/or "between at least one member of the group are deemed to be satisfied unless indicated to the contrary or apparent from the context. The present disclosure includes such embodiments: wherein exactly one member of the group is present in, applied to, or otherwise associated with a given product or process. The present disclosure includes such embodiments: wherein more than one or all of the group members are present in, applied to, or associated with a given product or process.

Furthermore, this disclosure covers all variations, combinations, and permutations in which at least one definition, element, term, and descriptive term from at least one of the listed claims is introduced into another claim. For example, any claim that depends from another claim may be modified to include at least one definition found in any other claim that depends from the same underlying claim. Where elements are presented as a list, for example in a markush group format, each sub-group of elements is also disclosed, and any elements may be removed from the group. It should be understood that, in general, where the present disclosure or aspects of the present disclosure are referred to as comprising particular elements and/or features, embodiments of the present disclosure or aspects of the present disclosure consist of or consist essentially of such elements and/or features. For the sake of simplicity, those embodiments are not specifically set forth herein. Where ranges are given (e.g., from [ X ] to [ Y ]), endpoints (e.g., [ X ] and [ Y ] in the phrase "from [ X ] to [ Y ]) are included unless otherwise indicated. Furthermore, unless otherwise indicated or apparent from the context and understanding of one of ordinary skill in the art, values expressed as ranges may, in different embodiments of the disclosure, represent any particular value or subrange within the range up to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

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

Examples

The following examples are intended to be illustrative and are not meant to limit the scope of the present disclosure in any way.

Abbreviations

% percent

aCSF artificial cerebrospinal fluid

ANCOVA covariance analysis

ANOVA analysis of variance

ASSR auditory steady-state response

ASST attention directed diversion tasks

Simple complete set of measurement and evaluation scale for cognitive function of BACS schizophrenia

BNSS concise negative symptom scale

CI confidence interval

Cognitive impairment associated with CIAS and schizophrenia

CR conditional reaction

CS Condition stimulation

CSF cerebrospinal fluid

day d

DAAO D-amino acid oxidase

DB double binding

EBC blink condition reflection

ECG electrocardiogram

EEG electroencephalogram

EPSP excitatory postsynaptic potential

fEPSP field excitatory postsynaptic potential

F/U follow-up

g

h hours

HFS high frequency stimulation

Hz hertz

kg of

LS least squares

LTD long-term inhibition

LTP long-term enhancement

m ² Square meter

mg

min

mL of

mm millimeter

MMN mismatch negative wave

NMDA N-methyl-d-aspartic acid

ns is not significant

PANSS NSFS Positive and negative symptom Scale-negative symptom factor score

PK pharmacokinetics

PD pharmacodynamics

qd once daily

s seconds

SCoRS cognitive function rating scale for schizophrenia

Standard deviation of SD

Standard error of SE

STP short-time-interval enhancement

Emergent adverse events in TEAE treatment

US unconditional stimulation

UR unconditional reaction

Example 1: preclinical evaluation of hippocampal long-term potentiation following acute and sub-chronic oral administration of Compound (I) in mice

DAAO inhibition increases the level of D-serine, a co-agonist of the N-methyl-D-aspartate (NMDA) receptor. DAAO enzymes are highly expressed in the cerebellum, and therefore, inhibition of DAAO by compound (I) should result in an increase in D-serine levels in the cerebellum, which can also be measured in cerebrospinal fluid (CSF). An increase in cerebellar D-serine levels may also affect distal areas of the brain (e.g., hippocampus) or cortical areas through mechanisms yet to be elucidated.

Preclinical studies in rodents have explored the effect of compound (I) on cognitive performance tasks (table 1). In table 1, + symbols indicate valid, -symbols indicate invalid, and blank cells indicate non-tested doses. In these preclinical studies, sub-chronic administration of compound (I) for 14 days resulted in sensitization to the behavioral response to the new object recognition task (i.e., reduced minimum effective dose, loss of efficacy at higher doses) compared to acute administration. These findings indicate that compound (I) may affect hippocampal synaptic plasticity following sub-chronic administration.

Table 1.Sensitization in an in vivo model following sub-chronic administration of Compound (I)

In this study, following acute and sub-chronic (14 day) administration of compound (I), hippocampal synaptic plasticity was assessed using a well-established long-term potentiation (LTP) paradigm.

Preparation of rat hippocampal slices

To obtain rat hippocampal slices, 4-week-old Sprague Dawley rats (supplied by Elevage Janvier, le Genest-Saint-Isle, france) were euthanized by quick-break without anesthesia. The brain was quickly removed and immersed in ice-cold oxygenated buffer: 2mM KCl, 1.2mM NaH ₂ PO ₄ 、7mM MgCl ₂ 、0.5mM CaCl ₂ 、26mM NaHCO ₃ 11mM glucose and 250mM sucrose. Hippocampus slices 400 μm thick were prepared with a McILWAIN tissue microtome. Sections were incubated at room temperature at artificial CSF (aCSF): 126mM NaCl, 3.5mM KCl, 1.2mM NaH ₂ PO ₄ 、1.3mM MgCl ₂ 、2mM CaCl ₂ 、25mM NaHCO ₃ And 11mM glucose for at least 1 hour. During the experiment, sections were perfused continuously with oxygenated aCSF. Animals were raised and used according to french and european legislation.

Preparation of mouse hippocampal slices

Wild-type mice of 5-6 weeks of age (97; n=5-8 total/condition) were given an acute or sub-chronic (14 days) oral dose of compound (I) (0.001 mg/kg to 10mg/kg, p.o.) or vehicle (0.5% methylcellulose solution of 1% tween 80). Hippocampus slices were collected after 5 hours. Cerebellum and plasma were also obtained to measure D-serine levels achieved in experimental animals.

Electrophysiological recordings were obtained from a single hippocampal slice placed on a compartment and perfused with aCSF at a constant rate. Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded in CA1 radial layer using glass micropipettes packed with aCSF. fEPSPs were induced by electrically stimulating the Sheff side branch/traffic pathway (commissural pathway) at 0.1Hz using glass stimulation electrodes placed in radial layers.

To test the effect of compound (I) on basal synaptic transmission, an input/output (I/V) curve was constructed at the beginning of the experiment. The slope of fEPSPs was measured and plotted against the different stimulus intensities (from 0 to 100. Mu.A). Long-term potentiation (LTP) was induced by a theta burst stimulation regimen (10 bursts of 4 pulses at 100Hz, 200ms between bursts) at baseline stimulation intensity. After this conditional stimulation, a test period of 1 hour was recorded, in which the response was re-elicited by a single stimulation every 10 seconds (0.1 Hz) at the same stimulation intensity.

Results

Acute high doses (1 mM) of D-serine induced hippocampal synaptic plasticity (short-term potentiation and long-term inhibition) in rat hippocampus compared to controls (FIGS. 1A-1C). The data in fig. 1A and 1B were normalized to the 10 minute control period. D-serine increases the enhancement of the amplitude of excitatory postsynaptic potential (EPSP), although this change is not statistically significant (p= 0.0603, unpaired t-test). However, D-serine significantly reduced the decrease in EPSP amplitude (p=0.0374, unpaired t-test).

Compound (I) at a single oral dose did not significantly affect LTP (vehicle administration in mouse hippocampus based on one-way analysis of variance [ ANOVA ]) (fig. 2). In contrast, low sub-chronic oral doses of compound (I) ((0.001 mg/kg and 0.01 mg/kg) induced increased LTP, whereas higher doses (0.1 mg/kg and 10 mg/kg) were associated with decreased LTP (based on a one-way ANOVA post multiplex comparison analysis, all doses p <0.05vs vehicle) (fig. 3), indicating an increase in synaptic plasticity furthermore, a dose dependent increase in plasma and cerebellar D-serine levels was observed following sub-chronic administration of compound (I) (fig. 4a,4 b). In particular, compound (I) produced a dose dependent increase in D-serine levels in the mouse brain (from 8.7nmol/g to 34 nmol/g) and in the mouse plasma (from 213ng/mL to 490 ng/mL).

Discussion of the invention

When administered for a long period of time, compound (I) induces sensitization of the in vivo response, indicating a potential change in synaptic plasticity. Acute administration of compound (I) does not alter LTP, a phenomenon that reflects changes in neuronal synaptic plasticity. Acute changes in D-serine levels are unlikely to produce structural changes in synapses; however, a plastic change can be observed after chronic increase of D-serine levels achieved after chronic administration of compound (I). Sub-chronic administration with lower doses of compound (I) significantly increased LTP, indicating increased synaptic plasticity. Higher doses (0.1 mg/kg and 10 mg/kg) induced a decrease in LTP, indicating an inverted U-shaped dose response. This phenomenon may be the basis for the behavioral response (i.e., new object recognition task) that is observed after acute vs chronic dosing to move to the left. The shift left in the dose-response relationship reported in this study suggests that low doses may be effective in clinical trials of DAAO inhibitors such as compound (I).

