Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

Abstract

To provide benzodiazepine derivatives, compositions, and methods for treating cognitive impairment.SOLUTION: The present invention relates to benzodiazepine derivatives, compositions including therapeutically effective amounts of those derivatives, and methods of using those derivatives or compositions in treating cognitive impairment associated with CNS disorders. The present invention also relates to the use of an α5-containing GABAA receptor agonist in treating cognitive impairment associated with CNS disorders in a subject in need thereof or at risk thereof, including age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI, Age-Associated Memory Impairment, Age-Related Cognitive Decline, dementia, Alzheimer's Disease (AD), prodromal AD, PTSD, schizophrenia, bipolar disorder, ALS, cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease, autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction. The present invention further relates to the use of an α5-containing GABAA receptor agonist in treating brain cancers (including brain tumors, such as medulloblastomas), and cognitive impairment associated therewith.SELECTED DRAWING: None

Description

Technical Field

[0001] Statement of Government Support This invention was made with government support under grant numbers U01 AG041140, grant number UH2NS101856, and grant number UH3NS101856, awarded by the National Institutes of Health (NIH), a United States government agency, particularly its National Institute on Aging (NIA) division. The United States government has certain rights in this invention.

[0002] Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 62 / 950,886, filed on December 19, 2019, which is hereby incorporated by reference in its entirety.

[0003] Field of the Invention The present invention relates to compounds, compositions, and methods for treating cognitive impairments associated with central nervous system (CNS) disorders, cognitive impairments associated with brain cancer, and brain cancer in subjects in need of treatment for CNS disorders, cognitive impairments associated with brain cancer, and brain cancer.

Background Art

[0004] Background of the Invention Cognitive ability may decline as a normal result of aging or as a result of a central nervous disorder.

[0005] For example, a significant elderly population experiences a decline in cognitive ability that exceeds what is typical in normal aging. Such age-related loss of cognitive function is clinically characterized by a progressive loss of memory, cognition, reasoning, and judgment. Mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical classifications are associated with such age-related loss of cognitive function. According to some estimates, more than 16 million people in the United States alone have AAMI (Barker et al., 1995), and it is estimated that 5.5 to 7 million people over 65 years old in the United States are suffering from MCI (Plassman et al., 2008).

[0006] Cognitive impairment is also associated with other central nervous system (CNS) disorders such as dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (especially mania), amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive disorder, and substance addiction.

[0007] Therefore, there is a need for effective treatments for cognitive impairment associated with central nervous system (CNS) disorders and for improving cognitive function in patients diagnosed with or at risk of developing age-related cognitive impairment, MCI, amnestic MCI, AAMI, ARCD, dementia, AD, prodromal AD, PTSD, schizophrenia or bipolar disorder (especially mania), ALS, cancer treatment-related cognitive impairment, mental retardation, PD, autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive disorder, and substance addiction, as well as similar CNS disorders associated with cognitive impairment.

[0008] GABA A receptor (GABA A R) forms a Cl−-permeable channel activated by the neurotransmitter γ-aminobutyric acid (GABA) and consists of various subunits (α1-6, β1 ~3, γ1~3, δ, ε, π, θ) and is a pentamer aggregate derived from a pool. Various pharmacological effects, including anxiety disorders, epilepsy, insomnia, pre-anesthetic sedation, and muscle relaxation, are mediated by various GABA A subtypes.

[0009] Various studies have demonstrated that a decrease in GABA signaling is associated with various CNS disorders related to cognitive impairment. In particular, α5-containing GABA, which is relatively low in density in the mammalian brain A R plays a role in the modification of learning and memory. From previous studies, in rats with age-related cognitive decline, it has been demonstrated that the expression of the α5 subunit of the GABA A receptor is decreased in the hippocampus (see International Patent Publication WO2007 / 019312). Such results suggest that upregulation of the function of α5-containing GABA A R may be effective in the treatment of cognitive impairment associated with the CNS disorders. Therefore, a positive allosteric modulator of α5-containing GABA A R that is useful in therapeutic preparations for treating cognitive impairment associated with the CNS disorders is needed.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0011] Summary of the Invention The present invention relates to a compound of formula V-a:

Chemical Formula

Chemical formula

Chem.

Chemical formula

[0012] In another aspect, the present invention provides a compound of formula A:

Chemical formula

Chemical formula

[0013] In another aspect, the present invention provides a compound of formula B:

Chemical formula

[0014] In another aspect, the present invention provides a compound of Formula C:

Chemical formula

[0015] The present invention also provides a pharmaceutical composition comprising a compound of Formula V-a, A, B or C, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

[0016] In some embodiments, the compound of Formula V-a is a GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of Formula A is a GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of Formula B is a GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of Formula C is a GABA A α5 receptor positive allosteric modulator. The compounds of Formula V-a, A, B and C can be used for treating the conditions described herein, such as by virtue of their activity as GABA A α5 receptor positive allosteric modulators.

[0017] In another aspect of the present invention, a method for treating cognitive impairment in a subject in need of treatment for a CNS disorder associated with cognitive impairment or a subject at risk thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In some embodiments, CNS disorders associated with cognitive impairment include, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive disorder, and substance addiction. In another aspect of the present invention, a method for protecting or improving cognitive function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In certain embodiments of the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof is administered every 12 or 24 hours.

[0018] In another aspect of the present invention, there is provided a method for treating brain cancer (including brain tumors, such as medulloblastoma), the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In another aspect of the present invention, there is provided a method for protecting or improving cognitive function in a subject suffering from brain cancer (including brain tumors, such as medulloblastoma), the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In certain embodiments of the present invention, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof is administered every 12 hours or 24 hours.

[0019] In another aspect of the present invention, there is provided a method for treating Parkinson's disease mental disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In certain embodiments of the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof is administered every 12 hours or 24 hours.

[0020] In some embodiments, the compounds and compositions of the invention are for use as medicaments. In some embodiments, the compounds and compositions of the invention are for use in the treatment of cognitive impairment in a subject in need thereof or at risk thereof associated with a CNS disorder. In some embodiments, CNS disorders associated with cognitive impairment include, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), preclinical AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive disorder, and substance addiction. In some embodiments, the compounds and compositions of the invention are for use as medicaments in the treatment of brain cancer (brain tumors, including, for example, medulloblastoma). In some embodiments, the compounds and compositions of the invention are for use as medicaments in the treatment of cognitive impairment associated with brain cancer (brain tumors, including, for example, medulloblastoma). In some embodiments, the compounds and compositions of the invention are for use as medicaments in the treatment of Parkinson's disease psychiatric disorders.

[0021] In some embodiments, the present application provides the use of a compound or composition described herein in the preparation of a medicament for treating cognitive impairment in a subject in need of treatment for or at risk of a cognitive impairment associated with a CNS disorder. In some embodiments, CNS disorders associated with cognitive impairment include, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive disorder, and substance addiction. In some embodiments, the compounds and compositions of the present invention are for use in the preparation of a medicament for treating brain cancer (brain tumors, including, for example, medulloblastoma). In some embodiments, the compounds and compositions of the present invention are for use in the preparation of a medicament for treating cognitive impairment associated with brain cancer (brain tumors, including, for example, medulloblastoma). In some embodiments, the compounds and compositions of the present invention are for use in the preparation of a medicament for treating Parkinson's disease mental disorders. The present invention provides, for example, the following items. (Item 1) A compound of formula A:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Table 9-1

Table 9-2

Table 9-3

Brief Description of the Drawings

[0022]

Figure 1

[0023]

Figure 2

[0024]

Figure 3

[0025]

Figure 4

[0026]

Figure 5

[0027]

Figure 6

[0028]

Figure 7

[0029]

Figure 8A

Figure 8B

Figure 8C

Mode for Carrying Out the Invention

[0030] Detailed Description of the Invention Definitions Unless otherwise specifically defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. In general, the nomenclature associated with and used in the techniques of chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neuroscience, virology, immunology, microbiology, pharmacology, genetics, and proteins, and nucleic acid chemistry, as described herein, are well known and commonly used in the art.

[0031] The methods and techniques of the present invention generally, unless otherwise indicated, are carried out in accordance with conventional methods well known in the art, as well as the conventional methods described in various general and more specific references cited and discussed throughout this specification. See, for example, "Principles of Neural Science," McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.," W. H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.," W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., "Developmental Biology, 6th ed.," Sinauer Associates, Inc., Sunderland, MA (2000).

[0032] The chemical terms used herein are used in accordance with their conventional usage in the art, as exemplified in "The McGraw-Hill Dictionary of Chemical Terms," Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0033] All publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, this specification, including its specific definitions, will control.

[0034] Throughout this specification, variations such as the words "comprise", "comprises" or "comprising" are to be understood to imply the inclusion of a stated integer (or element) or group of integers (or elements), but not the exclusion of any other integer (or element) or group of integers (or elements).

[0035] The singular forms "a", "an" and "the" include the plural unless the context clearly dictates otherwise.

[0036] The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0037] The term "agent" is used herein to represent an extract made from a chemical compound (including organic or inorganic compounds, such as the compounds of the present invention, mixtures of chemical compounds, etc.), a biological macromolecule (nucleic acid, antibody (including parts thereof, as well as humanized antibodies, chimeric antibodies and human antibodies, and monoclonal antibodies), protein or part thereof, such as peptide, lipid, carbohydrate), or a biological substance (such as cells or tissues of bacteria, plants, fungi, or animals (especially mammals)). Agents include, for example, those known with respect to structure a certain agent, and agents not known with respect to structure. The α5-containing GABA A receptor agonist activity of such agents may make them suitable as "therapeutic agents" in the methods and compositions of the present invention.

[0038] "Patient", "subject" or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals (including humans, primates, domestic animals (such as cows, pigs, etc.), companion animals (such as dogs, cats, etc.) and rodents (such as mice and rats)).

[0039] "Cognitive function" or "cognitive state" refers to any higher-order intellectual brain process or brain state related to learning and / or memory, including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, prospective memory, retrospective memory, memory retrieval, discriminative learning, decision-making, inhibitory response control, attentional set-shifting, delayed reinforcement learning, reversal learning, temporal integration of spontaneous behavior, interest display in the surrounding environment and self-care, processing speed, inference and problem-solving, and social cognition.

[0040] In humans, cognitive function can be measured, for example, but not limited to, by the Clinician's Interview-Based Impression of Change Plus (CIBIC-plus); Mini-Mental State Examination (MMSE); Neuropsychiatric Inventory (NPI); Clinical Dementia Rating (CDR); Cambridge Neuropsychological Test Automated Battery (CANTAB); Sandoz Clinical Assessment-Geriatric (SCAG); Buschke Selective Reminding Test (Buschke and Fuld, 1974); Verbal Paired Associates subtest; Logical Memory subtest; Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R). (Wechsler, 1997); can be measured by the Benton Visual Retention Test or an explicit 3 - alternative forced choice task or the MATRICS Consensus Neuropsychological Battery. See Folstein et al., J Psychiatric Res 12: 189 - 98, (1975); Robbins et al., Dementia 5: 266 - 81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168 - 79, (1999); Marquis et al., 2002 and Masur et al., 1994. Buchanan, R.W., Keefe, R.S.E., Umbricht, D., Green, M.F., Laughren, T., and Marder, S.R. (2011), The FDA - NIMH - MATRICS guidelines for clinical trial design of cognitive - enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209 - 1217 should also be referred to.

[0041] In animal model systems, cognitive function can be measured by various conventional methods known in the art, including the use of the Morris water maze (MWM), Barnes circular maze, elevated radial maze, T - maze, or any other maze in which animals use spatial information. Cognitive function can be evaluated by reversal learning, extradimensional set shifting, conditional discrimination learning and assessment of reward expectation. Other tests known in the art may also be used to evaluate cognitive function, such as the novel object recognition task and the odor recognition task.

[0042] Cognitive function may also be measured using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT), or any other imaging technique that enables measurement of brain function. In animals, cognitive function may be measured by electrophysiological techniques.

[0043] "Promotion" of cognitive function refers to affecting impaired cognitive function such that the impaired cognitive function resembles that of a normal subject without impairment. Cognitive function can be promoted to any detectable degree, but in humans, preferably, the impaired subject is sufficiently promoted such that the impaired subject can perform daily activities of normal life at a proficiency level as close as possible to that of a normal subject without impairment or a normal subject of the same age without impairment.

[0044] In some cases, "promotion" of cognitive function in a subject affected by age-related cognition refers to affecting impaired cognitive function such that the impaired cognitive function resembles that of a normal subject of the same age without impairment or that of a young adult subject without impairment. The cognitive function of the subject can be promoted to any detectable degree, but in humans, preferably, the impaired subject is sufficiently promoted such that the impaired subject can perform daily activities of normal life at a proficiency level as close as possible to that of a normal subject without impairment or a young adult subject without impairment or a normal subject of the same age without impairment.

[0045] "Protection" of cognitive function refers to affecting normal or impaired cognitive function such that it does not decline, or declines less than the cognitive function observed in the subject at the time of initial presentation or diagnosis, or such decline is delayed.

[0046] "Improvement" of cognitive function includes promotion of cognitive function and / or protection of cognitive function in a subject.

[0047] "Cognitive impairment" refers to the cognitive function in a subject that is less robust than the cognitive function expected in a normal, unimpaired subject. In some cases, the cognitive function is reduced by about 5%, about 10%, about 30% or more compared to the cognitive function expected in a normal, unimpaired subject. In some cases, "cognitive impairment" in a subject affected by age-related cognitive impairment refers to the cognitive function in a subject that is less robust than the cognitive function expected in a normal subject of the same age or the function of a young adult subject (i.e., a subject having an average score for a given age in a cognitive test).

[0048] "Age-related cognitive impairment" refers to cognitive impairment in an elderly subject, where the cognitive function of those subjects is less robust than the cognitive function expected in a normal subject of the same age or the cognitive function expected in a young adult subject. In some cases, the cognitive function is reduced by about 5%, about 10%, about 30% or more compared to the cognitive function expected in a normal subject of the same age. In some cases, the cognitive function is at the level expected in a normal subject of the same age, but is reduced by about 5%, about 10%, about 30%, about 50% or more compared to the cognitive function expected in a young adult subject. Age-related cognitive dysfunction may be associated with mild cognitive impairment (MCI) (including amnestic MCI and non-amnestic MCI), age-associated memory impairment (AAMI) and age-related cognitive decline (ARCD).

[0049] "Cognitive impairment" related to, associated with, or in Alzheimer's disease (AD) refers to the cognitive function in a subject that is less robust than the cognitive function expected in a subject not diagnosed with AD using conventional methods and criteria.

[0050] "Mild cognitive impairment" or "MCI" refers to a state characterized by isolated memory impairment without other cognitive abnormalities and relatively normal functional abilities. A set of diagnostic criteria for clinically characterizing MCI are as follows: (1) memory complaints (reported by the patient, informant, or physician), (2) normal activities of daily living (ADL), (3) normal overall cognitive function, (4) abnormal memory for age (defined as a score lower than the average for a given age by more than 1.5 standard deviations), and (5) the absence of dementia criteria (defined by the DSM-IV guidelines). Petersen et al., Srch. Neurol. 56: 303-308 (1999); Petersen, "Mild cognitive impairment: Aging to Alzheimer's Disease." Oxford University Press, N.Y. (2003). Agnosia in subjects with MCI can involve any cognitive domain or mental process, including memory, language, association, attention, perception, problem-solving, executive function, and visuospatial skills. For example, Winbald et al., J. Intern. Med. 256:240-240, 2004; Meguro, Acta. Neurol. Taiwan. 15:55-57, 2008; Ellison et al., CNS Spectr. 13:66-72, 2008, Petersen, See Semin. Neurol. 27:22-31, 2007. MCI is further subdivided into amnestic MCI (aMCI) and non-amnestic MCI, which are characterized by functional impairment (or loss) of memory in particular. MCI is defined as aMCI when memory is found to be impaired, taking into account the age and educational level of the subject. On the other hand, when the subject's memory is found to be intact with respect to age and education, but other non-memory cognitive domains (such as language, executive function, or visuospatial skills) are impaired, MCI is defined as non-amnestic MCI. Both aMCI and non-amnestic MCI can be further subdivided into single-domain MCI or multi-domain MCI. aMCI-single domain refers to a state where memory is not impaired but other cognitive domains are impaired. aMCI-multi domain refers to a state where memory and at least one other cognitive domain are impaired. Non-amnestic MCI is single-domain or multi-domain depending on whether more than one non-memory cognitive domain is impaired. For example, Peterson and Negash, See CNS Spectr. 13:45-53, 2008.

[0051] The diagnosis of MCI usually requires an objective assessment of cognitive impairment that can be obtained by using well-established neuropsychological tests (including the Mini-Mental State Examination (MMSE), the Cambridge Neuropsychological Test Battery (CANTAB), and individual tests such as the Rey Auditory Verbal Learning Test (AVLT), the Logical Memory subtest of the Wechsler Memory Scale Revised (WMS-R), and the New York University (NYU) Paragraph Recall Test). See Folstein et al., J Psychiatric Res 12: 189-98 (1975); Robbins et al., Dementia 5: 266-81 (1994); Kluger et al., J Geriatric Psychiatry Neurol 12:168-79 (1999).

[0052] "Age-associated memory impairment (AAMI)" refers to the decline in memory due to aging. A patient can be considered to have AAMI if the patient is at least 50 years old and meets all of the following diagnostic criteria: a) the patient is aware of a decline in memory ability; b) the patient has poor performance on standard memory tests compared to young adults; c) all other obvious causes of memory decline, excluding normal aging, are excluded (in other words, the memory decline cannot be attributed to other causes such as a recent heart attack or head trauma, depression, adverse reactions to medications, Alzheimer's disease, etc.).

[0053] "Age-related cognitive decline (ARCD)" refers to the decline in memory and cognitive abilities that is a normal result of aging in humans (e.g., Craik & Salthouse, 1992). This also applies to substantially all mammalian species. Age-associated memory impairment refers to older individuals who have an objective decline in memory compared to younger individuals but have normal cognitive function compared to their peers (Crook et al., 1986). Memory decline consistent with age is a normal developmental change (Crook, 1993; Larrabee, 1996), is not pathophysiological (Smith et al., 1991), and is a less stigmatizing classification that emphasizes that it rarely progresses to overt dementia (Youngjohn & Crook, 1993). DSM-IV (1994) systematizes the diagnostic classification of ARCD.

[0054] "Dementia" refers to a state characterized by severe loss of recognition that interferes with normal daily activities. Subjects with dementia also exhibit other symptoms such as impaired judgment, personality changes, loss of orientation, confusion, behavioral changes, speech difficulties, and motor disorders. There are various types of dementia, such as Alzheimer's disease (AD), vascular dementia, Lewy body dementia, and frontotemporal dementia.

[0055] Alzheimer's disease (AD) is characterized by memory loss in its early stage. Later symptoms include impaired judgment, disorientation, confusion, behavioral changes, speech difficulties, and movement disorders. Histologically, AD is characterized by beta-amyloid plaques and aggregates of tau protein.

[0056] Vascular dementia is caused by strokes. The symptoms overlap with those of AD, but the focus is not on memory impairment.

[0057] Dementia with Lewy bodies is characterized by abnormal deposits of alpha-synuclein that form inside neurons in the brain. Cognitive impairments, including memory and judgment dysfunction and behavioral changes, may resemble those of AD.

[0058] Frontotemporal dementia is characterized by gliosis, neuronal loss, superficial spongiform degeneration in the frontal cortex and / or anterior temporal lobes, and Pick bodies. Symptoms include changes in personality and behavior, including a decline in social skills and language expression / understanding.

[0059] "Post-traumatic stress disorder (PTSD)" refers to an anxiety disorder characterized by acute or delayed reactions to tragic events, characterized by re-experiencing the trauma, emotional numbing or avoidance of trauma-related stimuli, and increased arousal. Re-experiencing of the phenomenon includes intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to things that remind one of the trauma. Such reactions cause anxiety and can have significant effects on both the quality of the patient's life and their physical and emotional well-being, both chronically and acutely. PTSD is also associated with impaired cognitive abilities, and older individuals with PTSD have a greater decline in cognitive abilities compared to control patients.

[0060] "Schizophrenia" refers to a chronic debilitating disorder characterized by a series of psychopathologies, including positive symptoms such as abnormal or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminished volition and decreased adaptive goal-directed behavior (e.g., anhedonia, affective flattening, avolition), and cognitive impairment. Abnormalities in the brain are hypothesized to underlie the extensive psychopathology in schizophrenia, but currently available antipsychotic drugs are often ineffective in treating cognitive impairment in patients.

