A combination of a GABAA alpha-5 agonist and an SV2A inhibitor, and a method for using them in the treatment of cognitive impairment.

Abstract

The present disclosure relates to methods, uses, combinations, pharmaceutical compositions, combinations for use, and pharmaceutical compositions for use useful for treating cognitive impairment associated with central nervous system (CNS) disorders. In particular, the present disclosure relates to the use of a synaptic vesicle glycoprotein 2A (SV2A) inhibitor in the treatment of cognitive impairment associated with central nervous system (CNS) disorders in subjects in need of or at risk of treatment, including subjects with or at risk of age-associated cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis, cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease, autism, obsessive-compulsive behavior, and substance addiction. A For use in combination with an alpha5 receptor agonist.

Description

[Technical Field]

[0001] Statement of government support This invention was made with government support under grant number UH3NS101856, awarded by the National Institutes of Health (NIH), a U.S. government agency, particularly its National Institute on Aging (NIA) division. The U.S. government reserves certain rights in this invention.

[0002] Related applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 050,730, filed July 10, 2020, which is incorporated herein by reference in its entirety.

[0003] Areas of disclosure This disclosure describes synaptic vesicle glycoprotein 2A (SV2A) inhibitors as GABA A This disclosure relates to methods, uses, combinations, and pharmaceutical compositions that are useful for treating cognitive impairment and improving cognitive function when used in combination with α5 receptor agonists. In particular, this disclosure is not limited to, but includes, the treatment of cognitive impairment related to central nervous system (CNS) disorders in subjects who need treatment or are at risk of having such conditions, including, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-related 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, intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior, and subjective addiction, by using SV2A inhibitors in combination with GABA receptor agonists. AThis disclosure relates to use in combination with α5 receptor agonists. The disclosure also provides combinations for use and pharmaceutical compositions for use in the treatment of cognitive impairment and improvement of cognitive function. Furthermore, this disclosure relates to methods, uses, combinations, pharmaceutical compositions, combinations for use and pharmaceutical compositions for use in the treatment of cognitive impairment associated with brain cancer or brain cancer itself in subjects requiring treatment. Furthermore, this disclosure relates to methods, uses, combinations, pharmaceutical compositions, combinations for use and pharmaceutical compositions for use in the treatment of Parkinson's disease psychiatry in subjects requiring treatment. [Background technology]

[0004] Background of Disclosure Cognitive abilities may decline as a normal consequence of aging or as a result of central nervous system (CNS) disorders or brain cancer.

[0005] For example, a significant portion of older adults experience cognitive decline beyond what is typical for normal aging. Such age-related loss of cognitive function is clinically characterized by a progressive loss of memory, cognition, reasoning, and judgment. Age-related memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical classifications may be associated with such age-related loss of cognitive function. Some estimates suggest that more than 16 million people in the United States alone have AAMI (Barker et al., 1995).

[0006] Cognitive impairment is also associated with other central nervous system (CNS) disorders such as mild cognitive impairment (MCI), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (e.g., mania), amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior, and substance addiction. For example, it is estimated that 5.5 to 7 million people over the age of 65 in the United States have MCI (Plassman et al., 2008).

[0007] Therefore, effective treatments are needed for these cognitive impairments, as well as cognitive impairments associated with other central nervous system (CNS) disorders.

[0008] Furthermore, it is necessary to treat cognitive impairments associated with brain cancer or the brain cancer itself in patients requiring treatment. Additionally, it is necessary to treat Parkinson's disease-related mental disorders in patients requiring treatment. [Overview of the project] [Means for solving the problem]

[0009] Summary of Disclosure This disclosure provides methods, uses, combinations, and pharmaceutical compositions useful for treating cognitive impairment and improving cognitive function. In particular, this disclosure provides, but is not limited to, SV2A inhibitors and GABA inhibitors useful for treating cognitive impairment related to central nervous system (CNS) disorders in subjects who need treatment or are at risk of having such conditions, including, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-related 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 related to cancer treatment, intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior, and subjective addiction. A This disclosure relates to combinations of α5 receptor agonists. The disclosure also provides combinations for use and pharmaceutical compositions for use in the treatment of cognitive impairment and improvement of cognitive function. Furthermore, the disclosure provides methods, uses, combinations, pharmaceutical compositions, combinations for use and pharmaceutical compositions for use in the treatment of cognitive impairment associated with brain cancer or brain cancer itself in subjects requiring treatment. Furthermore, the disclosure provides methods, uses, combinations, pharmaceutical compositions, combinations for use and pharmaceutical compositions for use in the treatment of Parkinson's disease psychiatric disorder in subjects requiring treatment.

[0010] One aspect of the present disclosure is A) an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a polymorph thereof, and B) GABA A α5 receptor agonist, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a polymorph thereof relates to a pharmaceutical composition comprising. In some embodiments, GABA A α5 receptor agonist, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a polymorph thereof is i) a compound of formula I:

Chemical formula

Chemical formula

Chemical formula

[0011] In some embodiments, certain compounds that may be useful to this disclosure are compounds 1 to 471 disclosed in patent application publications WO2018130868 and WO2018130869. In other embodiments, certain compounds are compounds 180 to 730 disclosed in patent application publication WO2019246300. In other embodiments, certain compounds are compounds 731 to 740 disclosed in patent application publication WO2021127543. Each of these publications, in whole and in particular in the context of the listed compounds, is incorporated herein by reference.

[0012] In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is levetiracetam, celetracetam, brivalacetam, or any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorph or isomer. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is celetracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is brivalacetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer.

[0013] In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula II, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula IV, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA Aα5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, selected from the group consisting of any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers.

[0014] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is compound 1, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a crystalline form of compound 1, and the polymorphic crystalline form is form A, form B, form C, form E, or form F. In some embodiments, the pharmaceutical composition comprises one or more crystalline forms of compound 1, one or more crystalline forms selected from the group consisting of form A, form B, form C, form E, and form F. In some embodiments of the pharmaceutical compositions disclosed herein, GABA Aα5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers, or polymorphs thereof, are present in amounts between 5 mg and 1000 mg. In some embodiments of the pharmaceutical compositions disclosed herein, SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers, or polymorphs thereof, are present in amounts between 0.07 mg and 350 mg. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition is formulated as tablets, capsules, pills, lozenges, powders, granules, liquids, or suspensions. In some embodiments of the pharmaceutical compositions disclosed herein, SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers, or polymorphs thereof, are present in sustained-release, non-sustained-release, or immediate-release forms. In some embodiments of the pharmaceutical compositions disclosed herein, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph, is in a sustained-release form. In some embodiments of the pharmaceutical compositions disclosed herein, GABA A α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers, or polymorphs thereof, are available in sustained-release, non-sustained-release, or immediate-release forms. In some embodiments of the pharmaceutical compositions disclosed herein, GABA A α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers, or polymorphs thereof, are in sustained-release form. In some embodiments of the pharmaceutical compositions disclosed herein, GABA A α5 receptor agonists, or their pharmaceutically acceptable salts, hydrates, solvates, isomers, or polymorphs, are in a non-sustained-release form.

[0015] Another aspect of this disclosure is a first pharmaceutical composition comprising: Component A: an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer or polymorph, or an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and Component B: GABA A α5 receptor agonists, or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, isomers or polymorphs thereof, or GABA A The present invention relates to a combination comprising a second pharmaceutical composition containing an α5 receptor agonist or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0016] In some embodiments, GABA A The α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is selected from the group consisting of the compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer; the compound of formula II, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer; and the compound of formula IV, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula II, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA AAn α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula IV, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is selected from compounds 1 to 114, or from the group consisting of any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers. In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is compound 1, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a crystalline form of compound 1, where the polymorphic crystalline form is form A, form B, form C, form E, or form F. In some embodiments, the combination comprises one or more crystalline forms of compound 1, where one or more crystalline forms are selected from the group consisting of forms A, form B, form C, form E, and form F.

[0017] In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is levetiracetam, celetracetam, brivalacetam, or any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorph or isomer. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is celetracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is brivalacetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer.

[0018] In some embodiments of the combinations disclosed herein, GABA A α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers, or polymorphs thereof, are present in amounts between 5 mg and 1000 mg. In some embodiments of the combinations disclosed herein, SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers, or polymorphs thereof, are present in amounts between 0.07 mg and 350 mg. In some embodiments of the combinations disclosed herein, GABA A α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers or polymorphs thereof, and SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers or polymorphs thereof, are formulated as tablets, capsules, pills, lozenges, powders, granules, liquids or suspensions. In some embodiments of the combinations disclosed herein, GABA Aα5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers or polymorphs, and SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers or polymorphs, are formulated in a single pharmaceutical composition or separately. In some embodiments, the combination comprises: Component A: a first pharmaceutical composition comprising an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, solvate, polymorph or isomer; and Component B: a GABA selected from the group consisting of compounds of formula I, formula II, and formula IV, or any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers. A The first pharmaceutical composition comprises a second pharmaceutical composition comprising an α5 receptor agonist. In some embodiments of the combinations disclosed herein, the first and second pharmaceutical compositions comprise a pharmaceutically acceptable carrier. In some embodiments of the combinations disclosed herein, the first and second pharmaceutical compositions are formulated as tablets, capsules, pills, lozenges, powders, granules, liquids, or suspensions. In some embodiments of the combinations disclosed herein, the first and second pharmaceutical compositions are formulated as a single pharmaceutical composition or separately. In some embodiments of the combinations disclosed herein, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph, is in sustained-release, non-sustained-release, or immediate-release form. In some embodiments of the combinations disclosed herein, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph, is in sustained-release form. In some embodiments of the combinations disclosed herein, GABA A α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their isomers, or their polymorphs are available in sustained-release, non-sustained-release, or immediate-release forms. In some embodiments of the combinations disclosed herein, GABA A α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, solvates, isomers, or polymorphs thereof, are in sustained-release form. In some embodiments of the combinations disclosed herein, GABAA α5 receptor agonists, or their pharmaceutically acceptable salts, hydrates, solvates, isomers, or polymorphs, are in a non-sustained-release form.

[0019] One aspect of the present disclosure relates to a method for treating cognitive impairment related to central nervous system (CNS) disorders in a subject requiring treatment or at risk thereof, the method comprising the step of administering to the subject a pharmaceutical composition or combination of the present disclosure.

[0020] Another aspect of the present disclosure relates to a method for treating cognitive impairment associated with brain cancer in a subject requiring treatment, the method comprising the step of administering to the subject a pharmaceutical composition or combination of the present disclosure.

[0021] One aspect of the present disclosure relates to a method for treating brain cancer in a subject requiring treatment, the method comprising the step of administering to the subject a pharmaceutical composition or combination of the present disclosure.

[0022] Another aspect of the present disclosure relates to a method for treating Parkinson's disease psychiatric disorder in a subject requiring treatment, the method comprising the step of administering to the subject a pharmaceutical composition or combination of the present disclosure.

[0023] One aspect of this disclosure relates to the use of the pharmaceutical compositions or combinations of this disclosure for treating cognitive impairments associated with central nervous system (CNS) disorders in subjects requiring treatment or at risk thereof.

[0024] Another aspect of this disclosure relates to the use of the pharmaceutical compositions or combinations of this disclosure for treating cognitive impairment associated with brain cancer in subjects requiring treatment.

[0025] One aspect of this disclosure relates to the use of the pharmaceutical compositions or combinations of this disclosure for treating brain cancer in subjects requiring treatment.

[0026] Another aspect of the present disclosure relates to the use of the pharmaceutical compositions or combinations of the present disclosure for treating Parkinson's disease psychiatric disorders in subjects requiring treatment.

[0027] One aspect of this disclosure relates to the use of a pharmaceutical composition or combination of the disclosure in the manufacture of a pharmaceutical.

[0028] Another aspect of this disclosure relates to the use of the pharmaceutical compositions or combinations of this disclosure in the manufacture of pharmaceuticals for treating cognitive impairments associated with central nervous system (CNS) disorders in subjects requiring treatment or at risk thereof.

[0029] One aspect of this disclosure relates to the use of a pharmaceutical composition or combination of the disclosure in the manufacture of a pharmaceutical for treating cognitive impairment associated with brain cancer in subjects requiring treatment.

[0030] Another aspect of the present disclosure relates to the use of the pharmaceutical compositions or combinations of the present disclosure in the manufacture of a pharmaceutical for treating brain cancer in subjects requiring treatment.

[0031] One aspect of this disclosure relates to the use of a pharmaceutical composition or combination of the present disclosure in the manufacture of a pharmaceutical for treating Parkinson's disease psychiatric disorder in subjects requiring treatment.

[0032] Another aspect of this disclosure relates to a pharmaceutical composition or combination of the disclosure for use in the treatment of cognitive impairment associated with central nervous system (CNS) disorders in subjects requiring treatment or at risk thereof.

[0033] One aspect of this disclosure relates to a pharmaceutical composition or combination of the disclosure for use in the treatment of cognitive impairment associated with brain cancer in subjects requiring treatment.

[0034] Another aspect of this disclosure relates to a pharmaceutical composition or combination of the disclosure for use in the treatment of brain cancer in subjects requiring treatment.

[0035] One aspect of this disclosure relates to a pharmaceutical composition or combination of the disclosure for use in the treatment of Parkinson's disease psychiatric disorders in subjects requiring treatment.

[0036] Another aspect of this disclosure is a method for treating cognitive impairment associated with central nervous system (CNS) disorders in subjects requiring treatment or at risk thereof, the method for increasing the therapeutic index of an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer or polymorph thereof, wherein the subject is given GABA A The present invention relates to a method comprising the step of administering an α5 agonist, or a pharmaceutically acceptable salt thereof, hydrate, solvate, polymorph, or prodrug containing an α5 agonist or a pharmaceutical composition or combination thereof. In some embodiments, the therapeutic index of an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, hydrate, solvate, polymorph, or isomer thereof is GABA A The therapeutic index of an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, when administered in the absence of an α5 agonist, its pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its prodrug, is at least about 1.5 times, or about 2.0 times, or about 2.5 times, or about 3.0 times, or about 3.5 times, or about 4.0 times, or about 4.5 times, or about 5.0 times, or about 5.5 times, or about 6.0 times, or about 6.5 times, or about 7.0 times, or about 7.5 times, or about 8.0 times, or about 8.5 times, or about 9.0 times, or about 9.5 times, or about 10 times, or more than 10 times higher than that of an α5 agonist, its pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its prodrug.

[0037] One aspect of this disclosure relates to a method for treating cognitive impairment associated with central nervous system (CNS) disorders in subjects requiring treatment or at risk thereof, using GABA. AA method for increasing the therapeutic index of an α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph, comprising the step of administering to a subject an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer containing the pharmaceutical composition or combination of the present disclosure. In some embodiments, GABA A The therapeutic index of α5 receptor agonists, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers, is that of GABA when administered in the absence of SV2A inhibitors, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers. A The therapeutic index of an α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is at least about 1.5 times, or about 2.0 times, or about 2.5 times, or about 3.0 times, or about 3.5 times, or about 4.0 times, or about 4.5 times, or about 5.0 times, or about 5.5 times, or about 6.0 times, or about 6.5 times, or about 7.0 times, or about 7.5 times, or about 8.0 times, or about 8.5 times, or about 9.0 times, or about 9.5 times, or about 10 times, or more than 10 times higher.

[0038] In some embodiments of the methods, uses, combinations for use, or compositions for use, CNS disorder is age-related cognitive impairment. In some embodiments of the methods, uses, combinations for use, or compositions for use, CNS disorder is mild cognitive impairment (MCI). In some embodiments of the methods, uses, combinations for use, or compositions for use, CNS disorder is amnesic mild cognitive impairment (aMCI). In some embodiments of the methods, uses, combinations for use, or compositions for use, CNS disorder is dementia. In some embodiments of the methods, uses, combinations for use, or compositions for use, CNS disorder is Alzheimer's disease. In some embodiments of the methods, uses, combinations for use, or compositions for use, CNS disorder is cognitive impairment associated with schizophrenia, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior, substance addiction, bipolar disorder, or cancer treatment. In some embodiments of the methods, uses, combinations for use, or compositions for use, the pharmaceutical composition or combination is administered subcutaneously, intravenously, orally, sublingually, buccally in the oral cavity, percutaneously, arterially, intradermally, intramuscularly, intraperitoneally, into the eyeball, intranasally, intraspinally, or intracerebrally. In some embodiments of the methods, uses, combinations for use, or compositions for use, the pharmaceutical composition or combination is administered orally. In some embodiments of the methods, uses, combinations for use, or compositions for use, the subject is human. In some embodiments of the methods, uses, combinations for use, or compositions for use, the pharmaceutical composition or combination is administered once daily. In some embodiments of the methods, uses, combinations for use, or compositions for use, the pharmaceutical composition or combination is administered twice daily. In some embodiments of the methods, uses, or combinations for use, components A and B of the combination are administered simultaneously. In some embodiments of the methods, uses, or combinations for use, components A and B of the combination are administered sequentially.