Example 2: 10mg formulation (formulation 1) comprising compound (I)

Hydroxypropyl cellulose (810 g, grade l, manufactured by NIPPON SODA co., ltd.) was dissolved in purified water (12690 g) to prepare a binder solution. Compound (I) (900 g), D-mannitol (19620g,PEARLITOL 50C, manufactured by Roquette co.) and microcrystalline cellulose (2700 g, ceolus PH-101, manufactured by Asahi Kasei Corporation) were granulated in a fluidized bed granulator (FD-WGS-30, manufactured by Powrex co.) while spraying a binder solution, and then dried to obtain a granular powder. 2 batches of granular powder were prepared. The granular powder was then ground, 44060g of the obtained ground powder was weighed, low-substituted hydroxypropylcellulose (4950 g, lh-21 grade, manufactured by Shin-Etsu Chemical co., ltd.) (containing 11% hydroxypropoxy group (dry weight)) and magnesium stearate (495 g, manufactured by Taihei Chemical Industrial co., ltd.)) were added and mixed to obtain a mixed powder. The obtained mixed powder was made into tablets using a rotary tablet press (AQUARUS 08242L2JI, manufactured by KIKUSUI SEISAKUSHO LTD.) to obtain uncoated tablets having a weight of 300 mg/tablet and a diameter of 9 mm. 40500g of the obtained uncoated tablet was inserted into a Doria coater (DRC-900S, manufactured by Powrex co.) and an aqueous dispersion of hypromellose, polyethylene glycol 6000, titanium dioxide, red iron oxide, and yellow iron oxide was sprayed to prepare a film coat/tablet of 12.2mg and obtain a formulation 1 (film-coated tablet). The composition of formulation 1 (on a per tablet basis) is shown in table 2.

Table 2.Composition of each formulation 1 (10 mg formulation)

Example 3: 25mg formulation (formulation 2) comprising compound (I)

Hydroxypropyl cellulose (810 g, grade l, manufactured by NIPPON SODA co., ltd.) was dissolved in purified water (12690 g) to prepare a binder solution. Compound (a) (2250 g), D-mannitol (18270g,PEARLITOL 50C, manufactured by Roquette co.) and microcrystalline cellulose (2700 g, ceolus PH-101, manufactured by Asahi Kasei Corporation) were granulated in a fluidized bed granulator (FD-WGS-30, manufactured by Powrex co.) while spraying a binder solution, and then dried to obtain a granular powder. 2 batches of granular powder were prepared. The granular powder was then ground, 44060g of the obtained ground powder was weighed, low-substituted hydroxypropylcellulose (4950 g, lh-21 grade, manufactured by Shin-Etsu Chemical co., ltd.) (containing 11% of hydroxypropoxy groups (dry weight)) and magnesium stearate (495 g, manufactured by Taihei Chemical Industrial co., ltd.)) were added, and mixed to obtain a mixed powder. The obtained mixed powder was made into tablets using a rotary tablet press (AQUARUS 08242L2JI, manufactured by KIKUSUI SEISAKUSHO LTD.) to obtain uncoated tablets having a weight of 300 mg/tablet and a diameter of 9 mm. 40500g of the obtained uncoated tablet was inserted into a Doria coater (DRC-900S, manufactured by Powrex co.) and an aqueous dispersion of hypromellose, polyethylene glycol 6000, titanium dioxide, red iron oxide, and yellow iron oxide was sprayed to prepare 12.2mg film coat/tablet, and formulation 2 (film coated tablet) was obtained. The composition of formulation 2 (on a per tablet basis) is shown in table 3.

Table 3.Composition of each formulation 2 (25 mg formulation)

Example 4: 100mg formulation (formulation 3) comprising compound (I)

Formulation 3 (film coated tablet) containing 100mg of compound (I)/tablet can be produced by a similar production method. The composition of formulation 3 (on a per tablet basis) is shown in table 4.

Table 4.Composition of each formulation 3

Example 5: 50mg formulation (formulation 4) comprising compound (I)

Formulation 4 (film coated tablet) containing 50mg of compound (I)/tablet can be produced by a similar production method. The composition of formulation 4 (on a per tablet basis) is shown in table 5.

Table 5.Composition of each formulation 4

Example 6: evaluation of efficacy, safety, tolerability and pharmacokinetic studies of Compound (I) at 3 dose levels in adult Parametric (NCT 03382639) adjunctive treatment of negative symptoms with schizophrenia

Phase 2 randomized, double-blind, parallel group, placebo controlled, dose range discovery study clinical trial (INTERACT) was performed to determine if additional/adjuvant compound (I) was superior to placebo in treating adult patients with persistent negative symptoms of schizophrenia (clinical trial government identifier: NCT 03382639). The multicenter test was performed in the united states, bulgaric, czech republic, italy, poland, russian federation, selveya, spanish and uk. The study recruited 256 of the 503 patients to be eligible for screening (tables 5, 6). Qualified participants were 18-60 years old, had symptoms-stable schizophrenia, and had a baseline concise negative symptoms scale (BNSS) score of 28 points or more (12, excluding item 4). In addition, qualified participants are receiving a 2-6mg daily dose of stabilized antipsychotic medication of risperidone equivalent and are allowed to be treated with a second antipsychotic medication if they are used as hypnotics at sub-therapeutic doses (subject to sponsor approval). The most common combined antipsychotic agents are aripiprazole (25.4%), olanzapine (18.8%), risperidone (18.0%) and quetiapine fumarate (9.4%). To overcome potential confounding effects, those patients with depression and extrapyramidal symptoms were excluded.

Participants were randomly assigned (accidentally, e.g., coin thrown) to one of four treatment groups during the double blind period: (1) Compound (I) 50mg once per day (5 formulation 1 tablets); (2) Compound (I) 125mg once daily (5 formulation 2 tablets); (3) Compound (I) 500mg once daily (5 formulations 3 tablets); and (4) placebo, once daily (5 oral placebo tablets). Dose selection for this study was based on target occupancy and elevation of D-serine.

In general, 256 participants were randomly divided into 3:2:2:2, and each received placebo, 50mg of compound (I), 125mg of compound (I), and 500mg of compound (I), 228 (89.1%) participants completed the study. The average age of the participants was 40 years (18-60 years), 168 (65.6%) men, and 208 (81.3%) white. Demographic and baseline characteristics were evenly distributed in the treatment group.

Compound (I) is orally administered once daily in the form of a tablet for up to 14 weeks. Compound (I) placebo-matched tablets were similarly orally administered once daily for up to 14 weeks. Unless there is an urgent medical need, the treatment group remains secret to the participants and the researcher/field staff during the study.

Inclusion criteria for this study included:

1. current diagnosis of schizophrenia is as defined by brief international neuropsychiatric disorder interview (MINI) 7.0.2 for psychotic disorders, manual for diagnosis and statistics of psychotic disorders, 5 th edition (DSM-5) and general psychiatric assessments.

2. The initial diagnostic day must be greater than or equal to (> =1) years from screening.

3. The total daily dose of risperidone equivalent of 2-6mg is receiving the primary background (primary background) antipsychotic therapy (except clozapine). If used to treat a particular symptom, such as insomnia or anxiety, then a combination therapy with a subtherapeutic dose of a second antipsychotic agent (e.g., quetiapine 25-50mg or equivalent thereof as needed for anxiety) may be approved by the sponsor or designer, but not if used for refractory positive psychotic symptoms.

4. Treatment with the stable psychotropic regimen for 2 months at the prescribed dose was not clinically significant change (dose was not increased, less than or equal to [ < = ]25% [% ] tolerogenic dose reduction) prior to screening visit, and no dose adjustment was expected until day 84/premature termination of visit throughout study participation.

5. With BNSS total score (12 terms, excluding No. 4) > =28; stable single-blind placebo introduction and baseline BNSS total score (12, no. 4 included) (< = 20% change from screening).

6. There are no more than moderate-severe (< = 5) ratings on PANSS positive symptom items P1 (delusions), P3 (hallucinations behaviors), P4 (excitations), P5 (exaggerations), P6 (suspects), and/or G9 (unusual ideas), with a maximum of 2 items rated "5"; no medium (<=4) scale is exceeded on P2 (conceptual disorder).

7. There is evidence that participants had stable symptomatology > =3 months prior to screening visits (e.g., no hospitalization for schizophrenia, no emergency room entry due to symptoms of schizophrenia, no increase in psychiatric care levels due to worsening of symptoms of schizophrenia).

8. Having an adult informative, he would be able to provide input (e.g., family members, social workers, individual case workers, residential facility workers or nurses, at the expense of participants > =4 hours/week) for completing a study rating scale including PANSS and SCoRS, and be considered reliable by the researchers. The informative staff must be able and willing to provide written informed consent and participate in at least 1 in-person interview, and then be able to provide continuous input for other study visits including PANSS or SCoRS endpoints by participating in each clinical assessment visit or by participating in a telephone interview.

The exclusion criteria for this study included:

1. lifetime diagnosis of schizoaffective disorders based on MINI in combination with general psychiatric assessment; lifetime diagnosis of bipolar disorder; or lifetime diagnosis of obsessive-compulsive disorder.

2. Based on MINI and general psychiatric evaluations with respect to DSM-5, panic disorder, depressive episode or other co-morbid mental condition currently requiring clinical attention occurred recently (within the last 6 months).