[0061] "Bipolar disorder" or "BP" or "manic-depressive disorder" or "manic depression" refers to a chronic psychological / mood disorder that may be characterized by significant mood swings, including periods of depression and periods of euphoric mania. BP can be diagnosed by a skilled physician based on personal and medical history, clinical examination by interview, and physical examination. The terms "mania" or "manic episode" or other variants refer to a period in which an individual exhibits some or all of the following: competitiveness, rapid speech, increased levels of activity and agitation, and a sense of inflated self-esteem, euphoria, impaired judgment, insomnia, impaired concentration, and aggression.

[0062] "Amyotrophic lateral sclerosis", also known as ALS, refers to a progressive and fatal neurodegenerative disease characterized by the degeneration of motor neurons, which are nerve cells in the central nervous system that control voluntary movement of muscles. ALS is also characterized by neuronal degeneration in the olfactory cortex and hippocampus, memory deficits, and hyperexcitability of neurons in various brain regions such as the cortex.

[0063] "Cancer treatment-related cognitive impairment" refers to cognitive impairment that develops in subjects being treated for cancer, such as chemotherapy (e.g., chemo brain) and radiation therapy. The cytotoxic and other harmful side effects of cancer treatment on the brain result in cognitive impairment in functions such as memory, learning, and attention.

[0064] Parkinson's disease (PD) is a neurological disorder characterized by a decrease in voluntary movement. Affected patients have reduced motor activity and slower voluntary movements compared to normal individuals. Patients have a characteristic "mask-like" facial appearance, a tendency to hurry while walking, a stooped posture, and general muscle weakness. There is a typical "lead-pipe" rigidity during passive movement. Another important feature of this disease is tremors in the limbs that occur at rest and decrease during movement.

[0065] "Autism," as used herein, refers to an autism spectrum disorder characterized by impaired social interaction and communication due to restricted and repetitive behaviors. "Autism spectrum disorder" refers to a group of developmental disorders including autism; Asperger syndrome; pervasive developmental disorder not otherwise specified (PDD-NOS or atypical autism); Rett syndrome; and childhood disintegrative disorder.

[0066] Mental retardation is a general disorder characterized by significantly impaired cognitive function and deficits in adaptive behavior. Mental retardation is often defined as an intelligence quotient (IQ) score of less than 70. Congenital causes are the underlying cause of many cases of mental retardation. Dysfunction of neuron communication is also thought to be one of the underlying causes of mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0067] In some examples, mental retardation includes, but is not limited to, Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Included are Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Moersch-Wilson syndrome, ciliary-related diseases, Lowe syndrome and siderium type X-linked mental retardation. Down syndrome is a disorder that includes a combination of birth defects, including some degree of mental retardation, characteristic facial features, and often heart defects, many infections, vision and hearing problems, and other health problems. Fragile X syndrome is a common form of hereditary mental retardation that occurs at a frequency of 1 in 4,000 males and 1 in 8,000 females. This syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder and autistic-like behavior. There is no effective treatment for fragile X syndrome.

[0068] Obsessive-compulsive disorder (“OCD”) is most commonly a mental state characterized by intrusive, repetitive, unwanted thoughts (obsessions) that lead to behaviors and mental acts that an individual feels compelled to perform. Current epidemiological data indicate that OCD is the fourth most common mental disorder in the United States. Some studies have suggested that the prevalence of OCD is 1 to 3 percent, but it is suggested that the clinically recognized prevalence of OCD is much lower and that many individuals with the disorder may not be diagnosed. Patients with OCD are diagnosed by psychologists, psychiatrists or psychoanalysts according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) (2000), which includes the features of obsessions and compulsions.

[0069] Substance addiction (e.g., drug addiction, alcohol addiction) is a mental disorder. This addiction is not instantaneously caused when exposed to the abused substance. Rather, this addiction requires the adaptation of multiple complex neurons that occurs over different periods ranging from hours to days to months (Kauer J. A. Nat. Rev. Neurosci. 2007, 8, 844 - 858). The path to addiction generally begins with the voluntary use of one or more regulated substances ( such as any of narcotics, barbiturates, methamphetamine, alcohol, nicotine, and various other such regulated substances). Over a long period, the continuous use of those regulated substances impairs the voluntary ability to refrain from them due to the long - term use effects on brain function and thus on behavior. Thus, substance addiction is generally characterized by a compulsive substance craving, seeking, and use that persists despite negative consequences. That craving can correspond to underlying neurobiological changes in the patient, which are likely to have to be addressed in a meaningful way if recovery is to be achieved. Substance addiction also often features, in some substances, life - threatening withdrawal symptoms (e.g., alcohol, barbiturates), and in other cases, can result in substantial medical conditions (which can include nausea, vomiting, fever, dizziness, and profuse sweating), distress, and a reduced ability to recover. For example, alcohol addiction, also known as alcohol dependence, is one such substance addiction. Alcohol dependence is primarily characterized by four symptoms including craving, loss of control, physical dependence, and tolerance. These symptoms can also characterize addictions to other regulated substances. The craving for alcohol and other regulated substances is often as strong as the craving for food or water. Thus, alcoholics may continue to drink despite significant secondary effects on family, health, and / or the law.

[0070] "Treating" a condition or patient refers to taking steps to obtain a beneficial or desired result, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, prevention of or slowing the progression of the above-mentioned disease or disorder, or reduction, improvement or slowing the progression of one or more symptoms of a cognitive impairment (age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior and substance addiction, etc.) associated with a CNS disorder. In some embodiments, treatment includes prevention of or slowing the progression of a CNS disorder (such as those described herein). In certain embodiments, treatment includes reduction, improvement or slowing the progression of one or more symptoms associated with a CNS disorder. In certain embodiments, the symptoms being treated are cognitive impairment or agnosia. Treatment of age-related cognitive impairment further includes slowing the conversion from age-related cognitive impairment (including, but not limited to, MCI, ARCD and AAMI) to dementia (e.g., AD).

[0071] "Treating a cognitive impairment" refers to taking steps to improve the cognitive function in a subject having the cognitive impairment such that the performance in one or more cognitive tests of the subject is improved to any detectable extent or further decline is prevented. Preferably, the cognitive function of the subject closely resembles that of an unimpaired normal subject after treatment of the cognitive impairment. Treatment of a cognitive impairment in a human can improve the cognitive function to any detectable extent, but preferably is improved sufficiently to enable the impaired subject to perform the daily activities of normal life at the same level of proficiency as an unimpaired normal subject. In some cases, "treating a cognitive impairment" refers to taking steps to improve the cognitive function in a subject having the cognitive impairment such that the performance in one or more cognitive tests of the subject is improved to any detectable extent or further decline is prevented. Preferably, the cognitive function of the subject closely resembles that of an unimpaired normal subject after treatment of the cognitive impairment. In some cases, "treating a cognitive impairment" in a subject afflicted with age-related cognitive impairment refers to taking steps to improve the cognitive function in the subject such that the cognitive function of the subject closely resembles that of an unimpaired normal subject of the same age or a young adult subject after treatment of the cognitive impairment.

[0072] "Administering" a substance, compound or agent to a subject or "administration" of a substance, compound or agent to a subject can be effected using one of a variety of methods known to those of ordinary skill in the art. For example, a compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, dermally It can be administered to the eye, under the tongue, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and transdermally (by absorption, e.g., through the ducts of the skin) to the eyeball. The compound or agent can be suitably introduced by a refillable or biodegradable polymeric device or other device, such as patches and pumps, or by a formulation that provides sustained, slow, or controlled release of the compound or agent. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods. In some embodiments, administration includes both direct administration (including self-administration) and indirect administration (including the act of prescribing a drug). For example, as used herein, a physician who instructs a patient to self-administer a drug, or a physician who instructs another person to administer a drug to the patient, and / or a physician who provides a prescription for a drug to the patient is administering the drug to the patient.

[0073] Suitable methods for administering a substance, compound, or agent to a subject also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject has a cognitive impairment at the time of administration, the degree of dysfunction, as well as the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally, e.g., by ingestion or intravenously to the subject, e.g., by injection into the subject. In some embodiments, the compound or agent administered orally is a sustained-release formulation or a slow-release formulation, or is administered using a device for such slow or sustained release.

[0074] As used herein, "α5-containing GABA A receptor agonist", "α5-containing GABA A R agonist" or "GABA A α5 receptor agonist", and other variants used herein refer to a compound that enhances the function of the α5-containing GABA A receptor (GABA A R), i.e., a GABAergic Cl -Refers to a compound that increases current. In some embodiments, an α5-containing GABA A R agonist, as used herein, refers to a positive allosteric modulator that activates the activity of GABA. An α5-containing GABA A receptor agonist suitable for use in the present invention includes all forms of α5-containing GABA A receptor agonists described herein and specific α5-containing GABA A receptor agonists, as well as their hydrates, their solvates, their polymorphs, their salts (e.g., pharmaceutically acceptable salts), their isomers (e.g., stereoisomers, E / Z isomers and tautomers) and combinations thereof.

[0075] The term "antipsychotic drug", "antipsychotic agent", "antipsychotic medication" or "antipsychotic compound" refers to: (1) typical or atypical antipsychotic drugs; (2) dopamine agonists, glutamate agonists, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitors, metabotropic glutamate receptor (mGluR) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2 / 3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA / kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenaline agonists, serotonin receptor modulators, cholinergic agonists, cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors, nNOS inhibitors, neurosteroids and neurotrophic factors, alpha-7 agonists or positive allosteric modulators (PAMs) PAMs, serotonin 2C agonists, and / or (3) drugs useful for treating one or more signs or symptoms of schizophrenia or bipolar disorder, particularly mania.

[0076] As used herein, the term "typical antipsychotic drug" refers to conventional antipsychotic drugs that produce antipsychotic effects as well as adverse effects related to movement associated with dopamine system disorders in the substantia striatum. These extrapyramidal side effects (EPS) include parkinsonism, akathisia, tardive dyskinesia and dystonia. See Baldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basis of Therapeutics 10 Edition, 2001, pp. 485-520.

[0077] As used herein, "atypical antipsychotic drug" refers to an antipsychotic drug that produces antipsychotic effects with little or no EPS, including, but not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone, and ziprasidone. The "atypical" antipsychotic drugs have a pharmacological profile different from that of conventional antipsychotic drugs. Conventional antipsychotic drugs are mainly characterized by blockade of D2 dopamine receptors, while atypical antipsychotic drugs show antagonist effects and various degrees of receptor affinity for multiple receptors including 5HT a and 5HT c serotonin receptors. Atypical antipsychotic drugs are usually also referred to as serotonin / dopamine antagonists, and the fact that they have a higher affinity for 5HT2 receptors than for D2 receptors reflects the hypothesis underlying the action of "atypical" antipsychotic drugs or "second-generation" antipsychotic drugs. However, atypical antipsychotic drugs often show side effects including, but not limited to, weight gain, diabetes (e.g., type II diabetes), hyperlipidemia, prolongation of the QTc interval, myocarditis, sexual side effects, extrapyramidal side effects, and cataracts. Therefore, atypical antipsychotic drugs are not a homogeneous class considering the differences in both the reduction of clinical symptoms and the potential to induce side effects such as those listed above. Furthermore, the common side effects of the atypical antipsychotic drugs described above often limit the dosage of antipsychotic drugs that can be used for these agents.

[0078] Memantine is 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.1 3,7It is chemically known as dekan-1-amine and is a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist with moderate affinity. Trademarks of memantine include Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebixa® and Abixa® (Lundbeck), and Memox® (Unipharm). Memantine is approved in the United States for the treatment of moderate to severe Alzheimer's disease (AD) at a maximum dose of 28 mg / day. Derivatives or analogs of memantine that contain compounds structurally or chemically similar to memantine are also useful in the present invention. Such derivatives or analogs of memantine include, but are not limited to, U.S. Patent Nos. 3,391,142; 4,122,193; 4,273,774, and 5,061,703; U.S. Patent Application Publications US20040087658, US20050113458, US20060205822, US20090081259, US20090124659, and US20100227852; European Patent Application Publication EP2260839A2; European Patent EP1682109B1; and such compounds disclosed in PCT Application Publication WO2005079779, all of which are hereby incorporated by reference herein. Memantine, as used in the present invention, includes memantine and its derivatives and analogs, as well as their hydrates, polymorphs, prodrugs, salts, and solvates. Memantine, as used herein, also includes compositions containing memantine or its derivatives or analogs, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs thereof, where the composition optionally further includes at least one additional therapeutic agent (such as a therapeutic agent useful for the treatment of CNS disorders or cognitive disorders associated therewith). In some embodiments, a memantine composition suitable for use in the present invention comprises memantine and a second therapeutic agent which is donepezil (trade name Aric ept).

[0079] The term "acetylcholinesterase inhibitor" or "AChE-I", as used herein, refers to an agent that inhibits the ability of the cholinesterase enzyme to break down the neurotransmitter acetylcholine, thereby increasing the concentration and prolonging the duration of acetylcholine, mainly at the brain synapses or neuromuscular junctions. Suitable AChE-Is for use in the present application can include, for example, (i) reversible non-competitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors, and (iii) pseudo-irreversible inhibitors.

[0080] The term "co-administration", as used herein, refers to the administration of an α5-containing GABA A receptor agonist (e.g., an α5-containing GABA A receptor positive allosteric modulator) and a second therapeutic agent (e.g., an antipsychotic drug, memantine or an AChE-I) or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, at time intervals not exceeding about 15 minutes, and in some embodiments, not exceeding about 10 minutes. When the drugs are co-administered, the α5-containing GABA A receptor agonist (e.g., an α5-containing GABA A receptor positive allosteric modulator) and the second therapeutic agent (e.g., an antipsychotic drug, memantine or an AChE-I) or a salt, hydrate, solvate or polymorph thereof may be included in the same dosage form (e.g., a unit dosage form containing both an α5-containing GABA A receptor agonist (e.g., an α5-containing GABA A receptor positive allosteric modulator) and the second therapeutic agent (e.g., an antipsychotic drug, memantine or an AChE-I)), or may be included in separate dosage forms (e.g., an α5-containing GABA A receptor agonist (e.g., an α5-containing GABA AA receptor positive allosteric modulator) or a salt, hydrate, solvate or polymorph thereof is included in one dosage form, and a second therapeutic agent (e.g., an antipsychotic drug, memantine or AChE-I) or a salt, hydrate, solvate or polymorph thereof is included in a separate dosage form).

[0081] The term "sequential administration", as used herein, refers to α5-containing GABA A receptor agonist (e.g., α5-containing GABA A receptor positive allosteric modulator) and a second therapeutic agent (e.g., an antipsychotic drug, memantine or AChE-I) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs thereof are administered at time intervals greater than about 15 minutes, in some embodiments, greater than about 1 hour or at time intervals up to 12 - 24 hours. α5-containing GABA A receptor agonist (e.g., α5-containing GABA A receptor positive allosteric modulator) or the second therapeutic agent (e.g., an antipsychotic drug, memantine or AChE-I) may be administered first. For sequential administration, α5-containing GABA A receptor agonist (e.g., α5-containing GABA A receptor positive allosteric modulator) and the second therapeutic agent (e.g., an antipsychotic drug, memantine or AChE-I) or salts, hydrates, solvents, or polymorphs thereof may be contained in separate dosage forms placed in the same container or package as needed.

[0082] A "therapeutically effective amount" of a drug or agent is an amount of the drug or agent that, when administered to a subject, such as a patient having a cognitive impairment associated with a CNS disorder, has the intended therapeutic effect, such as an improvement in cognitive function. A complete therapeutic effect does not necessarily occur by administering a single dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The exact effective amount required for a subject depends on, for example, the size, health and age of the subject, the nature and extent of the cognitive impairment or other symptoms of the CNS disorder (age-related cognitive impairment, mild cognitive impairment (MCI), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, ALS, cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior and substance addiction, etc. ) and the nature and degree of the treatment agent or combination of treatment agents selected for administration, as well as the mode of administration. One of ordinary skill in the art can readily determine the effective amount for a given situation by routine experimentation.

[0083] The compounds of the present invention also include prodrugs, analogs or derivatives. The term "prodrug" is recognized in the art and encompasses compounds or agents that are converted to an α5-containing GABA A R positive allosteric modulator under physiological conditions. A general method for generating a prodrug is to select a moiety that is hydrolyzed or metabolized under physiological conditions to yield the desired compound or agent. In other embodiments, the prodrug is converted to a GABA A α5 receptor positive allosteric modulator by the enzymatic activity of the host animal.

[0084] "Analog" is used herein to refer to a compound that is functionally similar to another chemical entity but does not share the same chemical structure. For example, an analog is sufficiently similar to the base compound or parent compound such that, despite minor structural differences, it can serve as a substitute for the base compound in therapeutic applications.

[0085] "Derivative" is used herein to refer to a chemical modification of a compound. Chemical modifications of a compound can include, for example, replacement of hydrogen by an alkyl group, an acyl group, or an amino group. Many other modifications are possible.

[0086] The term "aliphatic", as used herein, refers to straight-chain or branched alkyl, alkenyl, or alkynyl. Embodiments of alkenyl or alkynyl are understood to require at least two carbon atoms in the aliphatic chain. Aliphatic groups typically contain from one (or two) to twelve carbon atoms, such as from one (or two) to four carbon atoms.

[0087] The term "aryl", as used herein, refers to a monocyclic or bicyclic carbocyclic aromatic ring system. As used herein, aryl includes (C6-C12)-aryl-. For example, aryl, as used herein, can be a C6-C10 monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system. In some embodiments, aryl, as used herein, can be (C6-C10)-aryl-. Phenyl (or Ph) is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems where both rings are aromatic, such as naphthyl, and systems where only one of the two rings is aromatic, such as tetralin.

[0088] As used herein, the term "heterocyclic" refers to a monocyclic or bicyclic non-aromatic ring system having from 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, S, SO or SO2 in a chemically stable arrangement. As used herein, "heterocyclic" includes 3- to 12-membered heterocyclyl- having from 1 to 4 heteroatoms independently selected from O, N, NH, S, SO or SO2. For example, as used herein, "heterocyclic" can be a 3- to 10-membered monocyclic or 8- to 12-membered bicyclic non-aromatic ring system having from 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, S, SO or SO2 in a chemically stable arrangement. In some embodiments, as used herein, "heterocyclic" can be 3- to 10-membered heterocyclyl- having from 1 to 4 heteroatoms independently selected from O, N, NH, S, SO or SO2. In embodiments of the bicyclic non-aromatic ring system of "heterocyclyl", one or both of the rings may contain said heteroatom or heteroatom group. In another embodiment of the bicyclic "heterocyclyl", one of the two rings can be aromatic. In yet another embodiment of the heterocyclic ring system, the non-aromatic heterocyclic ring may be optionally fused to an aromatic carbocyclic ring.

[0089] The complex cyclic ring includes 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane and 1,3-dihydro-imidazol-2-one.

[0090] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring system having 1 to 4 heteroatoms or heteroatomic groups selected from O, N, NH or S in a chemically stable arrangement. As used herein, heteroaryl includes 5- to 12-membered heteroaryl having 1 to 4 heteroatoms independently selected from O, N, NH or S. In some embodiments, heteroaryl, as used herein, can be a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from O, N, NH or S. For example, heteroaryl, as used herein, can be a 5- to 10-membered monocyclic or 8- to 12-membered bicyclic aromatic ring system having 1 to 4 heteroatoms or heteroatomic groups selected from O, N, NH or S in a chemically stable arrangement in one or both rings. In embodiments of such bicyclic aromatic ring systems of "heteroaryl", - both rings are aromatic and - One or both of the rings may contain said heteroatom or heteroatom group.

[0091] Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

[0092] The term "cycloalkyl or cycloalkenyl" refers to a non-aromatic, monocyclic carbocyclic system, or a fused or bridged bicyclic carbocyclic system. For example, cycloalkyl or cycloalkenyl, as used herein, can be a non-aromatic C3-C10 monocyclic carbocyclic system, or a fused or bridged C8-C12 bicyclic carbocyclic system. The cycloalkenyl ring has one or more unsaturated units. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl , including cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decalinyl.

[0093] The term "heteroalkyl" refers to an alkyl in which a heteroaryl group is substituted in place of an alkyl H atom. For example, the alkyl group can be any straight-chain hydrocarbon and can contain 1 to 12 carbon atoms (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl), and the alkyl group can be substituted by any heteroaryl group including, but not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

[0094] The replacement part is described without indicating an atom, and when such a part is bonded to a substituent via this atom, the substituent may be bonded via any appropriate atom in such a part. For example, in the case of a substituted 5- to 10-membered heteroaryl, the substituent on the heteroaryl may be bonded to any of the ring-forming atoms of the heteroaryl ring that can be substituted (i.e., the atoms bonded to one or more hydrogen atoms).