[0039] In some embodiments of the methods, uses, combinations for use, or compositions for use, the treatment involves GABA in the absence of an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. A The therapeutic effect obtained by administering an α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph, is at least 1.5 times, or at least 2.0 times, or at least 2.5 times, or at least 3.0 times, or at least 3.5 times, or at least 4.0 times, or at least 4.5 times, or at least 5.0 times, or at least 5.5 times, or at least 6.0 times, or at least 6.5 times, or at least 7.0 times, or at least 7.5 times, or at least 8.0 times, or at least 8.5 times, or at least 9.0 times, or at least 9.5 times, or at least 10 times, or more than 10 times, is longer in the subject than that obtained by administering an α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph. In some embodiments of the method, use, combination for use, or composition for use, the treatment is GABA A The therapeutic effect is at least 1.5 times, or at least 2.0 times, or at least 2.5 times, or at least 3.0 times, or at least 3.5 times, or at least 4.0 times, or at least 4.5 times, or at least 5.0 times, or at least 5.5 times, or at least 6.0 times, or at least 6.5 times, or at least 7.0 times, or at least 7.5 times, or at least 8.0 times, or at least 8.5 times, or at least 9.0 times, or at least 9.5 times, or at least 10 times, or more than 10 times longer in the subject than that obtained by administering an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph, in the absence of an α5 receptor agonist, or its pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph. [Brief explanation of the drawing]

[0040] [Figure 1]Figure 1 illustrates the effective plasma level range in aMCI patients based on studies in aged and disabled rats and Phase II studies. The acceptable range target is established based on the effective plasma level range in aged and disabled rats and aMCI patients, i.e., between 1.9 and 4.4 μg / ml. The preferred range target is established based on the effective plasma level range in aMCI patients, i.e., between 2.9 and 4.4 μg / ml.

[0041] [Figure 2] Figure 2 illustrates the effect of levetiracetam administration on spatial memory retention in six aged disabled rats (AIs) in the Maurice Water Maze (MWM) test. Three treatment conditions were used: vehicle control, levetiracetam (5 mg / kg / day), and levetiracetam (10 mg / kg / day). AI rats received one treatment per day before the training trial and trained for two consecutive days. AI rats were tested 24 hours later. Spatial memory retention was measured by the time spent swimming around the target quadrant or target ring in the memory recall trial, 24 hours after two days of training under various treatment conditions. The target quadrant refers to the quadrant of the maze (which is a circular pool) where the escape platform is placed during the training trial. The target ring refers to the exact location of the escape platform during the training trial.

[0042] [Figure 3]Figure 3 illustrates the effect of levetiracetam administration on spatial memory retention in 10 aged disabled rats (AI) in an 8-lane radial maze (RAM) test. Six treatment conditions were used: vehicle control, levetiracetam (1.25 mg / kg), levetiracetam (2.5 mg / kg), levetiracetam (5 mg / kg), levetiracetam (10 mg / kg), and levetiracetam (20 mg / kg). In the RAM task used, there was a 1-hour delay between the presentation of a subset of lanes (5 lanes passable and 3 lanes blocked) and the completion of an 8-lane win-shift task (8 lanes passable). Rats were pre-treated 30–40 minutes before each daily trial with a single drug / control treatment. The number of errors made by rats after the delay was used as a measure of spatial memory retention. An error was defined as a rat entering a run where food had already been retrieved in a component prior to the delay time of the trial, or a rat revisiting a run it had already visited in a session after the delay time. Paired t-tests were used to compare the number of errors between various doses of levetiracetam and vehicle controls.

[0043] [Figure 4] Figure 4 illustrates the experimental design for a human trial involving levetiracetam treatment.

[0044] [Figure 5A] Figure 5A illustrates the average activity in the left CA3 of aMCI subjects treated with placebo while placebo-treated same-age control subjects were presented with a decoy stimulus that they correctly identified as "similar."

[0045] [Figure 5B] Figure 5B illustrates the average activity in the left CA3 of aMCI subjects while they were presented with a decoy stimulus correctly identified as "similar" to either placebo-treated or levetiracetam-treated (125 mg twice daily for 2 weeks).

[0046] [Figure 5C]Figure 5C is a table of the data presented in Figures 5A and 5B.

[0047] [Figure 6A] Figure 6A illustrates the average activity in the left entorhinal cortex of aMCI subjects while they are presented with a decoy stimulus that correctly identifies as "similar" to a placebo-treated control subject of the same age.

[0048] [Figure 6B] Figure 6B illustrates the average activity in the left entorhinal cortex of the same aMCI subjects while they were presented with a decoy stimulus that they correctly identified as "similar," either through placebo treatment or levetiracetam treatment (125 mg twice daily for two weeks).

[0049] [Figure 6C] Figure 6C is a table of the data presented in Figures 6A and 6B.

[0050] [Figure 7A] Figure 7A illustrates an example of the order of images presented to the subject in the explicit three-library forced selection task described in Example 2.

[0051] [Figure 7B] Figure 7B shows a sample pair of similar ("decoy") images.

[0052] [Figure 8] Figure 8 shows the difference in performance between the aMCI (placebo) group and the same-age control (placebo) group in the explicit three-limb forced selection task described in Example 2. Each bar represents the percentage of the group's response (older, similar, or newer) when presented with a decoy image.

[0053] [Figure 9]Figure 9 shows the difference in performance on the explicit three-limb forced-selection task described in Example 1 between the same aMCI subjects treated with placebo or levetiracetam (125 mg twice daily for 2 weeks). Each bar represents the percentage of subjects who responded (old, similar, or new) when presented with a decoy image.

[0054] [Figure 10] Figure 10 is a table of the data presented in Figures 8 and 9.

[0055] [Figure 11A] Figure 11A shows the difference in performance on the Bushke Selective Recollection Test - Delayed Recall between aMCI subjects treated with placebo or levetiracetam (125 mg twice daily for 2 weeks) and a similar-age control group (placebo).

[0056] [Figure 11B] Figure 11B is a table of the data presented in Figure 11A.

[0057] [Figure 12A] Figure 12A shows the difference in Benton Visual Memory Scale scores between the control (placebo) group and the aMCI group treated with placebo or levetiracetam (125 mg twice daily for 2 weeks).

[0058] [Figure 12B] Figure 12B is a table of the data presented in Figure 12A.

[0059] [Figure 13A] Figure 13A shows the difference in performance on the Verbal Paired Associative Test-Recognition between the control (placebo) group and the aMCI group treated with placebo or levetiracetam (125 mg twice daily for 2 weeks).

[0060] [Figure 13B] Figure 13B is a table of the data presented in Figure 13A.

[0061] [Figure 14A] Figure 14A shows the difference in performance of the verbal paired association test - delayed recall between the control (placebo) subjects and aMCI subjects treated with placebo or levetiracetam (125 mg twice daily for 2 weeks).

[0062] [Figure 14B] Figure 14B is a table of the data presented in Figure 14A.

[0063] [Figure 15A] Figure 15A is a table showing the subject selection process for the human levetiracetam trial described in Example 1.

[0064] [Figure 15B] Figure 15B is a table showing the characteristics of subjects selected for the human levetiracetam trial described in Example 1.

[0065] [Figure 16] Figure 16 illustrates the effect of burivalacetam administration on memory ability in nine aged disabled rats on an 8-lane radial maze task. The burivalacetam doses administered to the AI ​​rats included 0.0625 mg / kg, 0.125 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg. The mean and standard error of the number of errors are shown on the y-axis.

[0066] [Figure 17] Figure 17 illustrates the effect of celetracetam administration on memory ability in nine aged disabled rats during an 8-lane radial maze test. The celetracetam doses administered to the AI ​​rats included 0.0625 mg / kg, 0.125 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg. The mean and standard error of the number of errors are shown on the y-axis.

[0067] [Figure 18] Figures 18A and 18B illustrate the 14-day outcomes of aged disabled rats (n=3 / group) treated with a dose of 2 mg / kg / day burivalacetam in the water maze task. Rats treated with 2 mg / kg / day burivalacetam (t(2)=10.000, p=0.010) compared to the vehicle (t(2)=1.964, p=0.188) showed a significantly greater spatial bias in the target quadrant compared to the other control quadrants. Burivalacetam-treated rats (2 mg / kg / day) also spent considerably more time in the target quadrant than vehicle-treated rats (t(4)=3.881, p=0.018). Rats treated with buribaracetam (2 mg / kg / day) spent significantly more time in the target ring shape (the area around the location of the escape platform) than rats treated with vehicle (t(4)=3.109, p=0.036).

[0068] [Figure 19] Figures 19A and 19B illustrate the effects of 62.5 mg BID and 250 mg BID doses of levetiracetam on fMRI activity in the dentate gyrus / CA3 region of aMCI patients.

[0069] [Figure 20] Figures 20A and 20B show the differences between aMCI (placebo) subjects and same-age control (placebo) subjects in the performance of the explicit three-limb forced selection task described in Example 3, at doses of 62.5 mg BID placebo and 250 mg BID placebo. Each bar represents the percentage of subjects who responded (older, similar, or newer) when presented with a decoy image.

[0070] [Figure 21] Figures 21A and 21B show the differences between the same aMCI subjects with placebo treatment and levetiracetam treatment (62.5 mg BID and 250 mg BID) in performance on the explicit three-limb forced selection task described in Example 3. Each bar represents the percentage of subjects who responded (old, similar, or new) when presented with a decoy image.

[0071] [Figure 22] Figure 22 shows that in aged, disabled rats, administration of levetiracetam and vehicle at a dose of 10 mg / kg / day via an osmotic minipump for 4 weeks restores somatostatin in the DG phylum.

[0072] [Figure 23] Figure 23 shows that in aged, disabled rats, administration of levetiracetam and vehicle at a dose of 10 mg / kg / day via an osmotic minipump for 4 weeks restores reelin in the entorhinal cortex (EC2).

[0073] [Figure 24] Figures 24A–24C illustrate the plasma levels of levetiracetam in aMCI patients at doses of 62.5 mg BID, 125 mg BID, and 250 mg BID levetiracetam.

[0074] [Figure 25] Figure 25 shows the superimposed XRPD patterns of the anhydrous polymorphic forms of compound 1. The top diffractogram corresponds to anhydrous form A, the second from the top corresponds to desolvated form B, the third from the top corresponds to anhydrous substance D (as a mixture with form A), and the bottom corresponds to anhydrous form E.

[0075] [Figure 26] Figure 26 shows superimposed XRPD patterns of the solvated polymorphs of compound 1. The upper diffractogram corresponds to the methanolate form C, and the lower one corresponds to the monohydrate form F.

[0076] [Figure 27] Figures 27A and 27B illustrate the thermograms of anhydrous form A. Figure 27A (top) corresponds to the thermogravimetric analysis (TGA) curve, and Figure 27B (bottom) corresponds to the differential scanning calorimetry (DSC) curve.

[0077] [Figure 28] Figure 28 illustrates the atomic displacement ellipsoid diagram of anhydrous form A. Non-hydrogen atoms are represented by anisotropic thermal vibration ellipsoids with a 50% probability.

[0078] [Figure 29] Figure 29 shows an overlay of the experimentally obtained (top) and calculated (bottom) XRPDs for the anhydrous form A.

[0079] [Figure 30] Figure 30 illustrates the dynamic water vapor sorption isotherm for anhydrous form A.

[0080] [Figure 31] Figure 31 illustrates the indexed XRPD pattern of desolvation form B.

[0081] [Figure 32] Figure 32 shows the XRPDs of substance D initially collected after preparation (top) and substance D after 7 weeks of ambient storage (center) superimposed. The XRPD pattern of morphology A is shown for reference (bottom).

[0082] [Figure 33] Figures 33A and 33B illustrate the thermogram of substance D (as a mixture with form A). Figure 33A (top) corresponds to the TGA curve, and Figure 33B (bottom) corresponds to the DSC curve.

[0083] [Figure 34] Figure 34 illustrates the atomic displacement ellipsoid diagram of the anhydrous form E. Non-hydrogen atoms are represented by an anisotropic thermal vibration ellipsoid with a 50% probability.

[0084] [Figure 35] Figure 35 shows an overlay of the experimentally obtained (top) and calculated (bottom) XRPDs of anhydrous form E.

[0085] [Figure 36] Figures 36A and 36B illustrate the thermograms of the anhydrous form E. Figure 36A (top) corresponds to the TGA curve, and Figure 36B (bottom) corresponds to the DSC curve.

[0086] [Figure 37] Figure 37 shows an overlay of the XRPD of monohydrate form F (top) and the HCl salt of compound 1 (bottom) for reference.

[0087] [Figure 38] Figure 38 shows the indexed XRPD pattern of monohydrate morphology F.

[0088] [Figure 39] Figures 39A and 39B illustrate the thermograms of monohydrate form F. Figure 39A (top) corresponds to the TGA curve, and Figure 39B (bottom) corresponds to the DSC curve.

[0089] [Figure 40] Figure 40 illustrates the dynamic vapor sorption (DVS) isotherm of monohydrate form F.

[0090] [Figure 41] Figure 41 shows the indexed XRPD pattern of metanolate morph C.

[0091] [Figure 42] Figures 42A and 42B illustrate thermograms of metanolate form C. Figure 42A (top) corresponds to the TGA curve, and Figure 42B (bottom) corresponds to the DSC curve.

[0092] [Figure 43] Figure 43 shows the superimposed XRPDs of crude compound 1 (top), calculated morphology A (center), and experimentally determined morphology B (bottom). The symbol * indicates additional peaks not attributable to either morphology A or morphology B.

[0093] [Figure 44]Figure 44 is a graph showing the effect of compound 1 compared to vehicle controls using a radial maze behavior task in aged disabled rats. The graph shows the average number of errors made by aged disabled rats treated with various doses of compound 1 (2.5 mg / kg, 5 mg / kg, and 10 mg / kg).

[0094] [Figure 45] Figures 45A and 45B are graphs showing the effect of compound 1 on the Morris water maze behavior task compared to vehicle controls in aged disabled rats. Figure 45A shows the amount of time spent in the target quadrant after acute treatment with compound 1 (10 mg / kg). Figure 45B shows the amount of time spent in the target quadrant after chronic treatment (12 weeks) with compound 1 (10 mg / kg).

[0095] [Figure 46] Figures 46A and 46B illustrate the effects of the combination of compound 1 and levetiracetam compared to a vehicle control using a radial maze behavior task in aged disabled rats. Figure 46A shows the average number of errors made by aged disabled rats treated with a combination of compound 1 at a dose of 2.5 mg / kg and levetiracetam at a dose of 2.5 mg / kg, or with a combination of compound 1 at a dose of 5 mg / kg and levetiracetam at a dose of 2.5 mg / kg. Figure 46B shows an isobolographic analysis of the combination of compound 1 and levetiracetam to evaluate whether there is a synergistic effect in the combination treatment compared to treatment with compound 1 or levetiracetam alone. [Modes for carrying out the invention]

[0096] Detailed explanation of disclosure GABA A Receptor (GABA) AR) is a pentamer aggregate derived from a pool of various subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ) that form Cl-permeable channels activated by the neurotransmitter gamma-aminobutyric acid (GABA). It exhibits a variety of pharmacological effects, including anxiety disorders, epilepsy, insomnia, pre-anesthetic sedation, and muscle relaxation, depending on the GABA. A It is mediated by subtypes.

[0097] Numerous studies have demonstrated that reduced GABA signaling is associated with various CNS disorders that lead to cognitive impairment. For example, some previous studies have shown that in rats with age-related cognitive decline, GABA A It has been demonstrated that the expression of the α5 subunit of the receptor is reduced in the hippocampus (see International Patent Publication WO2007 / 019312). In addition, other studies have shown that GABA A α5-containing GABA, an α5 receptor agonist A Positive allosteric modulators of R have been shown to be useful in treating CNS disorders, cognitive impairments associated with brain cancer, and cognitive impairments associated with brain cancer or Parkinson's disease psychiatry. See, for example, WO2015 / 095783, WO2018 / 130868, WO2016 / 205739, WO2018 / 130869, WO2019 / 246300, and US62 / 950,886 (all of which are incorporated herein by special reference).

[0098] Synaptic vesicle protein-2 (SV2) is a family of synaptic vesicle proteins consisting of three members designated as SV2A, SV2B, and SV2C. SV2A is the most widely distributed family member and is universally expressed in the brain. This protein is an endogenous membrane protein and has low levels of homology (20-30%) to the 12-transmembrane family of bacterial and fungal transporter proteins that transport sugars, citrates, and xenobiotics (Bajjalieh et al., Science, 257: 1271-1273 (1992)). SV2 family proteins are present in brain and endocrine cells, and are also present in all synaptic and endocrine vesicles. SV2 proteins play a vital role in normal synaptic function, as well as in vesicle transport. 2+It has been reported to play a role in the function of the primed vesicle maturation step, which converts to a synaptotagmin-responsive state (Sudhof et al., 2009). The SV2 protein has been reported to enhance the potential for neurotransmitter release by enhancing synaptic currents and maintaining a size of readily releaseable vesicle pools (Custer et al., 2006). Various studies have shown that SV2A inhibitors, compounds that bind to SV2A and reduce synaptic function by decreasing presynaptic vesicle release (see, for example, Noyer et al. 1995, Fuks et al. 2003, Lynch et al. 2004, Gillard et al. 2006, Custer et al., 2006, Smedt et al., 2007, Yang et al., 2007, Meehan, "Levetiracetam has an activity-dependent effect on inhibitory transmission," Epilepsia, 2012 Jan 31, and Example 8 of WO2001 / 62726 (all of which are incorporated herein by special reference)), may be useful in treating cognitive impairment associated with CNS disorders. For example, international patent applications PCT / US2009 / 005647 (publication number WO2010 / 044878), international patent applications PCT / US2011 / 024256 (publication number WO2011 / 100373), international patent applications PCT / US2012 / 024556 (publication number WO2012 / 109491), and international patent applications PCT / US2013 / 070144 (publication number WO2014 / 0785 See also International Patent Application No. 68), International Patent Application PCT / US2014 / 029170 (Publication No. WO2014 / 144663), International Patent Application PCT / US2014 / 029362 (Publication No. WO2014 / 144801), and International Patent Application PCT / US2016 / 033567 (Publication No. WO2016 / 191288) (all of which are incorporated herein by special reference).