3. Based on MINI and general psychiatric evaluations with respect to DSM-5, there was a diagnosis of substance use disorders (other than nicotine dependence) during the previous 6 months.

4. The non-pharmaceutical social psychology therapeutic treatment regimen (cognitive correction, cognitive-behavioral therapy, intensive symptoms/occupational rehabilitation) that is participating in formal structuring prior to randomization is less than (<) 3 months in duration. Furthermore, by day 84 access, such non-drug treatment procedures were not allowed to be initiated during study participation.

5. Participants exhibited parkinsonism symptoms that exceeded the minimum level of antipsychotics, as recorded by scores greater than (>) 6 on the modified Simpson Angus Scale (SAS) (item 10 No. is excluded, akathisia).

6. There was evidence of depression (> 9) measured by the Calgari Depression Scale Score (CDSS).

7. Researchers consider that there is an impending risk of suicide or injuring themselves, others or property, or that participants try suicide in the past year prior to screening. Participants with positive answers to item numbers 4 or 5 on the columbia suicide severity rating scale (C-SSRS) (based on the last year) prior to randomization were excluded.

8. With a history of brain trauma associated with > 15 minutes of loss of consciousness.

9. Diagnosis of schizophrenia occurs before age 12.

10. The electric shock therapy was received within 6 months (180 days) prior to screening.

11. Has a history of developing mental disorders or mental retardation.

12. The antipsychotic plasma level for the principal background antipsychotic of the participants was below the minimum acceptable concentration standard for each antipsychotic reference at the screening visit or placebo-introduced visit. This standard is not applicable to participants in major background antipsychotics where clinical trials are not available.

13. Is resistant to treatment. Treatment resistance is defined as the previous non-response of positive symptoms of schizophrenia to 2 courses of treatment with different chemical classes of antipsychotics for at least 4 weeks, each at a dose considered effective.

14. There is no stable home or home-free.

The study included a 28 day screening period, a 14 day single-blind placebo-introduced period to prospectively evaluate drug compliance and BNSS score stability, and a 12 week double-blind treatment period (fig. 5). The total time spent in the study was about 20 weeks. Participants who completed this study typically underwent 11 visits to the clinic and followed up safety assessment 10 to 14 days after the last administration of compound (I) (day 98). Demographic, baseline characteristics, and efficacy assessments were based on a full analysis set that included randomized participants who received at least one dose of study drug during the treatment period (table 6). The safety analysis set includes randomized participants who received at least one dose of study drug. All 256 enrolled patients were included in the full and safety analysis sets.

Table 6.Baseline demographics and clinical characteristics of enrolled patients in the INTERACT study (full analysis set)

BACS, a complete set of measurement and evaluation values for cognitive functions of schizophrenia; max, max; min, min; PANSS NSFS, positive and negative symptom scale-negative symptom factor score; SCoRS, cognitive function rating scale for schizophrenia; SD, standard deviation.

The primary endpoint of the evaluation was the change in negative symptoms measured as a 12 week change from baseline in the positive and negative symptom scale-negative symptom factor score (PANSS NSFS). For negative symptoms, no significant PANSS NSFS improvement over placebo (p=0.426, p=0.362 and p=0.808, respectively) was observed with 50mg, 125mg or 500mg of compound (I) at week 12. From baseline to week 12, regarding the Least Squares (LS) mean change of PANSS NSFS, compound (I) 50mg, 125mg and 500mg were-3.3 (95% confidence interval [ CI ], -4.3 to-2.2), -3.4 (95% CI, -4.4 to-2.3) and-2.5 (95% CI, -3.6 to-1.5), and placebo-3.1 (95% CI, -4.0 to-2.3), respectively (FIG. 6). In addition, no significant improvement was observed in negative symptoms as measured with BNSS.

Safety endpoints included assessment of adverse events (TEAE) that were emergent in treatment. A total of 76 participants (29.7%) experienced TEAE, of which 23 (9%) were considered drug-related by the investigator. Most TEAEs were mild or moderate in severity (table 7). TEAE present in more than 5 participants (greater than or equal to 2% of study participants) was headache, insomnia and weight gain, which was observed with similar frequency in compound (I) and placebo groups. Mild, moderate and severe TEAE occurred in 49 (19.1%), 24 (9.4%) and 3 (1.2%) participants, respectively. Severe events of rhabdomyolysis (placebo, n=1) and chronic cholecystitis (compound (I) 50mg, n=1) were not considered drug-related. Severe schizophrenia was reported in one participant taking 125mg of compound (I) and was considered to be drug-related severe TEAE. Four severe TEAEs were reported in the placebo group; none are considered drug related. Five participants, including three participants taking placebo, experienced TEAE (increased creatine phosphokinase, increased liver function test, psychiatric disorder) that resulted in interruption. No deaths were reported and no clinically significant findings were observed between groups in terms of safety, laboratory, vital sign or electrocardiographic assessment.

Table 7.Incidence of TEAE in enrolled patients in INTERACT study (safety analysis set)

To assess changes in cognitive impairment associated with schizophrenia (CIAS), secondary endpoints included 12 weeks from baseline in a brief set of cognitive function scores (BACS) score for schizophrenia (a measure of cognition across multiple areas) and a cognitive function rating scale for schizophrenia (SCoRS) score (a measure of daily cognitive function requiring input from an adult informative). Secondary endpoints were not corrected for multiplicity.

For CIAS, nominally significant improvement in cognitive assessment and patient cognitive function in BACS synthesis score (p=0.031; effector, 0.4, not corrected for multiplexing, fig. 7) and SCoRS interviewer total score (p=0.011; effector, 0.4, not corrected for multiplexing, fig. 8) was observed with compound (I) 50mg versus placebo, but either 125mg or 500mg of compound (I) was not observed. For BACS synthesis scores, an average change in LS of 4.6 (95% ci,2.7 to 6.5) was observed with compound (I) 50mg from baseline for 12 weeks versus 2.3 (95% ci,0.7 to 3.9) observed with placebo. For the SCoRS interviewer total score, an average change in LS from baseline of-3.8 (95% CI, -5.3 to-2.3) was observed with compound (I) 50mg over 12 weeks versus-1.6 (95% CI, -2.9 to-0.3) observed with placebo.

BACS is specifically designed to measure treatment-related cognitive improvements and includes alternative forms. BACS is a reliable and sensitive measure of cognitive function in schizophrenia. BACS is a cognitive assessment kit that assesses 6 domains of cognitive function found to be consistently impaired in schizophrenia: speech memory; a working memory; a movement speed; attention; executing a function; and speech fluency. The primary measurement from each test of the BACS was normalized by creating a T score, thereby setting the average of the test sessions of the matched reference healthy participants to 50 and the standard deviation to 10. Preliminary analysis of BACS assessment results are summarized in tables 10-16.

SCoRS is an interview-based measure of cognitive function that was developed to specifically evaluate multiple aspects of cognitive function in participants with schizophrenia. The project evaluates 7 cognitive domains of attention, memory, reasoning and solving problems, working memory, processing speed, language functions and social cognition. The SCoRS overall is divided into a sum of 20 items and varies from 20 to 80, with 20 being the best result and 80 being the worst result. The preliminary analysis from the SCoRS evaluation results is summarized in table 17.

Compound (I) did not show significant efficacy in treating negative symptoms of schizophrenia at the three doses assessed in the intermittent study. However, compound (I) 50mg showed improvement in cognitive test performance and also showed improvement in daily cognitive function from self-assessment and informative assessment, as measured by BACS synthesis score and SCoRS interviewer total score, respectively, with a clinically significant effector dose of 0.4 for each. For CIAS, an inverted U-shaped dose response was observed with compound (I) 50mg, 125mg and 500 mg. As described in example 1, an inverted U-shaped dose response was also observed in a long-term boost study in an in vitro model conducted in parallel with the intermittent study. Additional clinical studies were authorized to further evaluate the efficacy signal. In agreement with previous clinical experience, compound (I) is generally well tolerated in the intermittent study.

Table 8.Tendency of the subject (preliminary analysis)

Note 1:the percentages are based on the total number of subjects in the analysis set for each treatment group receiving at least one dose of study drug.

And (2) injection:the percentage of study drug/cause of study disruption is based on the total number of subjects prematurely interrupting the study drug/study.

Table 9.Demographic and baseline characteristics (preliminary analysis)

Note 1:the percentages are based on the total number of subjects in the analysis set for each treatment group.

And (2) injection:if a subject records more than one ethnic category on a CRF, the subject is only included in the multi-ethnic category.

And (3) injection:the age at screening was calculated from the date of informed consent.

And (4) injection:spanish race is entered only for american sites. The ethnicity for non-U.S. sites will be categorized as "unreported".

Table 10:baseline changes on BACS pool by interview analysis (preliminary analysis)

CI-confidence interval; LS-least squares method; SE-standard error.