[0095] When the bond to the substituent is described as crossing a bond connecting two atoms within the ring, such a substituent, unless otherwise specified or not particularly implied from the context, may be bonded to any of the ring-forming atoms within that ring that can be substituted (i.e., the atoms bonded to one or more hydrogen atoms). For example, when the R group is defined as pyridine and the pyridine is illustrated as follows:

Chemical formula

Chemical formula

[0096] The representation of carbon atoms, when used in this specification, can have the indicated integer and any intervening integers. For example, the number of carbon atoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that these representations refer to the total number of atoms in the appropriate group. For example, in a (C3-C10)-heterocyclyl, the total number of carbon atoms and heteroatoms is 3 (such as in aziridine), 4, 5, 6 (such as in morpholine), 7, 8, 9, or 10.

[0097] "Pharmaceutically acceptable salts" are used herein to refer to the pharmaceutically active non-toxic base and acid salt forms of the agents or compounds according to the invention. In their free form, the acid addition salt forms of compounds that exist as bases can be obtained by treating the free base form with a suitable acid such as an inorganic acid, for example, hydrohalic acid (such as hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid (for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.). See, for example, WO01 / 062726.

[0098] Compounds containing acidic protons may be converted into their pharmaceutically active non-toxic base addition salt forms, such as metal salts or amine salts, by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc., salts with organic bases, such as N-methyl-D-glucamine salts, hydrabamine salts, and salts with amino acids such as arginine, lysine, etc. Conversely, the said salt forms can be converted into the free form by treatment with a suitable base or acid.

[0099] Compounds and their salts can be in the form of solvates, which are included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, etc. See, for example, WO01 / 062726.

[0100] As used herein, the term "hydrate" refers to a combination of water and a compound, where the water retains its molecular state as water and is either absorbed, adsorbed, or included within the crystal lattice of the substrate compound.

[0101] As used herein, the term "polymorph" refers to different crystalline forms and other solid-state molecular forms (including pseudopolymorphs) of the same compound, such as hydrates (e.g., water of crystallization present in the crystal structure) and solvates (e.g., bound solvents other than water) of the same compound. Different crystal polymorphs have different crystal structures due to differences in the packing of molecules within their lattices. This results in different crystal symmetries and / or unit cell parameters, which directly affect their physical properties, such as the characteristics of X-ray diffraction of the crystal or powder. For example, different polymorphs generally diffract at different sets of angles, resulting in different values for their intensities. Thus, powder X-ray diffraction can be used to identify different polymorphs, or solid forms containing more than one polymorph, in a reproducible and reliable manner. Crystal polymorphic forms are of interest to the pharmaceutical industry and, in particular, to those involved in the development of suitable dosage forms. If the polymorphic form is not consistently maintained during clinical or stability studies, the dosage form that was used or studied may not be comparable from lot to lot. Since impurities present when a compound is used in clinical studies or products can have undesirable toxicological effects, it is also desirable to have a process for producing the compound in high purity with the selected polymorphic form. A particular polymorph may exhibit improved thermodynamic stability or may be more readily and easily manufactured in large quantities in high purity and is thus more suitable for inclusion in pharmaceutical formulations. A particular polymorph may exhibit other beneficial physical properties such as a lack of hygroscopic tendency, improved solubility, and improved dissolution rates due to different lattice energies.

[0102] ​This application contemplates all isomers of the compounds of formula V-a, A, B and C. As used herein, "isomers" include optical isomers (stereoisomers such as enantiomers and diastereoisomers), Z (zusammen) or E (entgegen) isomers, and tautomers. Many of the compounds useful in the methods and compositions of the present invention have at least one stereogenic center in their structure. This stereogenic center can exist in the R or S configuration, and the R and S notations are used according to the rules described in Pure Appl. Chem. (1976), 45, 11-30. The present invention also relates to all stereoisomers such as enantiomers and diastereoisomers of the present compounds, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO01 / 062726. Further, certain compounds containing an alkenyl group may exist as Z (zusammen) or E (entgegen) isomers. In each case, the present invention includes both mixtures and the individual separate isomers. Multiple substituents on the piperidinyl or azepanyl ring can also be in a cis or trans relationship to each other with respect to the plane of the piperidinyl or azepanyl ring. Some of the present compounds may exist as tautomers. Such forms are not explicitly shown in the formulas described herein but are intended to be included within the scope of the present invention. When referring to a compound (s) in relation to the methods and compositions of the present invention, unless a specific isomer is specifically mentioned, the compound is intended to encompass each of its possible isomers and mixtures thereof. See, for example, WO01 / 062726.

[0103] The compounds of the present invention enhance the function of α5-containing GABA A Rs, i.e., they are α5-containing GABA A R agonists (e.g., α5-containing GABA A receptor positive allosteric modulators) and can increase GABAergic Cl - currents.

[0104] The present invention further provides a pharmaceutical composition comprising one or more compounds of the present invention together with a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition of the present application may further comprise a second therapeutic agent such as an antipsychotic drug, memantine or AChE-I.

[0105] The present invention relates to a positive allosteric modulator of the α5-containing GABA A receptor and further provides a method for treating cognitive impairments associated with the CNS disorders responsive thereto, such as age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior and substance addiction. In certain embodiments, the method is a method for treating age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior and substance addiction. In certain embodiments, the treatment includes prevention of the CNS disorder (such as those described herein) or slowing of its progression. In certain embodiments, the treatment includes reduction, improvement or slowing of the progression of one or more symptoms associated with the CNS disorder. In certain embodiments, the condition being treated is cognitive impairment or agnosia. In another aspect of the invention, there is provided a method of protecting or improving cognitive function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0106] The various CNS disorders associated with cognitive impairment (e.g., age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive disorder and substance addiction) can have various etiologies. However, the symptoms of cognitive impairment in each of the above disorders may have overlapping causes. Thus, a composition or method of treating cognitive impairment in one CNS disorder can also treat cognitive impairment in another. Benzodiazepine derivatives

[0107] The present disclosure relates to a compound of formula V-a:

Chemical formula

Chemical formula

Chemical formula

[0108] In some embodiments, the compound of formula V-a is of formula A:

Chemical formula

Chemical formula

[0109] In some embodiments, the disclosure is directed to a compound having a structure according to Formula A, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein, R 1 Each is independently a halogen or -OMe, R 2 Each is -H or -CH2OMe, R 9 Each is

Chemical formula

[0110] In some embodiments, the compound of formula A has the structure according to formula B: [Chemical formula] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein R 1 , R 2 , R 9 , m and n are as defined for the compound having the structure according to formula A) having.

[0111] In some embodiments, the compound of formula A has the structure according to formula C: [Chemical formula] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein R 1 , R 2 , R 9 , m and n are as defined for the compound having the structure according to formula A) having.

[0112] Examples of specific compounds of this application are as follows: [Table 7-1] [Table 7-2] [Table 7-3] and including their pharmaceutically suitable salts, their hydrates, their solvates, their polymorphs, their isomers or combinations thereof.

[0113] Unless otherwise indicated, all embodiments described herein are also intended to encompass both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the same structural formulae as those depicted by the formulae shown herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, respectively, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I and other isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine. The present invention includes various isotopically labeled compounds as defined herein, for example, compounds in which radioactive isotopes such as 3 H, 13 C and 14 C are present. Such isotopically labeled compounds are useful in metabolic studies (preferably 14 C), in kinetic studies (e.g., using 2 H or 3 H), in detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates), or in radioactive treatment of patients. In particular, 18 F or labeled compounds may be particularly preferred for PET or SPECT studies. The isotopically labeled compounds and their prodrugs of the present invention can generally be prepared by replacing readily available isotopically labeled reagents with unlabeled reagents in the procedures disclosed in the schemes or examples and by performing the preparations described below.

[0114] Any of the individual embodiments recited in this specification can, individually or in combination, define Formulas V-a, A, B, or C to provide preferred embodiments of the present invention. General Synthetic Methods

[0115] The compounds of the present invention can generally be prepared by methods known to those of ordinary skill in the art. The following Schemes 1-9 present general synthetic routes for the preparation of compounds of Formulas V-a, A, B, and C. Other equivalent schemes will be readily apparent to the skilled organic chemist and can alternatively be used to synthesize the various moieties of the molecule as illustrated by the following general schemes. Scheme 1. General Synthesis of Compounds of Formula V-a, or Precursors to Compounds of Formula A or B, or Compounds of Formula B (wherein X, Y, Z, V, and W form a 1,2,3-triazole ring).

Chem.

Chem.

Chem.

Chem.

[0116] As will be recognized by those skilled in the art, compounds of formula V-a, A, B and C having variables other than those illustrated above can be prepared by varying chemical reagents or synthetic routes. Pharmaceutical Compositions and Modes of Administration

[0117] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula V-a, A, B and C, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0118] The basic nitrogen-containing groups present in the compounds of the present invention can be quaternized with agents such as lower alkyl halides (methyl chloride, ethyl chloride, propyl chloride and butyl chloride, methyl bromide, ethyl bromide, propyl bromide and butyl bromide, and methyl iodide, ethyl iodide, propyl iodide and butyl iodide, etc.); dialkyl sulfates (dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate, etc.), long-chain halides (decyl chloride, lauryl chloride, myristyl chloride and stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide and stearyl bromide, and decyl iodide, lauryl iodide, myristyl iodide and stearyl iodide, etc.), aralkyl halides (benzyl bromide and phenethyl bromide, etc.). Thereby, water-soluble or oil-soluble or water-dispersible or oil-dispersible products can be obtained.

[0119] It is recognized that the compounds and agents used in the compositions of the present invention, when administered peripherally, should preferably be able to easily cross the blood-brain barrier. However, compounds that cannot cross the blood-brain barrier can still be effectively administered directly to the central nervous system, for example, by the intracerebroventricular route or other neurocompatible routes.

[0120] In some embodiments of the present invention, α5-containing GABA AAn R positive allosteric modulator is formulated with a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that can be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of vegetable saturated fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. In other embodiments, no carrier is used. For example, an α5-containing GABA A R agonist (e.g., an α5-containing GABA A receptor positive allosteric modulator) can be administered alone or as a component of a pharmaceutical formulation (therapeutic composition). An α5-containing GABA A R agonist (e.g., an α5-containing GABA A receptor positive allosteric modulator) can be formulated for administration by any convenient method for use in pharmaceuticals for humans.

[0121] In some embodiments, the treatment methods of the present invention include the step of administering a composition of a compound or agent locally, systemically or topically. For example, the therapeutic composition of the compound or agent of the present invention may be formulated for administration by, for example, injection (e.g., intravenous, subcutaneous or intramuscular), inhalation or insufflation (via either the mouth or nose) or oral, buccal, sublingual, transdermal, nasal or parenteral administration. The composition of the compound or agent described herein may be formulated as part of an implant or device and may also be formulated for slow or sustained release. When administered parenterally, the therapeutic composition of the compound or agent for use in the present invention is preferably in a pyrogen-free physiologically acceptable form. Techniques and formulations can generally be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.

[0122] In certain embodiments, a pharmaceutical composition suitable for parenteral administration comprises an α5-containing GABA A R positive allosteric modulator in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile solutions or dispersions for injection immediately prior to use, and the above pharmaceutical composition may contain antioxidants, buffering agents, bacteriostatic agents, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0123] α5-containing GABAA Compositions containing an R-positive allosteric modulator may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phen nol, sorbic acid, etc. It may also be desirable to include in the composition isotonic agents such as sugars, sodium chloride, etc. Furthermore, by including agents that delay absorption such as aluminum monostearate and gelatin, long-term absorption of the injectable pharmaceutical form can be achieved.

[0124] In certain embodiments of the present invention, α5-containing GABA A Compositions containing an R-positive allosteric modulator can be orally administered, for example, in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as water-in-oil or oil-in-water liquid emulsions, or as elixirs or syrups, or as troches (using an inert base such as gelatin and glycerin, or sucrose and acacia), etc., each of which contains a predetermined amount of α5-containing GABA A containing the R-positive allosteric modulator as an active ingredient.

[0125] In the solid dosage forms (capsules, tablets, pills, dragees, powders, granules, etc.) of the present disclosure for oral administration, α5-containing GABA AOne or more compositions comprising an R positive allosteric modulator can be mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dibasic calcium phosphate), and / or any of the following: (1) fillers or extenders (such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid); (2) binders (such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia); (3) wetting agents (such as glycerol); (4) disintegrants (such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate); (5) dissolution retardants (such as paraffin); (6) absorption promoters (such as quaternary ammonium compounds); (7) wetting agents (such as cetyl alcohol and glycerol monostearate); (8) absorbents (such as kaolin and bentonite clay); (9) lubricants (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof); and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain a buffering agent. Solid compositions of the same type can also be used as fillings in soft and hard gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol.

[0126] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. The liquid dosage forms are α5-containing GABA AIn addition to the R positive allosteric modulator, it may include inert diluents (such as water or other solvents), solubilizing agents and emulsifying agents commonly used in the art (such as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, etc.), and mixtures thereof. Oral compositions can also include, in addition to inert diluents, adjuvants (such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavorings, colorants, fragrances and preservatives).

[0127] Suspensions may include, in addition to the active compound, suspending agents (such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, etc.), microcrystalline cellulose, aluminum hydroxide metas, bentonite, agar and tragacanth and mixtures thereof.

[0128] As described herein, the compounds, agents and their compositions can be administered so as to provide slow, controlled release or sustained release. The term "sustained release" is widely recognized in the field of pharmaceutical science and is used herein to refer to the controlled release of an active compound or agent from a dosage form into an environment over a long period of time, for example, over or equal to 1 hour (for a long time or during that time). Sustained release dosage forms release the drug at a substantially constant rate over a long period of time or a substantially constant amount of the drug is released incrementally over a long period of time. The term "sustained release" as used herein includes the terms "controlled release", "extended release", "sustained release", "delayed release" or "slow release" as used in pharmaceutical science. In some embodiments, the sustained release dosage form is administered in the form of a patch or a pump.

[0129] A person skilled in the art, such as a physician, can readily determine the required amount of an α5-containing GABA A R positive allosteric modulator for treating a subject using the compositions and methods of the present invention. The dosage regimen can be determined for an individual taking into account, for example, various factors that modify the action of the α5-containing GABA A R positive allosteric modulator, the severity or stage of the disease, the route of administration, as well as characteristics specific to that individual such as age, weight, size, and the degree of cognitive impairment.

[0130] It is well known in the art that normalization to body surface area is an appropriate method for extrapolating dosages across species. To calculate the human equivalent dose (HED) from the dose used in treating age-dependent cognitive impairment in rats, the equation HED (mg / kg) = dose in rats (mg / kg) × 0.16 can be used (see Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, December 2002, Center for Biologics Evaluation and Research). For example using that equation, a dose of 10 mg / kg in rats is equivalent to 1.6 mg / kg in humans. This conversion is based on the more general equation HED = dose in animal (mg / kg) × (weight of animal (kg) / weight of human (kg)) 0.33 ).

[0131] In certain embodiments of the present invention, the dosage of the α5-containing GABA A R positive allosteric modulator is from 0.0001 to 100 mg / kg / day (which, considering a typical human subject of 70 kg, is between 0.007 and 7000 mg / day).

[0132] In certain embodiments of the present invention, the dosing interval is once every 12 hours or 24 hours. Dosing at lower frequency intervals such as once every 6 hours may also be used.

[0133] When administered by an implant, device, or sustained or controlled release formulation, α5-containing GABA A The R positive allosteric modulator can be administered once, or, if necessary, periodically one or more times throughout the patient's lifetime. Other dosing intervals intermediate to or shorter than these for clinical use may be used and can be determined by one of ordinary skill in the art according to the methods of the present invention.

[0134] The desired dosing times can be determined by routine experimentation by one of ordinary skill in the art. For example, α5-containing GABA A The R positive allosteric modulator may be administered for a period of 1 to 4 weeks, 1 to 3 months, 3 to 6 months, 6 to 12 months, 1 to 2 years or longer, up to the patient's lifetime.

[0135] The compositions of the present invention may contain, in addition to the α5-containing GABA A R positive allosteric modulator, other therapeutically useful agents. These other therapeutically useful agents can be administered, according to the methods of the present invention, in a single formulation, with the α5-containing GABA A R positive allosteric modulator, simultaneously or sequentially.

[0136] It is understood by one of ordinary skill in the art that the compositions described herein can be adapted and modified to be appropriate for the use being addressed and that the compositions described herein can be used in other suitable applications. For example, the compositions of the present application may further contain a second therapeutic agent. Such other additions and modifications do not depart from the scope of the present invention. Pharmaceutical composition comprising an antipsychotic drug

[0137] The compounds or compositions of the present application can be used in combination with antipsychotic drugs in treating cognitive impairment associated with schizophrenia or bipolar disorder (e.g., mania) in a subject having or at risk of having said schizophrenia or bipolar disorder. Antipsychotic drugs or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof useful in the methods and compositions of the present invention include both typical and atypical antipsychotic drugs. In some embodiments, the compounds or compositions of the present invention can be used to treat one or more positive and / or negative symptoms and cognitive impairment associated with schizophrenia. In some embodiments, the compounds or compositions of the present invention can be used to treat one or more symptoms and cognitive impairment associated with bipolar disorder (particularly mania). In some embodiments of the present invention, the compounds or compositions of the present invention prevent or slow the progression of cognitive impairment in said subject with schizophrenia or bipolar disorder (particularly mania).

[0138] In some embodiments, the antipsychotic drugs suitable for use in the present invention are selected from atypical antipsychotic drugs. Such atypical antipsychotic drugs include, but are not limited to, for example, those disclosed in U.S. Patent Nos. 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925; and European Patents EP402644 and EP368388, and pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof.

[0139] In some embodiments, atypical antipsychotic drugs suitable for use in the present invention include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone, and ziprasidone, as well as pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. In some embodiments, antipsychotic drugs suitable for use herein are selected from aripiprazole (Bristol-Myers Squibb), olanzapine (Lilly), and ziprasidone (Pfizer), as well as pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0140] In some embodiments, antipsychotic drugs suitable for use in the present invention include, but are not limited to, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clothiapine, ciamemazine, diazepam, dixyrazine, droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyp rotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipothiazine, prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine, sulpiride, sultopride, tetrabenazine, thiopropazate , thioridazine, thia prid, thiotixene, trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol, and are typical antipsychotic drugs including pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0141] In some embodiments of the present invention, the antipsychotic drug or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is a dopamine agonist (dopamine D1 receptor antagonist or agonist, dopamine D2 receptor antagonist or partial agonist, dopamine D3 receptor antagonist or partial agonist, dopamine D4 receptor antagonist, etc.), glutamate agonist, N-methyl-D-aspartic acid (NMDA) receptor positive allosteric modulator, glycine reuptake inhibitor, glutamate reuptake inhibitor, metabotropic glutamate receptor (mGluR) agonist or positive allosteric modulator (PAM) (e.g., mGluR2 / 3 agonist or PAM), glutamate receptor glur5 positive allosteric modulator (PAM), M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulator (PAM), histamine H3 receptor antagonist, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) / kainic acid receptor antagonist, ampakine (CX-516), glutathione prodrug, noradrenergic agent (alpha-2 adrenergic receptor agonist or antagonist and catechol-O-methyltransferase (COMT) inhibitor, etc.), serotonin receptor modulator (5-HT 2A receptor antagonist, 5-HT 1A receptor partial agonist, 5-HT 2C agonist and 5-HT6 antagonist, serotonin 2C agonist, etc.), cholinergic agent (alpha-7 nicotinic receptor agonist or PAM, alpha4-beta2 nicotinic receptor agonist, allosteric modulator of nicotinic receptor and acetylcholinesterase inhibitor, muscarinic receptor agonist and antagonist, etc.), cannabinoid CB1 antagonist, neurokinin 3 antagonist, neurotensin agonist, monoamine oxidase (MAO) B inhibitor, PDE10 inhibitor, neuronal nitric oxide synthase (nNOS) inhibitor, neurosteroid and a compound which is a neurotrophic factor, and may be selected from.