[0099] Surprisingly, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or combinations of their isomers have been found to have synergistic and hyperadditive effects on the treatment of cognitive impairments associated with CNS disorders (such as age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-related 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, intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior, and substance addiction). The combined effect of the treatment of the aforementioned cognitive impairment was greater than the effect that would have been expected to be merely additive. Furthermore, this effect should be observed in the treatment of cognitive impairment associated with brain cancer, brain cancer, and Parkinson's disease psychiatry in subjects requiring treatment. Also, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740 and 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers, have different mechanisms of action, and their synergistic effects are remarkable.

[0100] SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A This synergistic combination of α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers, is also effective with SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A, form B, form C, form E, or form F of compound 1), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers, can be administered in lower therapeutic doses than those normally used when used alone to treat disorders with cognitive impairment. Such lower doses allow for the administration of SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers, and GABA ANegative side effects or toxicity that may occur in connection with the administration of α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers can be mitigated or prevented. Furthermore, despite lower dose administration, the synergistic effect of the combination may not only not result in loss of efficacy but may even improve it, allowing for longer-lasting therapeutic effects. The enhancement of therapeutic efficacy through the use of combinations can improve treatment outcomes without the need to increase the dose or frequency of administration. In some settings, increased dosage may be beneficial for treatment but may sometimes exacerbate negative side effects or lead to toxicity, thus necessitating new treatment regimens, particularly those tailored to chronic conditions or administered over long periods. Moreover, negative side effects and increased dosage may reduce patient adherence to treatment. SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, or combinations of their polymorphs or isomers, are useful for the long-term treatment of cognitive impairments associated with CNS disorders (such as age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-related 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, intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior, and substance addiction), and the observed synergistic effects are therefore advantageous. Furthermore, the combination is useful for treating cognitive impairments associated with brain cancer, brain cancer, and Parkinson's disease psychiatric disorders in patients requiring treatment. General information

[0101] Unless otherwise defined herein, scientific and technical terms used in this application have the meanings generally understood by those skilled in the art. In general, the nomenclature used in and relating to cell and tissue cultures, molecular biology, cell and cancer biology, neurobiology, neuroscience, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein is well known and commonly used in the art. For example, "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.," WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.," WH Freeman & Co., NY (1999); Gilbert et al., "Developmental Biology, 6th ed.," Sinauer Associates, Inc., Sunderland, MA (2000).

[0102] The chemical terms used herein are used in accordance with the conventional usage in the art, as illustrated in "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0103] All publications, patents, and published patent applications referenced in this application are incorporated by specific reference herein. In case of any conflict, this specification, including its specific definitions, shall prevail.

[0104] Throughout this specification, variations of the word “comprise,” “comprises,” or “comprising” are understood to mean the inclusion of a specified integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components).

[0105] The singular forms "a," "an," and "the" include the plural unless the context specifically indicates otherwise.

[0106] The term "including" is used to mean "including but not limited to these." "Including" and "including but not limited to these" are used interchangeably.

[0107] The terms “patient,” “subject,” or “individual” are used interchangeably and may refer to either a human or a non-human animal. Patients, subjects, or individuals include mammals (humans, primates, domestic animals (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.) and rodents (e.g., mice and rats). In some embodiments, the patient, subject, or individual is human.

[0108] "Cognitive function" or "cognitive state" can refer to any higher-order intelligent brain processes or states related to learning and / or memory, including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discriminative learning, decision-making, inhibitory response control, attentional set shift, delayed reinforcement learning, reverse learning, time integration of spontaneous behavior, as well as display of interest in the surrounding environment and self-care, processing speed, reasoning and problem-solving, and social cognition.

[0109] "Facilitation" of cognitive function can refer to the effect of influencing impaired cognitive function to closely resemble that of a normal individual. Cognitive function can be facilitated to any detectable degree, but in humans, it can be facilitated sufficiently so that an individual with impaired cognitive function can perform daily activities of normal life at a level of proficiency as close as possible to that of a normal individual or a normal individual of the same age.

[0110] In some embodiments, “facilitation” of cognitive function in an affected subject due to age-related cognition means that the impaired cognitive function is affected to such an extent that it closely resembles the function of a normal subject of the same age or a young adult subject. The subject’s cognitive function may be facilitated to any detectable degree, but in humans, it may be facilitated enough for the impaired subject to be able to perform the daily activities of normal life at a level of proficiency as close as possible to that of a normal subject, a young adult subject, or a normal subject of the same age.

[0111] "Protection" of cognitive function can refer to influencing normal or impaired cognitive function in such a way that it does not decline, does not fall below the level observed in the subject at the time of initial presentation or diagnosis, or delays such decline.

[0112] "Improvement" of cognitive function may include promoting and / or protecting cognitive function in the subject.

[0113] "Cognitive impairment" can refer to cognitive function in an individual that is not as robust as the cognitive function expected in a normal individual. In some cases, cognitive function is reduced by approximately 5%, 10%, 30%, or more compared to the cognitive function expected in a normal individual. In some cases, "cognitive impairment" in an individual affected by age-related cognitive impairment can refer to cognitive function in an individual that is not as robust as the cognitive function expected in an individual of the same age or in a young adult individual (i.e., an individual with an average score for a given age on a cognitive test).

[0114] In patients requiring treatment, “treating brain cancer-related cognitive impairment” or “treating brain cancer” can mean taking steps to achieve beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, improvement of cognitive function in patients with brain cancer; delay or slowing of the progression of brain cancer or cognitive impairment in patients with brain cancer; slowing of the rate of cognitive decline in patients with brain cancer; prevention or slowing of the progression of brain cancer or brain cancer-related cognitive impairment; or reduction, improvement, or slowing of the progression of one or more symptoms associated with brain cancer or brain cancer-related cognitive impairment.

[0115] In patients requiring treatment, “treating Parkinson’s disease psychiatry” can mean taking steps to achieve beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, improvement of Parkinson’s disease psychiatry; delay or slowing of its progression; prevention or slowing of its progression; or reduction, improvement, or slowing of the progression of one or more symptoms associated with Parkinson’s disease psychiatry.

[0116] "Treating cognitive impairment" can refer to taking steps to improve the cognitive function of an individual with cognitive impairment so that their performance on one or more cognitive tests improves to any detectable level or prevents further decline. The cognitive function of the individual may closely resemble that of an unimpaired, normal individual after treatment. Treatment of cognitive impairment in humans can improve cognitive function to any detectable level, but it can be sufficient to enable the impaired individual to perform daily activities of normal life at the same level of proficiency as a normal individual. In some cases, "treating cognitive impairment" can refer to taking steps to improve the cognitive function of an individual with cognitive impairment so that their performance on one or more cognitive tests improves to any detectable level or prevents further decline. The cognitive function of the individual may closely resemble that of a normal individual after treatment. In some cases, "treating cognitive impairment" in subjects affected by age-related cognitive impairment may refer to taking steps to improve the subject's cognitive function so that, after treatment, the subject's cognitive function closely resembles that of a normal subject of the same age or a young adult subject. In some cases, "treating cognitive impairment" in subjects may refer to taking steps to delay or slow the progression of cognitive impairment in subjects with cognitive impairment. In some cases, "treating cognitive impairment" in subjects may refer to taking steps to slow the rate of decline in cognitive function in subjects with cognitive impairment.Beneficial or desired clinical outcomes include, but are not limited to, improved cognitive function; delayed or slowed progression of cognitive impairment; slowed rate of cognitive decline; prevention of disease or impairment or slowed progression thereof; or reduction, improvement, or slowed progression of one or more symptoms associated with cognitive impairment related to CNS disorders (such as age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI, age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, PTSD, schizophrenia or bipolar disorder (especially mania), amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior, or substance addiction). Treatment of age-related cognitive impairment further includes slowing the transition from age-related cognitive impairment to dementia (e.g., AD). Compounds useful in the methods, uses, pharmaceutical compositions, and combinations disclosed herein

[0117] Compounds useful in the methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use of the present disclosure include synaptic vesicle glycoprotein 2A (SV2A) inhibitors, or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof or isomers thereof, and GABA A This includes α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. SV2A inhibitors

[0118] The term "SV2A inhibitor" can refer to any compound that binds to SV2A and reduces synaptic function by reducing presynaptic vesicle release (see, for example, Noyer et al. 1995, Fuks et al. 2003, Lynch et al. 2004, Gillard et al. 2006, Custer et al., 2006, Smedt et al., 2007, Yang et al., 2007, Meehan, "Levetiracetam has an activity-dependent effect on inhibitory transmission," Epilepsia, 2012 Jan 31, and Example 8 of WO2001 / 62726 (all of which are incorporated herein by special reference)). A compound can be an SV2A inhibitor insofar as it reduces synaptic function or its ability to do so by binding another compound to SV2A or by reducing presynaptic vesicle release, even if it does not bind to SV2A itself. Suitable SV2A inhibitors for the methods, uses, pharmaceutical compositions, or combinations of this disclosure include certain SV2A inhibitors described herein, their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, or their isomers.

[0119] In some embodiments of this disclosure, the SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is selected from the group consisting of levetiracetam, brivalacetam, and celetracetam, or any of the aforementioned pharmaceutically acceptable salts, solvates, hydrates, polymorphs or isomers.

[0120] In some embodiments of this disclosure, an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. Levetiracetam refers to the compound (2S)-2-(2-oxopyrrolidine-1-yl)butanamide (International Union of Pure and Applied Chemistry (IUPAC) name). Levetiracetam is a widely used antiepileptic drug. Levetiracetam has been shown to directly inhibit synaptic activity and neurotransmission by binding to synaptic vesicle protein 2A (SV2A), a specific site in the CNS (see, e.g., Noyer et al. 1995, Fuks et al. 2003, Lynch et al. 2004, Gillard et al. 2006), thereby inhibiting presynaptic neurotransmitter release (Yang et al., 2007). Levetiracetam is marketed as Keppra, an FDA-approved antiepileptic drug. Typically, the therapeutically effective dose of levetiracetam (Keppra) ranges from 1000 to 3000 mg / day.

[0121] In some embodiments of this disclosure, an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is buribaracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. Buribaracetam refers to the compound (2S)-2-[(4R)-2-oxo-4-propylpyrrolidine-1-yl]butanamide (IUPAC name). Buribaracetam has anticonvulsant activity and binds to SV2A in the brain.

[0122] In some embodiments of this disclosure, an SV2A inhibitor, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is celetracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. Celetracetam refers to the compound (2S)-2-[(4S)-4-(2,2-difluoroethenyl)-2-oxopyrrolidine-1-yl]butanamide (IUPAC name). Celetracetam is an antiepileptic agent that binds to SV2A in the brain. GABA A α5 receptor agonist

[0123] When used herein, "α5-containing GABA" A Receptor agonist, α5-containing GABA A "R agonist" or "GABA" A "α5 receptor agonists," and other variants used herein, are α5-containing GABA A Receptor (GABA) A Compounds that enhance the function of R), namely GABAergic Cl - This refers to a compound that increases electric current. In some embodiments, GABA A When used herein, the α5 receptor may refer to a positive allosteric modulator that activates GABA activity. GABA suitable for use in this disclosure A α5 receptor agonists include α5-containing GABA of all formulas described herein. A Receptor agonists and specific GABAs A This includes α5 receptor agonists, or their pharmaceutically acceptable salts, their hydrates, their solvates, their polymorphs, or their isomers. Exemplary GABA A α5 receptor agonists are disclosed in WO2015 / 095783, WO2016 / 205739, WO2018 / 130868, WO2018 / 130869, WO2019 / 246300, and WO2021 / 127543.