Note 1:using a Mixed Model of Repeated Measurements (MMRM), taking the baseline BACS synthesis score as covariate; the age (random factor) of the pooled sites, visit, treatment and classification as a fixed factor; and treatment-visit-and baseline-visit interactions, analyzing changes from baseline in BACS synthesis score. Based on the absence under the random assumption, the analysis will be performed using only observed cases. The P-value is unilateral, with the alternative assumption that compound (I) is better than placebo in a clinically favourable sense.

And (2) injection:(a) Baseline was defined as the last observed value before the first administration of study drug.

Table 11:baseline changes in BACS speech memory cognitive domain by interview analysis (preliminary analysis)

CI-confidence interval; LS-least squares method; SE-standard error.

Note 1:using a Mixed Model of Repeated Measurements (MMRM) with baseline BACS speech memory cognitive domain as covariates; the age (random factor) of the pooled sites, visit, treatment and classification as a fixed factor; and treatment-visit-and baseline-visit interactions, analyzing changes from baseline over the f-speech memory cognitive domain. Based on the absence under the random assumption, the analysis will be performed using only observed cases. The P-value is unilateral, with the alternative assumption that compound (I) is better than placebo in a clinically favourable sense.

Table 12:baseline changes in BACS working memory cognitive domain by interview analysis (preliminary analysis)

CI-confidence interval; LS-least squares method; SE-standard error.

Note 1:using a Mixed Model of Repeated Measurements (MMRM), taking the baseline BACS working memory cognitive domain as covariate; the age (random factor) of the pooled sites, visit, treatment and classification as a fixed factor; and treatment-visit-and baseline-visit interactions, analyzing changes from baseline over the BACS working memory cognitive domain. Based on the absence under the random assumption, the analysis will be performed using only observed cases. The P-value is unilateral, with the alternative assumption that compound (I) is better than placebo in a clinically favourable sense.

Note 2: (a) Baseline was defined as the last observed value before the first administration of study drug.

Table 13:baseline changes in BACS motor speed cognitive domain by interview analysis (preliminary analysis)

CI-confidence interval; LS-least squares method; SE-standard error.

Note 1:hybrid model (MMRM) using repeated measurements for baseline BACS transportThe motor speed cognitive domain is used as a covariate; the age (random factor) of the pooled sites, visit, treatment and classification as a fixed factor; and treatment-visit-and baseline-visit interactions, analyzing changes from baseline over the BACS motor speed cognitive domain. Based on the absence under the random assumption, the analysis will be performed using only observed cases. The P-value is unilateral, with the alternative assumption that compound (I) is better than placebo in a clinically favourable sense.

Table 14:baseline changes in BACS attention cognitive domain by interview analysis (preliminary analysis)

CI-confidence interval; LS-least squares method; SE-standard error.

Note 1:using a Mixed Model of Repeated Measurements (MMRM), taking the baseline BACS attention cognitive domain as covariate; the age (random factor) of the pooled sites, visit, treatment and classification as a fixed factor; and treatment-visit-and baseline-visit interactions, analyzing changes from baseline over the BACS attention cognitive domain. Based on the absence under the random assumption, the analysis will be performed using only observed cases. The P-value is unilateral, with the alternative assumption that compound (I) is better than placebo in a clinically favourable sense.

Table 15:baseline changes in the functional cognitive domain performed by the Access analysis (preliminary analysis)

CI-confidence interval; LS-least squares method; SE-standard error.

Note 1:performing a functional cognitive domain with a baseline BACS as covariates using a Mixed Model of Repeated Measurements (MMRM); the age (random factor) of the pooled sites, visit, treatment and classification as a fixed factor; and treatment-visit-and baseline-visit interactions, analyzing changes from baseline over the BACS executive function cognitive domain. Based on the absence under the random assumption, the analysis will be performed using only observed cases. The P-value is unilateral, with the alternative assumption that compound (I) is better than placebo in a clinically favourable sense.

Table 16:baseline changes in BACS speech fluency cognitive domain by interview analysis (preliminary analysis)

CI-confidence interval; LS-least squares method; SE-standard error.

Note 1:using a Mixed Model of Repeated Measurements (MMRM), taking the baseline BACS speech fluency cognitive domain as covariate; the age (random factor) of the pooled sites, visit, treatment and classification as a fixed factor; and treatment-visit-and baseline-visit interactions, analyzing changes from baseline over the BACS speech fluency cognitive domain. Based on the absence under the random assumption, the score will be performed using only observed cases And (5) separating. The P-value is unilateral, with the alternative assumption that compound (I) is better than placebo in a clinically favourable sense.

Table 17.Analysis of baseline changes in SCoRS interviewer total score at week 12 (preliminary analysis)

Note 1:using a Mixed Model of Repeated Measurements (MMRM), taking a baseline SCoRS interviewer total score as a covariate; the age (random factor) of the pooled sites, visit, treatment and classification as a fixed factor; and treatment-visit-by-visit and baseline-visit interactions, analyzing changes from baseline in the SCoRS interviewer total score. Based on the absence under the random assumption, the analysis will be performed using only observed cases. The P-value is unilateral, with the alternative assumption that compound (I) is better than placebo in a clinically favourable sense.

* Statistical significance (single sided) at the 0.025 level is indicated.

Example 7: evaluation of efficacy, tolerability, pharmacodynamics and pharmacokinetics studies of Compound (I) at various oral dosage levels in adults with schizophrenia (NCT 03359785)

NCT03359785 is a randomized, double-blind, placebo-controlled, cross-over phase 1b clinical trial in schizophrenic patients for evaluation of PD effects, safety, tolerability and pharmacokinetics of multiple oral doses of compound (I). The aim of this study was to assess the effect of the Pharmacodynamic (PD) biomarkers of compound (I) on cerebellar circuit function and NMDA pharmacology related measurements known to be affected in schizophrenia.

The study employed a two-sequence, two-way crossover design, in which participants received 50 or 500mg of compound (I) and placebo for 8 consecutive days in two periods separated by a 2-week or 3-week washout period (fig. 9).

The primary endpoint was the average percentage of conditional response during the blink conditioned reflex (EBC) test at day 8 of each treatment period (fig. 10). EBC was used to evaluate the effect of compound (I) on cerebellar circuit function. EBC is a highly conserved reflex that depends on the cerebellar circuit, where NMDA receptors play a key role. EBC was impaired in patients with schizophrenia compared to healthy controls. In preclinical studies, compound (I) has shown a powerful effect in reversing scopolamine induced EBC defects (see, e.g., example 2 of WO 2015/132608).

Evoked potentials in electroencephalograms were also tested to assess the effect of multiple oral doses of compound (I) on the NMDA-sensitive physiological response affected in schizophrenia. Specifically, mismatch negatives (MMN), auditory steady-state responses (ASSR), and P300 were measured at baseline and 8 days after treatment over two periods.

MMN is a singular event related potential that is pharmacologically sensitive to NMDA-receptors. MMN is an event-related potential (ERP) induced by an unattended change in response to background stimulus and increases in response to D-serine. There is evidence that D-serine administration improves MMN in schizophrenic patients. MMN reflects an automated process of detecting mismatch between the bias stimulus and the sensory memory trace (fig. 11a,11 b). Smaller MMN amplitudes have been consistently established in schizophrenic participants with large amounts of effects compared to healthy controls. In this study, MMN amplitudes were measured at the midline She Dianji (Fz) of the electroencephalogram [ EEG ].

The P300 wave is an ERP component (component) that results from the presentation of a novel, behavior-related target stimulus embedded in an uncorrelated stimulus in a manner similar to MMN, but requires active listening and response by participants. Auditory stimuli are presented in a stimulation sequence (oddball paradaigm) consisting of 1 standard tone and 1 target tone. Participants are instructed to press the button as soon as possible when they hear the target tone, but not when they hear the standard tone. P300 reflects the allocation of attention and the activation of immediate memory. The P300 amplitude indicates brain actions when the psychological characterization of the stimulus environment is updated, while the P300 latency indicates the stimulus classification speed independent of the response selection process. The P300 amplitude was measured at the midline top leaf electrode (Pz) of the EEG.

ASSR is an evoked oscillatory response that is entrained to the frequency and phase of the time modulated stimulus. Individuals suffering from schizophrenia experience subjective paresthesia and objective defects in sensory function assessment. These defects may be caused by aberrant signaling in sensory pathways and sensory cortex or by late disorders in cognitive processing of such inputs. ASSR may be used to assess the integrity of sensory pathways, including cortical processing. ASSR is measured at the midline central electrode (Cz) of the EEG.

Secondary endpoints of the study included: (1) Average mismatch negative wave (MMN) amplitude at day 8 of each treatment session; (2) Average Auditory Steady State Response (ASSR) on day 8 of each treatment period; and (3) a brief set of cognitive function assessment (BACS) scores for schizophrenia on day 7 of each treatment period.

All groups were also analyzed for D-serine and L-serine levels. Specifically, other secondary outcome measures include: (1) Average concentration of plasma D-serine and L-serine levels on day 8; (2) Average of the ratio of plasma D-serine to total serine at day 8; and (3) average plasma concentration of compound (I).

Safety goals include incidence of emergent adverse events (TEAE) in treatment, laboratory tests, vital signs, and Electrocardiographic (ECG) assessment.