[0142] In some embodiments, the α5-containing GABA A receptor positive allosteric modulators described herein and the antipsychotic drugs described herein, or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof, are administered simultaneously or sequentially, or in a single formulation or in separate formulations packaged together. In other embodiments, the α5-containing GABA A receptor positive allosteric modulators and antipsychotic drugs, or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof, are administered via various routes. As used herein, "combination" includes administration by any of these formulations or routes of administration. A pharmaceutical composition containing memantine

[0143] The compounds or compositions of the present application can be used in combination with memantine, or derivatives or analogs thereof, in treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need of treatment or at risk thereof (non-limitingly, age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI, age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS) and subjects having or at risk of having cognitive impairment associated with cancer treatment).

[0144] Memantine is also known chemically as 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.1 3,7 decane-1-amine, and is a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist with moderate affinity. Trademarks of memantine include Axura® and Akatinol® (Merz), Namenda® (Forest Examples include Laboratories), Ebixa (registered trademark), and Abixa (registered trademark) (Lundbeck), as well as Memox (registered trademark) (Unipharm). Memantine is currently available in the United States and in over 42 countries around the world. Memantine is approved in the United States for treating moderate to severe Alzheimer's disease (AD) at a maximum dose of 28 mg / day. Some of the memantine, its derivatives, and analogs useful in the present invention are disclosed in U.S. Patent Nos. 3,391,142; 4,122,193; 4,273,774; and 5,061,703, all of which are incorporated herein by reference. Other memantine derivatives or memantine analogs useful in the present invention include, but are not limited to, U.S. Patent Application Publications US20040087658, US20050113458, US20060205822, US20090081259, US20090124659, and US20100227852; European Patent Application Publication EP2260839A2; European Patent EP1682109B1; and compounds disclosed in PCT Application Publication WO2005079779, all of which are incorporated herein by reference. When used in the present invention, memantine includes memantine, its derivatives and analogs, as well as their hydrates, polymorphs, prodrugs, salts, and solvates. Memantine, as used herein, also includes a composition comprising memantine or its derivative or analog, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof, where the composition optionally further comprises at least one additional therapeutic agent (such as a therapeutic agent useful for treating CNS disorders or cognitive disorders related thereto). In some embodiments, a memantine composition suitable for use in the present invention comprises memantine and a second therapeutic agent which is donepezil (trade name Aricept).

[0145] In other embodiments of the present invention, α5-containing GABA AA receptor positive allosteric modulator and memantine (or a memantine derivative / analog) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug thereof are administered simultaneously or sequentially, or in a single formulation or in separate formulations packaged together. In other embodiments, α5-containing GABA A A receptor positive allosteric modulator and memantine (or a memantine derivative / analog) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug thereof are administered via various routes. As used herein, "combination" includes administration by any of these formulations or routes of administration. A pharmaceutical composition comprising an acetylcholinesterase inhibitor (AChE-I)

[0146] The compounds or compositions of the present application can be used in combination with an acetylcholinesterase inhibitor in treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need of treatment or at risk thereof for a CNS disorder (including, but not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI, age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS) and subjects having or at risk of having cognitive impairment associated with cancer treatment).

[0147] AChE-Is known to those skilled in the art can belong to sub-classifications of (i) reversible non-competitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors, and / or (iii) quasi-irreversible inhibitors.

[0148] In certain embodiments, AChE-Is useful in the present invention include those described in PCT applications WO2014039920 and WO2002032412; European Patent No. 468187; No. 481429-A; and U.S. Patent Nos. 4,816,456; 4,895,841; 5,041,455; 5,106,856; 5,602,176; 6,677,330; 7,340,299; 7,635,709; 8,058,268; 8,741,808; and 8,853,219, all of which are incorporated herein by reference.

[0149] In certain embodiments, exemplary AChE-Is that can be used in accordance with the present invention include, but are not limited to, ungeremine, ladostigil, demecarium, echothiophate (Phospholine), edrophonium (Tensilon), tacrine (Cognex), pralidoxime (2-PAM), pyridostigmine (Mestinon), physostigmine (serine, Antilirium), ambenonium (Mytelase), galantamine (Reminyl, Razadyne), rivastigmine (Exelon, SZD-ENA-713), Huperzine A, icopegil, neostigmine (Prostigmin, Vagostigmin), Aricept (Donepezil, E2020), lactucopicrin, monoamine acridine, and their derivatives, piperidine and piperazine derivatives, N-benzyl-piperidine derivatives, piperidinyl-alkanoyl heterocyclic compounds, 4-(1-benzyl:piperidyl) substituted condensed quinoline derivatives, and cyclic amide derivatives. Other exemplary AChE-Is include carbamate and organophosphonate compounds (such as metrifonate (trichlorfon)). Benzoazepinol such as galantamine is also a useful AChE-I. In some embodiments, AChE-Is suitable for use in combination with the compounds and compositions of the present application include donepezil (aricept), galantamine (razadyne), or rivastigmine (exelon).

[0150] In other embodiments of the present invention, α5-containing GABA A receptor positive allosteric modulators and AChE-Is, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof, are administered simultaneously or sequentially, or in a single formulation or in separate formulations packaged together. In other embodiments, α5-containing GABA A receptor positive allosteric modulators and AChE-Is, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof, are administered via various routes. As used herein, "combination" includes administration by any of these formulations or routes of administration.

[0151] In some embodiments, the compounds and compositions described herein are for use as medicaments. In some embodiments, the compounds and compositions of the present invention are for use in the treatment of cognitive impairment in a subject in need of treatment for or at risk of a CNS disorder associated with cognitive impairment. In some embodiments, CNS disorders associated with cognitive impairment include, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior and substance addiction.

[0152] In some embodiments, the present application provides the use of a compound or composition described herein in the preparation of a medicament for treating cognitive impairment in a subject in need of treatment for or at risk of a CNS disorder associated with cognitive impairment. In some embodiments, cognitive CNS disorders associated with impairment include, without limitation, age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction. Method for evaluating cognitive impairment

[0153] Animal models serve as an important source for developing and evaluating treatments for cognitive impairment associated with CNS disorders. The characteristics that characterize cognitive impairment in animal models are usually extrapolated to cognitive impairment in humans. Therefore, the effectiveness in such animal models is expected to predict effectiveness in humans. The degree of cognitive impairment in animal models for CNS disorders, and the effectiveness of treatment methods for said CNS disorders, can be tested and confirmed using various cognitive tests.

[0154] The radial arm maze (RAM) behavioral task is specifically an example of a cognitive test that examines spatial memory (Chappell et al. Neuropharmacology 37: 481-487, 1998). The RAM apparatus It consists of, for example, eight runways arranged at equal distances. The runways of the maze protrude from each side of the central platform. Food indentations are arranged at the distal end of each runway. Food is used as a reward. Blocks can be placed to prevent entry into any runway. There may also be numerous additional maze clues provided around the apparatus. After the habituation and training periods, the spatial memory of the subject can be tested in the RAM under conditions treated with a control compound or a test compound. As part of that test, the subject is pre-treated with a vehicle control or one of a series of doses of the test compound prior to the trial. At the start of each trial, a subset of the runways of the eight-runway maze is blocked. The subject can obtain food in the unblocked runways that are allowed entry during this initial "information period" of the trial. Next, the subject is removed from the maze for a delay period, for example, a delay period of 60 seconds, 15 minutes, 1 hour, 2 hours, 6 hours, 24 hours or a delay period exceeding that, between the information period and the subsequent "recall test" where the barriers on the maze are removed and thus entry into all eight runways is possible. After that delay period, the subject is returned to the central platform (with the barriers to the previously blocked runways removed), and it is possible to obtain the remaining food rewards during the recall test period of this trial. Which runways are blocked and their arrangement are changed for each trial. The number of "errors" committed by the subject during the recall test period is tracked. An error occurs in that trial if the subject enters a runway where food has already been found in the component prior to the delay period of that trial, or if the subject revisits a runway that has already been visited in the session after the delay period. A smaller number of errors indicates better spatial memory. Next, the number of errors committed by the test subjects in the treatment regimens of various test compounds can be compared for the effectiveness of that test compound in the treatment of cognitive impairments associated with CNS disorders.

[0155] Another cognitive test that can be used to evaluate the effect of a test compound on cognitive impairment in CNS disorder model animals is the Morris water maze. The water maze is a pool surrounded by a new series of patterns relative to the maze. The training protocol for the water maze can be based on a modified water maze task that has been shown to be hippocampus-dependent (de Hoz et al., Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999). The subject is trained to search for the position of a submerged escape platform hidden underwater beneath the surface of the pool. During the training trials, the subject is released into the maze (pool) from a random starting position at the perimeter of the pool. The starting position is changed for each trial. If the subject does not find the position of the escape platform within the set time, the experimenter guides the subject to the platform and places it on top in order to "teach" the position of the platform. After the last training trial After a delay time after the last training trial, a retention test is conducted in the absence of the escape platform to evaluate spatial memory. For example, the preference level of the subject for that position, as measured by the time the mouse spends at the position of the (now absent) escape platform or the number of times it crosses that position, indicates better spatial memory, i.e., treatment of cognitive impairment. Then, the preference for the position of the escape platform under different treatment conditions can be mapped to the effectiveness of the test compound in the treatment of cognitive impairment associated with CNS disorders.

[0156] There are various tests known in the art for evaluating cognitive function in humans, for example, but not limited to, the Clinical Global Impression of Change Scale (CIBIC-plus scale); the Mini-Mental State Examination (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating (CDR); the Cambridge Neuropsychological Test Battery (CANTAB); the Saint Louis University Clinical Assessment for the Elderly (SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates Sub Tests; Logical Memory subtest; Visual Reproduction subtest of the Wechsler Memory Scale Revised (WMS-R) (Wechsler, 1997); Benton Visual Retention Test, or tests of working memory, processing speed , attention, language learning, visual learning, reasoning and problem solving, and there is a MATRICS Consensus Neuropsychological Test Battery that includes tests of social cognition. Folstein et al., J See Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994. Similarly, see Buchanan, R.W., Keefe, R.S.E., Umbricht, D., Green, M.F., Laughren, T., and Marder, S.R. (2011) The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209-1217. Another example of a cognitive test in humans is the explicit three-alternative forced-choice task. In this test, subjects are presented with color photographs of common objects consisting of three types of image pairs: pairs of similar objects, identical pairs, and a mixture of unrelated foils. The second member of the pair of similar objects is called the "decoy". These image pairs are completely randomized and presented individually as a series of images. Subjects are instructed to judge whether the object they saw was new, old, or similar. A "similar" response to the presentation of the decoy stimulus indicates that the subject's memory search was successful. In contrast, an evocation of the decoy stimulus as "old" or "new" indicates that the correct memory search did not occur.

[0157] In addition to the assessment of cognitive ability, by evaluating surrogate changes in the brain of a subject, the progression of age-related cognitive impairment and dementia, as well as the transition from age-related cognitive impairment to dementia, can be monitored. Surrogate changes include, without limitation, changes in local brain volume, disruption of white matter tracts, and changes in brain function seen by resting-state fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Examples of local brain volumes useful for monitoring the progression of age-related cognitive impairment and dementia include a decrease in hippocampal volume and a decrease in the volume or thickness of the olfactory cortex. These volumes can be measured in a subject, for example, by MRI. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010). Disruption of white matter tracts has been shown to be associated with age and decline in cognitive function. For example, older individuals with more disrupted white matter tracts tend to have worse performance on hippocampal-dependent memory tests. Disruption of white matter tracts can be monitored in a subject by ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting-state fMRI (R-fMRI) involves imaging the brain at rest and recording large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in fMRI signals that are temporally correlated between functionally related regions. Seed-based functional connectivity, independent component analysis of the signals, and / or frequency domain analysis are used to reveal the functional connectivity between brain regions, particularly between regions whose coupling increases or decreases with age, as well as the degree of cognitive impairment and / or dementia. FDG-PET uses the uptake of FDG as a measure of local metabolic activity in the brain. A decrease in FDG uptake in regions such as the posterior cingulated cortex, lateral parietal cortex, and anterior commissure has been shown to be related to the degree of cognitive decline and dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 analysis and / or frequency domain analysis are used. FDG-PET uses the uptake of FDG as a measure of local metabolic activity in the brain. A decrease in FDG uptake in regions such as the posterior cingulated cortex, lateral parietal cortex, and anterior commissure has been shown to be related to the degree of cognitive decline and dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002). Age-related cognitive impairment

[0158] The present invention relates to an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharma- ceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. A Methods and compositions are provided for treating age-related cognitive impairment or its risk using receptor positive allosteric modulators (i.e., compounds of the present invention). In certain embodiments, treatment includes prevention of age-related cognitive impairment or slowing down its progression. In certain embodiments, treatment includes alleviation, improvement or slowing down the progression of one or more symptoms associated with age-related cognitive impairment. In certain embodiments, treatment of age-related cognitive impairment includes slowing down the transition from age-related cognitive impairment (including but not limited to MCI, ARCD and AAMI) to dementia (e.g., AD). The methods and compositions can be used on human patients in clinical applications in treating age-related cognitive impairment or its risk in conditions such as MCI, ARCD and AAMI. The dose of the composition and the administration interval for the method are safe and effective in their applications as described herein. In some embodiments of the present invention, there is provided a method of protecting or improving cognitive function in a subject having age-related cognitive impairment, comprising the step of administering to said subject a therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0159] In some embodiments, the subject treated by the methods and compositions of the present invention shows age-related cognitive impairment or is at risk of such impairment.In some embodiments, age-related cognitive impairment includes, but is not limited to, age-associated memory impairment (AAMI), mild cognitive impairment (MCI) and age-related cognitive decline (ARCD).

[0160] Animal models serve as an important source for developing and evaluating treatments for such age - related cognitive impairment. The characteristics that characterize age - related cognitive impairment in animal models are usually extended and applied to age - related cognitive impairment in humans. Therefore, the effectiveness in such animal models is expected to predict effectiveness in humans.

[0161] Various animal models of age - related cognitive impairment are known in the art. For example, through large - scale behavioral characterization, a form of cognitive impairment that naturally exists in non - inbred strains of aged Long - Evans rats has been identified (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107:618 - 626, (1993)). In behavioral evaluations using the Morris water maze (MWM), rats learn and remember the location of an escape platform guided by the arrangement of spatial cues surrounding the maze. The cognitive basis of this ability is tested in probe trials that use a measure of the animal's spatial bias when searching for the location of the escape platform. Aged rats in the study population do not have difficulty swimming to the visible platform, but when the platform is camouflaged, age - dependent dysfunction is detected and the use of spatial information is required. The performance of individual aged rats in the non - inbred Long - Evans strain varies widely. For example, a certain proportion of such rats achieve performance comparable to that of young adults. However, approximately 40 - 50% deviate from the range of young adult performance. This variability among aged rats reflects reliable individual differences. Therefore, within the aged population, some animals have cognitive impairment, denoted as aged impaired (AI), and other animals have no impairment, denoted as aged unimpaired (AU). For example, Colombo et al., Proc. Natl. Acad. Sci. 94: 14195 - 14199, (1997); Gallagher and Burwell, Neurobiol. Aging ​10: 691-708, (1989); Gallagher et al. Behav. Neurosci. 107:618-626, (1993); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93: 9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996); Nicolle et al., J. Neurosci. 19: 9604-9610, (1999); See International Patent Publication WO2007 / 019312 and International Patent Publication WO2004 / 048551. Such animal models of age-related cognitive impairment can be used to assay the effectiveness of the methods and compositions of the present invention in the treatment of age-related cognitive impairment.

[0162] The effectiveness of the methods and compositions of the present invention in the treatment of age-related cognitive impairment can be evaluated using various cognitive tests including the Morris water maze and the radial maze discussed herein. Dementia

[0163] The present invention also provides an α5-containing GABA selected from the compounds described herein or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, isomers thereof, or combinations thereof. AProvided are methods and compositions for treating dementia using a receptor positive allosteric modulator. In certain embodiments, treatment includes preventing dementia or slowing its progression. In certain embodiments, treatment includes reducing, ameliorating or slowing the progression of one or more symptoms associated with dementia. In certain embodiments, the symptom being treated is cognitive impairment. In some embodiments of the invention, there is provided a method of protecting or improving cognitive function in a subject having dementia, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In certain embodiments, the dementia is Alzheimer's disease (AD), vascular dementia, Lewy body dementia or frontotemporal dementia. The methods and compositions can be used in human patients in clinical applications for treating dementia. The dosage of the composition and the dosing interval in the case of the method are safe and effective in those applications as described herein.

[0164] Animal models serve as an important source for developing and evaluating treatments for dementia. Features that characterize dementia in animal models are typically extrapolated to dementia in humans. Thus, efficacy in such animal models is expected to predict efficacy in humans. Various animal models of dementia are known in the art, such as PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg and APP+PS1 transgenic mice. Sankaranarayanan, Curr. Top. Medicinal Chem. 6: 609-627, 2006; Kobayashi et al. Genes Brain Behav. 4: 173-196. 2005; Ashe and Zahns, Neuron. 66: 631-45, 2010. Such animal models of dementia can be used to assay the efficacy of the methods and compositions of the invention in the treatment of dementia.

[0165] The effectiveness of the methods and compositions of the present invention in the treatment of dementia or cognitive impairment associated with dementia can be evaluated in animal models of dementia and in human subjects with dementia using various cognitive tests known in the art, as discussed herein. Post-traumatic stress disorder

[0166] The present invention also provides methods and compositions for treating post-traumatic stress disorder (PTSD) using an α5-containing GABA A receptor positive allosteric modulator selected from the compounds described herein or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, isomers thereof, or combinations thereof. In certain embodiments, the treatment includes prevention of PTSD or slowing of its progression. In certain embodiments, the treatment includes reduction, improvement or slowing of the progression of one or more symptoms associated with PTSD. In certain embodiments, the symptom being treated is cognitive impairment. In some embodiments of the present invention, there is provided a method of protecting or improving cognitive function in a subject having PTSD, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, isomer thereof, or combination thereof. The methods and compositions can be used in human patients in clinical use in treating PTSD. The dosage of the composition and the dosing interval in the case of the method are safe and effective for such uses, as described herein.

[0167] Patients with PTSD (and, to a lesser extent, patients without PTSD who have been exposed to trauma) have smaller hippocampal volumes (Woon et al., Prog. Neuro-Psychopharm. & Biological Psych. 34, 1181-1188; Wang et al., Arch. Gen. Psychiatry 67:296-303, 2010). PTSD is also associated with impaired cognitive abilities. Elderly individuals with PTSD have greater cognitive decline compared to control patients (Yehuda et al., Bio. Psych. 60: 714-721, 2006) and are at higher risk of developing dementia (Yaffe et al., Arch. Gen. Psych. 678: 608-613, 2010).

[0168] Animal models serve as an important source for developing and evaluating treatments for PTSD. Features that characterize PTSD in animal models are typically extrapolated to PTSD in humans. Thus, effectiveness in such animal models is expected to predict effectiveness in humans. Various animal models of PTSD are known in the art.

[0169] One rat model of PTSD is time-dependent sensitization (TDS). TDS involves exposing animals to a severe stress event and subsequent recall of this prior stress situation. The following is an example of TDS. Rats are fitted with restraints and then placed in a swimming tank and allowed to swim for a fixed period, e.g., 20 minutes. After this, each rat is then immediately exposed to a gaseous anesthetic until unconscious and finally dried. The animals are allowed to recover for several days, e.g., 1 week. Next, the rats are exposed to a "restress" session consisting of the first stressor, e.g., a swimming session in the swimming tank (Liberzon et al., Psychoneuroendocrinology 22: 443-453, 1997; Harvery et al., Psychopharmacology 175:494-502, 2004). TDS results in enhancement of the rats' acoustic startle response (ASR) comparable to exaggerated acoustic startle, a prominent symptom of PTSD (Khan and (Liberzon, Psychopharmacology 172: 225-229, 2004). Such animal models of PTSD can be used to assay the effectiveness of the methods and compositions of the present invention in the treatment of PTSD. The effectiveness of the methods and compositions of the present invention in the treatment of PTSD or cognitive impairments associated with PTSD can also be evaluated in animal models of PTSD and in human subjects with PTSD using various cognitive tests known in the art, as discussed herein.