[0124] In some embodiments, GABA Aα5 receptor agonists are i) Compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer (in the formula, U, along with the two carbon atoms represented by α and β, together form a 5- or 6-membered aromatic ring having 0 to 2 nitrogen atoms. A is C, CR 6 , or N, B and F are C, CR 6 They are independently selected from the group consisting of , and N, and B and F cannot both be N. D is N, NR 7 , O, CR 6 or C(R 6 )2, E is N, NR 7 , CR 6 or C(R 6 )2, W is N, NR 7 , CR 6 or C(R 6 )2, X is N, NR 7 , O, CR 6 or C(R 6 )2, Y and Z are C, CR 6 They are independently selected from the group consisting of , and N, and Y and Z cannot both be N. V is C or CR 6 That is, Or Z is C or CR 6 In that case, V is C, CR 6 , or N, The ring formed by X, Y, Z, V, and W is [ka] If R 2 is -OR 8 , -SR8 ,-(CH2) n Ure 8 ,-(CH2) n O(CH2) n R 8 ,-(CH2) p R 8 or -(CH2) n N(R)R 10 And R 2 It is independently substituted by 0 to 5 R' values. m and n are independent integers selected from 0 to 4. p is an integer selected from 2 to 4. Combine ' [ka] Each instance of '' independently represents either a single bond or a double bond. R 1 , R 2 , R 4 , and R 5 Each time it appears, the following occurs: Halogen, -R, -OR, -NO2, -NCS, -CN, -CF3, -OCF2H, -OCF3, -SiR3, -N(R)2, -SR, -SOR, -SO2R, -SO2N(R)2, -SO3R, -(CR2) 1~3 R, -(CR2) 1~3 -OR, -(CR2) 1~3 -O(CR2) 1~3 -R, -(CR2) 0~3 -C(O)NR(CR2) 0~3 R, -(CR2) 0~3 -C(O)NR(CR2) 0~3 OR, -C(O)R, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)R, -C(S)OR, -C(O)OR, -C(O)C(O )OR, -C(O)C(O)N(R)2, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -C(S)N(R)2, -(CR2) 0~3NHC(O)R, -N(R)N(R)COR, -N(R)N(R)C(O)OR, -N(R)N(R)CON(R)2, -N(R)SO2R, -N(R)SO2N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(S)R, -N(R)C(O)N( R)2, -N(R)C(S)N(R)2, -N(COR)COR, -N(OR)R, -C(=NH)N(R)2, -C(O)N(OR)R, -C(=NOR)R, -OP(O)(OR)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(H)(OR), -C≡CR 8 , -CH2CF3, and CHF2 Each is independently selected from the group consisting of, R 8 Each instance is independently -H, -(C1~C6)alkyl, -(C3~C6)cycloalkyl, -(C1~C6)alkyl-(C3~C6)cycloalkyl, -(C1~C6)alkyl-(C6~C10)aryl, -(C6~C10)aryl, -5~10 member heteroaryl, or -(C1~C6)alkyl-5~10 member heteroaryl. R 8 Each of these is independently substituted with 0 to 5 of the following, excluding -H and -(C1~C6)alkyl groups: -halogen, -(C1~C6)alkyl, -CF3, -OCF3, or O-(C1~C6)alkyl. R 3 It does not exist, or is below: Halogen, -R, -OR, -NO2, -NCS, -CN, -CF3, -OCF3, -SiR3, -N(R)2, -SR, -SOR, -SO2R, -SO2N(R)2, -SO3R, -(CR2) 1~3 R, -(CR2) 1~3 -OR, -(CR2) 0~3 -C(O)NR(CR2) 0~3 R, -(CR2) 0~3 -C(O)NR(CR2) 0~3OR, -C(O)R, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)R, -C(S)OR, -C(O)OR, -C(O)C(O )OR, -C(O)C(O)N(R)2, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -C(S)N(R)2, -(CR2) 0~3 NHC(O)R, -N(R)N(R)COR, -N(R)N(R)C(O)OR, -N(R)N(R)CON(R)2, -N(R)SO2R, -N(R)SO2N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(S)R, -N(R)C(O)N( R)2, -N(R)C(S)N(R)2, -N(COR)COR, -N(OR)R, -C(=NH)N(R)2, -C(O)N(OR)R, -C(=NOR)R, -OP(O)(OR)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(H)(OR), C≡CR 9 COOMe, COOEt, -(C1~C6)alkyl-C≡CR 10 CH2-OR 10 , and CH2-O-CH2-R 10 Selected from the group consisting of, R 9 These are respectively -H, -(C1~C6)alkyl, -(C6~C10)aryl, -5~10 member heteroaryl, -(C1~C6)alkyl-(C6~C10)aryl, -(C1~C6)alkyl-5~10 member heteroaryl, -(C3~C6)cycloalkyl, -(C1~C6)alkyl-(C3~C6)cycloalkyl, -C(O)-(C6~C10)aryl, -(C3~C6)cycloalkyl-(C6~C10)aryl, [ka] Independently selected from the group consisting of, R 9 Each of these has 0 to 5 R 11 It is independently replaced by, R 11Each occurrence is independently selected from the group consisting of -halogens, -CF3, -OH, -OCF3, OCHF2, -O-(C1~C6)alkyl, -O-CH2-(C3~C6)cycloalkyl, -CN, -SCH3-(C6~C10)aryl, -(C1~C6)alkyl, and -5~10 member heteroaryls. R 10 It is selected from the group consisting of -H, -(C1~C6)alkyl, -(C6~C10)aryl, -5~10 member heteroaryl, -(C3~C6)cycloalkyl, -CH2-(C3~C6)cycloalkyl, -CH2-(C6~C10)aryl, and -CH2-5~10 member heteroaryl. R 10 Each of these is independently substituted by 0 to 5 R' elements. R7 is selected from the group consisting of -(C1~C6)alkyl, -(C3~C6)cycloalkyl, -5~10 member heteroaryl, -(C6~C10)aryl, -(C6~C10)aryl-(C1~C6)alkyl, -5~10 member heteroaryl-(C1~C6)alkyl, and -5~10 member heteroaryl. Each R7 is independently substituted by 0 to 5 R' elements. R 6 Each of these is independently -H or -(C1~C6)alkyl, R 7 Each of these is independently -H or -(C1~C6)alkyl, R 8 Each of these is independently a -(C1~C6)alkyl, -(C3~C10)-cycloalkyl, (C6~C10)-aryl, or a 5-10 member heteroaryl, and R 8 Each instance is independently substituted by 0 to 5 R' elements. R 10 Each of these is independently a -(C3~C10)-cycloalkyl, a 3-10 member heterocyclyl-, a (C6~C10)-aryl, or a 5-10 member heteroaryl, and R 10 Each instance is independently substituted by 0 to 5 R' elements. R is as follows: H-, (C1~C12)-aliphatic-, (C3~C10)-cycloalkyl-, (C3~C10)-cycloalkenyl-, [(C3~C10)-cycloalkyl]-(C1~C12)-aliphatic-, [(C3~C10)-cycloalkenyl]-(C1~C12)-aliphatic-, [(C3~C10)-cycloalkyl]-O-(C1~C12)-aliphatic-, [(C3~C10)-cycloalkenyl]-O-(C1~C12)-aliphatic-, (C6~C10) -Ayl-, (C6~C10)-aryl-(C1~C12)aliphatic-, (C6~C10)-aryl-O-(C1~C12)aliphatic-, (C6~C10)-aryl-N(R”)-(C1~C12)aliphatic-, 3-10 member heterocyclyl- (3-10 member heterocyclyl)-(C1-C12) aliphatic- (3-10 member heterocyclyl)-O-(C1-C12) aliphatic-, (3-10 member heterocyclyl)-N(R”)-(C1-C12) aliphatic-, 5-10 member heteroaryl complex (5-10 member heteroaryl)-(C1-C12)-aliphatic- (5-10 member heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 member heteroaryl)-N(R”)-(C1-C12)-aliphatic- Independently selected from the group consisting of, The heterocyclyl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, S, SO, and SO2, and the heteroaryl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, and S. Each instance of R is independently substituted by 0 to 5 R' elements. Alternatively, if two R groups are bonded to the same atom, the two R groups may, together with the atom to which they are bonded, form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from the group consisting of N, NH, O, S, SO, and SO2, wherein the ring is optionally substituted with 0-5 R' atoms, and the ring is optionally condensed with (C6-C10)aryl, 5-10 membered heteroaryl, (C3-C10)cycloalkyl, or 3-10 membered heterocyclyl. Each instance of R' is independently selected from the group consisting of halogen, -R'', -OR'', oxo, -CH2OR'', -CH2NR''2, -C(O)N(R''2), -C(O)OR'', -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R''2. Each instance of R'' is independently selected from the group consisting of H, -(C1~C6)-alkyl, -(C1~C6)-aliphatic, (C3~C6)-cycloalkyl, 3~6 member heterocyclyl, 5~10 member heteroaryl-, (C6~C10)-aryl-, (5~10 member heteroaryl)-(C1~C6)-alkyl-, (C6~C10)-aryl-(C1~C6)-alkyl-, (5~10 member heteroaryl)-O-(C1~C6)-alkyl-, and (C6~C10)-aryl-O-(C1~C6)-alkyl-, and each instance of R'' is independently selected from the group consisting of halogen, -R o , -OR o , oxo, -CH2OR o -CH2N(R o )2, -C(O)N(R o )2, -C(O)OR o -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R o ) is independently substituted by 0 to 3 substituents selected from the group consisting of 2, R o Each instance is independently selected from the group consisting of -(C1~C6)-aliphatic, (C3~C6)-cycloalkyl, 3~6-membered heterocyclyl, 5~10-membered heteroaryl-, and (C6~C10)-aryl-). ii) Compounds of formula II: [ka] or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer (in the formula, m is between 0 and 3. R 1 These are halogen, -H, -(C1~C6)alkyl, -OH, -O((C1~C6)alkyl), -NO2, -CN, -CF3, -OCF3, -OCHF2, -OMe, and -C≡CR, respectively. 8 Independently selected from the group consisting of -CHF2, -CH2CF3, -(C6~C10)aryl, -(C1~C6)alkyl-(C6~C10)aryl, -5~10 member heteroaryl, -(C1~C6)alkyl-5~10 member heteroaryl, and -(C3~C6)cycloalkyl, R 1 It is independently substituted by 0 to 5 R' values. R 2 The following: -H, halogen, -OH, -(C1~C6)aliphatic, -O((C1~C6)alkyl), -C(O)O((C1~C6)alkyl), -C(O)NR2, -(CR2) 1~3 -OR, -(CR2) 1~3 -O(CR2) 1~3 -R, -OR 9 , -C(O)R 8 , -CH2R 8 -CH3, -CH2-OR 8 , (C6~C10) -Ayl-, (C6~C10)-aryl-(C1~C12)aliphatic-, (C6~C10)-aryl-O-(C1~C12)aliphatic-, (C6~C10)-aryl-N(R”)-(C1~C12)aliphatic-, (5-10 member heteroaryl)-(C1-C12) aliphatic- (5-10 member heteroaryl)-O-(C1-C12)aliphatic- (5-10 member heteroaryl)-N(R”)-(C1-C12)aliphatic- (3-10 member heterocyclyl)-(C1-C12) aliphatic- (3-10 member heterocyclyl)-O-(C1-C12)aliphatic-, and (3-10 member heterocyclyl)-N(R)-(C1-C12) aliphatic- Selected from the group consisting of, R 2 It is independently substituted by 0 to 5 R' values. R 3 The following: -(C1~C6) alkyl, -(C2~C6) alkenyl, -C≡CH, -C≡CR 9 -CN, halogen, -SO2((C6~C10)-aryl), -SO2((C1~C6)alkyl), -C(O)N((C1~C6)alkyl)2, -C(O)NH2, -C(O)O((C1~C6)alkyl), -C(O)((C1~C6)alkyl), -(C6~C10)aryl, 5~10 member heteroaryl, 5~10 member heterocyclyl, -(C1~C6)alkyl-C≡CR 10 , -CH2-OR 10 -CH2-O-CH2-R 10 , [ka] Selected from the group consisting of, Each of the 5-membered heterocyclic rings or heteroaryls is substituted with 0 to 4 R7 atoms. R 3 It is independently substituted by 0 to 5 R' values. R 4 and R 5 Each of these is independently selected from the group consisting of -H, halogen, -(C1~C6)alkyl, or -(C1~C6)alkyl-(C6~C10)aryl, and the (C6~C10)aryl is independently substituted with 0 to 5 halogens. R 6 It is selected from the group consisting of -H and -(C1~C6)alkyl groups, R7 is selected from the group consisting of -(C1~C6)alkyl, -(C3~C6)cycloalkyl, -5~10 member heteroaryl, -(C6~C10)aryl, (C6~C10)aryl-(C1~C6)alkyl-, -5~10 member heteroaryl-(C1~C6)alkyl, and -5~10 member heteroaryl, and each of R7 is independently substituted with 0 to 5 R' members. R 8 Each is independently selected from the group consisting of -H, -(C1~C6)alkyl, -(C3~C6)cycloalkyl, -(C1~C6)alkyl-(C3~C6)cycloalkyl, -(C1~C6)alkyl-(C6~C10)aryl, -(C6~C10)aryl, -5~10 member heteroaryl, and -(C1~C6)alkyl-5~10 member heteroaryl. R 8 Each of these is independently substituted with 0 to 5 of the following, excluding -H and -(C1~C6)alkyl groups: -halogen, -(C1~C6)alkyl, -CF3, -OCF3, or O-(C1~C6)alkyl. R 9 These include -H, -(C1~C6)alkyl, -(C6~C10)aryl, -5~10 member heteroaryl, -(C1~C6)alkyl-(C6~C10)aryl, -(C1~C6)alkyl-5~10 member heteroaryl, -(C3~C6)cycloalkyl, -(C1~C6)alkyl-(C3~C6)cycloalkyl, -C(O)-(C6~C10)aryl, and 5~10 member heterocycles. [ka] [ka] Selected from the group consisting of, R 9 Each of these has 0 to 5 R 11 It is independently replaced by, R 10It is selected from the group consisting of -H, halogen, -(C1~C6)alkyl, -(C6~C10)aryl, -5~10 member heteroaryl, -(C3~C6)cycloalkyl, -CH2-(C3~C6)cycloalkyl, -CH2-(C6~C10)aryl, and -CH2-5~10 member heteroaryl. R 10 Each of these is substituted by 0 to 5 R's, R 11 Each occurrence is independently selected from the group consisting of -halogens, -CN, SCH3, -CF3, -OH, -OCF3, OCHF2, -O(C1~C6)alkyl, -(C6~C10)aryl, -(C1~C6)alkyl, and -5~10 member heteroaryls. R is as follows: H-, (C1~C12)-aliphatic-, (C3~C10)-cycloalkyl-, (C3~C10)-cycloalkenyl-, [(C3~C10)-cycloalkyl]-(C1~C12)-aliphatic-, [(C3~C10)-cycloalkenyl]-(C1~C12)-aliphatic-, [(C3~C10)-cycloalkyl]-O-(C1~C12)-aliphatic-, [(C3~C10)-cycloalkenyl]-O-(C1~C12)-aliphatic-, (C6~C10) -Ayl-, (C6~C10)-aryl-(C1~C12)aliphatic-, (C6~C10)-aryl-O-(C1~C12)aliphatic-, (C6~C10)-aryl-N(R”)-(C1~C12)aliphatic-, 3-10 member heterocyclyl- (3-10 member heterocyclyl)-(C1-C12) aliphatic- (3-10 member heterocyclyl)-O-(C1-C12) aliphatic-, (3-10 member heterocyclyl)-N(R”)-(C1-C12) aliphatic-, 5-10 member heteroaryl complex (5-10 member heteroaryl)-(C1-C12)-aliphatic- (5-10 member heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 member heteroaryl)-N(R”)-(C1-C12)-aliphatic- Independently selected from the group consisting of, The heterocyclyl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, S, SO, and SO2, and the heteroaryl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, and S. Each instance of R is independently substituted by 0 to 5 R' elements. Alternatively, if two R groups are bonded to the same atom, the two R groups may, together with the atom to which they are bonded, form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from the group consisting of N, NH, O, S, SO, and SO2, wherein the ring is optionally substituted with 0-5 R' atoms, and the ring is optionally condensed with (C6-C10)aryl, 5-10 membered heteroaryl, (C3-C10)cycloalkyl, or 3-10 membered heterocyclyl. Each instance of R' is independently selected from the group consisting of halogen, -R'', -OR'', oxo, -CH2OR'', -CH2NR''2, -C(O)N(R''2), -C(O)OR'', -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R''2. Each instance of R'' is independently selected from the group consisting of H, -(C1~C6)-alkyl, -(C1~C6)-aliphatic, (C3~C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl-, (C6~C10)-aryl-, (5-10 member heteroaryl)-(C1~C6)-alkyl-, (C6~C10)-aryl-(C1~C6)-alkyl-, (5-10 member heteroaryl)-O-(C1~C6)-alkyl-, (C6~C10)-aryl-O-(C1~C6)-alkyl-, and (C6~C10)-aryl-O-(C1~C6)-alkyl-. Each instance of "R" is a halogen, -R o , -OR o , oxo, -CH2OR o -CH2N(R o )2, -C(O)N(R o )2, -C(O)OR o -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R o ) is independently substituted by 0 to 5 substituents selected from the group consisting of 2, R o Each instance of a compound is independently selected from the group consisting of -(C1~C6)-aliphatic, (C3~C6)-cycloalkyl, 3~6-membered heterocyclyl, 5~10-membered heteroaryl-, and (C6~C10)-aryl compounds, and iii) Compounds of formula IV: [ka] or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer (in the formula, m is between 0 and 3. R 1 These are halogen, -H, -(C1~C6)alkyl, and -C≡CR, respectively. 9 Independently selected from the group consisting of -OH, -O((C1~C6)alkyl), -NO2, -CN, -CF3, -OCF3, -CHF2, -CH2CF3, -(C6~C10)aryl, -(C1~C6)alkyl-(C6~C10)aryl, -5~10 member heteroaryl, -(C1~C6)alkyl-5~10 member heteroaryl, and -(C3~C6)cycloalkyl, R 1 It is independently substituted by 0 to 5 R' values. R 2 is -OR 8 , -SR 8 ,-(CH2) n Ure 8 ,-(CH2) n O(CH2) n R 8 ,-(CH2) p R 8 and -(CH2) nN(R)R 10 The group consists of n being an integer selected from 0 to 4, and p being an integer selected from 2 to 4. R 2 It is independently substituted by 0 to 5 R' values. R 3 These are as follows: -H, -CN, halogen, -(C1~C6) aliphatic, -CH=CR 9 -C≡CR 9 -SO2((C1~C6)alkyl), -C(O)N((C1~C6)alkyl)2), -C(O)NH((C1~C6)aliphatic), (C6~C10)-aryl-(C1~C12)aliphatic-, -C(O)((C1~C6)alkyl), -C(O)O((C1~C6)alkyl), 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heteroaryl, -CH2-OR 10 -CH2-O-CH2-R 10 , [ka] Independently selected from the group consisting of, Each of the 5-10 membered heterocycles or heteroaryls is substituted with 0-3 R7 atoms. R 3 It is independently substituted by 0 to 5 R' values. R 4 and R 5 These are independently selected from the group consisting of -H, halogens, and -(C1~C6)alkyl groups. R 6 It is selected from the group consisting of -H and -(C1~C6)alkyl groups, R7 is selected from the group consisting of -(C1~C6)alkyl, -(C3~C6)cycloalkyl, -5~10 member heteroaryl, -(C6~C10)aryl, -(C6~C10)aryl-(C1~C6)alkyl, -5~10 member heteroaryl-(C1~C6)alkyl, and -5~10 member heteroaryl. Each R7 is independently substituted by 0 to 5 R' elements. R8 These are independently selected from the group consisting of -H, -(C1~C6)alkyl, -(C3~C10)-cycloalkyl, (C6~C10)-aryl, or 5~10 membered heteroaryl, 5~10 membered heteroaryl-(C1~C6)alkyl-, -(C1~C6)alkyl-(C6~C10)aryl, and -(C1~C6)alkyl-(C3~C6)cycloalkyl, R 8 Each instance is independently substituted by 0 to 5 R' elements. R 9 -H, -(C1~C6)alkyl, -(C3~C6)cycloalkyl, -(C1~C6)alkyl-(C3~C6)cycloalkyl, -(C1~C6)alkyl-(C6~C10)aryl, -(C6~C10)aryl, -5~10 membered heteroaryl, -(C1~C6)alkyl-5~10 membered heteroaryl, 5~10 membered heterocycle, -C(O)-(C6~C10)aryl, [ka] Selected from the group consisting of, R 9 Each of these has 0 to 5 R 11 It is independently replaced by, R 10 It is selected from the group consisting of -H, -(C1~C6)alkyl, -(C3~C10)-cycloalkyl, 3~10-membered heterocyclyl-, (C6~C10)-aryl, 5~10-membered heteroaryl, -CH2-(C3~C6)cycloalkyl, -CH2-(C6~C10)aryl, and -CH2-5~10-membered heteroaryl. R 10 Each instance is independently substituted by 0 to 5 R' elements. R 11 Each occurrence is independently selected from the group consisting of -halogens, -CF3, -OCF3, OCF2H, -O-(C1~C6)alkyl, -(C6~C10)aryl, -(C1~C6)alkyl, -O-CH2-(C3~C6)cycloalkyl, and -5~10 membered heteroaryls. Each instance of R' is independently selected from the group consisting of halogen, -R'', -OR'', oxo, -CH2OR'', -CH2NR''2, -C(O)N(R''2), -C(O)OR'', -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R''2. Each instance of R'' is independently selected from the group consisting of H, -(C1~C6)-aliphatic, -(C1~C6)-alkyl, (C3~C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl-, (C6~C10)-aryl-, (5-10 member heteroaryl)-(C1~C6)-alkyl-, (C6~C10)-aryl-(C1~C6)-alkyl-, (5-10 member heteroaryl)-O-(C1~C6)-alkyl-, and (C6~C10)-aryl-O-(C1~C6)-alkyl-. Each instance of "R" is a halogen, -R o , -OR o , oxo, -CH2OR o -CH2N(R o )2, -C(O)N(R o )2, -C(O)OR o -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R o ) 0 to 5 R independently selected from the group consisting of 2 t It is independently substituted by R o Each instance is independently selected from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl-, and (C6-C10)-aryl-. It is selected from the group consisting of the following.