All endpoints were analyzed as baseline changes compared to placebo in the same subject. Statistical comparisons were performed using the ANOVA model with treatment timing, time period, and treatment as fixed effects and subjects as randomized effects. As a complementary analysis, analysis of covariance model (ANCOVA) was applied to the primary endpoint with (time period) baseline as covariates, treatment timing, time period, treatment effect and treatment baseline as fixed effects, and subjects as randomized effects.

Covd-19 affected the study, resulting in fewer completors than originally planned, which affected the strength of the study. Thus, the data is considered exploratory in nature, and the focus of the study is the directionality of the changes and effects.

Phase 1b study recruited 31 patients 18-60 years old. The participants were symptomatically stable schizophrenic patients and received stable antipsychotics for more than 2 months. For each dose, 12 patients completed the active and placebo phases. The patients were mainly men (26/31) and african americans (26/31). 14 patients were randomly allocated to 50mg of Compound (I) (median age 45 years; 11 men), and 12 completed the study. 17 patients were randomly assigned to 500mg of Compound (I) (median age 34 years; 15 men), and 12 completed the study.

Inclusion criteria for this study included:

1. has a value greater than or equal to (> =) 18.5 and less than or equal to%<=) 40.0 (kg/square meter [ kg/m ] ² ]) Body Mass Index (BMI).

2. Using the current manual for diagnosis and statistics of mental disorders, the fifth edition (DSM-5) diagnosis of schizophrenia is receiving stable antipsychotic medication (no increase in dose, no greater than [ > ]20% decrease in dose over the previous 2 months).

3. Positive and negative symptom scale (PANSS) Negative Symptom Factor Score (NSFS) > =15, stable screening and baseline PANSS NSFS (< 25% change).

Panss total score < = 90; stable screening and baseline PANSS total score (less than [ < ]20% change).

5. Stable (no increase in dose over the previous 2 months, no > 25% decrease in dose) antipsychotics were received at doses not exceeding 6mg risperidone or its equivalent. If it is used as a hypnotic (maximum daily amount of quetiapine 300mg or equivalent thereof before sleep) and the subject does not exhibit morning sedation, it may be approved by the sponsor or designer to allow the use of a combination treatment of a sub-therapeutic dose of a second antipsychotic, but not if used for refractory positive psychotic symptoms. In this exceptional case, the total daily dose of the second antipsychotic agent is not necessarily included in the calculation of the equivalent limit of 6 mg/day risperidone.

The exclusion criteria for this study included:

1. with a history of cancer (malignancy), excluding treated basal cell carcinoma and treated stage 0 (in situ) cervical cancer.

2. Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy), or has had an allergic reaction or significant intolerance to prescription or over-the-counter drugs or foods.

3. In a screening visit or registration, QT interval (QTcF) > 450 ms (male) or > 470ms (female) using the friericia's correction method was confirmed with one repeat test.

4. Positive for drug screening results for alcohol or illicit substances including amphetamines, barbiturates, cocaine, marijuana, methadone, methamphetamine, 3, 4-methylenedioxymethamphetamine, phencyclidine, or over-the-counter benzodiazepines or opioids.

5. Positive for hepatitis b surface antigen (HBsAg), hepatitis c antibodies, or history of HIV (confirmatory test is allowed; most sensitive test should be preferred).

6. Major surgery was performed within 4 weeks prior to the pre-study (screening) visit, with 250 milliliters of [ mL ] blood being donated or lost.

7. Has a known hypersensitivity reaction to any of the components of the compound (I) formulation.

8. There is a history of significant skin reactions (hypersensitivity reactions) to adhesives, metals or plastics.

9. Researchers consider that there is an impending risk of suicide or injuring themselves, others or property, or that participants try suicide in the past year prior to screening. Participants with positive answers to item numbers 4 or 5 on the columbia suicide severity rating scale (C-SSRS) (based on the last year) prior to randomization were excluded.

Baseline changes in EBC for the primary endpoint. An improved trend was observed with compound (I) 50mg (p=0.109) compared to placebo, but no improved trend was observed with compound (I) 500mg (p=0.777) (fig. 12a,12 b). The effect amounts of 50mg of compound (I) and 500mg of compound (I) were 0.246 and-0.198 (ANCOVA), respectively.

At the secondary endpoint, 50mg of compound (I) improved MMN amplitude (became more negative than baseline) compared to placebo, but 500mg of compound (I) did not improve (fig. 13a,13 b). The difference between 50mg and placebo in the baseline variation of the LS mean was statistically significant (50 mg: -0.239 (-0.863 to 0.386), placebo: 0.669 (0.012 to 1.326), p= 0.0497, effector: -0.691). The 500mg dose was not significantly different from placebo in baseline variation (500 mg:0.594 (-0.245 to 1.432), placebo: -0.154 (-1.008 to 0.700), p= 0.8517, and effector: 0.389).

ASSR gamma band power showed a numerical increase from baseline of 50mg with compound (I) and no compound (I) 500mg compared to placebo (fig. 14a,14 b). The 50mg dose showed a larger baseline change in ASSR gamma band power than placebo, but only a trend towards significance (50 mg:2.135 (-13.127 to 17.396), placebo: -16.282 (-32.353 to-0.211), p=0.056, effector: 0.575). The baseline variation of the 500mg dose was similar to placebo (500 mg:9.411 (-26.018 to 44.480), placebo: 9.203 (-26.981 to 45.387), p=0.495, and effector: 0.003).

Compound (I) is generally well tolerated. No mortality, serious Adverse Events (AE) or TEAE led to discontinuation of study drug. In addition, there were no significant findings in safety, laboratory or ECG evaluations. Of the five adverse events reported, all were mild and not considered relevant to study drug, and all patients recovered.

In summary, compound (I) showed a statistically significant improvement in MMN amplitude and a numerical improvement in ASSR gamma band power in stable schizophrenic patients (fig. 15). These effects were only observed at the lower dose of 50mg, but not at 500 mg. These results support findings from a recently completed phase 2 INTERACT study (clinical trial government identifier: NCT 03382639) that showed improvements in BACS and cognitive function rating scale (SCoRS) in schizophrenic patients at 50mg for 12 weeks, but not in patients at 500 mg. The higher effect of lower doses observed (potential inverted U-shaped dose response) is consistent with preclinical data of compound (I) (e.g., preclinical studies of compound (I) on long-term enhancement of mice) and general NMDA receptor pharmacology. Although the effect on the primary EBC endpoint was not significant, this may be due to insufficient sample size for this assay. Overall, the data indicate that low doses of compound (I) improve the results of neural circuit activity associated with NMDA receptor pharmacology and with cognitive performance in schizophrenia. Furthermore, in conjunction with the INTERACT study, it was found that MMN is a potential biomarker for NMDA pharmacology that predicts prolonged post-treatment cognitive improvement.

Example 8: randomized, double-blind, placebo-controlled, parallel-group studies to evaluate the efficacy, safety and tolerability of compound (I) in subjects suffering from cognitive impairment associated with schizophrenia followed by open label treatment

A 2b phase, randomized, double-blind, parallel, placebo-controlled study with a 12 month open label extension will be performed to evaluate the efficacy, safety and tolerability as well as Pharmacokinetics (PK) of the treatment with compound (I) when administered orally once daily as an adjunctive treatment to improve the symptoms of cognitive impairment associated with schizophrenia (CIAS). In addition, the study will evaluate the long-term safety and tolerability of treatment with 50mg of compound (I) QD.

Phase 2b studies will be conducted at about 45 study centers in areas including, but not limited to, north america and europe, and will recruit about 308 adult subjects with schizophrenia. The expected study participation duration for each subject was approximately 72 weeks, including 4 weeks of screening, 14 weeks of double-blind treatment, 52 weeks of open label treatment, and 2 weeks of follow-up. In order to obtain as objectively as possible an assessment of the severity of symptoms during treatment with compound (I), the researchers and the staff interacting with the researchers will be blinded to: a randomization occasion; timing of endpoint assessment; and details of statistical analysis methodologies.

The study will recruit 18 to 50 year old male and female patients with schizophrenia as defined by MINI version 7.0.2, wherein the initial diagnosis of schizophrenia in the patients must occur more than one year prior to screening (visit 1). The subject must have stable symptomology for at least 3 months prior to screening, and must be currently receiving a prescribed dose of at least 2 months of a stable regimen of the therapeutic psychotic drug prior to screening without clinically significant changes (dose not increased, dose reduced <25% for tolerance). Furthermore, the subject must have limited PANSS symptoms.

The subject must meet all of the following inclusion criteria:

1. completed written informed consent.

2. The subject must be 18 to 50 years old (including 18 and 50 years old) and be able to follow all protocol procedures.

3. Diagnosis of psychotic disorders and diagnosis of schizophrenia as defined in the handbook of statistics 5 th edition (DSM-5).