[0170] The effectiveness of the methods and compositions of the present invention in the treatment of PTSD or cognitive impairments associated with PTSD can also be evaluated in animal models of PTSD and in human subjects with PTSD using various cognitive tests known in the art, as discussed herein. Schizophrenia and bipolar disorder

[0171] The present invention further provides methods and compositions for treating schizophrenia or bipolar disorder (particularly mania) using an α5-containing GABA receptor positive allosteric modulator selected from a compound described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In certain embodiments, the treatment includes preventing or delaying the progression of schizophrenia or bipolar disorder (particularly mania). Schizophrenia is characterized by a wide range of psychopathology including positive symptoms such as abnormal or distorted mental representations (e.g., hallucinations, delusions), or symptoms associated with dopaminergic dysregulation (e.g., hyperdopaminergic response, hyperdopaminergic behavioral response, dopaminergic hyperactivity or excessive spontaneous motor activity or psychosis), negative symptoms characterized by reduced motivation and decreased adaptive goal-directed behavior (e.g., anhedonia, blunted affect, avolition) and cognitive impairments. In certain embodiments, the treatment includes reducing, ameliorating or decelerating the progression of one or more positive and / or negative symptoms, and cognitive impairments associated with schizophrenia. Further, schizotypical disorders and schizoaffective disorders, other acute and chronic mental illnesses, and bipolar A The present invention further provides methods and compositions for treating schizophrenia or bipolar disorder (particularly mania) using an α5-containing GABA receptor positive allosteric modulator selected from a compound described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In certain embodiments, the treatment includes preventing or delaying the progression of schizophrenia or bipolar disorder (particularly mania). Schizophrenia is characterized by a wide range of psychopathology including positive symptoms such as abnormal or distorted mental representations (e.g., hallucinations, delusions), or symptoms associated with dopaminergic dysregulation (e.g., hyperdopaminergic response, hyperdopaminergic behavioral response, dopaminergic hyperactivity or excessive spontaneous motor activity or psychosis), negative symptoms characterized by reduced motivation and decreased adaptive goal-directed behavior (e.g., anhedonia, blunted affect, avolition) and cognitive impairments. In certain embodiments, the treatment includes reducing, ameliorating or decelerating the progression of one or more positive and / or negative symptoms, and cognitive impairments associated with schizophrenia. Further, schizotypical disorders and schizoaffective disorders, other acute and chronic mental illnesses, and bipolar In certain embodiments, the treatment includes reducing, ameliorating or decelerating the progression of one or more positive and / or negative symptoms, and cognitive impairments associated with schizophrenia. Further, schizotypical disorders and schizoaffective disorders, other acute and chronic mental illnesses, and bipolar There are several other psychiatric disorders, such as sexual disorders (especially mania), which have a symptomatology that overlaps with schizophrenia. In some embodiments, the treatment includes reducing, improving or slowing the progression of one or more symptoms associated with bipolar disorder (especially mania) and cognitive impairment. In some embodiments of the present invention, there is provided a method for protecting or improving cognitive function in a subject having schizophrenia or bipolar disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. The method and composition can be used in human patients in clinical applications when treating schizophrenia or bipolar disorder (especially mania). The dosage of the composition and the dosing interval in the case of the method are safe and effective for their uses as described herein.

[0172] Cognitive impairment is associated with schizophrenia. Cognitive impairment precedes the onset of mental illness and is present in non-affected relatives. Cognitive impairment associated with schizophrenia constitutes a good predictor of functional outcome and is a central feature of this disorder. The cognitive features of schizophrenia reflect dysfunction of the prefrontal cortex circuit and the hippocampal circuit. Patients with schizophrenia also exhibit hippocampal pathology, a decrease in hippocampal volume, a decrease in neuron size and hyperexcitability due to dysfunction. An imbalance between excitation and inhibition in these brain regions has also been demonstrated in schizophrenia patients, suggesting that drugs targeting inhibitory mechanisms may be therapeutic. For example, Guidotti et al., Psychopharmacology 180: 191-205, 2005; Zierhut, Psych. Res. Neuroimag. 183:187-194, 2010; Wood et al., NeuroImage 52:62-63, 2010; See Vinkers et al., Expert Opin. Investig. Drugs 19:1217-1233, 2009; Young et al., Pharmacol. Ther. 122:150-202, 2009.

[0173] Animal models serve as an important source for developing and evaluating treatments for schizophrenia. The characteristics that characterize schizophrenia in animal models are usually extended to schizophrenia in humans. Therefore, the effectiveness in such animal models is expected to predict effectiveness in humans. Various animal models of schizophrenia are known in the art.

[0174] One animal model of schizophrenia is long-term treatment with methionine. Methionine-treated mice show insufficient expression of GAD67 in the prefrontal cortex and hippocampus, similar to that reported in the brains of postmortem schizophrenia patients. Those mice also show deficits in prepulse inhibition of startle and social interaction (Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal model of schizophrenia is methylazoxymethanol acetate (MAM) treatment in rats. Pregnant female rats are administered MAM (20 mg / kg, intraperitoneally) on the 17th day of pregnancy. MAM treatment reproduces the pathophysiological process (pathogenesis) leading to a schizophrenia-like phenotype (including anatomical changes, behavioral deficits, and changes in neuronal information processing) in their offspring. More specifically, MAM-treated rats show low-density parvalbumin-positive GABAergic interneurons in parts of the prefrontal cortex and hippocampus. In behavioral tests ​, MAM-treated rats show a decrease in latent inhibition. Latent inhibition is a behavioral phenomenon in which learning about a stimulus pre-exposed without any consequence is impaired. This tendency to ignore previously benign stimuli and weaken the formation of associations with such stimuli is thought to prevent sensory overload. Low latent inhibition is indicative of mental illness. Latent inhibition can be examined in rats in the following manner. Rats are divided into two groups. One group is pre-exposed to one type of sound over multiple trials. The other group has no presentation of the sound. Next, both groups are exposed to an auditory fear conditioning procedure in which the same sound is presented simultaneously with an aversive stimulus, such as an electric shock to the foot. Subsequently, the sound is presented to both groups, and the change in the rats' spontaneous locomotor activity while the sound is being presented is monitored. After the fear conditioning, the rats respond to the presentation of the sound by strongly decreasing their spontaneous locomotor activity. However, the group that was pre-exposed to the sound prior to the conditioning period shows strong latent inhibition: the suppression of spontaneous locomotor activity in response to the presentation of the sound is reduced. In contrast, MAM-treated rats show impaired latent inhibition. That is, exposure to the sound prior to the fear conditioning procedure does not significantly affect the suppression of fear conditioning (see Lodge et al., J. Neurosci., 29:2344-2354, 2009). Using such an animal model of schizophrenia, the effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia or bipolar disorder (particularly mania) can be assayed.

[0175] MAM-treated rats show a significantly increased spontaneous motor response (or abnormal spontaneous motor activity) to low-dose D-amphetamine administration. MAM-treated rats also show a significant increase in the number of spontaneously firing ventral tegmental area dopamine (DA) neurons. These results suggest that in MAM-treated rats, inactivation of the ventral hippocampus (vHipp) (e.g., by intracerebroventricular administration of the sodium channel blocker tetrodotoxin (TTX) to MAM rats) completely reverses the activity of the increased DA neuron population and normalizes the increased amphetamine-induced spontaneous motor behavior, suggesting that it is a result of excessive hippocampal activity. The correlation between hippocampal dysfunction and increased sensitivity of the DA system is thought to underlie the enhanced response to amphetamine in psychiatric disorders in MAM-treated animals and patients with schizophrenia. See Lodge D. J. et al. Neurobiology of Disease (2007), 27(42), 11424-11430. The use of MAM-treated rats in the above studies may be suitable for use in assaying the effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia or bipolar disorder (particularly mania). For example, the methods and compositions of the present invention can be evaluated using MAM-treated animals for their effects on the regulation of the ventral hippocampus (vHipp), the increase in DA neuron population activity, and the hyperlocomotor response to amphetamine in MAM-treated animals.

[0176] In MAM-treated rats, hippocampal (HPC) dysfunction leads to hyperactivity of the dopaminergic system. GABA A A benzodiazepine-positive allosteric modulator (PAM) selective for the α5 subunit of the GABA receptor, SH-053-2’F-R-CH3, is tested for its effect on hippocampal (HPC) output. The effect of SH-053-2’F-R-CH3 on the hyperlocomotor response to amphetamine in MAM-treated animals is also examined. α5GABA AR PAM decreases the number of spontaneously active DA neurons in the ventral tegmental area (VTA) of MAM rats to levels observed in saline-treated rats (control group), both when administered systemically and when directly injected into the ventral HPC. Furthermore, HPC neurons in both saline-treated and MAM-treated animals are α5GABA A show a decrease in the cortical evoked response after R PAM treatment. Furthermore, the increase in the spontaneous locomotor response to amphetamine observed in MAM-treated rats is α5GABA A decreased after R PAM treatment. See Gill K. M et al. Neuropsychopharmacology (2011), 1-9. The use of MAM-treated rats in the above studies may be suitable for use in the present invention to assay the effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia or bipolar disorder (particularly mania). For example, the methods and compositions of the present invention can be evaluated, using MAM-treated animals, for their effects on the output of the hippocampus (HPC) and the hyperlocomotor response to amphetamine in MAM-treated animals.

[0177] Administration of MAM to pregnant rats on embryonic day 15 (E15) severely impairs the ability of their offspring to learn the spatial location of four items on the spatial memory or eight-arm radial maze. Furthermore, MAM-treated rats on embryonic day 17 (E17) can reach the level of performance of control rats at the initial stage of training, but when delayed by 30 minutes, they are unable to process and recover spatial information, indicating a significant functional impairment in working memory. See Gourevitch R. et al. (2004). Behav. Pharmacol, 15, 287-292. Using such an animal model of schizophrenia, the effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia or bipolar disorder (particularly mania) can be assayed.

[0178] Apomorphine-induced climbing behavior (AIC) and apomorphine accompanying behavior (AIS) in mice are another animal model useful in the present invention. A drug is administered to a mouse at a desired dose level (e.g., by intraperitoneal administration). Subsequently, for example, 30 minutes later, the experimental mouse is challenged with apomorphine (e.g., 1 mg / kg sc). Five minutes after the apomorphine injection, the sniffing - licking - gnawing syndrome (accompanying behavior) and climbing behavior induced by apomorphine are scored and recorded for each animal. Readings can be repeated every 5 minutes during a 30 - minute test session. For each syndrome (accompanying behavior and climbing behavior), the scores for each animal over the 30 - minute test session are summed. When the effect reaches at least 50% inhibition, the ID 50 value (95% confidence interval) is calculated using non - linear least - squares calculation by inverse prediction. The average values of the climbing behavior score and the accompanying behavior score can be expressed as a percentage of the control values observed in vehicle - treated (e.g., saline - treated) mice that received apomorphine. See Grauer S.M. et al. Psychopharmacology (2009) 204, 37 - 48. Using this mouse model, the effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia or bipolar disorder (particularly, mania) can be assayed.

[0179] In another well-established preclinical model of schizophrenia, rats chronically exposed to ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, develop positive and negative symptoms of mental illness, as well as cognitive impairments. Ketamine (30 mg / kg, twice daily) is injected intraperitoneally into Long-Evans male rats for two weeks during adolescence (2 months of age). When the rats reach adulthood (approximately 4-5 months of age), behavioral tests of the rats are performed for behavioral symptoms in response to ketamine exposure and the effectiveness of treatments that reduce those symptoms. See, for example, Enomoto et al. Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 668-675.

[0180] The effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia or related cognitive impairments can also be evaluated, as discussed herein, using various cognitive tests known in the art, in animal models of schizophrenia or bipolar disorder (particularly mania), as well as in human subjects having schizophrenia. Amyotrophic lateral sclerosis (ALS)

[0181] The present invention further provides methods and compositions for treating ALS using an α5-containing GABA A receptor positive allosteric modulator selected from those described herein, such as a compound or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In certain embodiments, the treatment includes preventing ALS or slowing its progression. In certain embodiments, the treatment is A It includes the reduction, improvement or deceleration of progression of one or more symptoms associated with LS. In certain embodiments, the symptom to be treated is cognitive impairment. In some embodiments of the invention, there is provided a method for protecting or improving cognitive function in a subject having ALS, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. The method and composition can be used in human patients in clinical applications in treating ALS. The dosage of the composition and the dosing interval in the case of the method are safe and effective in those applications as described herein.

[0182] In addition to motor neuron degeneration, ALS is characterized by neuronal degeneration in the olfactory cortex and hippocampus, memory impairment, and hyperexcitability of neurons in various brain regions such as the cortex.

[0183] The effectiveness of the methods and compositions of the invention in treating ALS or cognitive impairment associated with ALS can also be evaluated in animal models of ALS and human subjects having ALS using various cognitive tests known in the art as discussed herein. Cognitive impairment associated with cancer treatment

[0184] The present invention relates to α5-containing GABA, such as those selected from the compounds described herein or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, isomers thereof, or combinations thereof. AThere is further provided a method and a composition for treating cognitive impairment associated with cancer treatment using a receptor positive allosteric modulator. In certain embodiments, the treatment includes preventing or slowing the progression of cognitive impairment associated with cancer treatment. In certain embodiments, the treatment includes reducing, ameliorating or slowing the progression of one or more symptoms associated with cognitive impairment associated with cancer treatment. In some embodiments of the present invention, there is provided a method of protecting or improving cognitive function in a subject having cognitive impairment associated with cancer treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. The method and composition can be used in human patients in clinical applications in treating cognitive impairment associated with cancer treatment. The dosage of the composition and the dosing interval in the case of the method are safe and effective for their uses as described herein.

[0185] Therapies used in the treatment of cancer, including chemotherapy, radiation therapy or a combination thereof, can cause cognitive impairment of functions such as memory, learning and attention in patients. The cytotoxicity and other harmful side effects of cancer treatment on the brain are the basis for this form of cognitive impairment, which can persist for decades (Dietrich et al., Oncologist 13:1285-95, 2008; Soussain et al., Lancet 374:1639-51, 2009).

[0186] Cognitive impairment after cancer treatment reflects dysfunction of the prefrontal cortex and hippocampal circuits that are essential for normal cognition. In animal models, exposure to either chemotherapy or radiation impairs performance on tests of cognition that specifically depend on these brain systems, particularly the hippocampus (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93:487-494, 2010). Thus, drugs that target these cortical and hippocampal systems may be neuroprotective in cancer patients and may be effective in treating symptoms of cognitive impairment that persist beyond the interventions used as cancer treatment.

[0187] Animal models serve as an important source for developing and evaluating treatments for cancer treatment-related cognitive impairment. Characterizing cancer treatment-related cognitive impairment in animal models characteristics are typically extrapolated to cancer treatment-related cognitive impairment in humans. Thus, efficacy in such animal models is expected to predict efficacy in humans. Various animal models of cancer treatment-related cognitive impairment are known in the art.

[0188] Examples of animal models of cancer treatment-related cognitive impairment include antineoplastic agents such as cyclophosphamide (CYP) or radiation exposure, e.g., 60Treatment of animals with Co gamma rays is included (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93:487-494, 2010). Next, the cognitive functions of animal models of cognitive impairment related to cancer treatment can be examined using cognitive tests that assay the effectiveness of the methods and compositions of the present invention in the treatment of cognitive impairment related to cancer treatment. As discussed herein, the effectiveness of the methods and compositions of the present invention in the treatment of cognitive impairment related to cancer treatment, using various cognitive tests known in the art, as well as human subjects having cognitive impairment related to cancer treatment. Parkinson's disease (PD)

[0189] Parkinson's disease (PD) is a neurological disorder characterized by a decrease in voluntary movement. Affected patients have reduced motor activity and slower voluntary movements compared to normal individuals. Patients have a characteristic "mask-like" facial appearance, a tendency to hurry when walking, a stooped posture, and generalized muscle weakness. There is a typical "lead pipe-like" rigidity during passive movement. Another important feature of this disease is tremors in the limbs that occur at rest and decrease during movement.

[0190] Parkinson's disease psychosis is experienced by about one-third of PD patients and has a significant impact on the quality of life of patients. Psychosis is characterized by hallucinations, delusions, and other sensory disturbances, including illusions and hallucinations of a "presence." The underlying cause of psychosis in PD patients is not fully understood. However, the occurrence of cognitive impairment in PD patients has been identified as a risk factor associated with the onset of psychosis (Laura B. Zahodne and Hubert H. Fernandez, Drugs Aging. 2008, 25(8), 665-682).

[0191] Parkinson's disease has an unknown etiology and belongs to the most common group of movement disorders named Parkinsonism, affecting approximately 1 in 1000 people. These other disorders classified under the name Parkinsonism can be caused by viral infections, syphilis, arteriosclerosis and trauma, as well as exposure to harmful chemicals and drugs. Nevertheless, inappropriate loss of synapse stability is thought to lead to disruption of neuron circuits and risk of brain diseases. Whether as a result of genetics, drug use, the aging process, viral infection or various other causes, neuronal communication dysfunction is considered to be the root cause of many neurological diseases such as PD (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0192] Regardless of the cause of this disease, the main pathological feature is the degeneration of dopaminergic cells in the basal ganglia of the brain, particularly the substantia nigra. Due to the premature death of dopamine-containing neurons in the substantia nigra, the largest structure of the basal ganglia, the striatum reduces its input from the substantia nigra, resulting in a decrease in dopamine release. Understanding the underlying pathology led to the introduction of the first successful treatment that can alleviate Parkinson's disease. Substantially all approaches to the treatment of this disease are based on dopamine replacement. The drugs currently used in this treatment can be converted to dopamine after passing through the blood-brain barrier or enhance the synthesis of dopamine and reduce its degradation. Unfortunately, the degeneration of cells in the substantia nigra, the main pathological event, cannot be helped. This disease continues to progress and, after a certain period of time, dopamine replacement treatments often lose their effectiveness.

[0193] The present invention relates to α5-containing GABA selected from compounds described herein or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, isomers thereof, or combinations thereof, etc. AProvided are methods and compositions for treating PD using a receptor positive allosteric modulator. In certain embodiments, treatment includes prevention of PD or slowing of its progression. In certain embodiments, treatment includes reduction, improvement or slowing of the progression of one or more symptoms associated with PD. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to improve the movement disorder / cognitive impairment that is symptomatic of Parkinson's disease. Further, the methods and compositions of the present disclosure may be useful for treating the memory impairment that is symptomatic of Parkinson's disease. In some embodiments of the present invention, there is provided a method of protecting or improving cognitive function in a subject having PD, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In another embodiment of the present invention, there is provided a method of treating a Parkinson's disease psychiatric disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0194] There are several animal models of PD. Exemplary animal models of PD include the reserpine model, methamphetamine model, 6-hydroxydopamine (6-OHDA) model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, paraquat (PQ)-maneb model, rotenone model, 3-nitrotyrosine model, and genetic models using transgenic mice. Transgenic models include mice that overexpress α-synuclein, express human variants of α-synuclein, or express LRKK2 mutations. See a review of these models by Ranjita B. et al. (Ranjita B. et al. BioEssays 2002, 24, 308-318). Additional information on these animal models can also be found at Jackson Laboratories (http: / / research.jax.org / grs / parkinsons.html) and readily available from numerous publications that disclose the use of these validated models.

[0195] The effectiveness of the methods and compositions of the present invention in the treatment of PD or PD-related cognitive impairment can be evaluated in any of the above animal models of PD and in human subjects with PD using various cognitive tests known in the art, as discussed herein. Autism

[0196] Autism is a neurodevelopmental disorder characterized by dysfunction in three central behavioral dimensions: repetitive behaviors, social deficits, and impairments in recognition. The area of repetitive behaviors includes obsessive behaviors, unusual attachments to objects, strict adherence to routines or rituals, as well as repetitive motor habits such as perseverative behaviors and self-stimulatory behaviors. The dimension of social deficits includes deficits in reciprocal social interactions, lack of eye contact, low ability to sustain conversations, and impaired daily interaction skills. Impairments in recognition can also include language abnormalities. Autism is a neurological disorder that causes physical disabilities in thousands of Americans, encompasses several subtypes, has various putative causes, and few remission treatments have been reported. Disorders on the autism spectrum may be present at birth or may develop later, for example, at age 2 or 3. There is no clear biological marker for autism. The diagnosis of this disorder is made by considering the extent to which a child conforms to a behavioral syndrome characterized by poor communication skills, peculiarities in social and cognitive abilities, and maladaptive behavior patterns. Dysfunction in neuronal connectivity is thought to be one of the underlying causes of autism (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). Recent studies have shown that there are deficits in GAB A A α5 in autism spectrum disorder (ASD), supporting further investigation of the GABA system in this disorder (Mendez MA, et al. Neuropharmacology. 2013, 68:195-201).