[0125] In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA AAn α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula II, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A α5 receptor agonists, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers are compounds of formula IV, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers.

[0126] In some embodiments, GABA A α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, selected from the group consisting of any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers. In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, is compound 1, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0127] The compounds of this disclosure may also be useful in the methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use of GABA. AThis includes α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, or crystalline forms of their isomers. Such crystalline forms include form A (polymorphic crystalline form) of compound 1, form B (polymorphic crystalline form) of compound 1, form C (solvated crystalline form) of compound 1, form E (polymorphic crystalline form) of compound 1, and form F (hydrated crystalline form) of compound 1. In some embodiments, the methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use of the Disclosure may include one or more crystalline forms selected from the group consisting of form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, and form F of compound 1. In some embodiments, the crystalline form is form A of compound 1. In some embodiments, the crystalline form is form B of compound 1. In some embodiments, the crystalline form is form C of compound 1. In some embodiments, the crystalline form is form E of compound 1. In some embodiments, the crystalline form is form F of compound 1.

[0128] The compounds of this disclosure may also be useful in the methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use of GABA. AThis includes α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, or crystalline forms of their isomers. Such crystalline forms include form A (polymorphic crystalline form) of compound 1, form B (polymorphic crystalline form) of compound 1, form C (solvated crystalline form) of compound 1, form E (polymorphic crystalline form) of compound 1, and form F (hydrated crystalline form) of compound 1. In some embodiments, the methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use of the Disclosure may include one or more crystalline forms selected from the group consisting of form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, and form F of compound 1. In some embodiments, the crystalline form is form A of compound 1. In some embodiments, the crystalline form is form B of compound 1. In some embodiments, the crystalline form is form C of compound 1. In some embodiments, the crystalline form is form E of compound 1. In some embodiments, the crystalline form is form F of compound 1. Such crystalline forms include compound 1, which has been found to exist in at least five crystalline polymorphic forms (i.e., form A, form B, form C, substance D, form E, and form F). In some embodiments, a method, use, combination, pharmaceutical composition, combination for use, or pharmaceutical composition for use may include a crystalline form of compound 1, the crystalline form corresponding to form A, form B, form C, substance D, form E, or form F, or any mixture thereof. In some embodiments, the crystalline form is the anhydrous crystalline form of compound 1, the crystalline form corresponding to form A, form B, substance D, or form E. In some embodiments, the crystalline form is the solvated crystalline form of compound 1, the crystalline form corresponding to form C or form F. In certain such embodiments, the solvated crystalline form of compound 1 is a methanolate or hydrate.

[0129] In some embodiments, the crystalline morphology is morphology A of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 29, having at least one peak at 3.0 and / or 21.0 degrees 2θ ± 0.2 degrees 2θ, and further including one or more additional peaks selected from 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4, and 27.1 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline morphology is morphology A of compound 1, characterized by single-crystal X-ray diffraction of the C2 / c space group. In some embodiments, the crystalline morphology is parameter: a = 58.1415 (14) Å, b = 4.03974 (8) Å, c = 17.1204 (3) Å, α = 90°, β = 90.261 (2)°, γ = 90°, V = 4021.15 (14) Å 3 This is morphology A of compound 1, characterized by single-crystal X-ray diffraction of a unit cell having the following characteristics: In some embodiments, the crystalline morphology is morphology A of compound 1, characterized by a differential scanning calorimetry (DSC) curve substantially shown in Figure 27B. In some embodiments, the crystalline morphology is morphology A of compound 1, characterized by a differential scanning calorimetry (DSC) curve having an exothermic onset temperature of approximately 207°C. In some embodiments, the crystalline morphology is (a) an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 29, (b) single-crystal X-ray diffraction of the C2 / c space group, (c) parameters: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å 3 Form A of compound 1 is characterized by two or more of the following: (d) single-crystal X-ray diffraction of a unit cell having (e) a differential scanning calorimetry (DSC) curve substantially shown in Figure 27B, and (e) a differential scanning calorimetry (DSC) curve having an exothermic onset temperature of approximately 207°C.

[0130] In some embodiments, the crystalline form is Form B of Compound 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 34, having at least one peak selected from 13.0 and / or 15.3 degrees 2θ ± 0.2 degrees 2θ, and further including one or more of further peaks selected from 7.0, 9.3, 10.2, 10.4, 12.5, 13.6, 14.0, 22.0, 23.0, 23.6, and 27.3 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline form is Form B of Compound 1, characterized by single-crystal X-ray diffraction of a monoclinic unit cell. In some embodiments, the crystalline form is approximately 497 Å 3 This is form B of compound 1, characterized by the formula unit volume obtained by single-crystal X-ray diffraction. In some embodiments, the crystalline form is form B of compound 1, characterized by a differential scanning calorimetry (DSC) curve with an exothermic onset temperature of approximately 190°C. In some embodiments, the crystalline form is (a) an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 34, and (b) approximately 497 Å. 3 Form B of compound 1 is characterized by two or more of the following: (c) a single-crystal X-ray diffraction curve of the formula per unit volume, and (c) a differential scanning calorimetry (DSC) curve having an exothermic onset temperature of approximately 190°C.

[0131] In some embodiments, the crystalline form is morphology C of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 41, having at least one peak selected from 8.5 and / or 18.9 degrees 2θ ± 0.2 degrees 2θ, and further including one or more of further peaks selected from 7.1, 9.4, 10.3, 12.3, 12.5, 14.2, 20.7, 22.1, 23.2, 23.7, 24.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline form is morphology C of compound 1, characterized by single-crystal X-ray diffraction of a monoclinic unit cell. In some embodiments, the crystalline form is approximately 544 Å 3This is form C of compound 1, characterized by the formula unit volume obtained by single-crystal X-ray diffraction. In some embodiments, the crystalline form is form C of compound 1, characterized by the differential scanning calorimetry (DSC) curve substantially shown in Figure 42B. In some embodiments, the crystalline form is form C of compound 1, characterized by the differential scanning calorimetry (DSC) curve having an exothermic onset temperature of about 190°C. In some embodiments, the crystalline form is (a) an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 41, (b) single-crystal X-ray diffraction of a monoclinic unit cell, and (c) about 544 Å. 3 Form C of compound 1 is characterized by two or more of the following: (d) a single-crystal X-ray diffraction formula per unit volume, (e) a differential scanning calorimetry (DSC) curve substantially shown in Figure 42B, and (f) a differential scanning calorimetry (DSC) curve having an exothermic onset temperature of approximately 190°C.

[0132] In some embodiments, the crystalline morphology is morphology E of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 35, having at least one peak selected from 11.4, 18.1, and / or 21.6° 2θ ± 0.2° 2θ, and further including one or more of further peaks selected from 7.2, 22.0, 23.0, 24.2, 25.0, and 26.6° 2θ ± 0.2° 2θ. In some embodiments, the crystalline morphology is morphology E of compound 1, characterized by single-crystal X-ray diffraction of the P21 / n space group. In some embodiments, the crystalline form is as follows: parameters: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3This is morphology E of compound 1, characterized by single-crystal X-ray diffraction of a unit cell having the following characteristics: In some embodiments, the crystalline morphology is morphology E of compound 1, characterized by a differential scanning calorimetry (DSC) curve substantially shown in Figure 36B. In some embodiments, the crystalline morphology is morphology E of compound 1, characterized by a differential scanning calorimetry (DSC) curve having an exothermic onset temperature of approximately 201°C. In some embodiments, the crystalline morphology is (a) an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 35, (b) single-crystal X-ray diffraction of the P21 / n space group, (c) parameters: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3 Form E of compound 1 is characterized by two or more of the following: (d) single-crystal X-ray diffraction of a unit cell having (e) a differential scanning calorimetry (DSC) curve substantially shown in Figure 36B, and (e) a differential scanning calorimetry (DSC) curve having an exothermic onset temperature of approximately 201°C.

[0133] In some embodiments, the crystalline form is morphology F of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially shown in Figure 37, having at least one peak selected from 9.9, 11.9, 17.3, 19.4, and / or 25.7 degrees 2θ ± 0.2 degrees 2θ, and further including one or more of further peaks selected from 9.7, 12.1, 20.8, 23.2, 23.7, 24.2, 25.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline form is morphology F of compound 1, characterized by single-crystal X-ray diffraction of a triclinic unit cell. In some embodiments, the crystalline form is approximately 511 Å 3The crystalline form of compound 1 is characterized by the formula unit volume obtained by single-crystal X-ray diffraction. In some embodiments, the crystalline form of compound 1 is characterized by a differential scanning calorimetry (DSC) curve having an exothermic temperature greater than approximately 120°C. In some embodiments, the crystalline form is (a) an X-ray powder diffraction (XRPD) pattern substantially described in Figure 37, (b) single-crystal X-ray diffraction of a triclinic unit cell, and (c) approximately 511 Å. 3 Form F of compound 1 is characterized by two or more of the following: (d) a single-crystal X-ray diffraction curve of the formula per unit volume, and (d) a differential scanning calorimetry (DSC) curve having an exothermic temperature greater than approximately 120°C.

[0134] This disclosure includes pharmaceutically acceptable salts of the compounds described herein. Typical "pharmaceutically acceptable salts" include, but are not limited to, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bicarbonate, tartrate, borate, bromide, butyrate, calcium, calcium edetate, cansylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, gluceptinate, gluconate, glutamate, glycolyl arsanylate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, and isethionic acid. This includes sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucoate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-meten-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate.

[0135] Furthermore, "pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "pharmaceutically acceptable acid addition salts" retain the biological effects and properties of free bases and are desirable both biologically and otherwise, and include inorganic acids (but are not limited to, hydrohalic acids, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (but are not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonate, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucosulfate, etc.) This can refer to salts formed from heptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydroxyacetic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0136] "Pharmacologically acceptable base addition salts" can refer to salts that retain the biological effects and properties of a free acid and are desirable biologically or otherwise. These salts can be prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, alkali and alkaline earth metal salts, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, N-methyl-D-glucamine; primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; basic ion exchange resins; isopropylamine; trimethylamine; diethylamine; triethylamine; tripropylamine; diethanolamine; ethanolamine; deanol; 2-dimethylaminoethanol; 2-diethylaminoethanol; dicyclohexylamine; amino acids; lysine; arginine; histidine; caffeine; procaine; hydravamin; choline; betaine; benetamine; benzathine; ethylenediamine; glucosamine; methylglucamine; theobromine; triethanolamine; tromethamine; purines; piperazine; piperidine; N-ethylpiperidine; and salts of polyamine resins.

[0137] Conversely, the salt form can be converted back to the free form by treatment with a suitable base or acid.

[0138] SV2A inhibitors as described herein, or pharmaceutically acceptable salts thereof, polymorphs or isomers thereof, or GABA as described herein A α5 receptor agonists, or pharmaceutically acceptable salts thereof, their polymorphs or isomers, may also be in the form of solvates, which are included within the scope of this disclosure. Such solvates include, for example, hydrates, alkoxides, etc. See, for example, WO01 / 062726.

[0139] As used herein, the term “hydrate” refers to a combination of water and a compound, in which case the water retains its molecular state as water and is either absorbed, adsorbed, or contained within the crystal lattice of the compound.

[0140] As used herein, the term “polymorph” refers to different crystalline forms and molecular forms of other solid states (including pseudopolymorphs) of the same compound, such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water). Different crystalline polymorphs have different crystalline structures due to different molecular packing within their lattices. This results in different crystal symmetries and / or unit cell parameters, which directly affect their physical properties, such as the X-ray diffraction characteristics 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 solid states containing different polymorphs, or more than one polymorph, in a reproducible and reliable manner. Crystallographic polymorphisms are of interest to the pharmaceutical industry and, in particular, to those involved in the development of suitable dosage forms. If the polymorphisms are not kept constant during clinical or stability studies, the very dosage form used or studied may not be comparable from lot to lot. When a compound is used in clinical studies or in products, the presence of impurities may lead to undesirable toxicological effects; therefore, it is desirable to have a process for producing the compound in high purity with selected polymorphic forms. Certain polymorphic forms may exhibit improved thermodynamic stability or may be easier to produce in large quantities with high purity, and are therefore more suitable for inclusion in pharmaceutical formulations. Certain polymorphic forms may exhibit other beneficial physical properties, such as no tendency to absorb moisture, improved solubility, and improved dissolution rates due to different lattice energies.

[0141] This application intends all isomers of the compounds disclosed herein. As used herein, “isomer” includes optical isomers (stereoisomers, e.g., enantiomers and diastereoisomers), Z (zusammen) or E (entgegen) isomers, and tautomers. Many of the compounds useful in the methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use of this disclosure have at least one stereogenic center in their structure. This stereogenic center may exist in an R or S configuration, and the notation R and S is 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 compounds herein, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO01 / 062726. Furthermore, certain compounds containing an alkenyl group may exist as Z (zusammen) or E (entgegen) isomers. In each case, the disclosure includes mixtures of both and distinct individual isomers. Multiple substituents on the piperidinyl or azepanyl ring may also be in a cis or trans relationship with respect to the plane of the piperidinyl or azepanyl ring. Some of the compounds may also exist as tautomers. Such forms, though not expressly shown, are intended to be included within the scope of the disclosure. When referring to a compound(s) or compound(s) in relation to the methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use of the disclosure, it is intended that the compound be encompassed in each of its possible isomers and mixtures thereof unless a specific isomer is specifically mentioned. See, for example, WO01 / 062726.

[0142] The term “aliphatic,” as used herein, refers to linear or branched alkyl, alkenyl, or alkynyl groups. Embodiments of alkenyl or alkynyl groups are understood to require at least two carbon atoms in the aliphatic chain. Aliphatic groups typically contain one to twelve carbon atoms, such as one to four carbon atoms.

[0143] The term "aryl," as used herein, refers to monocyclic or bicyclic carbocyclic aromatic ring systems. As used herein, aryl includes (C6-C12)-aryl-. For example, aryl can be a C6-C10 monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system. In some embodiments, aryl 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, e.g., naphthyl, and systems where only one of the two rings is aromatic, e.g., tetralin.

[0144] The term “heterocyclic” as used herein refers to a monocyclic or bicyclic non-aromatic ring system having 1 to 4 heteroatoms or heteroatomic groups selected from O, N, NH, S, SO, or SO2 in a chemically stable configuration. Heterocyclics include 3 to 12-membered heterocyclyls having 1 to 4 heteroatoms independently selected from O, N, NH, S, SO, or SO2. For example, a heterocyclic can be a 3 to 10-membered monocyclic or 8 to 12-membered bicyclic non-aromatic ring system having 1 to 4 heteroatoms or heteroatomic groups selected from O, N, NH, S, SO, or SO2 in a chemically stable configuration. In some embodiments, a heterocyclic can be a 3 to 10-membered heterocyclyl having 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 rings may contain the heteroatom or heteroatomic group. In another embodiment of the bicyclic "heterocyclyl," one of the two rings may be aromatic. In yet another embodiment of the heterocyclic ring system, the non-aromatic heterocyclic ring may be fused with an aromatic carbon ring as needed.

[0145] Examples of heterocyclic rings include 3-1H-benzimidazole-2-one, 3-(1-alkyl)-benzimidazole-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-piperizinyl This includes nyl, 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-dihydroimidazole-2-one.

[0146] The term “heteroaryl,” as used herein, can refer 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 configuration. Heteroaryls, as used herein, include 5 to 12-membered heteroaryls having 1 to 4 heteroatoms independently selected from O, N, NH, or S. In some embodiments, heteroaryls may be 5 to 10-membered heteroaryls having 1 to 4 heteroatoms independently selected from O, N, NH, or S. For example, a heteroaryl may 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 one or both rings in a chemically stable configuration. In such bicyclic aromatic ring systems of “heteroaryls,” - Both rings are aromatic, and - One or both rings may contain the heteroatom or heteroatomic group.

[0147] 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-pyrimidinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-trizolyl). This includes azolyl, 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, prinyl, 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).

[0148] The term "cycloalkyl or cycloalkenyl" can refer to a non-aromatic, monocyclic carbocyclic system, or a condensed or cross-linked bicyclic carbocyclic system. For example, as used herein, a cycloalkyl or cycloalkenyl may be a non-aromatic, C3-C10 monocyclic carbocyclic system, or a condensed or cross-linked C8-C12 bicyclic carbocyclic system. A cycloalkenyl ring has one or more unsaturated units. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl, and dekalinyl.

[0149] The term "heteroaralkyl" can refer to an alkyl group in which a heteroaryl group is substituted with an alkyl hydrogen atom. For example, the alkyl group can be any linear hydrocarbon and may 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 is not limited to the following: 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-pyrimidinyl), 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 It may be substituted with any heteroaryl group, including triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, prinyl, 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).

[0150] If a substitution is described without indicating an atom, and such a substitution is bonded to a substituent via this atom, the substituent may be bonded via any suitable atom in such a substitution. 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 substitutionable heteroaryl ring (i.e., atoms bonded to one or more hydrogen atoms).

[0151] Where a bond to a substituent is described as intersecting a bond linking two atoms in a ring, such substituent may be bonded to any of the substituted ring-forming atoms in that ring (i.e., an atom bonded to one or more hydrogen atoms), unless otherwise specified or particularly implied in the context. For example, if the R group is defined as pyridine, and the pyridine is as follows: [ka] As illustrated, the pyridine ring may be bonded to the benzodiazepine derivative via any one of the ring carbon atoms within the pyridine ring. Alternatively, the R group may be defined as a pyrazole, and the pyrazole may be: [ka] When illustrated as shown, this pyrazole ring is any one of the ring carbon atoms within the pyrazole ring or sp 3 The N atom may be bonded to a benzodiazepine derivative.