4. The initial diagnosis of schizophrenia must be greater than or equal to 1 year prior to screening.

5. Subjects are currently receiving a stable regimen of drugs for treating psychosis.

6. Subjects had stable symptomatology ≡3 months prior to screening visit.

7. The subject must have an adult informative.

8. A body weight of at least 45kg and a weight of 18.0 to 40.5kg/m ² Body Mass Index (BMI), inclusive.

Furthermore, subjects will be excluded from the study if they meet any of the following criteria:

1. pregnancy or lactation or pregnancy during the study is planned.

2. Exhibit extrapyramidal signs/symptoms exceeding a minimum level.

3. Diagnosis of schizophrenia occurs before 12 years of age.

4. Lifetime diagnosis of schizoaffective disorder, bipolar disorder or obsessive-compulsive disorder.

5. Recent occurrences of panic disorder, depressive episode, or other co-morbid mental conditions.

6. The researcher considers that there is an impending risk of suicide or injury to himself, others or property, or that the subject tries suicide within 6 months prior to screening.

7. Moderate or severe substance use disorders (other than nicotine dependence) were diagnosed within 12 months prior to screening.

8. The screening of the drugs of forbidden substances is positive.

9. Any other medical or psychiatric condition or cognitive impairment that may interfere with study performance or clinical assessment.

Screening period (day-28 to day-1)

At screening visit, subjects who provided informed consent and met the current diagnosis of schizophrenia as defined by the brief international neuropsychiatric disorder interview (MINI) version 7.0.2 will undergo additional screening evaluations to determine eligibility. In addition, adult informative staff must provide written informed consent and participate in at least one screening interview at the study site during the screening period (day-28 to day-1). Compliance with background daily oral antipsychotic drug will be assessed throughout the screening period (day-28 to day-1) using drug compliance application; subjects using long-acting injectable antipsychotics do not use drug compliance applications during the screening period.

Double blind treatment period (day 1 to 98)

Qualified subjects were randomly assigned (1:1:2) to receive 20mg of compound (I), 50mg of compound (I) or placebo, orally QD, during a 14 week double-blind treatment period. Subsequently, all subjects who completed the double blind treatment period and continued study treatment will enter the open label treatment period of 12 months and receive 50mg QD of compound (I). Final safety follow-up was performed about 2 weeks after the last dose of study treatment (day 476 [ visit 21 ]). A study design schematic is provided in fig. 16A (screening and double blind treatment periods) and fig. 16B (open label treatment and safety follow-up period).

The subjects will be instructed to take two tablets QD with water or milk in the morning and avoid drinking the juice 1 hour before and 1 hour after the study treatment. Compound (I) will be provided for oral administration as a matched tablet dosage form of 10mg and 25 mg. Compliance with study treatment will be monitored by drug compliance application.

The subject will have a field study visit and a virtual study visit. Throughout the double-blind treatment period (day 1 to day 98), efforts were made at approximately the same time per day and using the same raters for cognitive and cognitive function assessment.

Throughout the double-blind treatment period (days 1 to 98), compliance with the background daily oral antipsychotic medication will continue to be assessed; subjects using long-acting injectable antipsychotics will use drug compliance applications to record study treatment intake alone.

Open label treatment period (day 99 to 462)

After having been evaluated on day 98 (visit 7), all subjects continuing the study treatment will enter the open label treatment period of 12 months and receive 50mg QD of compound (I). Dose reduction or adjustment will not be allowed during this period. The subjects were instructed to take two tablets (25 mg each) of QD starting in the morning on day 99. As in the double blind treatment period, subjects will be instructed to take two tablets with water or milk in the morning and avoid drinking juice 1 hour before and 1 hour after study treatment. The subject will have a field study visit and a virtual study visit.

Final safety follow-up was performed 14 days after the last administration of study treatment (day 476 [ visit 21 ]) for each subject.

Efficacy endpoint

The main endpoint of the study will be the baseline change in the cognitive function conciseness of the set of scores (BACS) for schizophrenia at day 98.

The key secondary endpoint would be a baseline change in the cognitive function rating scale (SCoRS) interviewer score for schizophrenia on day 98.

Additional secondary endpoints would include: (1) Baseline changes on day 98 continuous operation test-same paired (CPT-IP) test; (2) Baseline changes on the simple visual space memory test-revised (BVMT-R) test on day 98; (3) Baseline changes on Mayer-saloviy-caroso mood quiz (MSCEIT) on day 98; (4) Baseline changes on the Virtual Reality Functional Capability Assessment Tool (VRFCAT) on day 98; and (5) baseline change in clinical global impression-severity scale (CGI-S) score on day 98 BACS is a cognitive assessment kit that assesses the following 6 domains of cognitive function found to be consistently impaired in schizophrenia: speech memory, processing speed, working memory, speech fluency, motor function, and executive function. It is scientifically validated and has a high degree of reliability and susceptibility to damage (keefa et al 2004). The BACS evaluates the function of aspects related to cognitive improvement, and its overall score can be used to evaluate overall cognitive function. See, for example, bralet MC, navale M, eskenazi AM, lucas-Ross M, falisard b.int er e t d 'un nouvel instrument dans l' e valuation cognitive dans la schizophr e nie [ Interest of a new instrument to assess cognition in schizophrenia: the Bmief Assessment of Cognition in Schizophrenia (BACS) ], encephole.2008; 34 (6): 557-62.French. BACS assessment was designed to facilitate non-psychologist administration and scoring. It is specifically designed to measure treatment-related cognitive improvements, is available in a variety of languages, and has a large database of available normative data that can be used to generate normalized scores. BACS (BACApp) based tablet versions originally developed AS a paper pen assessment have been developed and validated against the original version (see, e.g., atkins AS, tseng T, vaughan A, et al validization of the tablet-administered Brief Assessment of Cognition (BACApp). Schizophr Res.2017;181: 100-6), and automated reaction capture and scoring was employed. BACS assessment takes about 35 minutes to complete. BACS will be managed and scored throughout the double-blind treatment period (day 1 to day 98) by researchers or other qualified field personnel.

Schizophrenic cognitive function rating scale (SCoRS) interviewer score is a scientifically validated measure of visitor-based cognitive function. It was developed to specifically evaluate the cognitive function of aspects found in each of the 7 cognitive domains, assessed by MATRICS recognized cognitive complete test (MCCB), which is the primary outcome measure of new drug clinical studies for improving cognition in schizophrenia. See, e.g., keefa RS, poe M, walker TM, kang JW, harvey PD. "The Schizophrenia Cognition Rating Scale: an interactive-based assessment and its relationship to cognition, real-world functioning, and functional capability, "Am J psychiatry.2006;163 (3): 426-32 the scale is intended to incorporate information from an information member whose response is based on his/her interaction with and knowledge of the subject. SCoRS includes 20 items focusing on cognitive impairment and the extent to which cognitive impairment affects daily functions, as well as an overall functional scale; at the time of follow-up, there is also an overall scale reflecting the changes from the subject's start of treatment assessed by the manager, the information staff and the subject. The SCoRS evaluation takes about 12 minutes to complete. SCoRS will be managed and scored by researchers or other qualified field personnel throughout the double-blind treatment period (day 1 to day 98).

Continuous operation test-the same paired (CPT-IP) test evaluates sustained attention and alertness. See, e.g., keilp JG, herrra J, stratzke P, cornblatt ba. "The continuous performance test, identical pairs version (CPT-IP): brain functioning during performance of numbers and shapes subtask. "Psychiatry res.1997;74 (1): the test is a variant of the original CPT and is designed to be more cognitively challenging than the original CPT. In this computerized test, 150 stimuli (4-digit numbers) will flash rapidly in sequence; the subject is required to press the response button every time 2 identical stimuli occur in a row. In each test there were 30 identical pairs and an equal number of "capture" trials (very similar but not identical pairs of stimuli). The remaining 90 stimuli were dissimilar and randomly organized. This version of CPT-IP includes a series of practical sequences that will initially use a 2-bit number as stimulus, but will then progress to a 4-bit number that requires shorter time memory to perform properly. CPT-IP requires attention and working memory because each stimulus must be processed first and then held in working memory until the next stimulus occurs and can be compared. CPT-IP assessment takes about 10 to 20 minutes to complete. CPT-IP will be administered and scored by a researcher or other qualified field personnel throughout the double blind treatment period (day 1 through day 98).

The simple visual space memory test-revised (BVMT-R) test is a reliable assessment of visual learning and memory designed to be used as part of a larger neuropsychological suite test and to record changes over time. See, e.g., tam JW, schmitter-edgecomb m. "The role of processing speed in the Brief Vi suospatial Memory Test-recycled." clin.ne μropsphshol.2013; 27 (6): 962-72 in this test, the subject was asked to reproduce 6 geometries (printed in a 2 x 3 array) from memory. A series of experiments will be performed. During the study trial, the subject browses the stimulus page for 10 seconds and is then asked to render as many arrays as possible in the correct position in response to the booklet page. A delayed recall test was then similarly applied, but with a 25 minute delay. In the identification test, the subject is required to identify which of the 12 arrays is included in the original geometry. BVMT-R evaluation takes about 45 minutes (including 25 minutes delay) to complete. BVMT-R will be managed and scored by a researcher or other qualified field personnel throughout the double blind treatment period (day 1 to day 98).