[0197] The present invention also relates to α5-containing GABA selected from compounds described herein or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, isomers thereof, or combinations thereof, etc. AProvided are methods and compositions for treating autism using a receptor positive allosteric modulator. In certain embodiments, the treatment includes preventing autism or slowing its progression. In certain embodiments, the treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with autism. In certain embodiments, the symptom being treated is cognitive impairment or agnosia. For example, the methods and compositions of the present disclosure can be used to improve the movement / agnosia that is symptomatic of autism. In some embodiments of the invention, a method of protecting or improving cognitive function in a subject having autism, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0198] The valproic acid (VPA) rat model of autism using in vitro electrophysiological techniques established by Rodier et al. (Rodier, P. M. et al. Reprod. Toxicol. 1997, 11, 417-422) is the most comprehensively established lesion-based animal model of autism is one of the observations that pregnant women treated with VPA in the 1960s had a higher risk of giving birth to children with autism than the normal population within a limited embryonic formation time frame. Offspring of pregnant rats exposed to VPA show some anatomical and behavioral symptoms typical of autism, such as a reduced number of cerebellar Purkinje neurons, impaired social interaction, repetitive behavior, and other symptoms of autism including enhanced fear memory processing. See Rinaldi T. et al. Frontiers in Neural Circuits, 2008, 2, 1-7. Another mouse model, the BTBR T+tf / J (BTBR) mouse, which has an established behavioral phenotype associated with the three diagnostic behavioral symptoms of autism, namely unusual social interaction, impaired communication, and repetitive behavior, was used to explore the efficacy of GRN-529, a selective negative allosteric modulator of the mGluR5 receptor. See, for example, Silverman J. L. et al. Sci Transl. Med. 2012, 4, 131. The efficacy of the methods and compositions of the present invention in the treatment of autism or autism-related agnosia can be evaluated in a rat model of autism treated with VPA or a BTBR T+tf / J (BTBR) mouse model, and in human subjects with autism, using various cognitive tests known in the art as discussed herein. Mental retardation

[0199] Mental retardation is a general disorder characterized by significantly impaired cognitive function and deficits in adaptive behavior. Mental retardation is often defined as an intelligence quotient (IQ) score of less than 70. Congenital causes are the most common underlying causes of mental retardation. Dysfunction of neuronal connectivity is also thought to be one of the underlying causes of mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). ​

[0200] In some examples, mental retardation includes, but is not limited to, Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Moattt-Wilson syndrome, cilia-related diseases, Lowe syndrome, and siderium type X-linked mental retardation. Down syndrome is a disorder that includes a combination of birth defects including some degree of mental retardation, characteristic facial features, and often heart defects, many infections, vision and hearing problems, and other health problems. Fragile X syndrome is a common form of hereditary mental retardation that occurs at a frequency of 1 in 4,000 males and 1 in 8,000 females. This syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autistic-like behavior. There is no effective treatment for fragile X syndrome.

[0201] The present invention contemplates the treatment of mild mental retardation, moderate mental retardation, severe mental retardation, profound mental retardation, and mental retardation of unspecified severity. Such mental retardation may be related to chromosomal changes (e.g., Down syndrome due to trisomy 21), genetics, pregnancy and perinatal problems, and other severe mental disorders, but need not be. The present invention relates to α5-containing GABA AA method and composition for treating mental retardation using a receptor positive allosteric modulator (such as a compound as described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof) are provided. In certain embodiments, the treatment includes prevention of mental retardation or deceleration of its progression. In certain embodiments, the treatment includes reduction, improvement, or deceleration of the progression of one or more symptoms associated with mental retardation. In certain embodiments, the symptom to be treated is agnosia / dysfunction. For example, the methods and compositions of the present disclosure can be used to improve the movement disorder / cognitive impairment that is symptomatic of mental retardation. In some embodiments of the present invention, there is provided a method of protecting or improving cognitive function in a subject having mental retardation, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0202] For mental retardation, several animal models have been developed. For example, knockout mouse models have been developed for fragile X syndrome. Fragile X syndrome is a common form of mental retardation caused by the absence of the FMR1 protein, FMRP. Two homologs of FMRP, FXR1P and FXR2P, have been identified. FXR2P shows high expression levels in the brain and testis, like FMRP. Both Fxr2 knockout mice and Fmr1 knockout mice, as well as Fmr1 / Fxr2 double knockout mice, are considered useful models for mental retardation such as fragile X syndrome. See Bontekoe C. J. M. et al. Hum. Mol. Genet. 2002, 11 (5): 487-498. Mental retardation or agnosia associated with mental retardation The effectiveness of the methods and compositions of the present invention in treating dysfunction can be evaluated in these mouse models and other animal models developed for mental retardation, as well as in human subjects with mental retardation, using various cognitive tests known in the art, as discussed herein. Obsessive - compulsive behavior (obsessive - compulsive disorder)

[0203] Obsessive - compulsive disorder ("OCD") is most generally a mental state characterized by intrusive, repetitive, unwanted thoughts (obsessions) that lead to obsessive behaviors and mental acts that an individual feels compelled to perform. Current epidemiological data indicate that OCD is the fourth most common mental disorder in the United States. Some studies have suggested that the prevalence of OCD is 1 - 3 percent, but the clinically recognized prevalence of OCD is much lower, suggesting that many individuals with the disorder may not be diagnosed. Patients with OCD are diagnosed by psychologists, psychiatrists, or psychoanalysts according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM - IV - TR) (2000), which includes features of obsessions and compulsions. Compulsion features include: (1) repetitive and persistent thoughts, impulses, or images that are experienced as intrusive and cause significant anxiety or distress; (2) those thoughts, impulses, or images are not mere excessive concerns about real - life problems; and (3) the person attempts to ignore or suppress such thoughts, impulses, or images or to neutralize them with some other thought or action. The person recognizes that the compulsive thoughts, impulses or images are the products of their own mind and not based in reality. The features of compulsion are: (1) repetitive behaviors or mental acts that the person feels driven to perform in response to an obsession or according to rules that must be applied rigidly; (2) the behaviors or mental acts are aimed at preventing or reducing distress or preventing some dreaded event or situation; however, these behaviors or mental acts are either not related to the actual problem or are excessive.

[0204] Individuals with OCD usually perform tasks (or compulsions) to seek relief from obsession-related anxiety. They often engage in repetitive behaviors (such as handwashing, counting, checking, or cleaning) with the desire to stop or eliminate obsessive thoughts. However, performing these "rituals" only provides temporary relief. People with OCD may also be diagnosed with other mental disorders such as generalized anxiety disorder, anorexia nervosa, panic attacks, or schizophrenia.

[0205] Dysfunction of neuron connections is considered to be one of the root causes of obsessive-compulsive disorder (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). From the study, OCD is associated with abnormalities in a neurotransmitter called serotonin It has been suggested that OCD may be related to normal levels of anxiety. First-line treatment for OCD consists of behavioral therapy, cognitive therapy, and pharmacotherapy. Medications for treatment include serotonin reuptake inhibitors (SRIs), such as paroxetine (Seroxat™, Paxil™, Xetanor™, ParoMerck™, Rexetin™), sertraline (Zoloft™, Stimuloton™), fluoxetine (Prozac™, Bioxetin™), escitalopram (Lexapro™) and fluvoxamine (Luvox™), as well as tricyclic antidepressants, particularly clomipramine (Anafranil™). Benzodiazepines are also used for treatment. However, as many as 40-60% of patients do not respond adequately to SRI treatment, and an even larger percentage of patients do not receive complete remission of their symptoms.

[0206] The present invention relates to an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharma- ceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. A Receptor agonists (e.g., α5-containing GABA A The present invention provides methods and compositions for treating OCD using a medicament ...

[0207] A quinpirole-sensitized rat model has been developed for OCD. The compulsive checking behavior, which is a trait specific to the compulsive behaviors of OCD in this quinpirole-sensitized rat, tends to be interrupted. Further, the effect of the novel 5-HT2C receptor agonist WAY-163909 was evaluated using the schedule-induced polydipsia (SIP) rodent model of obsessive-compulsive disorder. See, for example, Rosenzweig-Lipson S. et al. Psychopharmacology (Berl) 2007, 192, 159-70 See The effectiveness of the methods and compositions of the present invention in the treatment of OCD or OCD-related cognitive impairments or agnosia can be evaluated using various cognitive tests known in the art, in the above animal models and other animal models developed for OCD, as well as in human subjects having OCD, as discussed herein. Substance addiction

[0208] Substance addiction (e.g., drug addiction, alcohol addiction) is a mental disorder. This substance addiction is not instantaneously caused when exposed to the abused substance. Rather, this addiction requires the adaptation of multiple complex neurons that occurs over different periods ranging from hours to days to months (Kauer J. A. Nat. Rev. Neurosci. 2007, 8, 844-858). The path to substance addiction generally involves one or more It begins with the spontaneous use of substances (such as any of narcotics, barbiturates, methamphetamine, alcohol, nicotine and various other such regulated substances). Over a long period of time, continuous use of those regulated substances impairs the spontaneous ability to refrain from them due to the effects of long-term use on brain function and hence on behavior. Thus, substance addiction is generally characterized by compulsive substance cravings, seeking and use that persist despite negative consequences. Those cravings can correspond to underlying neurobiological changes in the patient, which are likely to have to be addressed in a meaningful way if recovery is to be achieved. Substance addiction also often features, in the case of some substances, life-threatening withdrawal symptoms (such as for alcohol, barbiturates), and in other cases can lead to substantial medical conditions (which can include nausea, vomiting, fever, dizziness and profuse sweating), distress, and a reduced ability to recover. For example, alcohol addiction, also known as alcohol dependence, is one such substance addiction. Alcohol dependence is mainly characterized by four symptoms including craving, loss of control, physical dependence and tolerance. These symptoms can also characterize substance addiction to other regulated substances. The cravings for alcohol and other regulated substances are often as strong as the cravings for food or water. Thus, alcoholics may continue to drink despite significant secondary effects on family, health and / or the law.

[0209] Recent studies exploring the effects of the abuse of alcohol, stimulants and opiates on the central nervous system (CNS) have demonstrated various adverse effects related to mental health, including substance-induced cognitive dysfunction. Nyberg F. Cognitive Impairments See Chapter 9 in Drug Addicts. Substantial damage to brain function has been observed in several laboratories and clinics to be caused by these drugs. The adverse effects of drug abuse on the brain contribute to accelerated degeneration. In recent years, an observation that has received particular attention is that chronic drug users show obvious damage in brain regions related to executive function and memory function. Neuroadaptations recognized to be caused by addictive drugs such as alcohol, stimulants, and opiates include a decrease in neurogenesis in the subgranular zone (SGZ) of the hippocampus. Indeed, it has been proposed that a decrease in adult neurogenesis in the SGZ can modify hippocampal function in such a way as to contribute to the recurrence and maintenance of addictive behavior. This also increases the likelihood that the decrease in neurogenesis can contribute to the amnesia induced by these abused drugs.

[0210] The present invention provides a method and a composition for treating substance addiction using an α5-containing GABA A receptor positive allosteric modulator (selected from a compound as described herein or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, its isomer, or a combination thereof). In certain embodiments, the treatment includes preventing substance addiction or slowing its progression. In certain embodiments, the treatment includes reducing, improving, or slowing the progression of one or more symptoms associated with substance addiction. In certain embodiments, the symptom to be treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to treat cognitive impairment and / or improve cognitive function in patients having substance addiction. In some embodiments of the present invention, a method for protecting or improving cognitive function in a subject having substance addiction, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, its isomer, or a combination thereof is provided.

[0211] ​Several animal models have been developed to study substance addiction. To study the neurobiology of alcoholism, for example, the genetically selected Marchigian Sardinian alcohol-preferring (msP) rat model has been developed. See Ciccocioppo R. et al. Substance addiction Biology 2006, 11, 339-355. The effectiveness of the methods and compositions of the present invention in the treatment of substance addiction or cognitive impairments associated with substance addiction can also be evaluated in animal models of substance addiction, as well as in human subjects with substance addiction, using various cognitive tests known in the art, as discussed herein. Brain cancer

[0212] Brain cancer is the abnormal growth of cells in the brain tissue that is usually associated with the growth of malignant brain tumors. Brain tumors, when growing, can compress adjacent areas of the brain, which may cause the functions that the part of the brain should originally perform to stop. Brain cancer rarely spreads to other tissues outside the brain. The difference between low-growing tumors and fast-growing tumors can be described using the grade of the tumor based on how abnormal the cancer cells look under a microscope. Brain tumors are classified according to the type of cells in which the tumor is thought to have originated. Diffuse fibrillary astrocytoma is the most common type of primary brain tumor in adults. These tumors are histopathologically divided into three grades of malignant tumors: World Health Organization (WHO) grade II astrocytoma, WHO grade III anaplastic astrocytoma, and WHO grade IV glioblastoma multiforme (GBM). WHO grade II astrocytoma is the most indolent form of the diffuse astrocytoma spectrum. Astrocytomas have a marked tendency to infiltrate the surrounding brain and worsen attempts at local control of treatment. These invasive capabilities are often evident in both low-grade and high-grade tumors.

[0213] Glioblastoma multiforme is the most malignant stage of astrocytoma, with a survival time of less than two years for most patients. Histologically, these tumors are characterized by high cellularity, a high proliferation index, endothelial proliferation, and nodular necrosis. The high proliferative nature of these lesions is likely due to multiple mitogenic effects. One of the prominent features of GBM is endothelial proliferation. Hosts of vascular endothelial growth factors and their receptors are found in GBM.

[0214] There are biological subsets of astrocytomas, which may reflect the clinical heterogeneity observed in these tumors. These subsets include brainstem gliomas, which are often a form of diffuse fibrillary astrocytoma in children that follows a malignant course. Brainstem GBM shares genetic features with adult GBMs that affect young patients. Pleomorphic xanthoastrocytoma (PXA) is a superficial low-grade astrocytic tumor that mainly affects young adults. These tumors have a strange histological appearance, but they are usually slow-growing tumors that may be suitable for surgical treatment. However, some PXAs may recur as GBM. Pilocytic astrocytoma is the most common astrocytic tumor in childhood and is clinically and histopathologically different from diffuse fibrillary astrocytoma that affects adults. Pilocytic astrocytoma does not have the same genomic alterations as diffuse fibrillary astrocytoma. Subependymal giant cell astrocytoma (SEGA) is a periventricular low-grade astrocytic tumor that is usually associated with tuberous sclerosis (TS) and is histologically identical to the so-called "candle-guttering" that lines the ventricles of TS patients. Like other tumor lesions of TS Similarly, these grow slowly and may resemble hamartomas rather than true neoplasms. Desmoplastic cerebral astrocytoma of infancy (DCAI) and desmoplastic infantile ganglioglioma (DIGG) are large, superficial, usually cystic benign astrocytic tumors that affect children between 1 and 2 years of age.

[0215] Oligodendrogliomas and oligoastrocytomas (mixed gliomas) are diffuse, usually cerebral tumors that are most closely related clinically and biologically to diffuse fibrillary astrocytomas. However, this tumor is much less common than astrocytomas and generally has a better prognosis than diffuse astrocytomas. Oligodendrogliomas and oligoastrocytomas may progress to either WHO grade III anaplastic oligodendrogliomas or anaplastic oligoastrocytomas, or WHO grade IV GBM. Therefore, the genetic changes leading to oligodendroglial tumors constitute an additional pathway to GBM.

[0216] Ependymomas are a clinically diverse group of gliomas that range from invasive intraventricular tumors in children to benign spinal cord tumors in adults. Transition from ependymoma to GBM is rare. Choroid plexus tumors are also a diverse group of tumors that preferentially occur in the ventricular system, ranging from invasive supratentorial intraventricular tumors in children to benign cerebellopontine angle tumors in adults. Choroid plexus tumors have occasionally been reported in patients with Li-Fraumeni syndrome and von Hippel-Lindau (VHL) disease.

[0217] Medulloblastoma is a very malignant primitive tumor that occurs mainly in the posterior fossa of children. Medulloblastoma is the most common malignant brain tumor in children. The most lethal medulloblastoma subtype shows high expression of the GABA A receptor alpha5 subunit gene and MYC amplification. See, for example, J Biomed Nanotechnol. 2016 Jun;12(6):1297-302.

[0218] Meningiomas are common intracranial tumors that occur in the meninges and compress the underlying brain. Meningiomas are usually benign, but some "atypical" meningiomas may recur locally, and some meningiomas, frankly speaking, are malignant and may invade or metastasize to the brain. Atypical and malignant meningiomas are not as common as benign meningiomas. Schwannomas are benign tumors that occur in peripheral nerves. Schwannomas can occur in cranial nerves, especially in the vestibular part of the eighth cranial nerve (vestibular schwannoma, acoustic neuroma), in which case they present as cerebellopontine angle tumors. Hemangioblastomas are tumors of unknown origin composed of endothelial cells, pericytes, and so-called stromal cells. These benign tumors occur most frequently in the cerebellum and spinal cord of young adults. Multiple hemangioblastomas are characteristic of von Hippel-Lindau disease (VHL). Hemangiopericytomas (HPCs) are dural tumors that may show locally invasive behavior and may metastasize. The histogenesis of dural-based hemangiopericytomas (HPCs) has been debated for a long time, and some authors classify it as a separate entity, while other authors classify it as a subtype of meningioma.

[0219] The present invention relates to α5-containing GABA AMethods and compositions for treating brain cancer (such as the brain tumors described herein) using a receptor positive allosteric modulator (such as those selected from compounds as described herein or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, isomers thereof, or combinations thereof) are provided. In certain embodiments, treatment includes prevention of brain cancer or slowing of its progression. In certain embodiments, treatment includes reduction, improvement, or slowing of progression of one or more symptoms associated with brain cancer. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to treat cognitive impairment and / or improve cognitive function in patients having brain cancer. In some embodiments of the present invention, a method of protecting or improving cognitive function in a subject having brain cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, isomer thereof, or combination thereof is provided. In some embodiments, the brain tumor is medulloblastoma. Research Domain Criteria (RDoC)

[0220] The present invention further provides methods and compositions for treating functional impairments of neuropathies and neuropathological conditions using the α5-containing GABA A R positive allosteric modulator, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, isomer thereof, or combination thereof. In certain embodiments, treatment includes reduction, improvement, or slowing of progression of one or more symptoms associated with such functional impairment. In another aspect of the present invention, methods and compositions for protecting or improving cognitive function in a subject in need thereof using a compound of the present invention or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, isomer thereof, or combination thereof are provided.

[0221] The Research Domain Criteria (RDoC) is expected to enhance clinical criteria such as DSM and ICD for diagnosing diseases and disorders affecting the nervous system (see, e.g., Am. J. Psychiatry 167:7 (2010)). RDoC aims to provide a classification based on discoveries in genomics and neuroscience, as well as clinical observations. High expression levels of α5-containing GABA A receptors in specific neuronal circuits of the nervous system may be therapeutic targets for dysfunctions of the neuronal circuits identified under RDoC. GABA A Assays for α5 subunit binding and receptor positive allosteric modulator activity

[0222] GABA A GABA containing the α5 subunit A The affinity of a test compound for the receptor can be determined using receptor binding assays known in the art. See, e.g., U.S. Patent No. 7,642,267 and U.S. Patent No. 6,743,789, which are incorporated herein by reference.

[0223] α5-containing GABA A The activity of a test compound as a positive allosteric modulator can be tested by electrophysiological methods known in the art. See, e.g., U.S. Patent No. 7,642,267 and Guidotti et al., Psychopharmacology 180: 191-205, 2005. Positive allosteric modulator activity is, for example, GABA A GABA containing the α5 subunit AIt can be tested by assaying the GABA-induced chloride ion conductance of the receptor. Cells expressing such receptors can be exposed to an effective amount of the compounds of the present invention. Such cells can be contacted in vivo with the compounds of the present invention by contact with a body fluid containing the compounds of the present invention, for example, contact with cerebrospinal fluid. In vitro tests can be performed by contacting cells with the compounds of the present invention in the presence of GABA A GABA containing the α5 subunit A An increase in GABA-induced chloride ion conductance in cells expressing the receptor in the presence of a test compound indicates that the compound has positive allosteric modulator activity. Changes in such conductance can be detected, for example, by GABA A receptor subunit mRNA (GABA A Xenopus oocytes injected with RNA containing the α5 subunit, GABA A HEK293 cells transfected with a plasmid encoding the receptor subunit, or by using a voltage clamp assay performed on in vivo, ex vivo or cultured neurons.

[0224] It will be understood by those skilled in the art that the methods described herein may be adapted and modified to be appropriate for the uses being addressed, and that the methods described herein may be used in other suitable applications, and that such other additional and modifications do not depart from the scope of the present invention.