[0152] The designation of carbon atoms, as used herein, may have the given integer and any intervening integer. For example, the number of carbon atoms in (C1-C4) alkyl groups is 1, 2, 3, or 4. It should be understood that these designations refer to the total number of atoms in the appropriate group. For example, in (C3-C10) heterocyclils, the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10. Pharmaceutical compositions and combinations of the present disclosure

[0153] In one embodiment, the Disclosure relates to an SV2A inhibitor (as used through any one or more of the SV2A inhibitors of the Disclosure; for example, in some embodiments the SV2A inhibitor is levetiracetam, in some embodiments the SV2A inhibitor is brivalacetam, and in some embodiments the SV2A inhibitor is celetracetam), or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph of GABA A α5 receptor agonist (GABA as disclosed herein) A The present disclosure provides pharmaceutical compositions and combinations that, as used through any one or more α5 receptor agonists, for example, in some embodiments, include one of the compounds of formula I, one of the compounds of formula II, or one of the compounds of formula IV; one of the specific compounds 1 to 740, one of the compounds 1 to 114; or one of the forms A, B, C, E, or F of compound 1) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In particular, in some embodiments, the pharmaceutical compositions and combinations of the present disclosure include levetiracetam and the specific GABAs mentioned above. A One of the α5 receptor agonists, brivalacetam, and the specific GABA mentioned earlier. A One of the α5 receptor agonists, as well as celetracetam and certain GABAs mentioned earlier. A It includes one of the α5 receptor agonists. For example, in some embodiments of this disclosure, the pharmaceutical composition or combination thereof may include levetiracetam and compound 1, brivalacetam and compound 1, brivalacetam and compound 17, and so on.

[0154] This disclosure provides pharmaceutical compositions comprising compounds disclosed herein. In some embodiments, the pharmaceutical compositions of this disclosure comprise SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the pharmaceutical compositions of this disclosure comprise GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the pharmaceutical compositions of the present disclosure include SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or both pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the pharmaceutical compositions of the present disclosure include levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the pharmaceutical compositions of the present disclosure include levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA AThe present invention includes α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the pharmaceutical composition of the present invention includes brivalacetam, or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the pharmaceutical composition of the present invention includes brivalacetam, or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, and GABA A The present invention includes α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the pharmaceutical composition of the present invention includes celetracetam, or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the pharmaceutical composition of the present invention includes celetracetam, or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, and GABA A This includes α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, GABA AThe α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is selected from the group consisting of the compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer; the compound of formula II, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer; and the compound of formula IV, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula II, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA AAn α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula IV, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is selected from compounds 1 to 114, or one or more of any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers. In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is compound 1, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the pharmaceutical composition of the present disclosure may comprise one or more crystalline forms selected from the group consisting of one or more of Form A, Form B, Form C, Form E, and Form F of Compound 1. In some embodiments, the crystalline form is Form A of Compound 1.

[0155] This disclosure also provides combinations comprising the compounds and pharmaceutical compositions disclosed herein. In some embodiments, the combinations of the disclosure comprise SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the combinations of the disclosure comprise GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the combinations of the present disclosure include SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA AThis includes α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In certain such embodiments, this includes SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are packaged together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 as described above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are packaged separately. The combinations of the present disclosure also include SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A The formulations include α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, together in one formulation or in separate formulations.

[0156] In some embodiments, the combinations of the Disclosure include levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the combinations of the Disclosure include levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and GABA A The present invention includes α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the present invention includes brivalacetam, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the present invention includes brivalacetam, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A The present invention includes α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the present invention includes celetracetam, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the present invention includes celetracetam, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA AThis includes α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, GABA A The α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is selected from the group consisting of the compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer; the compound of formula II, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer; and the compound of formula IV, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula II, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, GABA AAn α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is a compound of formula IV, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is selected from one of compounds 1 to 114, or from the group consisting of any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers. In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is compound 1, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the combination of the present disclosure may include one or more crystalline forms selected from the group consisting of form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, and form F of compound 1. In some embodiments, the crystalline form is form A of compound 1.

[0157] In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are all made together in a single formulation. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are distinct. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are packaged together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers shall be packaged separately.

[0158] In some embodiments, the combinations of the Disclosure include a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the combinations of the Disclosure include GABA AThe present invention includes a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the combinations of the present disclosure include an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA A The present invention includes a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A, form B, form C, form E, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the combination of the present invention comprises a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer (i.e., the first pharmaceutical composition), and GABA A The present invention includes a pharmaceutical composition (i.e., a second pharmaceutical composition) comprising an α5 receptor agonist (e.g., a compound of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In certain such embodiments, the first and second pharmaceutical compositions are formulated separately. In certain such embodiments, the first and second pharmaceutical compositions are packaged together. In some embodiments, the first and second pharmaceutical compositions are packaged separately. In some embodiments, the first and second pharmaceutical compositions are formulated together.

[0159] In some embodiments, the combinations of the Disclosure include a pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the combinations of the Disclosure include levetiracetam or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and GABA A The present invention includes pharmaceutical compositions comprising α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the combinations of the present invention include a pharmaceutical composition comprising levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorphs, or its isomers (i.e., the first pharmaceutical composition), and GABA A The present invention includes a pharmaceutical composition (i.e., a second pharmaceutical composition) comprising an α5 receptor agonist (e.g., a compound of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the combination of the present invention includes a pharmaceutical composition comprising brivalacetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA AThe present invention includes pharmaceutical compositions comprising α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the combinations of the present invention include a pharmaceutical composition comprising brivalacetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorphs, or its isomers (i.e., the first pharmaceutical composition), and GABA A The present invention includes a pharmaceutical composition (i.e., a second pharmaceutical composition) comprising an α5 receptor agonist (e.g., a compound of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the present invention includes a pharmaceutical composition comprising celetracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the present invention includes celetracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA A The present invention includes pharmaceutical compositions comprising α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the combinations of the present invention include a pharmaceutical composition comprising celetracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorphs, or its isomers (i.e., the first pharmaceutical composition), and GABA AThe first and second pharmaceutical compositions include α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers (i.e., the second pharmaceutical composition). In some embodiments, the first and second pharmaceutical compositions are formulated separately. In certain such embodiments, the first and second pharmaceutical compositions are packaged together. In some embodiments, the first and second pharmaceutical compositions are packaged separately. In some embodiments, the first and second pharmaceutical compositions are formulated together.

[0160] In some embodiments, a pharmaceutical composition or combination (or its components, e.g., an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam)), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and / or GABA) is used. A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) are in solid form. In some embodiments, the pharmaceutical composition or combination (or its components) is in liquid form. In some embodiments, the pharmaceutical composition or combination (or its components) is in aqueous solution. In some embodiments, the pharmaceutical composition or combination (or its components) is in suspension form. In some embodiments, the pharmaceutical composition or combination (or its components) is in unit dosage form. In some embodiments, the pharmaceutical composition or combination (or its components) is in capsule or tablet form. In some embodiments, the pharmaceutical composition or combination (or its components) is intended for oral administration.

[0161] The “components” of the combinations of this disclosure include SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and / or GABA. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 as described above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. The “components” of the combinations of the present disclosure may also include SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and / or GABA A Pharmaceutical compositions may include α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 as described above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers. The “components” of the combinations of the present disclosure may further include SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and / or GABA A This may include α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or other agents such as pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, which work to enhance and / or complement the efficacy of these.

[0162] In some embodiments, an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or ceretracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is GABA. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together with GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are formulated into monophasic compositions. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are formulated together. A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers may exist in a single unit dosage form (e.g., combined into a single capsule, tablet, powder, or liquid).

[0163] The pharmaceutical compositions or combinations described herein include one or more SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers (e.g., two, three, four, or five SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers), and / or one or more GABA. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof (e.g., 2, 3, 4, or 5 GABAs) A The pharmaceutically acceptable SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) may be included. In some embodiments, the pharmaceutically acceptable SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers (e.g., two, three, four, or five SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) may be included. In some embodiments, the pharmaceutically acceptable SV2A inhibitors (e.g., two, three, four, or five SV2A inhibitors), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) may be included. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof (e.g., 2, 3, 4, or 5 GABAs) AThe pharmaceutically acceptable agonists include α5 receptor agonists, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, the pharmaceutical compositions or combinations described herein include one or more SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers (e.g., two, three, four, or five SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers), and one or more GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof (e.g., 2, 3, 4, or 5 GABAs) A The pharmaceutically acceptable α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the pharmaceutical compositions or combinations described herein include one or more SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof (e.g., two, three, four, or five SV2A inhibitors, or pharmaceutically acceptable salts thereof, their hydrate, its solvate, its polymorph or isomer thereof), and one GABA. Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the pharmaceutical compositions or combinations described herein include one SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, and one or more GABAs. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof (e.g., 2, 3, 4, or 5 GABAs) A The pharmacopoeia comprises an α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the pharmaceutical compositions or combinations described herein contain only one SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and only one GABA. A This includes α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740 and 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof.

[0164] In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated separately. In certain such embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are packaged together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are packaged separately. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are also included. Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are formulated. A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof may exist in separate unit dosage forms.

[0165] The pharmaceutical compositions and combinations described herein include SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and / or GABA. AThe pharmaceutical compositions and combinations may further include other agents that work to enhance and / or complement the efficacy of α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. The pharmaceutical compositions and combinations may also include further agents known to be useful in treating cognitive impairment. Examples of such agents include antipsychotics, memantine, and acetylcholinesterase inhibitors. These further agents may include SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and / or GABA A The α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof may be a monophasic composition. In some embodiments, these further agents may be SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and / or GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or their pharmaceutically acceptable salts, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof may be formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0166] In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include one or more additional agents (e.g., antipsychotics, memantine, and acetylcholinesterase inhibitors). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include two or more additional agents (e.g., antipsychotics, memantine, and acetylcholinesterase inhibitors). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include three or more additional agents (e.g., antipsychotics, memantine, and acetylcholinesterase inhibitors). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include four or more additional agents (e.g., antipsychotics, memantine, and acetylcholinesterase inhibitors). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include five or more additional agents (e.g., antipsychotics, memantine, and acetylcholinesterase inhibitors). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include one additional agent (e.g., antipsychotics, memantine, and acetylcholinesterase inhibitors). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include two additional agents (e.g., an antipsychotic, memantine, and an acetylcholinesterase inhibitor). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include three additional agents (e.g., an antipsychotic, memantine, and an acetylcholinesterase inhibitor). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include four additional agents (e.g., an antipsychotic, memantine, and an acetylcholinesterase inhibitor). In some embodiments, the pharmaceutical compositions and combinations of the Disclosure include five additional agents (e.g., an antipsychotic, memantine, and an acetylcholinesterase inhibitor).

[0167] "Antipsychotic drugs," "antipsychotic agents," "antipsychotic medications," or "antipsychotic compounds" refer 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 (3) This can refer to drugs selected from ibuallosteric modulators (PAMs), M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA / kainate receptor antagonists, ampakine (CX-516), glutathione prodrugs, noradrenergic 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), serotonin 2C agonists, and / or (3) drugs useful for treating one or more signs or symptoms of schizophrenia or bipolar disorder (especially mania).

[0168] As used herein, “typical antipsychotics” can refer to conventional antipsychotics that produce antipsychotic effects as well as motor-related adverse effects associated with disorders of the dopamine system in the substantia nigra and striatum. These extrapyramidal side effects (EPS) include parkinsonism, zodiac immobility, tardive dyskinesia, and dystonia. See Baldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, 2001, pp. 485–520.

[0169] As used herein, “atypical antipsychotics” refers to antipsychotics that produce antipsychotic effects with little or no EPS, and these include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone, and ziprasidone. “Atypical” antipsychotics differ from conventional antipsychotics in their pharmacological profile. Conventional antipsychotics are primarily characterized by blockade of D2 dopamine receptors, while atypical antipsychotics are characterized by blockade of 5HT a and 5HT c Atypical antipsychotics exhibit antagonistic activity and varying degrees of receptor affinity to multiple receptors, including serotonin receptors. Often referred to as serotonin / dopamine antagonists, their higher affinity for 5HT2 receptors than for D2 receptors reflects the intriguing hypothesis that this underlies the action of “atypical” or “second-generation” antipsychotics. However, atypical antipsychotics often cause side effects, including, but are not limited to, weight gain, diabetes (e.g., type II diabetes), hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects, and cataracts. Therefore, atypical antipsychotics are not a homogeneous class, considering the differences in both clinical symptom relief and the potential for inducing side effects such as those listed above. Furthermore, the common side effects of atypical antipsychotics described above often limit the dosage of antipsychotics that can be used for these medications.

[0170] Memantine is 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.1 3,7It is chemically known as decane-1-amine and is a moderately affinity, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Trademark names for 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, including compounds structurally or chemically similar to memantine, are also useful in this disclosure. Such derivatives or analogs of memantine include, but are not limited to, compounds disclosed in U.S. Patent Nos. 3,391,142; 4,122,193; 4,273,774 and 5,061,703; U.S. Patent Publications US20040087658, US20050113458, US20060205822, US20090081259, US20090124659 and US20100227852; European Patent Publication EP2260839A2; European Patent EP1682109B1; and PCT Publication WO2005079779, all of which are incorporated herein by reference. Memantine, as used in this disclosure, includes memantine and its derivatives and analogs, as well as their hydrates, polymorphs, prodrugs, salts, and solvates. Memantine, as used herein, also includes compositions comprising memantine or its derivatives or analogs, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs, in which case the composition optionally further comprises at least one further therapeutic agent (such as a therapeutic agent useful for treating CNS disorders or associated cognitive impairments). In some embodiments, a memantine composition suitable for use in this disclosure comprises memantine and a second therapeutic agent, donepezil (trade name Aricept).

[0171] As used herein, “acetylcholinesterase inhibitor” or “AChE-I” refers to a drug that inhibits the ability of the cholinesterase enzyme to break down the neurotransmitter acetylcholine, thereby increasing the concentration and duration of acetylcholine, primarily at brain synapses or neuromuscular junctions. Suitable AChE-Is for use in this application may include, for example, the subcategories of (i) reversible non-competitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors, and (iii) quasi-irreversible inhibitors. Donepezil is an example of an AChE-I.

[0172] In some embodiments of this disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated with pharmaceutically acceptable carriers. These pharmaceutical compositions or combinations (or their components, e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and / or GABA) APharmacovigilant carriers that may be used in α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or their pharmaceutically acceptable salts, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof) include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (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 carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions or combinations (or components thereof) of this disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol) 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 maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0173] In some embodiments, no carrier is used. For example, an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and GABA Aα5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers may be administered alone or as components of pharmaceutical compositions or combinations. SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof may be formulated for use in pharmaceuticals and for administration in any convenient manner.

[0174] The pharmaceutical compositions or combinations (or their components) of the present disclosure (e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and / or GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 as described above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutical compositions or combinations (or their components) comprising pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof) may be formulated, in particular, for administration by any suitable route described herein and known in the art. Pharmaceutical compositions or combinations (or their components) of this disclosure may be formulated, in particular, for topical, systemic, and local administration. Pharmaceutical compositions or combinations (or their components) of the present disclosure for parenteral administration (e.g., subcutaneously, intravenously, arterially, intradermally, intramuscularly, intraperitoneally) or intraspinal or intracerebral administration include aqueous and nonaqueous sterile solutions, dispersions, suspensions or emulsions for injection, and sterile powders that are reconstituted into sterile solutions or dispersions for injection before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes to make the pharmaceutical composition or combination (or its components) isotonic with the blood of the intended recipient, or suspending agents or thickeners. When administered parenterally, the compounds of the present disclosure (e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof, and / or GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) may be in a physiologically acceptable form free of pyrogens. The technologies and formulations can generally be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.

[0175] Pharmaceutical compositions or combinations (or their components) of the present disclosure for oral and oral delivery (including sublingual and intraoral buccal administration, e.g., Danckwerts et al., and oral administration) include, but are not limited to, bioadhesive polymers, tablets, patches, thin films, liquids, and semi-solids (see, e.g., Smart et al.).

[0176] The pharmaceutical compositions or combinations (or their components) of the present disclosure (e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and / or GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutical compositions or combinations (or their components) comprising pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof) may be in solid dosage form (such as capsules, tablets, medicinal sugar-coated tablets, pills, lozenges, cachets, powders, troches, wafers, or granules). For solid dosage forms for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), one or more of the compounds of this disclosure (e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and / or GABA) Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) may be mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: (1) fillers or extenders (such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid), (2) binders (e.g., carboxymethylcellulose, alginate) (1) Similar types of solid pharmaceutical compositions or combinations (or their components) can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol.