Mayer-saloviy-Caruso emotional mental testing (MSCEIT) tests emotional intelligence by evaluating how subjects manage their emotion under daily conditions. MSCEIT was designed to measure the 4 branches of Mayer and Solvey's emotional mental models: sense emotion, promote thinking, understand emotion, and manage emotion. See, for example, mayer JD, salovey P, caroso d. "Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) Users Manual." Toronto, ontario: multi-Health systems.2002. The computerized test consists of 141 items. The MSCEIT generated 15 main scores (total emotional mental score, 2 regional scores, 4 branch scores, and 8 task scores) and 3 supplemental scores. The MSCEIT evaluation takes about 30 to 45 minutes to complete. MSCEIT will be managed and scored by researchers or other qualified field personnel throughout the double-blind treatment period (day 1 to day 98).

A Virtual Reality Functional Capability Assessment Tool (VRFCAT) is an immersive virtual reality-based computerized assessment for assessing the functional capabilities of the following 4 domains: traffic, finance, home management and planning. Briefly, VRFCAT consists of 4 small scenarios that include checking if kitchen has items available to complete a recipe and plan to go to a grocery store to shop, ride a bus and pay the right fee, purchase items at the store, and go home. VRFCAT is a reliable validated instrument and has proven to be susceptible to basic functional disability in schizophrenic patients. See, e.g., keefe RSE, davis VG, atkins AS, et al, "Validation of a computerized test of functional capability," schizophr.res.2016;175 (1-3): the vrfcat assessment takes about 20 minutes to complete.

The "clinical global impression of severity" or "CGI-S" is a 7-point scale (range: 1=not severe to 7=very severe) to be used to assess the global severity of schizophrenia. The scale is a modification of the scale developed by the psychopharmacology research department of the national institute of mental health to assess the overall improvement in clinical condition of the subject and to provide an overall assessment of improvement over time from the clinician's perspective. See, e.g., guy w.ed. Ecdeu Assessment Manual of Psychopharmacology, revised,1976.USDepartment of Health,Education,and Welfare.Pub.No (ADM), 76-338.Rockville (MD): national Institute of Mental Health-Clinical Global Impression-improvement.p.217-22.CGI-S will be managed and scored by researchers or other qualified field personnel. The researcher or designated qualified clinician will rate the scale at a predetermined time. CGI-S will be managed and scored by researchers or other qualified field personnel throughout the double-blind treatment period (day 1 to day 98).

The "positive and negative symptoms scales" or "PANSS" are reliable, well known, widely used, clinician managed, validated, 30-term scales designed to evaluate the severity of various symptoms of schizophrenia and are commonly used in clinical studies involving antipsychotics to measure the reduction of symptoms in patients taking antipsychotics. See, e.g., european Medicines Agency [ EMA ], committee for Medicinal Products for Human use, guide on the clinical investigation of medicinal products, including depot preparations in the treatment of schizophtrenia 2012; EMA/CHMP/40072/2010Rev 1; lehman AF, lieberman JA, dixon LB, et al tree recommendations for patients with schizophrenia. In: practice Guideline for the Treatment of Patients with schizophrenia secondary edition. American Psychiatric Association;2004:3-35 (Part A); and Kay SR, fisher LA. "The positive and negative syndrome scale (PANSS) for schizopherenia," schizophr. Bull.1987;13 (2): 261-76.

The fraction scale of PANSS and the 5-factor model of PANSS are commonly used to evaluate different symptomatic domains of schizophrenia. The scale was divided into 3 parts, 7 items designed to evaluate positive symptoms (symptoms of disease were characterized by the presence), 7 items designed to evaluate negative symptoms (symptoms were characterized by the absence), and 16 items to treat general psychopathology. Each item was scored on the 7-point severity scale (1=no; 2=minimum; 3=mild; 4=moderate; 5=moderate; 6=severe; 7=extreme). The scale also includes 3 supplemental items that constitute an offensiveness risk profile; however, these items were not scored because they were not suitable for the present study. The PANSS total score is derived from the sum of each item.

As used herein, the "modified Simpson Angus scale" or "SAS" is a clinician-managed rating scale widely used in the clinical practice and research setting to evaluate antipsychotic drug-induced parkinsonism. See, for example, simpson GM, angus JW. "A rating scale for extrapyramidal side effects," Acta psychiatr.scand.suppl.1970; 212:11-9. The study described herein used modified version 10 SAS (for screening and qualification evaluation on day 1), wherein the "leg drop" and "head drop" items included in the original version have been replaced by "head rotation" and "akathisia", the latter of which has been frequently used in schizophrenia clinical trials. See, for example, moore TJ, furberg cd. "The harms of antipsychotic drugs: evidence from key publications, "Drug saf.2017;40 (1): 3-14, rating each item using a 5-point scale (0-4); the modified SAS score may be 0 to 40.

As used herein, a "columbia suicide severity rating scale" or "C-SSRS" is a scale of validated evidence support for suicide assessment and prospective assessment of suicide ideas and behaviors. See, e.g., the World Wide Web at csrs.columbia.edu.C-SSRS would be managed and scored by a researcher or qualified research site personnel.

As used herein, "EuroQol 5 dimension 5 level" or "EQ-5D-5L" is a universal single index metric for describing and assessing health. See, e.g., herdman M, gudex C, lloyd a, janssen M, kind P, parkin D, et al, "Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)," qual. Life res.2011;20 (10): 1727-36, it defines health in 5 dimensions: mobility, self-care ability, daily activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, mild problems, moderate problems, severe problems and extreme problems. The subject indicates his/her health status by checking the box beside the most appropriate statement. The scores of the 5 dimensions may be combined into a 5-digit number describing the health status of the patient. Subjects also rated their overall health on a 0 to 100 hash-labeled vertical Vision Analog Scale (VAS). The endpoints are labeled "best health condition you can imagine" and "worst health condition you can imagine".

The EQ-5D young (EQ-5D-Y) version is a more understandable tool for use in children and adolescents. EQ-5D-Y includes 2 pages: EQ-5D descriptive system and EQ visual analog scale (EQ VAS). The EQ-5D-Y descriptive system includes the following five dimensions: mobility, self care, performing daily activities, having pain or discomfort, sensory concerns, sadness, or shortness. There are 3 levels per dimension: there are no problems, some problems, and many problems. A young patient is asked to indicate his/her health status by checking boxes next to the most appropriate statement in each of the five dimensions. EQ VAS records the subject's self-assessed health status on a vertical visual analog scale, with endpoints marked as "best health status you can imagine" and "worst health status you can imagine". EQ-5D-5L (subject > = 18 years) and EQ-5D-Y (subject 13 years to 17 years) will be managed by the researcher or qualified designer.

As used herein, a "concise international neuropsychiatric disorder interview" or "MINI" is a brief structural diagnostic interview for a major psychiatric disorder, including schizophrenia, in revised third edition of DSM, fourth edition of DSM, DSM-5, and international statistical classifications of diseases and related health problems, tenth edition (ICD-10). See, e.g., sheehan DV, lecubier Y, sheehan KH, et a1., "The Mini-International Neuropsychiatric Interview (m.i.n.i.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10, "J.Clin.Psychiary.1998; 59Suppl 20:22-33; quiz 4-57. Verification and reliability studies comparing MINI with other well known psychiatric diagnostic interviews have been performed. The results of these studies indicate that MINI has similar reliability and effectiveness as these tools, but can be managed in a much shorter time and can be used by clinicians after a short training period. See, e.g., seehan DV, lecrubier Y, seehan KH, et al, "The validity of the Mini International Neuropsychiatric Interview (MINI) according to the SCID-P and its reliability," Eur. Psychiatry 1997;12:232-41.

Assessment of inclusion criteria for schizophrenia will be standardized using MINI version 7.0.2. MINI will also be used to assess the presence of co-morbid psychiatric disorders to assess whether a subject is suitable for inclusion.

Safety endpoint

Safety endpoints include Adverse Events (AEs), clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital sign measurements (including standing blood pressure and pulse rate), 12-lead Electrocardiography (ECG), and golombian suicide severity rating scale (C-SSRS).

Other end point

Other endpoints to be evaluated include: (1) Baseline changes on the positive and negative symptom scale (PANSS) total score; (2) Baseline changes in the EQ-5D version 5 (EQ-5D-5L) Visual Analog Scale (VAS) score; and (3) plasma concentrations of compound (I) at days 1, 14, 42 and 98.

Claims

1. A method of treating cognitive impairment associated with schizophrenia (CIAS) in a patient in need thereof, comprising administering to the patient 1mg to 500mg once daily of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

2. A method of treating cognitive impairment associated with schizophrenia according to claim 1, wherein the method comprises:

3. The method of treating cognitive impairment associated with schizophrenia according to claim 1 or 2, wherein the at least one cognitive symptom associated with schizophrenia is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency and impaired executive function.

4. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 3, wherein the administration improves the patient's BACS synthesis score relative to a concise set of assessment of cognitive function (BACS) score measured on the patient prior to the administration.

5. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 4, wherein the at least one cognitive symptom associated with schizophrenia is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function and impaired social cognition.

6. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 5, wherein the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administration.

7. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1-6, wherein the administration improves at least one metric selected from the group consisting of:

8. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 7, wherein the patient has at least one stable negative symptom associated with schizophrenia prior to the administration.

9. The method of treating cognitive impairment associated with schizophrenia of claim 8, wherein the at least one stable negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social interaction.

10. The method of treating cognitive impairment associated with schizophrenia of claim 8, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a positive and negative symptom scale (PANSS).

11. The method of treating cognitive impairment associated with schizophrenia of claim 8 or 9, wherein the stability of the at least one stable negative symptom associated with schizophrenia is assessed using a concise negative symptom scale (BNSS) tool.

12. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 8 to 11, wherein the at least one stable negative symptom associated with schizophrenia is stable for at least one month prior to the administration.

13. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 7, wherein any negative symptoms associated with schizophrenia in the patient are not statistically significantly improved following the administration.

14. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 13, wherein the at least one compound is administered in combination with at least one additional active agent.

15. The method of treating cognitive impairment associated with schizophrenia of claim 14, wherein the at least one additional active agent treats at least one negative symptom associated with schizophrenia in the patient.

16. The method of treating cognitive impairment associated with schizophrenia of claim 15, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced social interest.

17. The method of treating cognitive impairment associated with schizophrenia of claim 14, wherein the at least one additional therapeutic agent is selected from the group consisting of aripiprazole, olanzapine, risperidone and quetiapine fumarate.

18. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 17, wherein the at least one compound is administered to the patient for more than 14 weeks.

19. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 18, wherein the at least one compound is administered to the patient for more than 20 weeks.

20. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 19, wherein 1mg to 100mg of the at least one compound is administered to the patient once daily.

21. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1-19, wherein 20mg or 50mg of the at least one compound is administered to the patient once daily.

22. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1-19, wherein 20mg of the at least one compound is administered to the patient once daily.

23. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1-19, wherein 50mg of the at least one compound is administered to the patient once daily.

24. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1-23, wherein the administration does not treat at least one negative symptom associated with schizophrenia.

25. The method of treating cognitive impairment associated with schizophrenia of claim 24, wherein the at least one negative symptom associated with schizophrenia is selected from social withdrawal, affective flattening, lack of pleasure, reduced energy, loss of motivation, and reduced interest in social interaction.

26. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1 to 25, wherein the patient is in a stable regime of a psychotropic drug.

27. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1-26, wherein the patient is diagnosed with schizophrenia at least one year prior to the administration.

28. The method of treating cognitive impairment associated with schizophrenia according to any one of claims 1-27, wherein the patient has stable symptomatology for at least 3 months prior to the administration.

30. A method of treating cognitive impairment according to claim 29, wherein the method comprises:

31. The method of treating cognitive impairment according to claim 29 or 30, wherein the at least one cognitive symptom is selected from the group consisting of impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency and impaired executive function.

32. The method of treating cognitive impairment according to any one of claims 29 to 31 wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function and impaired social cognition.

33. The method of treating cognitive impairment according to any one of claims 29-32 wherein the administering treats the at least one cognitive symptom.

34. The method of treating cognitive impairment according to any one of claims 29 to 33 wherein the at least one cognitive symptom is associated with a psychotic disorder.

35. The method of treating cognitive impairment of claim 34, wherein the psychotic disorder is selected from psychosis, schizophreniform disorder, schizoaffective disorder, and schizophreniform disorder unrelated to aggression.

36. The method of treating cognitive impairment according to claim 34 or 35, wherein the psychotic disorder is a schizophreniform disorder, a schizoaffective disorder, and an aggression-independent schizophrenia.

37. The method of treating cognitive impairment according to any one of claims 34 to 36 wherein the psychotic disorder is schizophrenia unrelated to aggression.

38. The method of treating cognitive impairment according to any one of claims 29 to 34 wherein the at least one cognitive symptom is associated with: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

39. The method of treating cognitive impairment according to any one of claims 29 to 34 wherein the at least one cognitive symptom is associated with: cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, fragile X syndrome, prader-willi syndrome and delirium.

40. The method of treating cognitive impairment according to any one of claims 29 to 39, wherein 50mg of the at least one compound is administered to the patient once daily.

41. The method of treating cognitive impairment according to any one of claims 29 to 39, wherein 20mg of the at least one compound is administered to the patient once daily.

42. The method of treating cognitive impairment according to any one of claims 29 to 41 wherein the at least one compound is administered in combination with at least one additional active agent.

43. The method of treating cognitive impairment according to claim 42, wherein the patient suffers from schizophrenia and the at least one additional active agent treats at least one negative symptom in the patient.

44. The method of treating cognitive impairment according to claim 43, wherein the at least one negative symptom is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social interaction.

45. The method of treating cognitive impairment according to any one of claims 29 to 44, wherein the patient has at least one stable negative symptom selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact prior to the administration.

46. The method of treating cognitive impairment according to any one of claims 1 to 45 wherein the at least one compound is administered in the form of at least one film-coated tablet.

47. The method of treating cognitive impairment according to any one of claims 1 to 46 wherein the at least one compound is administered with water or milk.

48. A method of treating at least one cognitive symptom associated with schizophrenia in a patient, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (grade <5 on PANSS positive symptom projects P1, P3, P4, P5, P6), the method comprising administering to the patient 1mg to 500mg once daily of at least one compound selected from compound (I) and pharmaceutically acceptable salts thereof:

49. A method of treating at least one cognitive symptom associated with schizophrenia according to claim 48, wherein the method comprises:

50. The method of treating at least one cognitive symptom associated with schizophrenia according to claim 48 or 49, wherein the administration improves the patient's cognitive function concise set of assessment (BACS) score of synthesis relative to BACS score measured on the patient prior to the administration.

51. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of claims 48-50, wherein the administration improves the patient's cognitive function rating scale (SCoRS) interviewer score relative to the patient's SCoRS interviewer score measured prior to the administration.

52. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of claims 48-51, wherein the administration improves at least one metric selected from the group consisting of:

53. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of claims 48-52, wherein any negative symptom associated with schizophrenia in the patient is not statistically significantly improved following the administration.

54. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of claims 48-53, wherein the administering does not treat at least one negative symptom associated with schizophrenia.

55. The method of treating at least one cognitive symptom associated with schizophrenia according to claim 54, wherein the at least one negative symptom associated with schizophrenia is selected from the group consisting of lack of hedonia, loss of motivation, and reduced interest in social contact.

56. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of claims 48-55, wherein 50mg of the at least one compound is administered to the patient once daily.

57. The method of treating at least one cognitive symptom associated with schizophrenia according to any one of claims 48-55, wherein the patient is administered 20mg of the at least one compound once daily.

58. A method of increasing D-serine levels, long term potentiation, and/or synaptic plasticity in a patient in need thereof, comprising administering to the patient less than 500mg once daily of at least one compound selected from the group consisting of compound (I) and pharmaceutically acceptable salts thereof:

59. the method of claim 58, wherein 50mg of the at least one compound is administered to the patient once daily.

60. The method of claim 58, wherein 20mg of the at least one compound is administered to the patient once daily.

61. The method of any one of claims 58 to 60, wherein the method increases D-serine levels in the patient.

62. The method of any one of claims 58 to 61, wherein the method increases long-term potentiation in the patient.

63. The method of any one of claims 58 to 62, wherein the method increases synaptic plasticity in the patient.

64. The method according to any one of claims 58 to 63, wherein the patient exhibits at least one cognitive symptom prior to the administration.

65. The method according to claim 64, wherein the at least one cognitive symptom is selected from impaired speech memory, impaired working memory, impaired motor function, impaired attention, impaired processing speed, impaired speech fluency, and impaired executive function.

66. The method according to claim 64, wherein the at least one cognitive symptom is selected from impaired attention, impaired memory, impaired reasoning, impaired resolution of problems, impaired working memory, impaired processing speed, impaired language function, and impaired social cognition.

67. The method of any of claims 58-66, wherein the administering improves at least one biomarker selected from the group consisting of blink conditional reflection (EBC) response of the patient, mismatching negative wave (MMN) amplitude of the patient, and auditory steady-state response (ASSR) gamma band power of the patient.

68. The method of any one of claims 58 to 67, wherein the patient has a disease selected from the group consisting of: attention deficit disorder, dementia, alzheimer's disease, parkinson's disease, huntington's disease, cushing's disease, lewy body disease, multiple sclerosis, stroke, addictive disorders, pervasive developmental disorders, autism, fragile X syndrome, anxiety disorders, prader-willi syndrome, bipolar disorder, depression, and delirium.

69. The method of any one of claims 58 to 67, wherein the patient has a disease selected from the group consisting of: psychosis, schizophreniform disorder, schizoaffective disorder and schizophreniform disorder not associated with aggression.

70. The method of any one of claims 58 to 67, wherein the patient has no more than moderate-severe positive symptoms associated with schizophrenia (PANSS positive symptoms item P1 (delusions), P3 (hallucinogenic behaviors), P4 (excitement), P5 (exaggeration) and/or <5 grade on P6 (suspicion)).