[0225] The compounds of the present disclosure can be synthesized using methods similar to those described in WO2018 / 130868. However, those skilled in the art will readily recognize that the specific methods and results discussed are merely illustrative of the invention, which will be more fully described in subsequent embodiments.

[0226] Compounds 731 and 736 were prepared by subjecting Compound 328 of WO2018 / 130868 to Sonogashira reaction conditions using appropriate starting materials. For exemplary reaction conditions, see Scheme 29 and Compound 285 of WO2018 / 130868.

[0227] Compounds 733 - 734 were prepared by subjecting Compound 356 of WO2018 / 130868 (Scheme 41) to Sonogashira reaction conditions using appropriate starting materials. For exemplary reaction conditions, see Scheme 29 and Compound 285 of WO2018 / 130868.

[0228] Compounds 732 and 735 were prepared by subjecting Compound 403 of WO2018 / 130868 to Sonogashira reaction conditions using appropriate starting materials. For exemplary reaction conditions, see Scheme 29 and Compound 285 of WO2018 / 130868.

[0229] Compound 737 was prepared by subjecting Compound 256 of WO2018 / 130868 (Scheme 29) to Sonogashira reaction conditions using appropriate starting materials. For exemplary reaction conditions, see Scheme 29 and Compound 285 of WO2018 / 130868.

[0230] Synthesis of Compound 633

Chemical formula

Chemical formula

[0231] Compound 17' (see Scheme 11 of WO2018 / 130868, 17: R 1 = OMe; 17': R 1To a stirred solution of [[Cl]] (2.96 g, 11.2 mmol), imidazole (1.91 g, 28.1 mmol), DMAP (274 mg, 2.24 mmol) and Et3N (4.7 mL, 33.7 mmol) was added TBSCl (3.37 g, 22.4 mmol). The reaction mixture was stirred overnight at room temperature under N2. After this time, the resulting reaction mixture was diluted with EtOAc (300 mL), washed with 10% aqueous LiCl (3 × 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 0% - 5% EtOAc / CH2Cl2 to give compound 633-1 as a white solid (3.67 g, 87%): MS [M+Na] = 401.

[0232] To a stirred solution of compound 633-1 (3.67 g, 9.69 mmol) in anhydrous DMF (50 mL) was added NaH (60% in mineral oil, 426 mg, 10.7 mmol) at -20 °C under N2.

[0233] The resulting mixture was stirred at -20 °C for 10 minutes. After this time, PMBCl (2.0 mL, 14.8 mmol) was added. The reaction mixture was warmed to room temperature overnight. The resulting mixture was quenched with 10% aqueous LiCl (100 mL) and extracted with EtOAc (3 × 100 mL). The combined extracts were washed with 10% aqueous LiCl (3 × 30 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 10% - 30% EtOAc / hexane to give compound 633-2 as a pale yellow solid (4.59 g, 95%): MS [M+1] = 499.

[0234] To a stirred solution of Compound 633-2 (4.59 g, 9.20 mmol) in anhydrous THF (100 mL) was added TBAF (1 M solution in THF, 18.4 mL, 18.4 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 2 h. After this time, the reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 50% - 100% EtOAc / hexane to give Compound 633-3 as a white foam (2.92 g, 83%): MS [M+1] = 385.

[0235] To a stirred solution of Compound 633-3 (2.92 g, 7.59 mmol) in anhydrous CH2Cl2 (150 mL) was added PPh3 (3.98 g, 15.2 mmol) at room temperature under N2, followed by CBr4 (3.02 g, 9.11 mmol). The reaction mixture was stirred at room temperature for 4 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 30% - 60% EtOAc / hexane to give Compound 633-4 as a white foam (2.59 g, 76%): MS [M+1] = 447.

[0236] To a stirred solution of compound 633-4 (576 mg, 1.29 mmol) in anhydrous THF (10 mL) and anhydrous MeOH (45 mL) was added portionwise NaH (60% in mineral oil, 515 mg, 12.9 mmol) over 40 minutes at 0 °C under N₂. The reaction mixture was stirred at 0 °C for 1.5 hours. After this time, the reaction was quenched with saturated aqueous NH₄Cl (100 mL) and the pH was neutralized to approximately 7 with 6N aqueous HCl. The resulting mixture was extracted with CH₂Cl₂ (3 × 100 mL). The combined extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 50% - 100% EtOAc / hexane to give compound 633-5 as a white foam (436 mg, 85%): MS [M+1] = 399.

[0237] A solution of compound 633-5 (1.66 g, 4.16 mmol) in TFA (15 mL) was heated to reflux for 2 days (85 °C, oil bath). After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH₂Cl₂ (100 mL), washed with saturated NaHCO₃ (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 50% - 100% EtOAc / hexane to give compound 633-6 as an off-white solid (810 mg, 70%): MS [M+1] = 279.

[0238] To a stirred solution of 1,2,4-triazole (506 mg, 7.33 mmol) in anhydrous CH₃CN (30 mL) was added DIPEA (1.3 mL, 7.46 mmol) followed by POCl₃ (0.2 mL, 2.15 mmol) at 0 °C under N₂. The reaction mixture was stirred at 0 °C for 2 hours. After this time, a solution of compound 633-6 (1.02 g, 3.66 mmol) in anhydrous CH₃CN (50 mL) was added. The reaction mixture was warmed to room temperature and then heated to reflux overnight (100 °C oil bath). The reaction mixture was cooled to room temperature and ice-cooled It was quenched with water (50 mL). The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 50% - 100% EtOAc / CH2Cl2 to give Compound 633-7 as a yellow solid (950 mg, 79%): MS [M+1] = 330.

[0239] To a stirred solution of KOt-Bu (485 mg, 4.32 mmol) in anhydrous DMF (10 mL) was added CNCH2CO2Et (0.47 mL, 4.30 mmol) at -50 °C under N2. The reaction mixture was stirred at -50 °C for 1 h. After this time, a solution of Compound 633-7 (950 mg, 2.88 mmol) in anhydrous DMF (15 mL) was added. The reaction mixture was slowly warmed to room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined extracts were washed with 10% aqueous LiCl (3 × 30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 0% - 8% MeOH / EtOAc to give Compound 633-8 as a yellow solid (815 mg, 76%): MS [M+1] = 374.

[0240] To a stirred solution of Compound 633-8 (150 mg, 0.401 mmol) in THF (15 mL) and water (7 mL) was added LiOH·H2O (84 mg, 2.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting mixture was acidified to pH ~2 using 2N aqueous HCl. The solid was collected by filtration. The filter cake was washed with water (10 mL) and dried under high vacuum to give Compound 633-9 as a white solid (125 mg, 90%): MS [M+1] = 346.

[0241] A suspension of Compound 633-9 (122 mg, 0.353 mmol), I₂ (269 mg, 1.06 mmol) and K₃PO₄ (75 mg, 0.353 mmol) in anhydrous DMF (9 mL) was sealed and placed in a microwave reactor at 170 °C for 30 minutes. After this time, the reaction mixture was cooled to room temperature and diluted with 10% aqueous LiCl solution (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined extracts were washed with 10% aqueous LiCl solution (3 × 30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1% - 4% MeOH / CH₂Cl₂ to give Compound 633-10 as a white solid (35 mg, 23%): MS [M+1] = 428.

[0242] A suspension of Compound 633-10 (32 mg, 0.0748 mmol), Compound 633-11 (37 μL, 0.303 mmol) and CuI (4 mg, 0.0210 mmol) in anhydrous DMF (4 mL) was bubbled with argon for 5 minutes. After this time, Et₃N (52 μL, 0.373 mmol) and then Pd(dppf)Cl₂·CH₂Cl₂ (12 mg, 0.0147 mmol) were added. The resulting mixture was heated under argon at 40 °C for 2 hours. Next, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined extracts were washed with 10% aqueous LiCl solution (3 × 20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 0% - 4% MeOH / CH₂Cl₂ to give Compound 633 as an off-white solid (13 mg, 41%): 1 H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J = 1.8 Hz, 1H), 8.27 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 8.7, 2.3 Hz, 1H), 7.92 (dd, J = 8.6, 2 .3 Hz, 1H), 7.86 (dd, J = 8.7, 2.3 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 4.64 (s, 2H), 4.43 (br s, 2H), 3.91 (s, 3H), 3.26 (s, 3H); ESI MS, m / z = 433 [M+H] + .

[0243] Compounds 738 - 740 were prepared by subjecting compound 633 - 10 in Scheme 11 to Sonogashira reaction conditions using appropriate starting materials under the conditions described for compound 633 in Scheme 11.

[0244] Compounds 731 - 740 were identified by MS and 1 1H NMR. The identification by MS is summarized in Table 5 below. Table 5. Characterization of the MS of Compounds 731 - 740: [Table 5 - 1] [Table 5 - 2] [Table 5 - 3] Example 105 α5 - containing GABA A receptor (GABA A R) positive allosteric modulator activity evaluation

[0245] Step 1: Establishment of clones of the GABA A R subunits (α5, β3, γ2, α1, α2 and α3) and preparation of the corresponding cRNA: The human clones of GABA A -Rα5, β3, γ2, α1, α2 and α3 subunits were obtained from commercial sources (e.g., OriGene, http: / / www.origene.com and Genescript, http: / / www.genescript.com) or Obtain these clones. Manipulate these clones into pRC, pCDM, pcDNA, and pBluescript KSM vectors (for expression in oocytes) or other equivalent expression vectors. Transiently transfect the host cells using conventional transfection agents (e.g., FuGene, Lipofectamine 2000, or others).

[0246] Step 2 - Functional GABA of α5β3γ2, α1β3γ2, α2β3γ2, and α3β3γ2 subtypes in Xenopus oocyte expression system A R assay: cRNAs encoding α5, β3, γ2, α1, α2, and α3 subunits are transcribed in vitro using the T3 mMESSAGE mMACHINE Kit (Ambion) and injected into freshly prepared oocytes from Xenopus laevis (at a ratio of α:β:γ = 2:2:1 or other optimized conditions). After 2 days of culture, GABA-activated Cl− currents from the oocytes are measured using a TEVC setup (Warner Instruments, Inc., Foster City, CA). To verify this system, GABA, benzodiazepine, and diazepam are used as reference compounds.

[0247] Evaluation of the positive allosteric modulator activity of test compounds against the α5β3γ2 subtype, and off-target activity of the test when reaching an EC50 = 5 μM selectivity cutoff: GABAergic Cl− currents from oocytes are measured in a TEVC setup in the presence of the test compound. The positive allosteric modulator activity of each test compound is tested in a 5-point dose-response assay. The test compounds include several reference compounds (the literature EC50 values for the α5β3γ2 subtype are in the range of 3 - 10 μM). The EC50 in the α5β3γ2 subtype for each compound is obtained. If the EC50 in α5β3γ2 is ≤ 5 μM, the EC50s of the other three subtypes (α1β2γ2, α2β3γ2, and α3β3γ2) are further individually determined to test the selectivity of the compound in the α5β3γ2 subtype over the other subtypes.

[0248] Step 4 - Evaluation of further test compounds against the α5β3γ2 subtype, and off-target activity of the test when reaching an EC50 = 0.5 μM selectivity cutoff: A second batch of test compounds is tested using the same strategy but with a lower EC50 cutoff (0.5 μM). Again, the EC50 of the α5β3γ2 subtype for each compound is determined. Only if the EC50 for the α5-containing receptor is < 0.5 μM, the β3γ2 subtypes with α1 - α3 bound are tested. Example 106 GABA A Evaluation of compounds for binding activity and positive allosteric modulator activity against the α5 receptor (A) GABA A Binding activity of test compounds against R

[0249] Tissue culture and membrane preparation: GABA ABinding was performed against Ltk cells (provided by Merck Co., NJ, USA) that stably express α1β1γ2, α2β3γ2, α3β3γ2, and α5β3γ2. The cells were seeded into 100 mm culture plates in DMEM / F12 medium containing 10% serum and antibiotics at 5% CO2 and grown for 1 - 2 days. Next, GABA A R expression was induced with dexamethasone as follows: for α5-containing GABA A R, at 0.5 μM for 1 day, and for α1, α2, and α3-containing GABA A R, at 2 μM for 3 days. After induction, the cells were harvested by scraping into Dulbecco's phosphate buffered saline (DPBS, pH 7.4, Invitrogen, Carlsbad, CA, USA) and centrifuged at 150 × g for 10 minutes. The pellet was washed twice by resuspension and centrifugation. Cell pellets from at least 5 different preps were combined and suspended in binding assay buffer (50 mM KH2PO4; 1 mM EDTA; 0.2 M KCl, pH 7.4), and membranes were prepared by sonication (3 - 5 times, 30 seconds) using a Branson Sonifier 150 (G. Heinmann, Germany). Protein content was determined using a BCA assay (Bio-Rad Labs, Reinach, Switzerland) with bovine serum albumin (Sigma Aldrich, St. Louis, MO, USA) as a standard. Aliquots were prepared and stored at -20 °C for further use in binding assays.

[0250] Ligand binding: 3 Saturation binding curves were obtained by incubating membranes while increasing the concentration of [3H]Rol5-1788 (Flumazepil, 75 - 85 Ci / mmol, PerkinElmer, MA, USA) (0.01 - 8 nM), and non-specific binding was measured in the presence of 10 μM diazepam. The K A values for α1, α2, α3, and α5-containing GABA d R determined from the saturation curves, or K dAt the concentration of the radioactive ligand at the value, the inhibition of the 3 H]Rol5-1788 binding of the test compound was carried out.

[0251] All binding assays were performed at 4 °C for 1 hour in assay buffer. The total assay volume was 0.5 ml containing 0.2 mg / ml protein for the α5-containing GABA A R membrane, and 0.5 ml containing 0.4 mg / ml for the α1, α2 and α3-containing GABA A R membrane. Incubation was terminated by filtering through a GF / B filter using a 24-Cell Harvestor (Brandel, Gaithersburg, MD, USA) and then washing three times with ice-cold assay buffer. The filter was transferred to a scintillation vial, 5 ml of scintillation fluid was added, vortexed to mix, and maintained in the dark. The next day, radioactivity was obtained using a scintillation counter (Beckman Coulter, Brea, CA, USA). All assays were performed in triplicate.

[0252] Data analysis: Saturated curves and inhibition curves were obtained using GraphPad Prism software (GraphPad Software, Inc., CA, USA). The equilibrium dissociation constant (K i value) of the unlabeled ligand was determined using the Cheng-Prusoff equation K i =IC 50 / (1 + S / K d ) (where IC 50 is the concentration of the unlabeled ligand that inhibits 50% of the binding of the 3 H]ligand, S is the concentration of the radioactive ligand, and K d is the equilibrium dissociation constant of the radiolabeled ligand). The K i value, expressed as the mean ± SD from the triple assays, was determined using the log range of the compound (1 nM to 10 μM). (B) Positive allosteric modulator activity of the test compound for the α5β2γ2 subtype GABA A R

[0253] First, using a protocol substantially similar to the protocol presented above, the compounds of the present invention were screened at 100 nM for their ability to activate the EC A concentration of GABA in oocytes expressing the GABA 20 receptor (α5β2γ2).

[0254] On day 1, 1 ng / 32 nL of GABA A α5β2γ2 cDNA was injected into one oocyte. The test was started from day 2. The cDNA injected into the oocyte was a mixture of alpha, beta, and gamma, and their ratio was 1:1:10 (by weight), and the total weight of the three subunits mixed and injected into one oocyte was 1 ng in a volume of 32 nl. The injected oocytes can also be tested on day 3. In such a case, the amount of cDNA injected into the oocytes should be reduced by 20%.

[0255] The compounds of the present invention were tested using the following procedure.

[0256] GABA dose-response 1). Eight oocytes were placed in eight chambers of OpusXpress and superfused on the surface with modified Barth's saline (MBS) at 3 mL / min. A glass electrode (0.5 - 3 MΩ) backfilled with 3 M KCl was used. The membrane potential of the oocytes was voltage-clamped at -60 mV. 2). To stabilize the oocytes, the average EC 20 GABA obtained from the previous test was applied 5 - 6 times. Between each application of GABA, the oocytes were washed with MBS for 5 - 10 minutes. 3). A GABA dose-response was performed to obtain the EC 20 GABA value.

[0257] Control test (diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate) 1). A new test was performed using new oocytes. 2). To stabilize the oocytes, the EC 20GABA was applied 5-6 times, and between each GABA application, the oocytes were washed with MBS for 5-10 min. 3).EC 20 GABA was applied to the GABA The oocytes were washed with MBS for 5 to 10 minutes. 4) Pre-apply 1 μM diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate for 40 seconds, followed by 1 μM diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate and EC 20 GABA and I were administered simultaneously. test I test I GABA Activation (%) was obtained by dividing by .

[0258] Test Compound at Multiple Doses 1) In the control test, repeat steps 1), 2) and 3) above. 2) A first concentration of test compound is pre-applied for 40 seconds, followed by a second concentration of test compound and EC 20 By simultaneously applying GABA, I test I test I GABA Divide by to get % activation. 3) All tested oocytes were discarded and new oocytes were used to repeat steps 1) and 2) above to test the same compound at a second concentration. Each oocyte was used for only one concentration test for a single test compound. These steps were repeated for the other test compounds.

[0259] In some embodiments, the compounds of the present application have an α5-containing GABA concentration of less than 200 nM, less than 180 nM, less than 150 nM, or less than 100 nM. A The binding affinity of R (K i In some embodiments, the compounds of the present application have an α5-containing GABA A The binding affinity of R (K i In some embodiments, the compounds of the present application have an α5-containing GABA AThe binding affinity (K i represented by) of R.

[0260] In some embodiments, the compounds of the present application are α1-containing GABA A more selective for α5-containing GABA A than for R. In some embodiments, the compounds of the present application are α1-containing GABA A more than 50-fold, 100-fold, 500-fold or 1000-fold more selective for α5-containing GABA A than for R.

[0261] In some embodiments, the compounds of the present application have an α5-containing GABA A EC of less than 500 nM, less than 100 nM or less than 50 nM for R. 50 In some embodiments, the compounds of the present application have an α5-containing GABA A EC of less than 25 nM for R. 50

[0262] In some embodiments, the compounds of the present application activate α5-containing GABA A R by more than 10%, more than 25%, more than 50% or more than 75% at 100 nM. In some embodiments, the compounds of the present application activate α5-containing GABA A R by more than 10%, more than 25%, more than 50% or more than 75% at 1000 nM.

[0263] The screening results of the binding activity test and the PAM functional activity test are summarized in Tables 1 and 2 below.

[0264] Table 1 below illustrates the range of GABAα5 binding Ki associated with the compounds of the present disclosure: Table 1

Table 1

[0265] Table 2 below illustrates the range of functional activation of GABAα5 associated with the compounds of the present disclosure: Table 2

Table 2

[0266] The selected compounds of the present invention exhibit >10-fold binding selectivity for GABAα5 compared to GABAα1, GABAα2 or GABAα3. Some compounds of the present application demonstrate binding selectivity for GABAα5 that exceeds 20-fold, 50-fold or 100-fold compared to GABAα1, GABAα2 or GABAα3.

[0267] The following Table 6 illustrates the range of binding selectivity of the compounds of the present disclosure for GABAα5 compared to GABAα1, GABAα2 or GABAα3. Table 6

Table 6

[0268] Compound No. 6 in van Niel et al. J. Med. Chem. 48:6004-6011 (2005) The corresponding methyl 3,5-diphenylpyridazine-4-carboxylate is a selective α5-containing GABA A R agonist. It has an α5 in vitro efficacy that results in +27 (EC 20 ). The effect of methyl 3,5-diphenylpyridazine-4-carboxylate in aged-impaired rats was examined using the RAM task. Furthermore, receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate at the α5-containing GABA A receptor was also examined. (A) Effect of methyl 3,5-diphenylpyridazine-4-carboxylate in aged-impaired rats using the radial arm maze (RAM) behavioral task

[0269] The effect of methyl 3,5-diphenylpyridazine-4-carboxylate on in vivo spatial memory retention in aged-impaired (AI) rats was evaluated in a radial arm maze (RAM) behavioral task using vehicle control and four different dosage levels of methyl 3,5-diphenylpyridazine-4-carboxylate (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, and 3 mg / kg, ip). The RAM behavioral task was performed on eight AI rats. All five treatment conditions (vehicle and four dosage levels) were tested on all eight rats.