[0177] The pharmaceutical compositions or combinations (or their components) of the present disclosure (e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and / or GABA Aα5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutical compositions or combinations (or components thereof) comprising pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, may also be aqueous or non-aqueous liquid dosage forms, including liquids, emulsions, microemulsions, suspensions, syrups, lozenges, or elixirs. In some embodiments, the pharmaceutical compositions or combinations (or components thereof) of the Disclosure are aqueous solutions. In some embodiments, the pharmaceutical compositions or combinations (or components thereof) of the Disclosure are suspensions. Where appropriate, the pharmaceutical compositions or combinations (or their components) of the present disclosure may be prepared by coating (such as enteric coating) or by methods well known in the art, one or more of the compounds of the present disclosure (e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers, and / or GABA) Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) may be formulated to provide sustained release (e.g., controlled release, long-term release, sustained release, delayed release, or slow release). Liquid dosage forms may include inert diluents commonly used in the art (such as water or other solvents), solubilizers and emulsifiers (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, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan), as well as mixtures thereof. Oral pharmaceutical compositions or combinations (or their components) may also include adjuvants (such as humectants, emulsifiers and suspending agents, sweeteners, flavorings, colorants, fragrances, and preservatives) in addition to inert diluents. The suspension is a compound of the Disclosure (e.g., an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam)), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and / or GABA A In addition to α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers), the materials may also include suspending agents (such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, as well as mixtures thereof.

[0178] Pharmaceutical compositions or combinations (or their components) of the present disclosure for respiratory delivery (lung and nasal delivery) include, but are not limited to, a variety of pressurized metered-dose inhalers, dry powder inhalers, nebulizers, aqueous mist inhalers, drops, solutions, suspensions, sprays, powders, gels, ointments, and special systems, such as liposomes and microspheres (see, for example, Owens et al., "Alternative Routes of Insulin Delivery" and Martini et al.). Pharmaceutical compositions or combinations (or their components) of the present disclosure for transdermal delivery include, but are not limited to, colloids, patches, and microemulsions.

[0179] Other suitable dosage forms for the pharmaceutical compositions or combinations (or their components) of this disclosure include depot injection formulations, suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, devices, formulations for ocular administration, and the like.

[0180] The pharmaceutical compositions or combinations (or their components) of this disclosure may also include adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenol sorbic acid. It is also desirable to include isotonic agents such as sugars and sodium chloride in the pharmaceutical composition or combination (or its components). Furthermore, the inclusion of absorption-delaying agents such as aluminum monostearate and gelatin can lead to prolonged absorption of the injectable pharmaceutical form.

[0181] The pharmaceutical compositions or combinations (or their components) of this disclosure can be prepared by methods well known in the field of pharmaceuticals; see, for example, Goodman et al., 2001, Ansel, et al., 2004, Stoklosa et al., 2001, and Bustamante, et al., 1993.

[0182] In certain embodiments of the present disclosure, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises an amount of 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to 50 mg, or 3 mg to 60 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, contains an amount of 0.05 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 7 mg to 350 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, contains an amount of 0.07 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.In some embodiments, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 7 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 50 mg to 350 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 190 mg to 220 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 190 mg to 240 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises about 220 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.In some embodiments, the pharmaceutical composition is GABA. A The present invention further includes α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof.

[0183] In certain embodiments of this disclosure, a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, is available in doses of 0.05 mg to 35 mg, 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 15 mg, 5 mg to 30 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to This includes 50 mg, or amounts of 0.07 mg to 50 mg, 3 mg to 60 mg, or approximately 0.1 mg to 500 mg, 0.1 mg to 350 mg, 0.7 mg to 350 mg, 3 mg to 300 mg, 3 mg to 150 mg, 3 mg to 110 mg, 7 mg to 70 mg, 70 mg to 350 mg, 100 mg to 300 mg, or 125 mg to 250 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In other embodiments, the amount of the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is less than 500 mg, less than 350 mg, less than 300 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 110 mg, less than 100 mg, less than 70 mg, less than 50 mg, less than 35 mg, less than 10 mg, less than 7 mg, less than 5 mg, less than 3 mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg. In some embodiments, the pharmaceutical composition is GABA AThe following are further included: α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof.

[0184] In certain embodiments of this disclosure, pharmaceutical compositions comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, are available in doses of 0.1 mg to 500 mg, 0.1 mg to 300 mg, 0.7 mg to 300 mg, 3 mg to 300 mg, 3 mg to 150 mg, 3 mg to 110 mg, 7 mg to 70 mg, 7 mg to 300 mg, 70 mg to 300 mg, 100 mg to 300 mg, 125 mg to 250 mg, 0.5mg~50mg, 0.5mg~75mg, 0.5mg~100mg, 0.5mg~150mg, 0.5mg~200mg, 0.5mg~225mg, 0.5mg~250mg, 0.5mg~300mg, 1.5mg~50mg, 1.5mg~75m g, 1.5mg~100mg, 1.5mg~150mg, 1.5mg~200mg, 1.5mg~225mg, 1.5mg~250mg, 1.5mg~300mg, 3mg~50mg, 3mg~75mg, 3mg~100mg, 3mg~150mg, 3m g~200mg, 3mg~225mg, 3mg~250mg, 3mg~300mg, 5mg~50mg, 5mg~75mg, 5mg~100mg, 5mg~150mg, 5mg~200mg, 5mg~225mg, 5mg~250mg, 5mg~300m g, 7mg~50mg, 7mg~75mg, 7mg~100mg, 7mg~150mg, 7mg~200mg, 7mg~225mg, 7mg~250mg, 7mg~300mg, 15mg~50mg, 15mg~75mg, 15mg~100mg, 15m The pharmaceutical composition contains an amount of SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, in amounts of 150 mg, 15 mg, 200 mg, 250 mg, 30 mg, 250 mg, or 30 mg, 30 mg, 300 mg. AThe following are further included: α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof.

[0185] In certain embodiments of this disclosure, GABA A A pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, containing 0.05 mg to 5000 mg or 5 mg to 1000 mg of GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the pharmaceutical composition contains about 0.5 mg, about 5 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 2500 mg, about 3500 mg, or 5000 mg of GABA. A The pharmacopoeia may further comprise α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the pharmacopoeia may further comprise SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof.

[0186] In certain embodiments of this disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A A combination of α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, contains 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to 50 mg, or 3 mg to 60 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A A combination comprising an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, contains 0.05 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA AA combination comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, contains 7 mg to 350 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the combination includes an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA A A combination comprising an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, contains 0.07 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA AA combination comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, contains 7 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the combination includes an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA A A combination comprising an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, contains 50 mg to 350 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA AA combination comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, contains 190 mg to 220 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the combination includes an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA A A combination comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, contains 190 mg to 240 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the combination includes an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA. A A combination comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, contains approximately 220 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0187] In certain embodiments of this disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or combinations including pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, are available in doses of 0.05 mg to 35 mg, 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 15 mg, 5 mg to 30 mg, 5 mg to 140 mg, and 0.7 mg. This includes SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) in amounts of g-180 mg, 125 mg-240 mg, 3 mg-50 mg, or 0.07 mg-50 mg, 3 mg-60 mg, or approximately 0.1 mg-500 mg, 0.1 mg-350 mg, 0.7 mg-350 mg, 3 mg-300 mg, 3 mg-150 mg, 3 mg-110 mg, 7 mg-70 mg, 70 mg-350 mg, 100 mg-300 mg, or 125 mg-250 mg, or SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In other embodiments, the amount of the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is less than 500 mg, less than 350 mg, less than 300 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 110 mg, less than 100 mg, less than 70 mg, less than 50 mg, less than 35 mg, less than 10 mg, less than 7 mg, less than 5 mg, less than 3 mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg.

[0188] In certain embodiments of this disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or combinations including pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, are available in doses of 0.1 mg to 500 mg, 0.1 mg to 300 mg, 0.7 mg to 300 mg, 3 mg to 300 mg, 3 mg to 150 mg, 3 mg to 110 mg, 7 mg to 70 mg, and 7 mg to 300 mg. g, 70mg~300mg, 100mg~300mg, 125mg~250mg, 0.5mg~50mg, 0.5mg~75mg, 0.5mg~100mg, 0.5mg~150mg, 0.5mg~200mg, 0.5mg~225mg, 0.5mg~250mg, 0 .5mg~300mg, 1.5mg~50mg, 1.5mg~75mg, 1.5mg~100mg, 1.5mg~150mg, 1.5mg~200mg, 1.5mg~225mg, 1.5mg~250mg, 1.5mg~300mg, 3mg~50mg, 3mg~75m g, 3mg~100mg, 3mg~150mg, 3mg~200mg, 3mg~225mg, 3mg~250mg, 3mg~300mg, 5mg~50mg, 5mg~75mg, 5mg~100mg, 5mg~150mg, 5mg~200mg, 5mg~225mg, 5mg~250mg, 5mg~300mg, 7mg~50mg, 7mg~75mg, 7mg~100mg, 7mg~150mg, 7mg~200mg, 7mg~225mg, 7mg~250mg, 7mg~300mg, 15mg~50mg, 15mg~75mg, 15 This includes SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) in amounts of mg to 100 mg, 15 mg to 150 mg, 15 mg to 200 mg, 15 mg to 225 mg, 15 mg to 250 mg, 15 mg to 300 mg, 30 mg to 50 mg, 30 mg to 75 mg, 30 mg to 100 mg, 30 mg to 150 mg, 30 mg to 200 mg, 30 mg to 225 mg, 30 mg to 250 mg, or 30 mg to 300 mg, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers.

[0189] In certain embodiments of the present disclosure, a combination comprising a pharmaceutical composition containing an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises an amount of 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to 50 mg, or 3 mg to 60 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a combination of a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 0.05 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a combination of a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 7 mg to 350 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a combination of a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 0.07 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.In some embodiments, a combination of a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 7 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a combination of a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 50 mg to 350 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a combination of a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 190 mg to 220 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, a combination of a pharmaceutical composition comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 190 mg to 240 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.In some embodiments, a combination comprising a pharmaceutical composition containing an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, contains about 220 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the combination contains GABA. A The pharmaceutical composition further comprises an α5 receptor agonist (for example, a compound of formula I, formula II, or formula IV; compounds 1 to 740, compounds 1 to 114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0190] In certain embodiments of this disclosure, combinations of pharmaceutical compositions comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, are available in doses of 0.05 mg to 35 mg, 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 15 mg, 5 mg to 30 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, and 3 mg. This includes SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) in amounts of mg to 50 mg, or 0.07 mg to 50 mg, 3 mg to 60 mg, or approximately 0.1 mg to 500 mg, 0.1 mg to 350 mg, 0.7 mg to 350 mg, 3 mg to 300 mg, 3 mg to 150 mg, 3 mg to 110 mg, 7 mg to 70 mg, 70 mg to 350 mg, 100 mg to 300 mg, or 125 mg to 250 mg, or SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In other embodiments, the amount of SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is less than 500 mg, less than 350 mg, less than 300 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 110 mg, less than 100 mg, less than 70 mg, less than 50 mg, less than 35 mg, less than 10 mg, less than 7 mg, less than 5 mg, less than 3 mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg. In some embodiments, the combination is GABA A The pharmaceutical composition further comprises an α5 receptor agonist (for example, a compound of formula I, formula II, or formula IV; compounds 1 to 740, compounds 1 to 114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0191] In certain embodiments of this disclosure, combinations of pharmaceutical compositions comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, are available in doses of 0.1 mg to 500 mg, 0.1 mg to 300 mg, 0.7 mg to 300 mg, 3 mg to 300 mg, 3 mg to 150 mg, 3 mg to 110 mg, 7 mg to 70 mg, 7 mg to 300 mg, 70 mg to 300 mg, 100 mg to 300 mg, and 125 mg to 2 mg. 50mg, 0.5mg~50mg, 0.5mg~75mg, 0.5mg~100mg, 0.5mg~150mg, 0.5mg~200mg, 0.5mg~225mg, 0.5mg~250mg, 0.5mg~300mg, 1.5mg~50mg, 1.5mg ~75mg, 1.5mg~100mg, 1.5mg~150mg, 1.5mg~200mg, 1.5mg~225mg, 1.5mg~250mg, 1.5mg~300mg, 3mg~50mg, 3mg~75mg, 3mg~100mg, 3mg~150mg , 3mg~200mg, 3mg~225mg, 3mg~250mg, 3mg~300mg, 5mg~50mg, 5mg~75mg, 5mg~100mg, 5mg~150mg, 5mg~200mg, 5mg~225mg, 5mg~250mg, 5mg~30 0mg, 7mg~50mg, 7mg~75mg, 7mg~100mg, 7mg~150mg, 7mg~200mg, 7mg~225mg, 7mg~250mg, 7mg~300mg, 15mg~50mg, 15mg~75mg, 15mg~100mg, 15 The combination contains an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam) in amounts of mg to 150 mg, 15 mg to 200 mg, 15 mg to 225 mg, 15 mg to 250 mg, 30 mg to 300 mg, 30 mg to 50 mg, 30 mg to 75 mg, 30 mg to 100 mg, 30 mg to 150 mg, 30 mg to 200 mg, 30 mg to 225 mg, 30 mg to 250 mg, or 30 mg to 300 mg, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer. In some embodiments, the combination contains GABA AThe pharmaceutical composition further comprises an α5 receptor agonist (for example, a compound of formula I, formula II, or formula IV; compounds 1 to 740, compounds 1 to 114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0192] In certain embodiments of this disclosure, GABA A A combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, contains 0.05 mg to 5000 mg or 5 mg to 1000 mg of GABA. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the combinations include about 0.5 mg, about 5 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 2500 mg, about 3500 mg, or 5000 mg of GABA. AThe pharmaceutical composition may include an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the combination further includes a pharmaceutical composition containing an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0193] In certain embodiments of this disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A A combination of a pharmaceutical composition containing an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, contains an amount of 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to 50 mg, or 3 mg to 60 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA AA combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, comprises 0.05 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA A A combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, comprises 7 mg to 350 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA AA combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, comprises 0.07 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA A A combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 7 mg to 35 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA AA combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, comprises 50 mg to 350 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA A A combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, comprises 190 mg to 220 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof. In some embodiments, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof, and GABA AA combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises 190 mg to 240 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. In some embodiments, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA A A combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, comprises approximately 220 mg of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0194] In certain embodiments of this disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA ACombinations of pharmaceutical compositions containing α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are available in doses of 0.05 mg to 35 mg, 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 15 mg, 5 mg to 30 mg, 5 mg to 140 mg, This includes SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) in amounts of 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to 50 mg, or 0.07 mg to 50 mg, 3 mg to 60 mg, or approximately 0.1 mg to 500 mg, 0.1 mg to 350 mg, 0.7 mg to 350 mg, 3 mg to 300 mg, 3 mg to 150 mg, 3 mg to 110 mg, 7 mg to 70 mg, 70 mg to 350 mg, 100 mg to 300 mg, or 125 mg to 250 mg, or SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In other embodiments, the amount of the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is less than 500 mg, less than 350 mg, less than 300 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 110 mg, less than 100 mg, less than 70 mg, less than 50 mg, less than 35 mg, less than 10 mg, less than 7 mg, less than 5 mg, less than 3 mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg.

[0195] In certain embodiments of this disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA ACombinations of pharmaceutical compositions containing α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are available in doses of 0.1 mg to 500 mg, 0.1 mg to 300 mg, 0.7 mg to 300 mg, 3 mg to 300 mg, 3 mg to 150 mg, 3 mg to 110 mg, 7 mg to 70 mg, and 7 mg. g~300mg, 70mg~300mg, 100mg~300mg, 125mg~250mg, 0.5mg~50mg, 0.5mg~75mg, 0.5mg~100mg, 0.5mg~150mg, 0.5mg~200mg, 0.5mg~225mg, 0.5mg~25 0mg, 0.5mg~300mg, 1.5mg~50mg, 1.5mg~75mg, 1.5mg~100mg, 1.5mg~150mg, 1.5mg~200mg, 1.5mg~225mg, 1.5mg~250mg, 1.5mg~300mg, 3mg~50mg, 3mg ~75mg, 3mg~100mg, 3mg~150mg, 3mg~200mg, 3mg~225mg, 3mg~250mg, 3mg~300mg, 5mg~50mg, 5mg~75mg, 5mg~100mg, 5mg~150mg, 5mg~200mg, 5mg~225 mg, 5mg~250mg, 5mg~300mg, 7mg~50mg, 7mg~75mg, 7mg~100mg, 7mg~150mg, 7mg~200mg, 7mg~225mg, 7mg~250mg, 7mg~300mg, 15mg~50mg, 15mg~75mg, This includes SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) in amounts of 15mg-100mg, 15mg-150mg, 15mg-200mg, 15mg-225mg, 15mg-250mg, 15mg-300mg, 30mg-50mg, 30mg-75mg, 30mg-100mg, 30mg-150mg, 30mg-200mg, 30mg-225mg, 30mg-250mg, or 30mg-300mg, or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers.

[0196] In certain embodiments of this disclosure, GABA A A combination of a pharmaceutical composition comprising an α5 receptor agonist (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, contains 0.05 mg to 5000 mg or 5 mg to 1000 mg of GABA. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the combinations include about 0.5 mg, about 5 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 2500 mg, about 3500 mg, or 5000 mg of GABA. A The pharmaceutical composition may include an α5 receptor agonist (for example, a compound of formula I, formula II, or formula IV; compounds 1 to 740, compounds 1 to 114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer.

[0197] In certain embodiments of this disclosure, GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and combinations containing SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, in amounts of 0.05 mg to 5000 mg or 5 mg to 1000 mg of GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof. In some embodiments, the combinations include about 0.5 mg, about 5 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 2500 mg, about 3500 mg, or 5000 mg of GABA. A The materials may include α5 receptor agonists (for example, compounds of formula I, formula II, or formula IV; compounds 1-740 and 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof.

[0198] In some embodiments, the compounds or pharmaceutical compositions of the Disclosure are in a sustained-release form (e.g., controlled-release, long-release, sustained-release, delayed-release, or slow-release form). The term “sustained-release” is widely recognized in the field of pharmaceutical science and can refer to the controlled release of an active compound from a dosage form into an environment over a long period of time, for example, over a period of time greater than or equal to one hour (throughout or during a long period of time). A sustained-release dosage form releases the compound of the Disclosure at a substantially constant rate over a long period of time, or a substantially constant amount of the compound of the Disclosure is released in an increasing manner over a long period of time. When used herein, the term “sustained-release” may include the terms “controlled-release,” “long-release,” “sustained-release,” “delayed-release,” or “slow-release” as they are used in pharmaceutical science. In some embodiments, the sustained-release dosage form may be administered in the form of a patch or a pump. "Sustained-release dosage form" or "sustained-release form" as used herein can refer to a dosage form containing one or more active ingredients, wherein, when placed in water or other biological fluids or solvents, the release of at least one of the active ingredients may occur over a long period of time, for example, over a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 10 days, at least about 20 days, at least about 30 days, at least about 60 days, at least about 90 days, or at least about 150 days. Alternatively, the compounds or pharmaceutical compositions of this disclosure may be in "immediate-release" form or "non-sustained-release" form.

[0199] In some embodiments of this disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA AOnly α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or one of their isomers, are available in sustained-release formulations (e.g., controlled-release, long-release, sustained-release, delayed-release, or slow-release). In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are available. A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are each in sustained-release formulations (e.g., controlled-release, long-release, sustained-release, delayed-release, or slow-release). In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated together or separately in formulations. In certain such embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof may be combined into one pharmaceutical composition or separately into two pharmaceutical compositions.

[0200] In some embodiments, the pharmaceutical composition of the present disclosure (e.g., an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer thereof; GABA A Pharmaceutical compositions comprising α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers; or SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutical compositions comprising both pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) are in a sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form). In some embodiments, the pharmaceutical compositions of the present disclosure (e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutical compositions comprising both pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers; GABA APharmaceutical compositions comprising α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers; or SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutical compositions comprising both pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers) are in immediate-release form. In some embodiments, the pharmaceutical compositions of the present disclosure (e.g., SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutical compositions comprising both pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers; GABA A Pharmaceutical compositions comprising α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers; or SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutical compositions comprising both their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers) are in a non-sustained-release form. Pharmaceutical compositions comprising SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers, and GABA A In some embodiments, which include α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, the compounds are of the same release form (e.g., both are sustained-release forms (e.g., controlled-release, long-release, sustained-release, delayed-release, or slow-release forms)). The pharmaceutical composition includes an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA. A In some embodiments, including α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, or isomers thereof, the compounds are in different release forms (e.g., one is a sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form) and the other is an immediate-release form).

[0201] In some embodiments of the combinations of the present disclosure, an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or ceretracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are in a sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form). In some embodiments of the combinations of the present disclosure, an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are in immediate-release form. In some embodiments of the combinations of the present disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are in a non-sustained-release form. In some embodiments of the combinations of the present disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABAA α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are of the same release form (e.g., both are sustained-release forms (e.g., controlled-release, long-release, sustained-release, delayed-release, or slow-release forms)). In some embodiments of the combinations of the present disclosure, an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are of different release forms (e.g., one is a sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form) and the other is an immediate-release form). In some embodiments of the combinations of the present disclosure, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are formulated together. In some embodiments of the combinations of the present disclosure, an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 as described above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated separately and packaged together or separately. In some embodiments of the combinations of the present disclosure, an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, constitute a single pharmaceutical composition. In some embodiments of the combinations of the present disclosure, an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorphs, or its isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0202] In some embodiments, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is in a sustained-release form (e.g., controlled-release, long-release, sustained-release, delayed-release, or slow-release form). In some embodiments, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is in an immediate-release form. In some embodiments, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, is in a non-sustained-release form.

[0203] In some embodiments, GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are in a sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form). In some embodiments, GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are in immediate-release form. In some embodiments, GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740 and 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or isomers are in non-sustained-release form.

[0204] In some embodiments, SV2A inhibitors in sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form) (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, SV2A inhibitors in sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form) (e.g., levetiracetam, brivalacetam, or celetracetam) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together with GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together in a single pharmaceutical composition.

[0205] In some embodiments, SV2A inhibitors in sustained-release forms (e.g., controlled-release, long-release, sustained-release, delayed-release, or slow-release forms) (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated separately and packaged together or separately. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam) in sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0206] In some embodiments, an immediate-release form of SV2A inhibitor (e.g., levetiracetam, brivalacetam, or ceretracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, an immediate-release form of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam) or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is formulated together with GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together in a single pharmaceutical composition.

[0207] In some embodiments, immediate-release SV2A inhibitors (e.g., levetiracetam, brivalacetam, or ceretracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated separately and packaged together or separately. In some embodiments, immediate-release SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0208] In some embodiments, a non-sustained-release form of SV2A inhibitor (e.g., levetiracetam, brivalacetam, or ceretracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is GABA. Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, non-sustained-release SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together with GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1) or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together in a single pharmaceutical composition.

[0209] In some embodiments, non-sustained-release SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated separately and packaged together or separately. In some embodiments, non-sustained-release forms of SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0210] In some embodiments, GABA is used in a sustained-release form (e.g., controlled-release form, long-term release form, sustained-release form, delayed-release form, or slow-release form). A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, solvates, polymorphs, or isomers thereof are formulated together with SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, solvates, polymorphs, or isomers thereof. In some embodiments, GABA in a sustained-release form (e.g., controlled-release, long-release, sustained-release, delayed-release, or slow-release form) is used. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are formulated together with SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, into monopharmaceutical compositions.

[0211] In some embodiments, GABA is used in a sustained-release form (e.g., controlled-release form, long-term release form, sustained-release form, delayed-release form, or slow-release form). A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, may be formulated separately and packaged together or separately. In some embodiments, GABA in sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form) may be used. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0212] In some embodiments, immediate-release form of GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together with SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, immediate-release form of GABA is used. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are formulated together with SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, into monopharmaceutical compositions.

[0213] In some embodiments, immediate-release GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, are formulated separately. In some embodiments, immediate-release GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0214] In some embodiments, non-sustained-release form of GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A, form B, form C, form E, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together with SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers. In some embodiments, non-sustained-release GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are formulated together with SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, into monopharmaceutical compositions.

[0215] In some embodiments, non-sustained-release form of GABA Aα5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, may be formulated separately and packaged together or separately. In some embodiments, non-sustained-release forms of GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, and SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs or isomers, are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0216] In some embodiments, where the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is in a sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form), GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are also in sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form). In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are formulated together. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, constitute a single pharmaceutical composition. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated separately and packaged together or separately. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0217] In some embodiments, where the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is in a sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form), GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are in a non-sustained-release form. In certain such embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are formulated together. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, constitute a single pharmaceutical composition. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated separately and packaged together or separately. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0218] In some embodiments, where the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is in a sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form), GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are in immediate-release form. In certain such embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are formulated together. Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, constitute a single pharmaceutical composition. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated separately and packaged together or separately. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0219] In some embodiments, the immediate form of an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or ceretracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is GABA. Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are also in sustained-release form (e.g., controlled-release form, long-release form, sustained-release form, delayed-release form, or slow-release form). In certain such embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are formulated together. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, constitute a single pharmaceutical composition. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, may be formulated separately and packaged together or separately. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, II, or IV; compounds 1-740, 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated into separate pharmaceutical compositions. In certain such embodiments, the separate pharmaceutical compositions are packaged together. In some embodiments, the separate pharmaceutical compositions are packaged separately.

[0220] In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, in an immediate-release form, include GABA. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, are in a non-sustained-release form. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA Aα5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers are formulated together. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA are formulated together. A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, constitute a single pharmaceutical composition. In some embodiments, SV2A inhibitors (e.g., levetiracetam, brivalacetam, or celetracetam), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomers, and GABA A α5 receptor agonists (e.g., compounds of formula I, formula II, or formula IV; compounds 1-740, compounds 1-114 mentioned above; or form A of compound 1, form B of compound 1, form C of compound 1, form E of compound 1, or form F of compound 1), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, their polymorphs, or their isomer...

Claims

1. A pharmaceutical composition for use in treating cognitive impairment related to central nervous system (CNS) disorders in subjects requiring treatment for such impairment or subjects at risk thereof, A) Levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer or polymorph thereof, wherein the levetiracetam is present in an amount between 0.07 mg and 350 mg, and B) 【Chemistry 142】 【Chemistry 143】 【Chemistry 144】 【Chemistry 145】 【Chemistry 146】 【Chemistry 147】 【Chemistry 148】 【Chemistry 149】 [Chemical 150] 【Chemistry 151】 【Chemistry 152】 【Chemistry 153】 【Chemistry 154】 【Chemistry 155】 【Chemistry 156】 【Chemistry 157】 【Chemistry 158】 【Chemistry 159】 [Chemical 160] 【Chemistry 161】 【Chemistry 162】 【Chemical 163】 【Chemistry 164】 【Chemistry 165】 【Chemistry 166】 【Chemistry 167】 GABA selected from the group consisting of Ａ An α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph, wherein the GABA A α5 receptor agonist is present in an amount between 5 mg and 1000 mg. A pharmaceutical composition containing the above.

2. The aforementioned GABAA α5 receptor agonist has a structure 【Chem.98】 The pharmaceutical composition according to claim 1, which is a compound having, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or an isomer thereof.

3. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from 3.0 and 21.0 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4, and 27.1 degrees 2θ ± 0.2 degrees 2θ. The pharmaceutical composition according to claim 1 or 2, wherein the polymorphic crystalline form A is XRPD containing XRPD.

4. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from 13.0 and 15.3 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 7.0, 9.3, 10.2, 10.4, 12.5, 13.6, 14.0, 22.0, 23.0, 23.6, and 27.3 degrees 2θ ± 0.2 degrees 2θ. The pharmaceutical composition according to claim 1 or 2, wherein the polymorphic crystalline form B is XRPD containing XRPD.

5. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from 8.5 and 18.9 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 7.1, 9.4, 10.3, 12.3, 12.5, 14.2, 20.7, 22.1, 23.2, 23.7, 24.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ. The pharmaceutical composition according to claim 1 or 2, wherein the solvated crystalline form C is XRPD containing XRPD.

6. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from the group consisting of 11.4, 18.1, and 21.6 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 7.2, 22.0, 23.0, 24.2, 25.0, and 26.6 degrees 2θ ± 0.2 degrees 2θ. The pharmaceutical composition according to claim 1 or 2, wherein the polymorphic crystalline form E is XRPD containing XRPD.

7. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from the group consisting of 9.9, 11.9, 17.3, 19.4, and 25.7 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 9.7, 12.1, 20.8, 23.2, 23.7, 24.2, 25.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ. The pharmaceutical composition according to claim 1 or 2, wherein the hydrated crystalline form F exhibits XRPD containing XRPD.

8. A pharmaceutical composition according to any one of claims 1 to 7, further comprising a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is formulated as a tablet, capsule, pill, lozenge, powder, granule, liquid, or suspension.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a sustained-release form, a non-sustained-release form, or an immediate-release form.

11. The pharmaceutical composition according to claim 10, wherein the levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a sustained-release form.

12. The aforementioned GABA Ａ The pharmaceutical composition according to any one of claims 1 to 11, wherein the α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a sustained-release form, a non-sustained-release form, or an immediate-release form.

13. The aforementioned GABA Ａ The pharmaceutical composition according to claim 12, wherein the α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a sustained-release form.

14. The aforementioned GABA Ａ The pharmaceutical composition according to claim 12, wherein the α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a non-sustained-release form.

15. A combination for use in treating cognitive impairment related to central nervous system (CNS) disorders in subjects requiring treatment for such impairment or subjects at risk thereof, Component A: Levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer or polymorph, or a first pharmaceutical composition comprising the levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph or isomer, wherein the levetiracetam is present in an amount between 0.07 mg and 350 mg, and Component A Component B: 【Chemical 168】 【Chemistry 169】 【Chemistry 170】 【Chemistry 171】 【Chemistry 172】 【Chemistry 173】 【Chemistry 174】 【Chemistry 175】 【Chemistry 176】 【Chemistry 177】 【Chemistry 178】 【Chemistry 179】 【Chemistry 180】 【Chemistry 181】 【Chemistry 182】 【Chemistry 183】 【Chemistry 184】 【Chemistry 185】 【Chemical 186】 【Chemistry 187】 【Chemical 188】 【Chemical 189】 【Chemistry 190】 【Chemistry 191】 【Chemistry 192】 【Chemistry 193】 GABA selected from the group consisting of Ａ α5 receptor agonists, or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, isomers thereof or polymorphs thereof, or the GABA Ａ A second pharmaceutical composition comprising an α5 receptor agonist, a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, wherein the GABA A α5 receptor agonist is present in an amount between 5 mg and 1000 mg, and component B and A combination that includes this.

16. The aforementioned GABAA α5 receptor agonist has a structure 【Transformation 136】 The combination according to claim 15, which is a compound having, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or an isomer thereof.

17. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from 3.0 and 21.0 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4, and 27.1 degrees 2θ ± 0.2 degrees 2θ. The combination according to claim 15 or 16, which is a polymorphic crystalline form A that includes XRPD.

18. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from 13.0 and 15.3 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 7.0, 9.3, 10.2, 10.4, 12.5, 13.6, 14.0, 22.0, 23.0, 23.6, and 27.3 degrees 2θ ± 0.2 degrees 2θ. The combination according to claim 15 or 16, which is a polymorphic crystalline form B exhibiting XRPD including XRPD.

19. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from 8.5 and 18.9 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 7.1, 9.4, 10.3, 12.3, 12.5, 14.2, 20.7, 22.1, 23.2, 23.7, 24.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ. The combination according to claim 15 or 16, wherein the solvated crystalline form C is XRPD containing XRPD.

20. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from the group consisting of 11.4, 18.1, and 21.6 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 7.2, 22.0, 23.0, 24.2, 25.0, and 26.6 degrees 2θ ± 0.2 degrees 2θ. The combination according to claim 15 or 16, which is a polymorphic crystalline form E exhibiting XRPD including XRPD.

21. The aforementioned GABAA α5 receptor agonist, a. At least one peak selected from the group consisting of 9.9, 11.9, 17.3, 19.4, and 25.7 degrees 2θ ± 0.2 degrees 2θ, and b. At least one additional peak selected from the group consisting of 9.7, 12.1, 20.8, 23.2, 23.7, 24.2, 25.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ. The combination according to claim 15 or 16, wherein the hydrated crystal form F exhibits XRPD containing XRPD.

22. The aforementioned GABA Ａ The combination according to any one of claims 15 to 21, wherein an α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer or polymorph, and the levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer or polymorph, are independently formulated as tablets, capsules, pills, lozenges, powders, granules, liquids or suspensions.

23. The aforementioned GABA Ａ The combination according to claim 22, wherein an α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer or polymorph, and the levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer or polymorph, are formulated in a single pharmaceutical composition or separately.

24. The combination according to any one of claims 15 to 23, wherein the first pharmaceutical composition and the second pharmaceutical composition include a pharmaceutically acceptable carrier.

25. The combination according to claim 23 or 24, wherein the first pharmaceutical composition and the second pharmaceutical composition are independently formulated as tablets, capsules, pills, lozenges, powders, granules, liquids, or suspensions.

26. The combination according to any one of claims 23 to 25, wherein the first pharmaceutical composition and the second pharmaceutical composition are formulated as a single pharmaceutical composition or separately.

27. The combination according to any one of claims 15 to 26, wherein the levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a sustained-release form, a non-sustained-release form, or an immediate-release form.

28. The combination according to claim 27, wherein the levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a sustained-release form.

29. the GABA Ａ The combination according to any one of claims 15 to 27, wherein the α5 receptor agonist, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an isomer thereof or a polymorph thereof is in a sustained release form, a non-sustained release form or an immediate release form.

30. The aforementioned GABA Ａ The combination according to claim 29, wherein the α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a sustained-release form.

31. The aforementioned GABA Ａ The combination according to claim 30, wherein the α5 receptor agonist, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its isomer, or its polymorph is in a non-sustained-release form.

32. The pharmaceutical composition according to claim 1 or the combination according to claim 15, wherein the CNS disorder is age-related cognitive impairment.

33. The pharmaceutical composition according to claim 1 or the combination according to claim 15, wherein the CNS disorder is mild cognitive impairment (MCI).

34. The pharmaceutical composition according to claim 1 or the combination according to claim 15, wherein the mild cognitive impairment is amnesic mild cognitive impairment (aMCI).

35. The pharmaceutical composition according to claim 1 or the combination according to claim 15, wherein the CNS disorder is dementia.

36. The pharmaceutical composition according to claim 1 or the combination according to claim 15, wherein the CNS disorder is Alzheimer's disease.

37. The pharmaceutical composition according to claim 1 or the combination according to claim 15, wherein the CNS disorder is schizophrenia, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior, substance addiction, bipolar disorder, or cognitive impairment related to cancer treatment.

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