[0270] The RAM apparatus used consisted of eight alleys at equidistant intervals. The alleys of the elevated maze (width 7 cm × length 75 cm) protruded from each side of an octagonal central platform (diameter 30 cm, height 51.5 cm). The transparent side walls on the alleys were 10 cm high and bent at a 65° angle to form indentations. Food wells (diameter 4 cm, depth 2 cm) were placed at the distal ends of each alley. Froot Loops (trademark) (Kellogg Company) were used as rewards. To prevent entry into any alley, blocks (height 30 cm × width 12 cm) constructed from Plexiglas (trademark) could be placed. Numerous additional maze cues were provided around the apparatus.

[0271] AI rats were first subjected to a pre-training test (Chappell et al. Neuropharmacology 37: 481-487, 1998). The pre-training test consisted of an acclimation period (4 days), a training period (18 days) for the standard win-shift task, and another training period (14 days) imposing a short delay while presenting a subset of alleys designated by the experimenter (e.g., 5 alleys passable and 3 alleys blocked), as well as completion of the 8-alley win-shift task (i.e., all 8 alleys passable). from the completion of the 8-alley win-shift task (i.e., all 8 alleys were passable). which consisted of a training period (14 days) imposing a short delay while presenting a subset of alleys designated by the experimenter (e.g., 5 alleys were passable and 3 alleys were blocked), as well as completion of the 8-alley win-shift task (i.e., all 8 alleys were passable).

[0272] During the habituation period, rats were habituated to the maze for 8-minute sessions over 4 consecutive days. In each of these sessions, food rewards were initially scattered on the RAM, on the central platform and on the runways, and then gradually confined to the runways. After this habituation period, a standard training protocol was used, in which food pellets were placed at the ends of each runway. Rats were given one trial per day for 18 days. Each daily trial ended when all 8 food pellets were obtained, or when 16 choices were made, or when 15 minutes had elapsed. After this training period was completed, a second training period was conducted, where the memory demands were increased by imposing a short delay period during the trial. At the start of each trial, 3 of the 8 runways of the maze were blocked. Rats were able to obtain food on the 5 runways that were allowed access during this initial "information period" of the trial. Next, the rats were removed from the maze for 60 seconds, during which the barriers on the maze were removed to allow access to all 8 runways. The rats were then returned to the central platform and were allowed to obtain the remaining food rewards during the "recall test" period of this trial. Which blocked runways and their arrangement were changed for each trial.

[0273] The number of "errors" committed by the AI rats during the recall test period was tracked. An error occurred in a trial if the rats entered a runway where the food had already been retrieved in the pre-delay component of that trial, or if they revisited a runway that had already been visited during the post-delay session.

[0274] After the pre-training test was completed, the delay interval between the information period (presentation of several interrupted runways) and the retention test (presentation of all runways) was further extended, i.e., rats were subjected to trials with a 2-hour delay. During the delay interval, the rats were kept on a cart in an individual home cage next to the maze in the test room. 30 - 40 minutes before each daily trial, the AI rats were pretreated by intraperitoneal (i.p.) injection with one of the following five conditions: 1) vehicle control - 5% dimethyl sulfoxide, 25% polyethylene glycol 300, and 70% distilled water; 2) 0.1 mg / kg of methyl 3,5-diphenylpyridazine-4-carboxylate; 3) 0.3 mg / kg of methyl 3,5-diphenylpyridazine-4-carboxylate; 4) 1 mg / kg of methyl 3,5-diphenylpyridazine-4-carboxylate; and 5) 3 mg / kg of methyl 3,5-diphenylpyridazine-4-carboxylate. The injections were administered every other day with a washout day in between. Each AI rat was treated under all five conditions during the test period. To counteract any potential bias, an ascending-descending dose series was used, i.e., a series of doses was first administered in ascending order and then repeated in descending order to evaluate the drug effect. Thus, each dose was determined twice.

[0275] Parametric statistics (paired t-test) were used to compare the retention test performance of the AI rats in the 2-hour delay version of the RAM task in the context of various doses of methyl 3,5-diphenylpyridazine-4-carboxylate and vehicle control (see Figure 1). The mean number of errors committed during the trials was significantly less in the case of 3 mg / kg of methyl 3,5-diphenylpyridazine-4-carboxylate treatment (mean number of errors ± standard error = 1.31 ± 0.40) than when using the vehicle control (mean number of errors ± standard error of the mean = 3.13 ± 0.62). Compared to the vehicle control treatment, methyl 3,5-diphenylpyridazine-4-carboxylate significantly improved the memory ability at 3 mg / kg (t(7) = 4.233, p = 0.004).

[0276] The AI rats were given 0.3 mg / kg of α5-containing GABA AT, an inverse agonist of R When co-treated with B21007, a therapeutic dose of 3 mg / kg became ineffective. The mean number of errors committed by rats in the case of co-treatment with TB21007 / methyl 3,5-diphenylpyridazine-4-carboxylate (0.3 mg / kg of TB21007 and 3 mg / kg of methyl 3,5-diphenylpyridazine-4-carboxylate) was 2.88 ± 1.32, showing no difference from that of rats treated with vehicle control (mean number of errors of 3.13 ± 1.17). Therefore, the effect of methyl 3,5-diphenylpyridazine-4-carboxylate on spatial memory is a GABA A α5 receptor-dependent effect (see Figure 1). (B) Effect of methyl 3,5-diphenylpyridazine-4-carboxylate on α5-containing GABA A receptor occupancy Animals

[0277] Adult male Long Evans rats (265 - 295 g, Charles River, Portage, MI, n = 4 / group) were used for the study of GABA A α5 receptor occupancy. The rats were individually housed in ventilated stainless steel racks under a 12:12 light / dark cycle. Food and water were available ad libitum. In further studies evaluating the exposure of the compounds at behaviorally active doses, young or old Long Evans rats (n = 2 - 4 / group) were used in these studies. Compounds

[0278] Ro15-4513 was used as a receptor occupancy (RO) tracer for the GABA A α5 receptor sites in the hippocampus and cerebellum. Compared with other alpha subunit-containing GABA A receptors, based on the selectivity of Ro15-4513 for the GABA A α5 receptor, and since Ro15-4513 has been successfully used in GABA A α5 RO studies in animals and humans (e.g., Lingford-Hughes et al., J. Cereb. Blood See Flow Metab. 22:878-89 (2002); Pym et al, Br. J. Pharmacol. 146: 817-825 (2005); and Maeda et al., Synapse 47: 200-208 (2003). ) Ro15-4513 was selected as the tracer. Ro15-4513 (1 μg / kg) was dissolved in 25% hydroxyl-propyl-beta-cyclodextrin and administered i.v. 20 min before RO assessment. Methyl 3,5-diphenylpyridazine-4-carboxylate (0.1-10 mg / kg) was synthesized by Nox Pharmaceuticals (India), dissolved in 25% hydroxyl-propyl-beta-cyclodextrin, and administered i.v. 15 min before tracer injection. Except for the case of the highest dose of methyl 3,5-diphenylpyridazine-4-carboxylate (10 mg / kg) administered at a volume of 1 ml / kg due to solubility limitations, the compounds were administered at a volume of 0.5 ml / kg. Tissue preparation and analysis

[0279] Twenty minutes after tracer injection, the rats were sacrificed by cervical dislocation. The whole brain was quickly removed and gently rinsed with sterile water. Blood from the trunk was collected into Eppendorf tubes coated with EDTA and stored on wet ice until the examination was completed. The hippocampus and cerebellum were excised and stored in 1.5 ml Eppendorf tubes and placed on wet ice until tissue extraction. Six cortical brain tissue samples were collected for use in preparing blank samples and standard curve samples in naïve rats.

[0280] To each sample, acetonitrile containing 0.1% formic acid in a volume 4 times the weight of the tissue sample was added. For the standard curve (0.1 - 30 ng / g) samples, the calculated volume of the standard was adjusted to reduce the volume of acetonitrile. The samples were homogenized (FastPrep-24, Lysing Matrix D; 5.5 m / s, 60 seconds, or using a sonication probe dismembrator at an output of 7 - 8 watts; Fisher Scientific) and centrifuged at 14,000 rpm for 16 minutes. The supernatant solution (100 μl) was diluted with 300 μl of sterile water (pH 6.5). Next, this solution was thoroughly mixed and analyzed for Ro15-4513 (tracer) and methyl 3,5-diphenylpyridazine-4-carboxylate by LC / MS / MS.

[0281] For plasma exposure, blood samples were centrifuged at 14,000 rpm for 16 minutes. After centrifugation, 50 μl of the supernatant (plasma) from each sample was added to 200 μl of acetonitrile + 0.1% formic acid. For the standard curve (1 - 1000 ng / ml) samples, the calculated volume of the standard was adjusted to reduce the volume of acetonitrile. The samples were sonicated in an ultrasonic water bath for 5 minutes and then centrifuged at 16,000 RPM for 30 minutes. 100 μl of the supernatant was withdrawn from each sample vial, placed in a new glass auto-sampler vial, and then 300 μl of sterile water (pH 6.5) was added. Next, this solution was thoroughly mixed and methyl 3,5-diphenylpyridazine-4-carboxylate was analyzed by LC / MS / MS.

[0282] Hippocampus (region with high density of GABA A α5 receptor) occupancy and cerebellum (region with low density of GABA A α5 receptor) occupancy were compared by the ratio method, and furthermore, high-dose GABA A α5 negative allosteric modulator L-655,708 (10 mg / kg, i.v.) was used to measure receptor occupancy to define full occupancy.

[0283] When the vehicle was administered followed by the tracer Ro15-4513 at 1 μg / kg, i.v., levels of Ro15-4513 more than 5-fold higher were produced in the hippocampus (1.93 ± 0.05 ng / g) compared to the cerebellum (0.36 ± 0.02 ng / g). Methyl 3,5-diphenylpyridazine-4-carboxylate (0.01 - 10 mg / kg, i.v.) did not affect the cerebellar levels of Ro15-4513 (Figure 2), but decreased the binding of Ro15-4513 in a dose-dependent manner in the hippocampus, and a dose of 10 mg / kg, i.v. demonstrated >90% occupancy (Figure 3). Both methods for calculating RO gave very similar results, and the ED50 value for methyl 3,5-diphenylpyridazine-4-carboxylate was 1.8 mg / kg based on the ratio method or 1.1 mg / kg when L-755,608 was used to define occupancy.

[0284] Methyl 3,5-diphenylpyridazine-4-carboxylate exposure was below the limit of quantification (BQL) at 0.01 mg / kg, i.v. in both plasma and the hippocampus, but was detectable at low levels in the hippocampus at 0.1 mg / kg, i.v. (see Table 3). Hippocampal exposure was linear with a 10-fold increase at doses of 0.1 - 1 mg / kg, i.v., resulting in a 12-fold increase in exposure. Increasing the dose from 1 - 10 mg / kg, i.v. only improved exposure by about 5-fold. Plasma exposure improved 12-fold when the dose increased from 1 to 10 mg / kg, i.v. Table 3: % Methyl 3,5-diphenylpyridazine-4-carboxylate (0.01 - 10 mg / kg, i.v.) GABA A α5 receptor occupancy. Hippocampal and plasma exposure to methyl 3,5-diphenylpyridazine-4-carboxylate for each treatment group in young Long Evans rats. [Table 3]

[0285] To determine exposure at behaviorally relevant doses in cognitive studies, further studies were conducted in aged Long-Evans rats. Exposure in young Long-Evans rats was also determined for bridging with receptor occupancy studies conducted in young Long-Evans rats. Exposure in young and aged Long-Evans rats was relatively similar (Table 4, Figure 4). Increasing the dose 3-fold from 1 to 3 mg / kg, ip resulted in an increase in exposure in both the hippocampus and plasma in young and aged rats that was greater than proportional to the dose increase, resulting in a 4.5 - 6.6-fold increase. Table 4: Exposure of methyl 3,5-diphenylpyridazine-4-carboxylate in hippocampus and plasma for each treatment group in young Long Evans rats

Table 4

[0286] In this RO study, an exposure of 180 ng / g in the hippocampus (1 mg / kg, i.v.) showed 32 - 39% receptor occupancy depending on the method used to determine RO. This exposure is comparable to that observed in aged rats at 3 mg / kg, i.p., suggesting that 30 - 40% RO is required for cognitive efficacy in this model.

[0287] These studies demonstrated that methyl 3,5-diphenylpyridazine-4-carboxylate dose-dependently increased GABA A α5 receptor occupancy. Methyl 3,5-diphenylpyridazine-4-carboxylate also demonstrated good brain exposure with a brain / plasma ratio > 1. These studies further demonstrated that methyl 3,5-diphenylpyridazine-4-carboxylate exerted its cognitive enhancing effect through positive allosteric modulation at the GABA A a5 subtype receptor. Example 108 Effect of Ethyl 3-Methoxy-7-Methyl-9H-Benzo[f]Imidazo[1,5-a][1,2,4]Triazolo[4,3-d][1,4]Diazepine-10-Carboxylate in Aged Impaired (AI) Rats

[0288] Ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate corresponding to compound number 49 in Achermann et al. Bioorg. Med. Chem. Lett., 19:5746-5752 (2009) is a selective α5-containing GABA A R agonist.

[0289] The effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate on in vivo spatial memory retention in aged impaired (AI) rats was evaluated in a radial arm maze (RAM) behavioral task substantially similar to the task described in Example 107(A), using a vehicle control (25% cyclodextrin, which was tested 3 times: at the beginning, middle, and end of an ascending / descending series) and six different dose levels of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, and 30 mg / kg, with each dose tested 2 times). The same experiment was repeated using the same vehicle control and the same doses of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate, where the vehicle control was tested 5 times, the 3 mg / kg dose of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate was tested 4 times, and the other doses of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate were tested 2 times).

[0290] Using parametric statistics (paired t - test), the performance of the AI rats in the 4 - hour delayed version of the RAM task in the presence of various doses of ethyl 3 - methoxy - 7 - methyl - 9H - benzo[f]imidazo[1,5 - a][1,2,4]triazolo[4,3 - d][1,4]diazepine - 10 - carboxylate and vehicle control was compared (see Figure 5). Compared to the vehicle control treatment, ethyl 3 - methoxy - 7 - methyl - 9H - benzo[f]imidazo[1,5 - a][1,2,4]triazolo[4,3 - d][1,4]diazepine - 10 - carboxylate significantly improved memory ability at 3 mg / kg (t(7)=4.13, p = 0.004 or t(7)=3.08, p = 0.018) and 10 mg / kg (t(7)=2.82, p = 0.026).

[0291] α5 - containing GABA A The effect of ethyl 3 - methoxy - 7 - methyl - 9H - benzo[f]imidazo[1,5 - a][1,2,4]triazolo[4,3 - d][1,4]diazepine - 10 - carboxylate on receptor occupancy was also examined according to a procedure substantially similar to that described in Example 107(B) (see above). This examination demonstrated that ethyl 3 - methoxy - 7 - methyl - 9H - benzo[f]imidazo[1,5 - a][1,2,4]triazolo[4,3 - d][1,4]diazepine - 10 - carboxylate (0.01 - 10 mg / kg, i.v.) decreased the binding of Ro15 - 4513 in the hippocampus without affecting the level of Ro15 - 4513 in the cerebellum (Figure 6), and it was demonstrated that a dose of 10 mg / kg, i.v. resulted in >90% occupancy (Figure 7). Example 109 Effect of 6,6 - dimethyl - 3-(3 - hydroxypropyl)thio - 1-(thiazol - 2 - yl)-6,7 - dihydro - 2 - benzothiophen - 4(5H)-one in aged - impaired rats using the Morris water maze behavioral task

[0292] 6,6 - dimethyl corresponding to compound 44 in J. Med. Chem. 46:2227 - 2240 (2003) R-3-(3-Hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one is a selective α5-containing GABA A R agonist.

[0293] The effect of 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one on in vivo spatial memory retention in aged-impaired (AI) rats was evaluated using the Morris water maze behavioral task. The water maze is a pool surrounded by a novel set of patterns relative to the maze. The training protocol for the water maze can be based on a modified water maze task that has been shown to be hippocampus-dependent (de Hoz et al., Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999).

[0294] A cannula was implanted unilaterally into the lateral ventricle of cognitively impaired aged rats. Stereotaxic coordinates were 1.0 mm posterior to bregma, 1.5 mm lateral to the midline and 3.5 mm ventral to the skull surface. After about one week of recovery, the rats were pre-trained for 2 days in the water maze to search for the position of a submerged escape platform hidden under the surface of the pool (6 trials per day), and the position of the escape platform was changed daily. During pre-training, no intracerebroventricular (ICV) injections were made.

[0295] After pre-training, rats were injected intracerebroventricularly (ICV) with either 100 μg of 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one in 5 μl of DMSO (n = 6) or vehicle DMSO (n = 5) 40 min before water maze training and testing. Training consisted of 8 trials per day for 2 days with the hidden escape platform kept in the same position. Rats were given 60 s to search for the location of the platform and a 60 s interval was provided between trials. The rats were given a probe test (120 s) with the escape platform removed 24 h after the end of training. During training, there were 4 blocks, each block having 4 training trials.

[0296] Rats treated with vehicle and 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one found the escape platform almost simultaneously at the start of training (block 1). In this training block, both vehicle- and 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one-treated rats took approximately 24 seconds to find the escape platform. However, rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one were able to find the platform better (i.e., faster) than vehicle-treated rats at the end of training (block 4). In block 4, rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one took approximately 9.6 seconds to find the escape platform, while vehicle-treated rats took approximately 19.69 seconds. These results suggest that learning of the water maze task was improved in rats by 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (see Fig. 8(A)).

[0297] In the test trial 24 hours after training, the escape platform was removed. To test the long-term memory of the rats, the exploration / swimming pattern of the rats was used to determine the escape platform during pre-trial training It was measured whether rats remembered the location where the toform was placed. In this trial, the "target annulus" refers to a designated area that is 1.5 times the size of the escape platform around the area where the platform was placed during pre-trial training. The "opposite annulus" is a control area of the same size as the target annulus and is located on the opposite side of the target annulus in the pool. If rats have good long-term memory, those rats tend to explore the area around the position where the platform existed during pre-trial training (i.e., the "target" annulus, not the "opposite" annulus). The "time in annulus" is the amount of time in seconds that a rat spent in the area of the target annulus or the opposite annulus. The "number of crossings in annulus" refers to the number of times a rat swam across the area of the target annulus or the opposite annulus.

[0298] Rats that received vehicle administration spent the same amount of time in the target annulus and the opposite annulus, indicating that these rats do not seem to remember the position where the platform existed during pre-trial training. In contrast, rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one spent significantly more time in the "target annulus" and crossed the "target annulus" more frequently compared to the time spent in the "opposite annulus" or the number of crossings of the "opposite annulus". These results suggest that 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one improved the long-term memory of rats in the water maze task (see Figures 8(B) and 8(C)).

[0299] The compound of the present invention A has been demonstrated to have a positive allosteric regulatory effect on the GABA AEnhances the effect of GABA on the α5 receptor. Therefore, the compounds of the present invention should produce a cognitive enhancement effect similar to that produced by other GABA A α5 receptor selective agonists (such as methyl 3,5-diphenylpyridazine-4-carboxylate, ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate and 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, etc.) (see, for example, Examples 28 to 30). (Item 1) Compounds of formula A: [Chemical formula] Or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein Y and Z are each independently selected from C and N, and Y and Z cannot both be N, The bond " [Chemical formula] " is either a single bond or a double bond each time it appears, R 1 Each is independently halogen, -OH or -O(C1-C6)alkyl, R 2 Each is -H, -OR 8 , -SR 8 , -(CH2) n OR 8 , -(CH2) n SR 8 And R 9 Each is -H, (C6-C12)aryl or 5- to 10-membered heteroaryl, and R 9 Each is substituted by 0 to 5 R 11 And R11 is independently selected, for each occurrence, from -halogen, -CF3, -OH, -OCF3, OCHF2, -O-(C1-C6)alkyl, -CN, -SCH3, -(C6-C10)aryl, and -(C1-C6)alkyl, m and n are each independently an integer selected from 0 to 4, a compound, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. (Item 2) R 1 is each halogen or -OMe, R 2 is each -H or -CH2OMe, R 9 is each [Chemical formula] and R 9 is each substituted by 0 to 5 R 11 and R 11 is, for each occurrence, independently selected from -halogen, -CF3, -OH, -OCF3, OCHF2, or -OMe, the compound according to item 1, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. (Item 3) the compound has a structure according to formula B: [Chemical formula] and the compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. (Item 4) the compound has a structure according to formula C: [Chemical formula] ​The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, its isomer, or a combination thereof, having (Item 5) as follows:

Table 8-1

Table 8-2

Claims

【Claim 1】 The invention described in the specification.

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